Home   Chapter Home   Jobs   Conferences   Fellowships   Books



Advertisement

Kidney non tumor

Superpage - Part 1

Revised: 10 January 2013
Copyright: (c) 2001-2013, PathologyOutlines.com, Inc.

Anatomy


Reviewers: Nikhil Sangle, M.D. (see Reviewers page)
Revised: 4 April 2012, last major update March 2012
Copyright: (c) 2003-2012, PathologyOutlines.com, Inc.

General
=========================================================================

● Posterior abdomen on either side of vertebral column, in retroperitoneum
● Surrounded by fat and loose areolar tissue
● Superior border is at T12, inferior border is at L3
● 11cm long x 5-8cm x 3cm
● Weighs 125-170g in males, 115-155g in females
Capsule: covers kidney, is surrounded by perirenal fat
Cortex: outer 1.2 cm of kidney, surrounds inner medulla containing pyramids and lacking glomeruli
Renal sinus: fatty compartment within confines of kidney not delineated from renal cortex by a fibrous capsule
Gerota’s fascia: fibromembranous tissue surrounding the kidney that separates it from adjacent musculature
● Ureter ascends into renal pelvis, divides into calyces (2-3 major, 12 minor total)
● Related to a calyx are renal pyramids with apices called papillae
Vasculature: receives 25% of cardiac output, 90% goes to cortex, via interlobar, arcuate, interlobular, afferent arterioles, then into glomeruli, efferent arterioles and peritubular vascular network
● Deeper juxtamedullary glomeruli give rise to vasa recta, which supply outer and inner medulla
● Since arteries are end vessels, their occlusion causes infarction
● Glomerular disease causes tubular disease, since efferent arterioles supply tubules
Regional lymph nodes: renal hilar, paracaval, aortic and retroperitoneal

Diagrams
=========================================================================


   
Vertical section

               
Relation to other organs

Gross images
=========================================================================


       
Normal adult kidney

Virtual slides
=========================================================================



Normal kidney

Additional references
=========================================================================

Wikipedia, eMedicine, WebMD



Congenital anomalies


Reviewers: Nikhil Sangle, M.D. (see Reviewers page)
Revised: 11 April 2012, last major update April 2012
Copyright: (c) 2003-2012, PathologyOutlines.com, Inc.

General
=========================================================================

● 10% of individuals have urinary tract malformations, although many are asymptomatic
● 15% of congenital urogenital anomalies are secondary to an underlying chromosomal disorder
● In children, 20% of chronic renal failure is due to renal dysplasia or hypoplasia
● In adults, 10% of chronic renal failure is due to adult polycystic kidney disease
● Mass ultrasound screening detects congenital renal and urinary tract anomalies in 1%, but not recommended since most would ultimately be detected via symptoms; most commonly vesicoureteral reflux, ureteropelvic junction obstruction, ectopic kidney, renal dysplasia (Pediatr Nephrol 2012 Jan 24 [Epub ahead of print])


Agenesis

General
=========================================================================

● Complete absence of renal tissue; unilateral or bilateral; 0.03% of newborns but 0.3% of stillborn
● Bilateral agenesis: incompatible with life; associated with large adrenal glands; leads to Potter’s (oligohydramnios) sequence; possible causes include maternal insulin dependent diabetes mellitus and male sex of fetus, but usually no specific etiology (PLoS One 2010;5:e12375)
● Unilateral agenesis: not fatal

Case reports
=========================================================================

● 36 week gestational age male with Klinefelter’s syndrome and bilateral renal agenesis (Arch Pathol Lab Med 2004;128:e44)

Gross images
=========================================================================


   
Bilateral renal agenesis


1: posterior view of stillborn with no kidneys and downwardly displaced adrenal glands (arrows); 2: 47, XXY


Duplication of ureters

General
=========================================================================

● < 1% of individuals
● Usually asymptomatic; may be associated with obstruction

Gross images
=========================================================================


   
Left: duplication on right side; right: with obstructive renal dysplasia

   
Left: bilateral duplication; right: incomplete duplication


Ectopic (displaced) kidneys

General
=========================================================================

● Usually at pelvic brim, may have kinking of ureters
Urologia 2010;77:212
Clin Exp Nephrol 2009;13:531

Gross images
=========================================================================


   

Ectopic kidney

   

With multiple stones; medial portion


Horseshoe kidney

General
=========================================================================

● Most common congenital kidney anomaly, 0.15-0.25% of all newborns
● 90% are fused at lower pole
● Associated with obstruction, anomalous superior vena cava (Circ J 2012 Feb 17 [Epub ahead of print])
● Complete fusion of the kidneys produces a formless mass in the pelvis (pancake kidney)

Gross images
=========================================================================


           

   
Fusion at lower poles


Hypoplasia

General
=========================================================================

● Rare; failure of kidney to develop to normal size without scarring
● Usually unilateral, with a reduced number of nephrons and pyramids (6 or less), but otherwise normal architecture
● Associated with PAX2 mutations (J Am Soc Nephrol 2001;12:1769)
Oligomeganephronia: type of hypoplasia with small kidney but hypertrophied nephrons due to compensatory hypertrophy caused by reduced number of nephrons

Diagrams / gross images
=========================================================================


   
Renal hypoplasia

Micro images
=========================================================================



Oligomeganephronic renal hypoplasia


Renal tubular dysgenesis

General
=========================================================================

● Rare congenital abnormality of renal development characterized by short and poorly developed proximal convoluted tubules without dysplasia or cystic disease (Hum Pathol 1986;17:1259)
● Characterized by oligohydramnios and the Potter sequence, pulmonary hypoplasia, calvarial bone hypoplasia with enlarged fontanels
● Causes: acquired (associated with renal hypoperfusion, Pediatr Dev Pathol 1999;2:25) or autosomal recessive (mutations in genes associated with angiotensinogen, renin, angiotensin-converting enzyme, or angiotensin II receptor type 1, J Am Soc Nephrol 2006;17:2253, Hum Mutat 2012;33:316)
● Identified in 1% of perinatal autopsies in 1991 (Hum Pathol 1991;22:147)

Micro images
=========================================================================


               
Various images



Embryology


Reviewers: Nikhil Sangle, M.D. (see Reviewers page)
Revised: 4 April 2012, last major update March 2012
Copyright: (c) 2003-2012, PathologyOutlines.com, Inc.

General
=========================================================================

Metanephric blastema: forms glomerulus, proximal convoluted tubules, loops of Henle, distal convoluted tubules and connective tissue of renal interstitium
Ureteric bud: forms cortical and medullary collecting tubules and medullary collecting ducts

Stages of kidney development:
● Pronephros (based on Wolffian duct, kidneys non-functional)
● Mesonephros (appear at week 4, form nephron-like tubules but degenerate)
● Metanephros (form at week 5, function by week 11)

Gross images
=========================================================================



Fetal kidneys at 25 weeks gestation


Infant kidney with fetal lobulations

Videos
=========================================================================

UNSW Embryology-animation of kidney development

Additional references
=========================================================================

Wikipedia



Glomeruli


Reviewers: Nikhil Sangle, M.D. (see Reviewers page)
Revised: 19 September 2012, last major update March 2012
Copyright: (c) 2003-2012, PathologyOutlines.com, Inc.

General
=========================================================================

● Tuft-like vascular structure composed of lobules of specialized capillaries that arise from an afferent arteriole and eventually coalesce to drain into an efferent arteriole
● 200 microns in diameter, 20% larger in juxtamedullary area

Structure
=========================================================================

● Layers (inner to outer) are: fenestrated endothelium, then glomerular basement membrane (lamina rare interna, lamina densa and lamina rare externa), then podocytes (visceral epithelium with foot processes); also parietal epithelium which lines Bowman’s space (which contains the ultrafiltrate of plasma)
● Glomerular basement membrane (GBM): normally 250-380nm, composed of type IV collagen, laminin, polyanionic proteoglycans (mostly heparan sulfate), fibronectin and entactin
● Type IV collagen forms suprastructure to which other glycoproteins attach; composed of 3 alpha chains
● Each alpha chain has amino 7S domain, middle triple helical domain and a carboxyl non-collagenous (NC1) domain; NC1 domain is site of anti-GBM nephritis and dimer formation
Mesangial cells: type of myofibroblast that supports glomerular tuft, regulates capillary width and blood flow; are phagocytic and can proliferate; the mesangium on the capillary side is covered by endothelial cell; the capillary basement membrane extends to form the paramesangial basement membrane; at ultrastructural level, the mesangium shows cell membrane dense bodies (attachment plaques), which anchors the mesangial cell to the cell membrane
Podocytes (visceral epithelium): their foot processes embed in lamina rare externa of glomerular basement membrane; the distal diffusion barrier to filtration of proteins is a filtration slit diaphragm between foot processes

Glomerular filtration
=========================================================================

● Glomeruli are highly permeable to water and solutes through fenestrated endothelium, but impermeable to large proteins like albumin (proteins are more permeable if smaller and more cationic)

Diagrams
=========================================================================


   
Normal glomerulus


Vessels surrounding glomeruli and tubules

Micro description
=========================================================================

Hypercellularity: the presence of more than 3 cells in an individual glomerular mesangial region away from the vascular pole

Micro images
=========================================================================


       
Normal glomerulus


A: light microscopy; B: fluorescence microscopy with Hollande’s fixative distinguishes proximal (heavy star) and distal (asterisk) convoluted tubules; fluorescence microscopy shows thin and delicate glomerular loops, smooth mesangial matrices

Special stains
=========================================================================

● PAS stain allows assessment of glomerular basement membranes, mesangial matrix and tubular basement membranes
● Jones methenamine silver (JMS) highlights these better than PAS
● Masson trichrome stain highlights hyalinosis, scarring, immune deposits and fibrinoid deposits

Additional references
=========================================================================

Mod Pathol 2002;15:988, Wikipedia



Physiology of kidney


Reviewers: Nikhil Sangle, M.D. (see Reviewers page)
Revised: 11 April 2012, last major update April 2012
Copyright: (c) 2003-2012, PathologyOutlines.com, Inc.

General
=========================================================================

● Filters 1700L of blood to 1L of urine per day
● Excretes metabolic waste; regulates water, salt, and pH
● Secretes renin, prostaglandins and erythropoietin
● Nephron production ceases at birth, are 1.3 million / kidney
● Renal intercalated cells may regulate pH through expression of soluble adenylate cyclase, a sensor that detects luminal bicarbonate and activates the vacuolar proton-pumping ATPase via cAMP (Am J Physiol Cell Physiol 2012 Mar 28 [Epub ahead of print])
Nephron: glomerulus filters blood, ultrafiltrate enters Bowman’s space, filtrate enters proximal convoluted tubule, to pars recta of proximal tubule, to thin descending limp of loop of Henle, to thick ascending limb of loop of Henle, to macula densa (adjacent to glomerulus), to distal convoluted tubule, to collecting tubule, to collecting duct of Bellini and to calyx (Wikipedia)
Clearance: amount of plasma cleared of a substance per minute to appear in urine

Diagrams
=========================================================================


       
Details on physiology



Renal disease-general


Reviewers: Nikhil Sangle, M.D. (see Reviewers page)
Revised: 11 April 2012, last major update April 2012
Copyright: (c) 2003-2012, PathologyOutlines.com, Inc.

General
=========================================================================

● 20% of women get urinary tract infections
● 1% of Americans develop renal stones
● Divided for analytical purposes into diseases of glomeruli, tubules, interstitium and vessels
● Glomerular diseases tend to be immunologically mediated; tubular and interstitial disorders are often due to toxins / infections
● Glomerular and tubular disease affect each other because glomerular disease impairs the tubular blood supply and increases tubular toxins, and tubular disease causes increased intraglomerular pressure


Acute nephritic syndrome

General
=========================================================================

● Grossly visible hematuria, hypertension, azotemia, oliguria, mild edema, red blood cell casts and variable proteinuria (Wikipedia)
● Associated with postinfectious glomerulonephritis, early Lupus, diffuse crescentic and membranoproliferative glomerulonephritis


Acute renal failure

General
=========================================================================

● Abrupt anuria or oliguria with rapidly progressive azotemia identified by increase in BUN or ammonia


Azotemia

General
=========================================================================

● Increased serum BUN (blood urea nitrogen) and creatinine, due to reduced glomerular filtration rate (GFR)
● Causes are prerenal (hemorrhage, shock, congestive heart failure, volume depletion), renal and postrenal (obstruction)


Chronic renal failure

General
=========================================================================

● Azotemia progressing to uremia over a period of years

Stages of chronic renal failure:
● Diminished renal reserve (GFR 50% normal) with normal BUN/Creatinine
● Renal insufficiency: azotemia, anemia, hypertension, polyuria and nocturia
● Renal failure: GFR < 20% normal, kidneys cannot regulate volume of solutes and patient develops edema, metabolic acidosis and hypocalcemia
● End stage renal disease: GFR <5% normal, represents the end stage of various renal diseases


Nephrotic syndrome

General
=========================================================================

● Proteinuria > 3.5 g/day, hypoalbuminemia (serum level < 3 g/dl), hyperlipidemia, lipiduria and severe edema (anasarca)
● Due to derangement in glomerular capillary walls, which leads to increased permeability to plasma proteins, causing massive (non-selective) proteinuria, microhematuria in 50%, hypoalbuminemia and generalized edema (pitting, periorbital and dependent edema), hypertension in up to 25% and thrombotic tendency
● Hyperlipidemia is due to increased lipoprotein synthesis and decreased catabolism
● Lipiduria is due to leakage of lipoproteins with albumin
● Patients are prone to staphylococcus and pneumococcal infections due to loss of immunoglobulins and factor B of complement
● Thrombosis and thromboemboli are due to loss of anticoagulants such as antithrombin III and antiplasmin
● Associated with minimal change disease (more common in children), focal and segmental glomerulosclerosis, membranous glomerulonephritis (more common in adults), systemic disease (SLE, diabetes, amyloidosis) and congenital nephrotic syndrome


Uremia

General
=========================================================================

● Azotemia plus clinical signs / symptoms (gastroenteritis, peripheral neuropathy, fibrinous pericarditis, secondary hyperparathyroidism); associated with chronic renal failure
● Tubular defects cause polyuria, nocturia and electrolyte disorders; due to diseases directly or indirectly affecting tubular function



Renal hormones


Reviewers: Nikhil Sangle, M.D. (see Reviewers page)
Revised: 11 April 2012, last major update April 2012
Copyright: (c) 2003-2012, PathologyOutlines.com, Inc.

General
=========================================================================

● Age related changes occur; are affected by hypertension and heart failure (Kidney Int 1997;51:1196)

Aldosterone:
● Causes increased reabsorption of NaCl to increase blood volume

Antidiuretic hormone (vasopressin):
● Stimulates water reabsorption by stimulating insertion of "water channels" or aquaporins into the membranes of kidney tubules
● These channels transport solute-free water through tubular cells and back into blood, leading to a decrease in plasma osmolarity and an increased osmolarity of urine
● In diabetes insipidus (without ADH), kidney tubules are virtually impermeable to water, which flows out as urine (up to 10 liters of dilute urine / day)

Erythropoietin:
● Secreted in response to low serum pO2, promotes red blood cell production

Natriuretic hormones:
● Cause increase in glomerular filtration rate after nephron destruction

Renin:
● Produced by juxtaglomerular apparatus in response to hypotension, converts angiotensinogen to angiotensin I, which is converted to angiotensin II in the lung by angiotensin converting enzyme (ACE)
● Angiotensin II increases aldosterone production and promotes vasoconstriction

Diagrams
=========================================================================


   
Renin pathway



Tubules and interstitium


Reviewers: Nikhil Sangle, M.D. (see Reviewers page)
Revised: 11 April 2012, last major update April 2012
Copyright: (c) 2003-2012, PathologyOutlines.com, Inc.

General
=========================================================================

Juxtaglomerular apparatus: close to glomerulus where afferent arteriole enters it; consists of juxtaglomerular cells (modified smooth muscle cells) plus macula densa (region of distal tubule as it returns to vascular pole of parent glomeruli) plus lacis or Goormaghtigh cells (nongranular cells that reside near afferent arteriole, macula densa and glomerulus and resemble mesangial cells); produces renin; cells of macula densa show reverse polarity (with abluminal nuclei and basal cytoplasmic clearing due to Golgi apparatus) to direct the synthesized molecules towards the glomerulus
Interstitium: contains fibroblast like cells and peritubular capillaries; expands due to edema and inflammation
Medullary rays: in cortex, contain cortical collecting tubules and loops of Henle of superficial nephrons
Proximal tubules: long microvilli, numerous mitochondria and extensive intercellular interdigitations assist in reabsorption of sodium, water, proteins, glucose, potassium, phosphate and amino acids; vulnerable to toxins and ischemic damage
Renal columns of Bertin: cortical tissue extending into spaces between pyramids

Diagrams / Gross images
=========================================================================


   
Juxtaglomerular apparatus

       
Renal column


Vessels supplying tubule


Vessels surrounding glomeruli and tubules

Micro images
=========================================================================



Collecting duct: brush border

       
Juxtaglomerular apparatus and macula densa

       
Medullary rays

Cytology images
=========================================================================



Glomeruli (1A), tubules (1B)



Primary glomerular diseases

Biopsy-general


Reviewers: Nikhil Sangle, M.D. (see Reviewers page)
Revised: 10 April 2012, last major update April 2012
Copyright: (c) 2003-2012, PathologyOutlines.com, Inc.

General
=========================================================================

● Helps establish diagnosis and determine prognostic factors for renal disorders and transplant recipients
● Needle core or open biopsies are relatively safe, and only rarely cause morbidity or mortality; outpatient complication rate is 8% (Clin Nephrol 2011;76:464)
● Also important for appropriate management of elderly and very elderly patients with kidney disease (Adv Chronic Kidney Dis 2012;19:61)
● Percutaneous ultrasound-guided renal biopsy is safe, reliable and effective in children; most common indication is steroid resistant, steroid dependent or frequent relapsing idiopathic nephrotic syndrome (Hippokratia 2011;15:258)
● Pathology should correlate complete clinical and laboratory information (using a clinical form is recommended) with light microscopy, immunofluorescence and electron microscopy; cannot diagnose certain diseases without immunofluorescence or EM (Mod Pathol 2004;17:1555)
● Must carefully evaluate glomeruli, tubules, interstitium and vessels

Procedure
=========================================================================

● Specimen must be handled gently
Don’t: use forceps, pull or stretch tissue, place tissue on dry gauze or water-soaked gauze, freeze entire sample or place on ice-cold saline
Do: transport with tissue culture medium on saline-moistened gauze; cut with fresh scalpel
● Dissecting microscope helps assess adequacy of glomeruli; place sample on glass slide with saline
● Two cores recommended
Core #1: take samples 0.5 to 1.0 mm thick from each end with razor / scalpel and put in glutaraldehyde for EM; place remainder in saline, then fixative for light microscopy
Core #2: take samples for EM, snap freeze the remainder for immunofluorescence
● Wrap light microscopy specimens in lens paper prewetted with fixative (avoid sponges or plastic embedding bags)
● If only one core or a small specimen is obtained, use tissue for EM and immunofluorescence because EM semi-thin sections can also provide light microscopic information
Fixative: mercury fixatives (Zenker’s, Bouin’s, other) provide optimal architectural and cytologic detail; ethanol fixation helps find glycogen or crystals of urate / uric acid
● Recommended to section through entire specimen, put 3-4 sections on each slide; for every batch of 5 slides, stain 1 with H&E, 1 with PAS and keep 3 unstained slides for possible future use
● Can detect immune complexes with antibodies or using fluorescence microscopy of H&E stained sections, fixed in Hollande’s fixative (Mod Pathol 2002;15:988)

Immunofixation
=========================================================================

● Best performed on unfixed, frozen sections
● Examine for IgG, IgM, IgA, C3, C1q, C4, fibrin, kappa and lambda
● Should include positive and negative controls for each run
● Immunoperoxidase may be a substitute (cheaper, can correlate with H&E, doesn’t fade), but complement antigens are difficult to detect, may have higher background staining

Minimum glomeruli:
● 5-10 in general
● 10 for crescentic disorders
● 1 may be sufficient for diffuse lesions such as membranous glomerulonephritis

Immunohistochemistry: IgG, IgA, IgM, C1q, C3, C4, fibrinogen and fibrin
Frozen section: requested to determine adequacy (% sclerotic glomeruli) in donor kidney for transplant
Transplant biopsies: performed to assess rejection

Images and diagrams
=========================================================================



A: renal cortex with round red glomeruli; b: renal medulla without glomeruli


Diagram about dividing up core tissue if no dissecting microscope is present

Electron microscopy description
=========================================================================

● Uses osmium tetroxide or glutaraldehyde for fixation (cannot perform if tissue exposed to B5, Zenker’s or other mercury-based fixatives, can reprocess tissue from paraffin block)
● Embed in epoxy resin, stain semi-thin (one micron thick) sections with toluidine blue or methylene blue
● Obtain thin sections for EM, stained with uranyl acetate and lead citrate



Primary glomerular diseases

Glomerular disease-general


Reviewers: Nikhil Sangle, M.D. (see Reviewers page)
Revised: 4 September 2012, last major update September 2012
Copyright: (c) 2003-2012, PathologyOutlines.com, Inc.

General
=========================================================================

Glomerulonephritis: inflammation of glomerulus
Glomerulopathy: any disorder affecting glomerulus
Primary: kidney is only or predominant organ involved
● Changes can be diffuse (all glomeruli) or focal; global (entire glomerulus) or segmental (part of glomerulus) or mesangial
● Minimal change disease, diffuse mesangial hypercellularity and focal and segmental glomerulosclerosis may be a continuum of the same disease
● EGFR pathway may be new therapeutic target in glomerular disease (Nephrol Dial Transplant 2012;27:1297)

Micro description
=========================================================================

Hypercellularity: due to cellular proliferation (mesangial, endothelial, parietal epithelial cells); white blood cells (acute and chronic) or crescents (white blood cells and epithelial cells)
Basement membrane thickening is highlighted by PAS stain and electron microscopy; EM also shows electron-dense deposits (usually immune complexes) in or adjacent to basement membrane (subepithelial is most common)
Hyalinization and sclerosis of glomeruli are the end result of glomerular damage from various causes

Micro images
=========================================================================



Hypercellularity

Additional references
=========================================================================

Cleveland Clinic



Primary glomerular diseases

Pathogenesis of glomerular injury


Reviewers: Nikhil Sangle, M.D. (see Reviewers page)
Revised: 15 April 2012, last major update April 2012
Copyright: (c) 2003-2012, PathologyOutlines.com, Inc.

General
=========================================================================

● Usually immune mediated via antibody deposition, cell-mediated injury or activation of alternative complement pathway (Nephrol Dial Transplant 1998;13(suppl 1):10, Med Chrome)
● Antibodies deposited are either to in situ antigen (intrinsic or planted) or are circulating immune complexes
Intrinsic: Goodpasture’s disease-antigens are in basement membrane; Heymann nephritis-antigens are on visceral epithelial cells; produce linear immunofluorescence patterns
Planted antigens are deposited in basement membrane; may be exogenous (drugs, infectious agents) or endogenous (DNA, immunoglobulin, immune complexes); their cationic proteins bind to glomerular anionic sites and produce granular lumpy staining by immunofluorescence
Circulating immune complexes may be endogenous (DNA, tumors) or exogenous (infectious products); they usually localize within glomeruli and activate complement; deposits are usually mesangial or subendothelial and resolve by macrophage phagocytosis, unless there are repeated cycles of formation (Hepatitis B/C, lupus)
Cell-mediated immune injury is by sensitized nephritogenic T cells
Progression to end stage renal disease occurs when the glomerular filtration rate (GFR) is 30-50% of normal, due to compensatory hypertrophy of remaining glomeruli and systemic hypertension (inhibited by angiotensin converting enzyme inhibitors), eventually causing glomerulosclerosis

Diagrams
=========================================================================


       
Pathogenesis of glomerular injury

Micro description
=========================================================================

● Injured epithelial cells have vacuoles, retract and detach from basement membrane, lose foot processes

Immunofluorescence
=========================================================================

● Granular deposits represent immune complexes that settle out of blood or form in situ; linear deposits are due to anti-basement membrane antibodies or light chain nephropathy
● Can detect via fluorescent antibodies or using fluorescence microscopy of H&E stained sections fixed in Hollande’s fixative (Mod Pathol 2002;15:988)



Primary glomerular diseases

C1q nephropathy


Reviewers: Nikhil Sangle, M.D. (see Reviewers page)
Revised: 15 April 2012, last major update April 2012
Copyright: (c) 2003-2012, PathologyOutlines.com, Inc.

General
=========================================================================

● Heterogeneous disease (J Am Soc Nephrol 2008;19:2237) first described in 1985 (Am J Kidney Dis 1985;6:103)
● Considered by some an independent disorder, by others a subgroup of primary focal segmental glomerular sclerosis (Clin Exp Nephrol 2009;13:263)
● Rare; causes proteinuria that may progress to end-stage renal failure; rarely presents with gross hematuria (Pediatr Nephrol 2010;25:165)
● Teenagers and young adults, higher incidence among blacks and females
● Presents as nephrotic syndrome, renal insufficiency or hematuria
● Collapsing C1q nephropathy with rapid progression to end-stage renal disease appears to reside in the MYH9-associated disease spectrum (Am J Kidney Dis 2010;55:e21)
● Laboratory testing for lupus and HIV negative, normal complement levels and no evidence of infectious or autoimmune disease

Treatment
=========================================================================

● Clinical course is unpredictable; variable response to corticosteroids or cytotoxic drugs but high rate of renal survival (Pediatr Nephrol 2009;24:77)
● Rituximab may be effective (Clin Exp Nephrol 2011;15:164)

Case reports
=========================================================================

● 42 year old man with acute renal failure (Saudi J Kidney Dis Transpl 2011;22:324)

Micro description
=========================================================================

● Focal and segmental glomerulosclerosis and minimal change disease patterns most common
● Variable mesangial hypercellularity with increase in mesangial matrix
● Variable segmental glomerulopathy

Micro images
=========================================================================


   
Increase in mesangial cellularity

           
Various images: H&E, global granular mesangial staining for C1q, EM


Segmental sclerosis and hypercellularity

Immunofluorescence
=========================================================================

● Prominent mesangial C1q deposition; also co-deposition of IgG, IgM, IgA and/or C3
● Some cases overlap with IgG nephropathy (Clin Nephrol 2009;72:360)

Electron microscopy description
=========================================================================

● Paramesangial electron-dense immune complex deposits

Differential diagnosis
=========================================================================

IgA nephropathy: IgA immunofluorescence
Lupus nephritis: may have prominent deposition of C1q, C3 and immunoglobulins; good response to steroids



Primary glomerular diseases

Chronic glomerulonephritis


Reviewers: Nikhil Sangle, M.D. (see Reviewers page)
Revised: 4 September 2012, last major update September 2012
Copyright: (c) 2003-2012, PathologyOutlines.com, Inc.

General
=========================================================================

● An end stage disease, due to progression of various types of glomerulonephritis; occasionally no prior history of kidney disease (eMedicine)
Rates of progression: rapidly progressive (90%), post-streptococcal (1% kids, 5% adults), focal and segmental glomerulosclerosis (50-80%, rapid), membranous (50%), membranoproliferative (50%), IgA nephropathy (30-50%, slow)
● Paradoxically, nephrotic syndrome symptoms decrease as glomeruli disappear

Gross description
=========================================================================

● Symmetrically small kidneys with thin granular cortex and increased peripelvic fat

Gross images
=========================================================================



Due to hypertension


Chronic glomerulonephritis


Bilaterally small kidneys

Micro description
=========================================================================

● Glomerulosclerosis, tubular atrophy and thyroidization, interstitial fibrosis and lymphocytic inflammation
● Arterial and arteriolar sclerosis

Micro images
=========================================================================


       
End stage kidney with sclerotic glomeruli, tubular thyroidization, interstitial fibrosis and thickened arterial walls


Various images

Virtual slides
=========================================================================



Chronic glomerulonephritis

Videos
=========================================================================



By WashingtonDeceit



Primary glomerular diseases

Collapsing glomerulopathy


Reviewers: Nikhil Sangle, M.D. (see Reviewers page)
Revised: 4 September 2012, last major update September 2012
Copyright: (c) 2003-2012, PathologyOutlines.com, Inc.

General
=========================================================================

● Resembles special form of focal and segmental glomerulosclerosis in IV drug abuse and AIDS (rapid progression to renal failure with severe proteinuria, poor response to treatment and similar microscopic changes), but HIV negative
● Usually black men; associated with genetic variants in the nonmuscle myosin heavy chain 9 gene (MYH9) (Semin Nephrol 2010;30:111)
● May be due to altered hemodynamics
● Renal allografts: important cause of graft dysfunction that may lead to allograft failure (Indian J Nephrol 2011;21:10); similar histologic changes, but process may have different origin (Hum Pathol 2002;33:437)
● May be associated with various disorders, which may have podocyte injury in common: mixed connective tissue disease (Clin Nephrol 2011;75 Suppl 1:32), natural killer cell leukeima (Am J Kidney Dis 2011;58:855), sickle cell disease (J Med Case Reports 2011;5:71), sirolimus treatment (Ann Transplant 2011;16:113), systemic lupus erythematosus or lupus-like disease (Clin J Am Soc Nephrol 2012 Mar 29 [Epub ahead of print]), tuberculosis (Ren Fail 2010;32:143)

Case reports
=========================================================================

● 58 year old man effectively treated with lisinopril and deflazacort (Clin Exp Nephrol 2010;14:385)

Micro description
=========================================================================

● Accentuation of lobules due to widespread collapse of glomerular capillary loops with localized hyperplasia and hypertrophy of epithelial cells overlying sclerotic segment
● Cells are vacuolated and swollen, contain abundant resorption droplets
● Severe tubulointerstitial injury with degenerative changes, dilated tubules, tubular casts and lymphocytic infiltrate

Micro images
=========================================================================


       
Collapsed glomerulus

       
With other disorders (left: Adult-onset Still's disease, middle: systemic lupus erythematosus, right: sickle cell disease)

   
Series of images

Immunofluorescence
=========================================================================

● Segmental IgM and C3

Electron microscopy description
=========================================================================

● Wrinkling but little/no basement membrane thickening; marked podocyte hypertrophy; no electron-dense deposits of tubuloreticular inclusions (compared to HIV associated nephropathy)



Primary glomerular diseases

Congenital nephrotic syndrome


Reviewers: Nikhil Sangle, M.D. (see Reviewers page)
Revised: 15 April 2012, last major update April 2012
Copyright: (c) 2003-2012, PathologyOutlines.com, Inc.

General
=========================================================================

● Heterogenous conditions with nephrotic syndrome within first 3 months of life
● Onset between 3–12 months is called infantile nephrotic syndrome
● No response to steroids or immunosuppressive therapy
● Divided into Finnish type and diffuse mesangial sclerosis (see below), but may also be a part of a more generalized syndrome or caused by a perinatal infection (Pediatr Nephrol 2009;24:2121)

Diagrams
=========================================================================



Normal glomerular capillary and capillary wall

Treatment
=========================================================================

● Renal transplant

Differential diagnosis
=========================================================================

● Infectious causes: congenital syphilis or toxoplasmosis
● Idiopathic: minimal change disease, diffuse mesangial hypercellularity, focal and segmental glomerulosclerosis
● Other rare causes include hemolytic-uremic syndrome or sytemic lupus erythematosus


Finnish type

General
=========================================================================

● Autosomal recessive disorder (OMIM #256300)
● Also called NPHS1, Finnish congenital nephrosis
● 1.5% of cases of nephrotic syndrome in childhood
● Occurs in 1 per 10,000 newborns in Finland, lower incidence elsewhere (1 in 50,000 in North America)
● Nephrin protein is produced by glomerular podocyte, encoded by NPHS1 at 19q13.1; normally expressed at slit diaphragm of glomerular podocyte, but missing or defective (due to misfolding or defective intracellular trafficking) in patients with Finnish type syndrome
● Can diagnose in utero via genetic testing; suggested by heavy proteinuria in utero, increased AFP levels in maternal serum or amniotic fluid
● At birth, large placentas, proteinuria, edema, infections, premature birth, mild facial / limb abnormalities and poor development
● Doesn’t respond to steroids or immunosuppression; death without kidney transplant
● Dramatic improvement with transplant, but 20% have recurrence of nephrotic syndrome, which may respond to rituximab (Pediatr Transplant 2011 Jun 15 [Epub ahead of print])

Case reports
=========================================================================

● Genetically confirmed cases in Korea (J Korean Med Sci 2009;24 Suppl:S210)

Gross description
=========================================================================

● Enlarged kidneys due to tubular dilation and interstitial edema

Micro description
=========================================================================

● Proximal and distal tubular ectasia with flattening of tubular epithelium, microcysts with or without tubular PAS+ hyaline casts, glomerulosclerosis, mesangial hypercellularity, occasional immature glomeruli
● May evolve to focal and segmental glomerulosclerosis
● At renal failure stage, is interstitial fibrosis, global glomerulosclerosis and tubular atrophy

Micro images
=========================================================================



Patchy interstitial edema and cystically dilated tubules with attenuated epithelium


Mesangial hypercellularity and diffuse increase of mesangial matrix

   
Various immunostains

Immunofluorescence
=========================================================================

● Non-specific IgM and C3 in mesangium and capillaries

Electron microscopy description
=========================================================================

● Obliteration (effacement) of foot processes

Electron microscopy images
=========================================================================


       
Wide effacement of epithelial foot processes


Diffuse mesangial sclerosis

General
=========================================================================

● Clinically and genetically heterogeneous group of disorders in non-Finnish patients (J Am Soc Nephrol 2010;21:1209)
● Early onset of severe proteinuria (50% within months 0-2, 50% in months 3–9 months), with rapid progression to end stage renal disease by age 3 years
● May be associated with WT1 abnormalities and Denys-Drash syndrome (OMIM #256370), PLCE1 mutations (Nephrol Dial Transplant 2008;23:1291) or be isolated (Pediatr Nephrol 2009;24:1013)
● Normal placenta, no premature births, but is associated with cataracts and corneal clouding, aniridia, microencephaly, mental retardation and hypertelorism
● Does not recur after transplantation

Case reports
=========================================================================

● Two cases of isolated diffuse mesangial sclerosis with WT1 mutations (J Korean Med Sci 2006;21:160)

Micro description
=========================================================================

● Diffuse mesangial sclerosis; tubular atrophy with focal tubular dilatation and interstitial fibrosis

Micro images
=========================================================================


       
Mesangial sclerosis

   
WT1-associated

Immunofluorescence
=========================================================================

● Non-specific staining with mesangial deposits of IgM, C3 and C1q

Electron microscopy description
=========================================================================

● Obliteration of foot processes, basement membrane thickening and increase in mesangial matrix



Primary glomerular diseases

Diffuse mesangial hypercellularity with nephrotic syndrome


Reviewers: Nikhil Sangle, M.D. (see Reviewers page)
Revised: 15 April 2012, last major update March 2012
Copyright: (c) 2003-2012, PathologyOutlines.com, Inc.

General
=========================================================================

● 2-10% of renal biopsies from patients with idiopathic nephrotic syndrome
● Presents with nephrotic syndrome, more likely to have hypertension and hematuria
● In adults, represents a heterogeneous group with different clinical courses (Ren Fail 2009;31:192, Nephrol Dial Transplant 2000;15:981)
● Associated with steroid resistant or steroid dependent minimal change glomerulopathy, focal and segmental glomerulosclerosis
● Note: minimal change disease, diffuse mesangial hypercellularity and focal and segmental glomerulosclerosis may be a continuum of the same disease

Micro description
=========================================================================

● Mild mesangial hypercellularity, patent capillary lumens and normal basement membrane thickness

Micro images
=========================================================================


       
Left to right: mild, moderate, severe disease

   
Various images

Immunofluoresence
=========================================================================

● Non-specific; IgM and variable C3

Electron microscopy description
=========================================================================

● Obliteration of foot processes, sparse mesangial deposits

Differential diagnosis
=========================================================================

● Differentiate using immunofluorescence and electron microscopy:

Acute postinfectious glomerulonephritis-resolving phase
C1q nephropathy
IgA nephropathy
Mesangial proliferative lupus nephritis
Mild membranoproliferative glomerulonephritis



Primary glomerular diseases

Fibrillary glomerulonephritis


Reviewers: Nikhil Sangle, M.D. (see Reviewers page)
Revised: 17 April 2012, last major update April 2012
Copyright: (c) 2003-2012, PathologyOutlines.com, Inc.

General
=========================================================================

● Not a disease, but the morphologic expression of a diverse group of diseases incompletely defined (Hum Pathol 2001;32:660)
● Deposition of extracellular non-amyloid fibrillary material in glomerular basement membranes, mesangium and tubular basement membranes (“nephropathy” better term than glomerulonephritis)

Clinical features
=========================================================================

● Rare, < 1% of renal biopsies
● More common in whites and females
● Associated with malignancy (most commonly carcinoma), dysproteinemia, autoimmune disease
● Patients present with heavy proteinuria, hematuria, renal insufficiency, systemic hypertension
● 50% develop end-stage kidney disease within 2-4 years from diagnosis
● No evidence of extrarenal fibrillary deposits
● Features overlap with hepatitis C virus induced cryoglobulinemic glomerulonephritis
Diagnosis: based on ultrastructural (EM) findings; some authors require exclusion of cryoglobulins

Treatment
=========================================================================

● Kidney transplantation appears safe, with low risk of recurrence; in contast, patients with monoclonal gammopathy with fibrillary deposits have a significant risk for post-transplant recurrence (Kidney Int 2009;75:420)
● Treatment with rituximab may be helpful (Am J Kidney Dis 2008;52:1158)

Case reports
=========================================================================

● 43 year old man with polyclonal gammopathy but IgG1 deposits (Mod Pathol 1998;11:103)
● 50 year old man (Arch Pathol Lab Med 2001;125:534)

Micro description
=========================================================================

● Most common histologic patterns are mesangial proliferative / sclerosing followed by membranoproliferative glomerulonephritis (Clin J Am Soc Nephrol 2011;6:775)
● Mesangial expansion with PAS-positive material, diffuse thickening of the glomerular basement membrane
● Variable proliferative lesions, 25% have crescents (Am J Kidney Dis 2012 Mar 5 [Epub ahead of print])
● Silver stain highlights thickening of basement membrane and mesangial expansion by material that has a distinct ‘motheaten’ appearance (due to silver-negative deposits)

Micro images
=========================================================================


           
Fibrillary glomerulonephritis


Case with crescents

   
Various images


IgG immunofluorescence

Immunofluorescence
=========================================================================

● Glomerular capillary wall and mesangial deposition of IgG4, C3, kappa and lambda light chains

Electron microscopy description
=========================================================================

● Randomly arranged non-amyloid fibrils in the mesangium and glomerular capillary walls, 18-22 nm thick vs. 10 nm thick fibrils for amyloid and 30-50 nm thick organized tubules for immunotactoid glomerulopathy
● Usually extensive effacement of epithelial foot processes

Electron microscopy images
=========================================================================


       
Randomly oriented subepithelial fibrils


Fibrillar deposits in the mesangium

   
Series of images



Primary Glomerular Diseases

Focal proliferative and necrotizing glomerulonephritis


Reviewers: Nikhil Sangle, M.D. (see Reviewers page)
Revised: 25 July 2012, last major update July 2012
Copyright: (c) 2003-2012, PathologyOutlines.com, Inc.

General
=========================================================================

● Only parts of some glomeruli affected; proliferative, not sclerotic; also necrosis and fibrin deposition
● Hematuria varies from microscopic to gross, occasionally with nephrotic syndrome
● Seen early in systemic diseases (SLE, polyarteritis nodosa, Henoch-Schonlein purpura, Goodpasture’s syndrome, endocarditis, Wegener’s granulomatosis)
● May be part of IgA nephropathy or idiopathic

Micro images
=========================================================================



Various images

   
IgA nephropathy with focal proliferative glomerulonephritis and a small crescent


Focal segmental necrotising glomerulonephritis in a patient with SLE


Focal necrotizing and crescentic glomerulonephritis



Primary glomerular diseases

Focal and segmental glomerulosclerosis


Reviewers: Nikhil Sangle, M.D. (see Reviewers page)
Revised: 24 April 2012, last major update April 2012
Copyright: (c) 2003-2012, PathologyOutlines.com, Inc.

General
=========================================================================

● A histologic pattern of glomerulosclerosis (affecting some glomeruli, and only part of capillary tuft) associated with heavy proteinuria (> 3.5 g/day) and progressive renal failure
● In normal adults at autopsy, ages 55 or less, glomerulosclerosis affects < 3% of glomeruli (Arch Pathol Lab Med 1989;113:1253)

Primary (idiopathic) form:
● Causes 10% of nephrotic syndrome in children (usually < 5 years old), 20% in adults (20-39 years)
● Associated with hematuria, hypertension, hypercholesterolemia, hypoalbuminemia, non-selective proteinuria and edema
● Rarely is familial
● Overall incidence higher in African-Americans

Secondary forms:
● Causes: congenital heart disease, congenital kidney disease (associated with 19q13 or nephrin alterations), focal proliferative and necrotizing glomerulonephritis-healed, glycogen, heroin addiction, HIV, hypertension, IgA nephropathy, morbid obesity, obstruction, reflux, renal ablation nephropathy, sickle cell disease, storage disease, unilateral renal agenesis
● Similar glomerular lesions as idiopathic forms
● May be due to circulating mediator (proteinuria may recur with allografts in 24 hours, overall in 25-50% of allografts)
● Children have better prognosis than adults, who often progress to renal failure (40-60% overall within 10-20 years)
● Note: minimal change disease, diffuse mesangial hypercellularity and focal segmental glomerulosclerosis may be a continuum of the same disease

Classification
=========================================================================

● Columnbia University classification: perihilar, cellular, tip lesion, collapsing and not otherwise specified (Am J Kidney Dis 2004;43:368); correlates with prognosis

Treatment
=========================================================================

● Steroids and cytotoxic therapy in children (Saudi J Kidney Dis Transpl 2010;21:87)
● Gastric bypass surgery may be effective for obesity related disease (Pediatr Nephrol 2009;24:851)
● Also transplant
● Rrituximab may reduce recurrence prior to a second transplant (Transpl Int 2012;25:e62)
● Intensive and prolonged treatment of recurrence may also be effective (Am J Transplant 2009;9:1081)
● Rarely, recurrence post-transplant may spontaneously regress (Saudi J Kidney Dis Transpl 2011;22:1219)

Micro description
=========================================================================

● Focal and segmental glomerulosclerosis and mesangial sclerosis in lobules that appear to adhere to Bowman’s capsule (begins in corticomedullary region), inframembranous hyaline deposits (PAS+, trichrome red, silver negative) and endocapillary foam cells or lipoid droplets in focal glomeruli, initially mild mesangial hypercellularity that becomes hypocellular in advanced lesions
● Focal tubular atrophy with interstitial fibrosis, hyaline thickening of afferent arterioles
● Note: the defining glomerular lesions may not be sampled in needle core biopsy due to their focal nature

Micro images
=========================================================================


       

       
Focal and segmental glomerulosclerosis

           
Various images

Positive stains
=========================================================================

● High levels of malondialdehyde (Saudi J Kidney Dis Transpl 2010;21:886)

Immunofluorescence
=========================================================================

● IgM and C3 deposited in focal and segmental manner in the sclerotic segments

Electron microscopy description
=========================================================================

● Epithelial cell detachment from glomerular basement membrane
● Extensive foot process obliteration (even in non-sclerotic glomeruli), mesangial sclerosis with increased matrix and collapsed glomerular loops

Electron microscopy images
=========================================================================



Series of images


Cellular variant

General
=========================================================================

● Compared to classic focal segmental glomerulosclerosis (NOS), presents with more severe proteinuria (Kidney Int 2006;70:1783)

Micro description
=========================================================================

● Focal and segmental endocapillary hypercellularity occluding lumens, with foam cells and karryorrhexis, podocyte hypertrophy and hyperplasia; resembles crescents
● May resemble focal proliferative glomerulonephritis, but no glomerular immune deposits are present

Micro images
=========================================================================


       
Various images

Immunofluorescence
=========================================================================

● Segmental IgM and C3

Electron microscopy description
=========================================================================

● Severe podocyte foot process effacement, occlusion of capillaries by endocapillary hypercellularity including foam cells, and hyaline deposits



Primary glomerular diseases

Focal and segmental glomerulosclerosis-
Special form in IV drug abuse and AIDS


Reviewers: Nikhil Sangle, M.D. (see Reviewers page)
Revised: 6 May 2012, last major update May 2012
Copyright: (c) 2003-2012, PathologyOutlines.com, Inc.

General
=========================================================================

● Rapid progression to end stage renal failure in AIDS (3-4 months) and IV drug abuse (2-4 years, Am J Med 1989;87:389)
● 54% of the patients were black, 35% were white, and 11% were Hispanic. Thirty-three percent of the patients had a history of intravenous drug abuse (Am J Kidney Dis 2000;35:884)
● Note: HIV also causes acute renal failure, postinfectious, membranous or membranoproliferative glomerulonephritis (Hum Pathol 1987;18:1293)

Pathogenesis
=========================================================================

● Nef and Vpr are key viral genes; Nef induces podocyte dysfunction, Vpr induces renal tubular epithelial cell apoptosis (Curr Opin Nephrol Hypertens 2011;20:306)
● Genetic variants in nonmuscle myosin heavy chain 9 gene (MYH9) have a major influence on both FSGS and human immunodeficiency virus-associated collapsing glomerulopathy, with odds ratios from 4 to 8 and attributable fractions of 70% to 100% (Semin Nephrol 2010;30:111, Nat Genet 2008;40:1175)

Micro description
=========================================================================

● Often collapse and sclerosis of entire glomerular tuft with hypertrophic podocytes filling Bowman’s space
● Large tubular hyaline casts, flattened epithelium
● Also manifestations of severe tubulointerstitial injury such as epithelial degenerative changes, microcystic dilation of tubules and interstitial inflammatory infiltrate (primarily activated T cells)

Micro images
=========================================================================



Various images including EM


No capillary loops, matrix collapse with no adhesions (even though there is global sclerosis), conspicuous hypertrophied epithelial cells (silver stain)


Microscystic dilation of tubules (trichrome stain)

Electron microscopy description
=========================================================================

● Tubuloreticular structures in endothelium (non-specific for infection, helps distinguish this from collapsing variant of FSGS, Hum Pathol 1988;19:1060), induced by interferon alpha

Electron microscopy images
=========================================================================



Tubuloreticular structures



Primary glomerular diseases

Glomerular tip lesion


Reviewers: Nikhil Sangle, M.D. (see Reviewers page)
Revised: 24 April 2012, last major update April 2012
Copyright: (c) 2003-2012, PathologyOutlines.com, Inc.

General
=========================================================================

● Segmental glomerular lesions at the tubular opening, or tip changes, are found in the renal biopsies of adults in many disorders
● In focal and sclerosing glomerulosclerosis, appears to have similar response to therapy as classic disease (Nephrol Dial Transplant 2011;26:2215)
● Associated with childhood minimal change nephropathy (Pediatr Nephrol 2008;23:1281)

Micro description
=========================================================================

● Sclerosis only in portion of glomerulus opposite the hilus, forming an adhesion near the opening of Bowman’s space into proximal tubule
● Capillary lumina of sclerotic loops may be obliterated by swollen endothelial cells with vacuoles and foam cells

Micro images
=========================================================================


           

       
Glomerular tip lesion

Immunofluorescence
=========================================================================

● Segmental IgM and C3

Electron microscopy description
=========================================================================

● Lesions resemble FSGS, except for their location at the tubular pole

Electron microscopy images
=========================================================================



Severe effacement of foot processes overlying patent capillaries



Primary glomerular diseases

Idiopathic nodular glomerulosclerosis


Reviewers: Nikhil Sangle, M.D. (see Reviewers page)
Revised: 6 May 2012, last major update May 2012
Copyright: (c) 2003-2012, PathologyOutlines.com, Inc.

General
=========================================================================

● Resembles nodular diabetic glomerulosclerosis (Kimmelstiel-Wilson changes), but in non-diabetic patients
● Mean age 68 years, 74% white and 78% men (Hum Pathol 2002;33:826)
● Typically presents with renal insufficiency (83%, mean serum creatinine of 2.4 mg/dL), proteinuria > 3g/day (70%) and nephrotic syndrome (22%)
● Associated with hypertension (96%), smoking (91%, mean 53 pack-years), hypercholesterolemia (90%) and extrarenal vascular disease (44%, Hum Pathol 2002;33:826); also increased body mass index / overweight (Hum Pathol 2008;39:1771)
● A diagnosis of exclusion
Poor prognostic factors for end stage renal disease: continued smoking, lack of angiotensin II blockage and degree of arteriosclerosis

Micro description
=========================================================================

● Prominent diffuse and nodular mesangial sclerosis, glomerular basement membrane thickening, arteriosclerosis and arteriolosclerosis
● Also neovascularization of glomeruli

Micro images
=========================================================================


       

   
Idiopathic nodular glomerulosclerosis

Positive stains
=========================================================================

● CD34 highlights increased number of vascular channels within glomeruli compared with normal controls

Differential diagnosis
=========================================================================


Table



Primary glomerular diseases

IgA nephropathy (Berger’s disease)


Reviewers: Nikhil Sangle, M.D. (see Reviewers page)
Revised: 1 July 2012, last major update July 2012
Copyright: (c) 2003-2012, PathologyOutlines.com, Inc.

General
=========================================================================

● A type of diffuse mesangioproliferative glomerulonephritis (others: Henoch-Schonlein purpura, SLE, IgM nephropathy, resolving stage of postinfectious glomerulonephritis)
● IgA present in mesangium and elevated serum IgA
● Note: thromboangiitis obliterans is also known as Buerger's disease

Pathophysiology
=========================================================================

● Excess amounts of poorly galactosylated serum immunoglobulin IgA1 trigger the generation of glycan-specific IgG and IgA autoantibodies, resulting in circulating IgA immune complexes (Kidney Int 2012;81:833)
● IgA immune complexes are deposited in mesangium and activate alternative complement pathway and possibly the lectin pathway (J Biomed Biotechnol 2012;2012:476739)
● Podocyte injury, due to epithelial to mesenchymal transition, plays an important role in glomerulosclerosis in IgA nephropathy (Cell Physiol Biochem 2012;29:743)

Clinical features
=========================================================================

● Most common form of primary glomerulonephritis worldwide; causes 10% of cases of end stage renal failure in many countries (eMedicine)
● Common at ages 10-29 years, usually males who present with gross or microscopic hematuria after respiratory infection, but no systemic disease (Pediatr Nephrol 2012;27:1293)
● More common in southern Europe, Asia and Native Americans, less common in individuals of African lineage
● Slowly progressive: 25%-50% have renal failure at 20 years; recurs in 20-60% of allografts
● Rarely causes death due to pulmonary hemorrhage (Arch Pathol Lab Med 1994;118:542)
● Note: IgA deposits are also present in Henoch-Schonlein purpura; diseases may be related
● Secondary disease associated with gluten enteropathy (celiac disease), liver disease and dermatitis herpetiformis (Arch Pathol Lab Med 1983;107:324)
Poor prognosis: prominent arteriolar hyalinization, older age, heavy proteinuria and hypertension

Treatment
=========================================================================

● Controlling proteinuria and blood pressure reduces loss of kidney function (Am J Kidney Dis 2012;59:865)
● Tonsillectomy improved clinicopathologic features in relatively severe pediatric IgA nephropathy, especially with early-surgery (Nephrology (Carlton) 2012 May 23 [Epub ahead of print])
● Steroids (Clin Exp Nephrol 2012 May 23 [Epub ahead of print]); tacrolimus if refractory (Am J Nephrol 2012;35:312)

Case reports
=========================================================================

● 8 year old boy with Wiskott-Aldrich syndrome (Int Urol Nephrol 2012 May 1 [Epub ahead of print])
● 42 year old man with bilateral nodular scleritis (J Ophthalmic Inflamm Infect 2012 Mar 13 [Epub ahead of print])

Micro description
=========================================================================

● Diffuse proliferation of mesangial cells and matrix without significant involvement of capillary walls or lumina
● Mesangial involvement is often uneven and resembles focal and segmental glomerulosclerosis
● Normal or hypercellular glomeruli with diffuse necrotizing crescentic glomerulonephritis

Micro images
=========================================================================



Various images including EM


Mild mesangial expansion


Granular mesangial staining for IgA

Immunofluorescence
=========================================================================

● IgA, often granular IgG and C3 in mesangium
● IgA also in capillaries of dermis, lung, liver and intestine
● IgA more intense or equally intense compared to IgG and IgM
● Staining for C1q should raise the suspicion for lupus nephritis

Electron microscopy description
=========================================================================

● Electron dense deposits in mesangium of all glomeruli

Electron microscopy images
=========================================================================



Electron dense deposits in mesangium

Differential diagnosis
=========================================================================

Lupus nephritis
● Mesangial IgA deposition associated with obstructive jaundice (Hum Pathol 1987;18:1149)



Primary glomerular diseases

Immunotactoid glomerulopathy


Reviewers: Nikhil Sangle, M.D. (see Reviewers page)
Revised: 2 July 2012, last major update July 2012
Copyright: (c) 2003-2012, PathologyOutlines.com, Inc.

General
=========================================================================

● Rare (<1% of renal biopsies) disorder with extracellular glomerular deposition of nonamyloid fibrils
● Patients have monoclonal immunoglobulin deposition in glomeruli and may have circulating paraproteins
● More common in whites and females
● Related to fibrillary glomerulonephritis, but different fibril size and arrangement
● May overlap with hepatitis C virus-induced cryoglobulinemic glomerulonephritis

Clinical features
=========================================================================

● Presents with nephrotic syndrome
● Patients with circulating or urinary paraproteins are more likely to have lymphoproliferative disorders
● Poor long term survival
● Diagnosis based on EM findings, and exclusion of other possible causes of fibrillary deposits, such as amyloidosis, cryoglobulinemia, systemic lupus erythematosus or paraproteinemia

Treatments
=========================================================================

● Hypertensive control, possibly steroids (Clin Exp Nephrol 2009;13:378), possibly Rituximab (Transplant Proc 2009;41:3953), kidney transplant

Case reports
=========================================================================

● 43 year old woman with spontaneous remission (Neth J Med 2011;69:341)
● 59 year old woman with proteinuria, immunotactoid glomerulopathy, heavy chain disease and follicular lymphoma (Arch Pathol Lab Med 2004;128:689)
● 69 year old man with lobular glomerulonephritis (Clin Nephrol 2005;63:368)
● Progression to end-stage renal disease within 1 week of initial presentation (ScientificWorldJournal 2009;9:1348)

Micro description
=========================================================================

● Mesangial widening and occasional hypercellularity, capillary wall thickening; 25% have crescents

Micro images
=========================================================================


   
Various images including EM

Immunofluorescence
=========================================================================

● Variable IgG, C3; occasional IgM, IgA

Negative stains
=========================================================================

● Congo red, thioflavin T

Electron microscopy description
=========================================================================

● Extracellular, non-amyloid deposits 30-50 nm wide, focally arranged in parallel arrays and with a visible lumen (microtubules), usually within mesangium but also involving basement membrane
● In comparison, fibrillary glomerulonephritis has smaller fibrils, 10–30 nm diameter, with only focal parallel arrangement

Electron microscopy images
=========================================================================


   
Various images


Figures e-h

       
With fibrillary glomerulonephritis



Primary glomerular diseases

Membranoproliferative glomerulonephritis


Reviewers: Nikhil Sangle, M.D. (see Reviewers page)
Revised: 26 May 2012, last major update May 2012
Copyright: (c) 2003-2012, PathologyOutlines.com, Inc.

General
=========================================================================

● Also called hypocomplementemic (C3), lobular or mesangiocapillary / mesangiopathic glomerulonephritis
● Pattern of injury with alterations in basement membrane and proliferation of mesangial cells, due to subendothelial and mesangial deposition of immunoglobulins, caused by persistent antigenemia or circulating immune complexes
● Either immunoglobulin mediated or complement mediated (although all types stain for C3)
● Immunoglobulin mediated: due to chronic infections, autoimmune diseases, monoclonal gammopathy/dysproteinemias
● Complement mediated: due to subendothelial and mesangial deposition of complement from dysregulation of alternative pathway; includes dense deposit disease (membranoproliferative glomerulonephritis type 2) and proliferative glomerulonephritis with C3 deposits; due to genetic mutations or development of autoantibodies to complement (Semin Nephrol 2011;31:341)
● Intermittent remissions but overall downhill course
● Diagnosis of MPGN-I or MPGN-II reduces overall primary allograft survival compared with other forms of glomerulonephritis (10 year graft survival drops from 65% to 56%, Am J Kidney Dis 2011;57:291)

Case reports
=========================================================================

● 27 year old man with recurrent episodes of hypokalemic quadriparesis (type not specified, J Assoc Physicians India 2011;59:735)

Micro images
=========================================================================



Type I and Type II (text and images)

Differential diagnosis
=========================================================================

● Cryoglobulinemic glomerulonephritis: may have similar features (Pathol Res Pract 2012;208:254)
● C3 glomerulopathy: all membranoproliferative GN stains for C3, but C3 glomerulopathies are immunoglobulin negative (Kidney Int 2012;81:434)


Type I: Classical

General
=========================================================================

● 5% of cases of glomerulonephritis affecting children and young adults; 2/3 of membranoproliferative glomerulonephritis cases
● Immune complex deposition and activation of classical and alternative complement pathway
● Typically presents with nephrotic syndrome and hypertension in patients 8-16 years old; less commonly nephritis
● Also associated with Staphylococcus epidermidis infection with ventriculoatrial or ventriculojugular shunts
● 2/3 have persistent decrease in serum C3 due to its hypercatabolism; also reduction in total hemolytic complement (CH) 50 levels and borderline / reduced levels of C1q, C4 and properdin
● Secondary disease occurs with chronic immune complex disorders (SLE, hepatitis B/C, HIV, schistosomiasis), alpha-1-antitrypsin deficiency and malignancies
● May cause high rates of non-diabetic end stage renal disease in Navajo Indians in US (Arch Pathol Lab Med 1989;113:158)

Case reports
=========================================================================

● 16 year old girl with refractory disease and dramatic response to eculizumab, a monoclonal antibody to C5 (N Engl J Med 2012;366:1165)

Treatment
=========================================================================

● No established treatment in adults, but plasmapharesis and Rituximab may reduce proteinuria (Clin Nephrol 2012;77:290, Transplant Proc 2011;43:4005)

Micro description
=========================================================================

● Large glomeruli with accentuation of lobules
● Irregular thickening of glomerular basement membrane by interposition of mesangial cells between endothelium and basement membrane
● Causes tram track / double contour appearance (PAS or silver stain), crescents in 20%
● Neutrophils often present
● May have hyaline aggregates of immune complexes in capillary lumina

Micro images
=========================================================================


       
Series of images including immunofluorescence and EM


With hepatitis B related disease, showing duplication of capillary wall and tram-track appearance (silver stain)


Hypercellular glomeruli with accentuated lobules


Fluorescence microscopy shows deposits corresponding to immune complexes along glomerular basement membrane


IgG in glomerular capillary loops

Immunofluorescence
=========================================================================

● Lumpy bumpy (granular) for C3, IgG, early complement (C1q, C4); pattern is mesangial and subendothelial

Electron microscopy description
=========================================================================

● Subendothelial and mesangial electron-dense deposits, increased mesangial matrix, mesangialization of capillary loops and foot process fusion

Electron microscopy images
=========================================================================


   
Splitting and reduplication of basement membrane


Series of images


Large subendothelial electron-dense deposit along glomerular basement membrane


Type II: Dense deposit

General
=========================================================================

● Essential diagnostic feature is not the membranoproliferative pattern but the presence of electron dense transformation of the glomerular basement membranes
● Occurs in 1/3 of cases of membranoproliferative glomerulonephritis, but some authors believe this entity is actually distinct from membranoproliferative glomerulonephritis (Mod Pathol 2007;20:605)
● Familial or associated with partial lipodystrophy (loss of subcutaneous fat from fat and upper body)
● Associated with uncontrolled activation of alternative complement pathway because of C3 nephritic factor (stabilizes C3 convertase; promotes C3 degradation)
● Tends to present with nephritis more than nephrotic syndrome
● Poorer prognosis than type I; 50% have renal failure in 10 years; 80-100% recur after renal transplant
● Also deposits in basement membranes of spleen, choroid and Bruch’s membrane of retina
● Rarely abnormalities in factor H (Hum Pathol 2011;42:1305, Iran J Kidney Dis 2012;6:149)

Micro description
=========================================================================

● Similar to type I, but less prominent cellular proliferation
● Eosinophilic, refractile and ribbon-like thickening of glomerular basement membrane and basement membrane of Bowman’s capsule and tubules
● Strongly PAS+, stains red with trichrome but dense deposits are negative with silver stain

Micro images
=========================================================================


       

Type II

Immunofluorescence
=========================================================================

● Linear or double contoured C3 and properdin staining of glomerular capillary walls and bright nodular or ring-like reaction in mesangium, NOT in dense deposits
● C3 staining also in mesangium, Bowman’s capsule and tubular basement membranes
● Usually no immunoglobulins

Immunofluorescence images
=========================================================================



Fluorescent ribbons of variable thickness seen along glomerular capillary loops (arrows)

Electron microscopy description
=========================================================================

● Dense deposits in lamina densa of glomerular basement membrane, Bowman's capsule; causes long ribbon of hazy material
● Also nodular deposits of similar material in mesangium

Electron microscopy images
=========================================================================



Ribbon-like dense deposits within glomerular basement membrane

Additional references
=========================================================================

Mod Pathol 2002;15:988


Type III: Mixed

General
=========================================================================

● Two rare morphologic subtypes (Burkholder and Anders) that are clinically similar to each other and to type I membranous glomerulonephritis


Type III: Burkholder variant

General
=========================================================================

● Combined features of type I membranoproliferative glomerulonephritis and membranous glomerulonephritis
● Associated with Hepatitis C and HIV coinfection (J Am Soc Nephrol 1999;10:1566)

Micro images
=========================================================================



Series of images including immunofluorescence and EM

Electron microscopy description
=========================================================================

● Subendothelial and subepithelial deposits and mesangial interposition associated with basement membrane spikes


Type III: Anders variant

General
=========================================================================

● Hybrid of type I and II membranoproliferative glomerulonephritis

Electron microscopy description
=========================================================================

● Massive accumulation of deposits within basement membrane with membranous disruption, highlighted by silver stain



Primary glomerular diseases

Membranous glomerulonephritis


Reviewers: Nikhil Sangle, M.D. (see Reviewers page)
Revised: 1 July 2012, last major update July 2012
Copyright: (c) 2003-2012, PathologyOutlines.com, Inc.

General
=========================================================================

● Most common cause of nephrotic syndrome in adults (40%); 5% of cases in children
● Diffuse glomerular wall thickening due to in situ immune complexes (electron dense) in glomerular basement membrane but NOT in mesangium

Pathophysiology
=========================================================================

● 75% of adult and 20% of childhood cases are idiopathic autoimmune disease linked to HLA, caused by antibodies to a renal autoantigen (including α-enolase, J Proteomics 2011;74:2008 and others, Proteomics Clin Appl 2011;5:90)
● Considered the human model of Heymann nephritis, which in rats is produced by antibody to megalin antigen complex on basal surface of visceral epithelial cells (megalin is homologous to LDL receptor)
● Secondary cases are associated with cancer (lung, colon, melanoma), hepatitis B/C, malaria, schistosomiasis, drugs (penicillamine, captopril, gold, NSAID), heavy metals, lupus, diabetes, thyroiditis and angiofollicular lymph node hyperplasia (Arch Pathol Lab Med 1979;103:591)
● Proteinuria may be due to C5b-C9 (MAC complex of complement)
● Allograft recurrences represent idiopathic MGN due to IgG4, with different pathogenic mechanism than de novo MGN (Transplant Proc 2011;43:3743)

Clinical features
=========================================================================

● Insidious onset of nephrotic syndrome, occasionally hematuria and hypertension
● Must rule out and treat secondary causes
● 10% die or develop renal failure in 10 years (40% eventually develop renal failure)
● Rarely, tubulointerstitial nephritis due to anti-tubular basement membranes
● Hepatitis B cases resemble lupus nephritis class V, but are HepB+ and lack SLE’s extrarenal manifestations and autoantibodies (Mod Pathol 2000;13:166)

Variants of membranous glomerulonephritis (MGN):
● MGN with crescents
● MGN with antitubular basement membrane nephritis
● Transplant associated MGN
● MGN with superimposed renal vein thrombosis

Treatment
=========================================================================

● Variable course of disease makes it difficult to evaluate therapy
● Alternating steroids and chlorambucil or cyclophosphamide (Ponticelli protocol) for six months
● If no remission after protocol, consider cyclosporine, adrenocorticotropic hormone, mycophenolate mofetil, rituximab (J Biol Regul Homeost Agents 2012;26:135)
● Treatment is effective on post-transplant recurrences (Am J Transplant 2012;12:1029)

Case reports
=========================================================================

● 22 year old man with acute renal failure caused by Hodgkin's lymphoma (Ren Fail 2011;33:363)
● 24 year old woman with tuberculous peritonitis (J Infect Dev Ctries 2011;5:550)
● 27 year old man with syphilis (Nefrologia 2011;31:372)
● 43 year old man with C1q deposits followed by development of psoriasis (Nefrologia 2012;32:228)
● 45 year old woman with HIV infection and features of lupus nephritis (Lupus 2012;21:900)
● 55 year old man with pulmonary embolism (Case Report Med 2010;32:649)
● 60 year old woman with severe ankylosing spondylitis (Ann Pharmacother 2011;45:e62)
● HIV+ man (HJ Infect Public Health 2012;5:207)

Micro description
=========================================================================

● Early biopsies may be normal
● Later: uniform diffuse capillary wall thickening without hypercellularity, without mesangial sclerosis and without inflammatory cells
● Proximal convoluted tubules contain hyaline droplets, reflecting protein reabsorption
● With progression, get membrane thickening, narrow capillary lumina, mesangial sclerosis and glomerulosclerosis

Micro images
=========================================================================


   
Various images, including EM

       
Thickened glomerular capillary loops

       
Various images of fluourescence microscopy based on Hollande's fixative


Silver stain shows basement membrane spikes


Diffuse granular immunofluoresence for IgG

Immunofluorescence
=========================================================================

● Granular diffuse peripheral deposits, usually IgG and C3, also C5b-C9 and occasionally IgM or IgA
● C4d immunostaining may be diagnostic (Histol Histopathol 2011;26:1391)

Stages:
Stage I: LM - normal or slightly thickened BM, slight GMB vacuolization; IF - fine granular IgG, C3; EM - scattered small subepithelial electron dense deposits, no foot process effacement or spikes
Stage II: LM - moderately thickened BM with spikes and vacuolization; IF - moderate sized, granular IgG, C3; EM - diffuse spikes due to subepithelial deposits, diffuse foot process effacement
Stage III: LM - markedly thickened GBM, residual spikes and vacuoles, chain like appearance; IF - coarsely granular IgG, C3; EM - intramembranous deposits, spikes, neomembrane formation and diffuse foot process effacement
Stage IV: LM - markedly thickened GBM, few spikes, vacuoles and glomerulosclerosis; IF - focal IgG, C3; EM - sclerotic GBM, few deposits and lacunae

Virtual slides
=========================================================================



Membranous glomerulonephritis

Electron microscopy images
=========================================================================


   
Intramembranous deposits


Stage I with electron dense deposits along glomerular basement membrane


Hepatitis B with subepithelial and mesangial electron dense deposits (M) and fusion of epithelial foot processes (arrows)



Primary glomerular diseases

Minimal change glomerulopathy


Reviewers: Nikhil Sangle, M.D. (see Reviewers page)
Revised: 4 September 2012, last major update September 2012
Copyright: (c) 2003-2012, PathologyOutlines.com, Inc.

General
=========================================================================

● Also called minimal change disease, nil disease, lipoid nephrosis and foot process disease
● Causes 80% of cases of nephrotic syndrome in children (usually ages 2-6), 20% in adults

Pathophysiology
=========================================================================

● Extensive foot process "fusion" appears to be due to epithelial injury with loss of glomerular anionic charge
● Overproduction of angiopoietin-like 4 (ANGPTL4) in podocytes causes it to bind to glomerular basement membrane, leading to selective proteinuria, diffuse effacement of foot processes and loss of glomerular basement membrane charge (Am J Kidney Dis 2012;59:284, Nat Med 2011;17:117); due in part to sialic acid residue deficency in ANGPTL4 (oral supplementation with sialic acid precursor N-acetyl-d-mannosamine improves sialylation of podocyte-secreted ANGPTL4 and significantly decreases proteinuria)
● "Fusion" is actually simplification of epithelial architecture with flattening, retraction and swelling of foot processes; also seen in membranous glomerulopathy and diabetes; reverts to normal with remission


Lipoid nephrosis


Clinical features
=========================================================================

● Nephrotic syndrome, proteinuria selective for albumin, causing hypoalbuminemia leading to severe edema
● Elevated serum cholesterol, but with minimal microscopic glomerular alterations and usually no hypertension, no hematuria and no azotemia
● Note: minimal change disease, diffuse mesangial hypercellularity and focal and segmental glomerulosclerosis may be a continuum of the same disease
● Associated with respiratory infections, immunizations, lead or mercury ingestion, allergies, acute interstitial nephritis and Hodgkin’s lymphoma; in elderly, associated with NSAIDs

Case reports
=========================================================================

● Intravascular B cell lymphoma of kidney associated with minimal change disease (Hum Pathol 1989;20:263)

Treatment
=========================================================================

● 90% of children respond to steroids initially (foot processes return to normal), may require immunosuppression, < 5% develop renal failure after 25 years
● Some children become steroid dependent / resistant, but this usually resolves at puberty
● Older adults with hypertension and severe proteinuria have a higher risk of reversible renal failure
● Rituximab may be effective in adults (Clin Nephrol 2011;76:151)
● May develop nephrocalcinosis due to hypercalciuria from chronic furosemide use (Hum Pathol 2000;31:1363)

Gross images
=========================================================================



Lipoid nephrosis

Micro description
=========================================================================

● Normal glomeruli, tubules have lipid droplets due to reabsorption of lipoproteins that leak from glomeruli ("lipoid nephrosis")

Micro images
=========================================================================


           
Relatively normal appearing glomeruli and lipoid nephrosis

Immunofluorescence
=========================================================================

● Generally negative
● May show weak non-specific IgM in mesangial distribution, but no deposits in GBM
● Albumin in proximal tubular epithelial cells

Immunofluorescence images
=========================================================================



Only background staining by immunofluorescence

Electron microscopy description
=========================================================================

● Extensive foot process effacement (foot processes retract into cell bodies, not actually fusion)
● Microvillous transformation of epithelial cells, cyst formation

Electron microscopy images
=========================================================================


           
Foot process effacement

Differential diagnosis
=========================================================================

Focal and segmental glomerulosclerosis: tubular atrophy and interstitial scarring; global glomerular sclerosis may be present in minimal change disease if there is underlying arterionephrosclerosis; minimal change disease may also be associated / superimposed on other conditions such as IgA nephropathy



Primary glomerular diseases

Post-infectious glomerulonephritis


Reviewers: Nikhil Sangle, M.D. (see Reviewers page)
Revised: 2 July 2012, last major update July 2012
Copyright: (c) 2003-2012, PathologyOutlines.com, Inc.

General
=========================================================================

● Also called post-streptococcal or acute glomerulonephritis; a type of diffuse endocapillary proliferative glomerulonephritis

Pathophysiology
=========================================================================

● Deposition of immune complexes from antibodies against organisms elicits acute inflammatory response and nephritic syndrome
● Associated with nephritogenic strains of Streptococcus pyogenes (beta hemolytic Strep group A)
● Similar histologic findings also associated with endemic malaria, toxoplasmosis, hepatitis B/C, HIV, varicella, spirochetes, staphylococci (Clin J Am Soc Nephrol 2006;1:1179), meningococci and other bacteria
● Similar process occurs in response to endogenous antigen in SLE


Diagram


Clinical features
=========================================================================

● Post-streptococcal disease is decreasing in US (eMedicine)
● 95% recover with conservative therapy; 1% develop rapidly progressive glomerulonephritis, 1-2% develop chronic glomerulonephritis
● Poor prognosis more likely if massive proteinuria and abnormal GFR; 2-5% die from pulmonary edema, hypertensive encephalopathy or crescentic glomerulonephritis; children with obesity may have greater renal injuries (Clin Nephrol 2009;71:632)
Children age 6-10: nephritic presentation with abrupt onset of hematuria, oliguria, fever, malaise and nausea 1-4 weeks after strep infection of pharynx or skin (impetigo); RBC casts, proteinuria, periorbital edema and hypertension
Adults: may have atypical presentation with sudden hypertension, edema and elevated BUN; 60% recover, others develop rapidly progressive glomerulonephritis (Arab J Nephrol Transplant 2012;5:93, J Med Assoc Thai 2006;89 Suppl 2:S157)
Laboratory (children and adults): high antistreptococcal antibody titers, low C3 (due to consumption)

Subclinical:
● Typical immune complex deposition of clinical disease, but with minimal symptoms or urinary abnormalities
● Important to recognize, since present in 10% of renal biopsies (Hum Pathol 2003;34:3)

Case reports
=========================================================================

● 6 year old girl and 12 year old boy with simultaneous occurrence with hemolytic uraemic syndrome (Eur J Pediatr 2001;160:173)
● 11 year old boy with sinus related orbital abscess (Arq Bras Oftalmol 2008;71:579)
● 42 year old male kidney transplant recipient with Salmonella infection (Clin Nephrol 2007;67:321)
● 4 year old boy with adenovirus infection (Isr Med Assoc J 2009;11:758, free full text)

Micro description
=========================================================================

● Glomeruli are globally and diffusely enlarged and hypercellular due to neutrophils and macrophages and proliferation of mesangial and endothelial cells (also called ‘exudative’ glomerulonephritis)
● Swelling of endothelial cells and presence of inflammatory cells obstructs capillary lumina
● Returns to normal within months
● Slight mononuclear leucocytic infiltrate and edema in the interstitium
● Tubules contain red blood cells

Micro images
=========================================================================


           

   
Various images

       
Markedly hypercellular glomeruli due to neutrophils

Immunofluorescence
=========================================================================

● Lumpy-bumpy (granular) deposition of IgG, IgM and C3 in peripheral glomerular loops
● Also properdin; no C1q or C4

Immunofluorescence images
=========================================================================



Lumpy bumpy (granular) or starry scar immunofluoresence


Starry-sky pattern


A: light microscopy shows glomerular lobular accentuation, endocapillary cell proliferation and neutrophils, but no immune complexes
B: fluorescence microscopy shows deposits corresponding to immune complexes bulging from outer surfaces of glomerular capillary loops


Electron microscopy description
=========================================================================

● Subepithelial ‘humps’ (finely granular, dome-shaped, electron dense, representing immune complex deposits), no spikes (compare to membranous glomerulonephritis)
● Obliteration of epithelial cell foot processes
● Subepithelial, intramembranous, subendothelial and mesangial deposits in the acute phase

Electron microscopy images
=========================================================================


   
Subepithelial deposits



Primary glomerular diseases

Rapidly progressive (crescentic) glomerulonephritis


Reviewers: Nikhil Sangle, M.D. (see Reviewers page)
Revised: 25 July 2012, last major update July 2012
Copyright: (c) 2003-2012, PathologyOutlines.com, Inc.

General
=========================================================================

● Rapid, usually irreversible, loss of renal function (usually 50% decline in glomerular filtration rate within 3 months), with glomerular crescent formation in 50-75% of biopsied glomeruli (eMedicine, Wikipedia)
● Also called extracapillary proliferative glomerulonephritis, because cell proliferation is primarily in Bowman’s space

Etiology
=========================================================================

● Due to deposition of fibrin, epithelial cells and inflammatory cells; may have various causes

Clinical features
=========================================================================

● Symptoms of nephritic syndrome, nephrotic syndrome and renal failure
● Unresponsive to steroids
● Causes death within weeks if untreated
● Prominent feature is crescents, the end result of damage to glomerular basement membrane or Bowman's capsule
● Crescents affect 50% of glomerular circumference, 70% of glomeruli

Case reports
=========================================================================

● 14 year old boy with Henoch-Schönlein Vasculitis and familial Mediterranean fever (Pediatr Rheumatol Online J 2009;7:8)
● 67 year old man with AL amyloidosis (Nephrol Dial Transplant 2010;25:2786)
● After Hepatitis B infection (Mod Pathol 1992;5:262)
● Associated with IgA myeloma (Nephron Extra 2011;1:69)

Gross description
=========================================================================

● Enlarged, pale kidneys with cortical petechial hemorrhages

Micro description
=========================================================================

● Crescents in glomeruli are proliferation of parietal epithelium of Bowman’s capsule with macrophages, neutrophils, lymphocytes, fibrin and collagen
● Also see glomerular capillary collapse, atrophic tubules and interstitial inflammation

Micro images
=========================================================================


       

           
Various images (H&E and PAS)

           

PAS-Silver stain and immunofluorescence

Virtual slides
=========================================================================



Numerous crescents

Electron microscopy description
=========================================================================

● Wrinkling and focal disruptions in glomerular basement membrane

Differential diagnosis
=========================================================================

Fibrillary glomerulonephritis: 20-30 nm fibrils in glomeruli by EM


3 subtypes based on immunofluorescence and EM

TYPE 1: Anti-glomerular basement membrane antibody crescentic glomerulonephritis (15%)

General
=========================================================================

Goodpasture’s syndrome: antibody to alpha 3 chain of type 4 collagen (part of non-collagenous domain) in lung alveolar basement membrane; associated with smoking and HLA-DRB1
● Usually young adult males with pulmonary involvement or age 50+ women limited to kidney
● Pulmonary hemorrhage present, treated with plasmapheresis, steroids and cytotoxic agents
● Most cases of Goodpasture’s are associated with rapidly progressive glomerulonephritis; but only 50% have both renal and pulmonary syndromes
Laboratory: 1/3 have circulating anti-neutrophil cytoplasmic antibodies (ANCA), especially ANCA specific for myeloperoxidase

Case reports
=========================================================================

● Co-existing vasculitis (Arch Pathol Lab Med 1980;104:300)

Micro description
=========================================================================

● Hypercellular glomeruli, crescents in > 50% glomeruli at time of biopsy, variable neutrophils, no / rare intracapillary cell proliferation and earliest lesion is focal segmental fibrinoid necrosis

Micro images
=========================================================================



Various images


Diffuse linear staining for IgG

Immunofluorescence
=========================================================================

● Diffuse linear staining of glomerular basement membrane, IgG > IgM, also C3 and focal fibrin in capillary loops, IgG should be at least 3+ or 4+ and no staining in mesangium

Electron microscopy description
=========================================================================

● No deposits; fibrin at glomerular basement membrane breaks

Differential diagnosis
=========================================================================

Based on clinical presentation:
● Microscopic polyarteritis
● Wegener’s granulomatosis
● Similar immunofluorescent findings in diabetic nephropathy
● SLE


TYPE 2: Immune complex crescentic glomerulonephritis (35%)

General
=========================================================================

● Immune complex deposition with complement activation due to postinfectious glomerulonephritis, types I and II membranoproliferative glomerulonephritis, cryoglobulinemic glomerulonephritis, SLE, IgA nephropathy, Henoch-Schonlein purpura and idiopathic
● Usually children
● Must treat underlying disease; plasmapheresis NOT helpful (in contast to anti-GBM glomerulonephritis)

Micro description
=========================================================================

● Depends on underlying glomerular disease
● Mild-moderate necrosis of glomerular segments adjacent to crescents, less than types 1 or 3
● Various combinations of capillary wall thickening and endocapillary cell proliferation

Immunofluorescence
=========================================================================

● Lumpy bumpy for IgG and C3 (like postinfectious)

Electron microscopy description
=========================================================================

● Immune complex deposits as subepithelial humps or mesangial deposits, fibrin at glomerular basement membrane breaks


TYPE 3: Pauci-immune crescentic glomerulonephritis (50%)

General
=========================================================================

● No anti-glomerular basement membrane antibodies, no immune complexes (hence called ‘pauci-immune’)
● Usually elderly
● Either limited to kidney or associated with clinical vasculitis (Wegener’s granulomatosis, microscopic polyarteritis)
● Rare complication of Sjogren's syndrome (J Formos Med Assoc 2011;110:473)
● Often have serum C-ANCA (against proteinase 3 PR3-ANCA; associated with Wegener’s) or P-ANCA (against myeloperoxidase MPO-ANCA; in those without extrarenal vasculitis)
● Those with microscopic polyarteritis have either
● Better prognosis than type 1
● Poorer prognosis if high serum creatinine at presentation and focal C3c depositions in areas of glomerular and arteriolar fibrinoid necrosis (Int J Immunopathol Pharmacol 2012;25:287)

Micro description
=========================================================================

● Resembles type 1

Micro images
=========================================================================


   
Various images

Immunofluorescence
=========================================================================

● Ig negative, possibly C3 and fibrin / fibrinogen with crescents (pauci-immune only refers to intensity of staining and does not imply that an immune process does not mediate the injury)

Electron microscopy description
=========================================================================

● Same as type 1 (no deposits, focal segmental glomerular necrosis and fibrin at glomerular basement membrane breaks)



Hereditary renal disease

Alport’s syndrome


Reviewers: Nikhil Sangle, M.D. (see Reviewers page)
Revised: 12 June 2012, last major update June 2012
Copyright: (c) 2003-2012, PathologyOutlines.com, Inc.

General
=========================================================================

● Due to defects in collagen IV synthesis affecting basement membranes, caused by mutations in COL4A3, COL4A4 and COL4A5 genes, important structural component of basement membranes in kidney, inner ear, eye
● Nephritis, subtle nerve deafness (55%, seen in adults), eye disorders (15-30%, anterior lens dislocation, posterior cataracts, corneal dystrophy)
● Called hereditary nephritis if no hearing or vision defects
● May share genetic defects and clinical features with thin glomerular basement membrane syndrome (Hum Pathol 2002;33:836)
● First described in 1927 by Alport (eMedicine)

Clinical features
=========================================================================

● Incidence of 1 per 5-10,000 in US
● Ages 5-20 years, usually males (or mosaic females)
● Causes 2.5% of end stage renal failure cases in US children, 0.3% in adults
● Presents with gross or microscopic hematuria, red blood cell casts, often mild proteinuria, progressive loss of renal function and hypertension
● 3-4% of males develop anti-glomerular basement membrane nephritis, usually due to antibodies to NC1 domain of alpha 5 chain of type IV collagen
● Rate of progression to end stage renal disease and deafness (bilateral, sensorineural and high tone, Acta Otolaryngol 2009;129:982) are mutation dependent, and each kindred reported has different mutations
● More likely to progress to renal failure in males

Variants
=========================================================================

Juvenile variant: end stage renal disease develops in males before age 31 years; clinical course similar among all patients
Adult variant: end stage renal disease develops in males after 31 years; variable clinical course
● X linked form (80%): due to mutations in alpha 5 gene at Xq22 coding collagen type IV (component of glomerular basement membrane); mutation interferes with its suprastructure, reducing production of alpha 3 (Goodpasture’s antigen) and alpha 4; some X linked patients also have diffuse leiomyomatosis (Hum Pathol 1998;29:404)
● Autosomal recessive: mutations in collagen type IV alpha 3 or alpha 4 genes, males and females have similar prognosis
● Autosomal dominant form may exist, but is controversial
Screening: segmental glomerular basement membrane staining is suggestive
Diagnosis: skin or kidney biopsy; if necessary, can use skin biopsy for analysis of COL4A5 gene for X linked cases (Nephrol Dial Transplant 2011;26:4003) and peripheral WBC analysis of COL4A3 and COL4A4 for autosomal recessive (Zhonghua Yi Xue Za Zhi 2008;88:573)

Case reports
=========================================================================

● 28 year old man with development of anti-glomerular and anti-tubular basement membrane antibodies after renal transplant (Arch Pathol Lab Med 1994;118:728)

Treatment
=========================================================================

● Kidney transplant has acceptable graft and patient survival rates (Transplant Proc 2012;44:261)

Clinical images
=========================================================================



Perifoveal dot and fleck retinopathy

Micro description
=========================================================================

Early:
● Segmental proliferation or sclerosis of glomeruli, increased mesangial matrix or cells causing mesangial widening (detected by JMS or PAS stain)
● Thinned basement membranes (BM) fail to stain, while thickened BM may show reduplication mimicking membranoproliferative glomerulonephritis
● May see fetal type glomeruli, foam cells in glomeruli or tubules

Late:
● Glomerulosclerosis, tubular atrophy

Micro images
=========================================================================


   
Foamy renal tubular cells plus EM images


Variant with late onset renal failure, no hearing loss, no eye abnormalities


Immunofluorescence for alpha 3, 4 and 5 shows segmental staining

Immunofluorescence
=========================================================================

● Negative or segmental staining for alpha 3, 4 and 5 collagen in glomerular basement membrane (normals have strong continuous staining); negative for alpha 5 collagen in skin biopsies (positive in normals)
● Negative for immunoglobulin and complement

Electron microscopy description
=========================================================================

Early:
● Thinning (< 150 nm) of glomerular basement membrane

Later:
● Splitting and lamination of lamina densa and granular inclusions
● Children and women may have only thin glomerular basement membranes without other alterations
● Abnormal distribution of laminin alpha1 and laminin alpha5 in glomerular basement membrane correlates with GBM thickening and splitting (Beijing Da Xue Xue Bao 2009;41:630)

Electron microscopy images
=========================================================================


       
Splitting and lamellation of basement membrane

           
Irregular contours of glomerular basement membrane


Long term effects of cyclosporine A

Differential diagnosis
=========================================================================

Secondary changes following a variety of glomerular diseases such as:
Membranous glomerulonephritis-resolving stage
Familial thin glomerular basement membrane disease: positive staining with anti-GBM antibodies, which is negative in Alport’s syndrome



Hereditary renal disease

Bartter’s syndrome


Reviewer: Nikhil Sangle, M.D. (see Reviewers page)
Revised: 6 August 2012, last major update August 2012
Copyright: (c) 2003-2012, PathologyOutlines.com, Inc.

General
=========================================================================

● Rare, < 150 cases reported
● Hypokalemia, metabolic alkalosis, hyperaldosteronism, growth retardation, normal blood pressure but with blunted pressor response to exogenous angiotensin II (eMedicine)
● Also polyuria, impairment of concentrating ability, increased renin, angiotensin II and prostaglandins
● Hyperuricemia and gouty arthritis are common (Saudi J Kidney Dis Transpl 2010;21:1129)
Neonatal type: more severe, presents with polyhydramnios due to intrauterine polyuria; also high urinary calcium, nephrocalcinosis, severe failure to thrive and marked growth retardation
Classic type: develops during first months or years with failure to thrive, dehydration, growth retardation, at most mild hypercalciuria and no significant nephrocalcinosis
● Pseudo-Bartter's syndrome: hypokalemic metabolic alkalosis and persistent failure to thrive due to cystic fibrosis (Acta Paediatr 2011;100:e234)

Etiology
=========================================================================

● Due to primary molecular defect in NaCl reabsorption in thick ascending limb of Henle’s loop
● Causes increased delivery of NaCl to distal and collecting tubules, which promotes increased potassium and acid secretion in collecting tubules; leads to hypokalemia, metabolic alkalosis
● Lack of NaCl reabsorption is associated with lack of calcium reabsorption
● Salt wasting and volume depletion cause renin secretion and increased serum angiotensin II and aldosterone, further stimulating potassium and acid secretion, causing hypokalemia and acidosis

Case reports
=========================================================================

● Presentation in two sisters (J Bras Nefrol 2012;34:82)

Treatment
=========================================================================

● Large doses of oral KCl with spironolactone; possibly ACE inhibitors, indomethacin, ibuprofen (Indian J Nephrol 2010;20:207)
● Potassium sparing diuretics may not be indicated during pregnancy (Am J Med Sci 2009;338:500)

Micro description
=========================================================================

● Hyperplasia of juxtaglomerular apparatus

Micro images
=========================================================================



Neonatal variant

Electron microscopy description
=========================================================================

● Epithelioid cells associated with afferent and sometimes efferent arterioles, with prominent Golgi complexes and secretory granules and some rhomboidal
● Also immature glomeruli in children, nephrocalcinosis

Differential diagnosis
=========================================================================

● High dose loop diuretics
● Conditions causing severe GI potassium chloride loss (have low chloride levels)
● Cystinosis: Ren Fail 2010;32:277



Hereditary renal disease

Collagen type III glomerulopathy


Reviewers: Nikhil Sangle, M.D. (see Reviewers page)
Revised: 28 August 2012, last major update August 2012
Copyright: (c) 2003-2012, PathologyOutlines.com, Inc.

General
=========================================================================

● Hereditary glomerulpathy related to nail-patella syndrome (Pediatr Nephrol 1993;7:354)
● Also called primary glomerular fibrosis, collagenofibrotic glomerulopathy
● Autosomal recessive and sporadic, due to deposition of type III collagen, normally absent in kidneys

Clinical features
=========================================================================

● Either gender, variable age
● Most reported cases are in Japan (Am J Kidney Dis 2007;49:499), but also reported in South America (Diagn Pathol 2009;4:33)
● Children: increasing proteinuria and nephrotic syndrome, hypertension, hematuria, progressive renal failure, possibly hemolytic uremic syndrome
● Adults: indolent course
● Markedly elevated serum precursor collagen type III protein (Adv Chronic Kidney Dis 2012;19:101)

Case reports
=========================================================================

● 26 year old man with simultaneous Hodgkin lymphoma (Saudi J Kidney Dis Transpl 2011;22:126)
● 43 year old woman and 20 year old man (Indian J Nephrol 2011;21:52)

Micro description
=========================================================================

● Diffuse increase in mesangial matrix, generalized widening of glomerular capillary walls

Micro images
=========================================================================



Various images including EM


Left: diffuse thickening of capillary walls and moderate expansion of mesangial matrix; right: thickening associated with podocyte hypertrophy

   
Left: enlarged glomerulus with hyaline cap deposits; right: lobular appearance


With Hodgkin's lymphoma

   
Stains: left-silver, right-Congo Red

Negative stains
=========================================================================

● Congo Red; stains poorly with PAS, trichrome and GMS

Immunofluorescence
=========================================================================

● Strong anti-collagen type III staining in capillary loops and mesangium (normally absent in kidneys)
● Negative or focal IgM deposition

Immunofluorescence images
=========================================================================



Deposits were negative for all IgG, IgM and complements

Electron microscopy description
=========================================================================

● Large accumulation of collagen fibrils in subendothelial glomerular basement membrane and mesangial matrix

Electron microscopy images
=========================================================================


       
Left to right: collagen fibrils; marked thickening of capillary wall; bundles of collagen fibrils in mesangial matrix and capillary wall


Abundant subendothelial deposits of large fibers with long spacing striations

Differential diagnosis
=========================================================================

● Hereditary onycho-osteodysplasia: also called nail-patella syndrome; fibers located in lamina densa of glomerular basement membrane versus subendothelial or mesangial location in collagenofibrotic glomerulopathy
Membranoproliferative glomerulonephritis: electron microscopy findings are distinctive



Hereditary renal disease

Fabry’s disease


Reviewers: Nikhil Sangle, M.D. (see Reviewers page)
Revised: 28 August 2012, last major update August 2012
Copyright: (c) 2003-2012, PathologyOutlines.com, Inc.

General
=========================================================================

● Also called alpha-galactosidase A deficiency, angiokeratoma corporis diffusum universale
● X linked (Xq22.1) recessive lysosomal storage disease which causes deficiency in lysosomal alpha-galactosidase A, which catabolizes neutral glycosphingolipids
● Deficiency causes intracellular accumulation of galabiosylceramide (ceramide trihexoside) and digalactosyl ceramide within skin, renal glomeruli, renal tubular epithelium, blood vessels, corneal epithelium, myocardium and ganglion cells

Clinical features
=========================================================================

● Affects 1 per 40,000
● Highly penetrant in hemizygous males with symptoms at infancy or childhood
● Later presentation in heterozygous females, who have more variable severity due to variable lyonization of X chromosome and may have normal leukocyte alpha-galactosidase A activity
● Clinical symptoms include angiokeratomas on skin of abdomen, buttocks, lips, genitalia and upper thighs
● Also hematuria and proteinuria progressing to renal failure, corneal dystrophy and recurrent shooting pains in legs
● Death due to renal, cardiac or cerebrovascular disease at age 40+ years

Diagnosis
=========================================================================

● Low blood or urine levels of alpha-galactosidase by enzymatic assay (may be normal in female heterozygotes)
● Elevated ceramide trihexoside in urine by thin layer chromatography
● Immunostains for ceramide trihexoside
● In women, must perform DNA mutation analysis of alpha-galactosidase A gene to exclude carrier state
● Patients may present with advanced disease identifiable only by ultrastructural studies (Ultrastruct Pathol 2010;34:307)

Case reports
=========================================================================

● 23 year old man with congenital agammaglobulinemia (J Korean Med Sci 2011;26:966)
● 34 year old man with atypical variant (Arch Pathol Lab Med 1996;120:86)
● 42 year old woman with persistent proteinuria (Arch Pathol Lab Med 1985;109:89)
● Cases with accumulation in heart, not kidney or liver (Hum Pathol 1990;21:1067)

Treatment
=========================================================================

● Recombinant human alpha-galactosidase A replacement therapy

Micro description
=========================================================================

Kidney:
● Enlarged and bubbly, clear vacuoles in visceral epithelium (demonstrated by trichrome stain), parietal epithelium, mesangial cells, endothelial cells, vascular smooth muscle and distal tubular cells
● Narrowing and thrombosis of arteries and arterioles
● Patchy tubular atrophy and interstitial fibrosis
● Progression to focal segmental and global glomerulosclerosis

Micro images
=========================================================================


   
Various images including EM

       
Foamy cytoplasm and inclusions


Birefringent glycosphingolipid deposits


Global sclerosis, segmental sclerosis with moderate interstitial fibrosis, diffuse foamy changes of podocyte and tubular epithelial cell cytoplasm


Reduction in inclusions after enzyme therapy


Figure 1: vacuolar change in renal tubular cells with large nodular aggregates of foam cells
Figure 2: enlarged glomeruli due to segmental vacuolar changes in visceral epithelial cells
Figure 3: strong oil-red-O staining of vacuolated cells
Figure 4: EM shows abundant whorled lamellated electron dense myelin-like bodies lined by single membranes; various images including EM


Immunofluorescence
=========================================================================

● Negative

Positive stains
=========================================================================

● PAS, Oil red O, Sudan black and Luxol fast blue (stain glycolipid and phospholipid-like material)

Electron microscopy description
=========================================================================

● Characteristic single membrane bound intracellular inclusions (myelin-like figures, zebra bodies), that are 0.1 to 10 microns in diameter, round and lamellated with concentric electron dense layers, found in endothelial and smooth muscle cells, myocardium, fibroblasts and glomerular epithelium; deposits reduced after enzyme therapy (Clin Nephrol 2009;71:550)
● Changes also present in urine sediment (Arch Pathol Lab Med 1981;105:361)

Electron microscopy images
=========================================================================



Lamellated lipid inclusions of visceral epithelial cells

       
Electron-dense laminated myelin figures


A: Numerous electron dense lamellar inclusion bodies in cytoplasm of skin fibroblasts and B/C: renal podocytes

Molecular description
=========================================================================

● Wide molecular heterogeneity (Rev Med Interne 2010;31 Suppl 2:S275)

Differential diagnosis
=========================================================================

● Foam cell change of Gaucher’s disease, gangliosidoses, fucosidosis, mucopolysaccharidoses (all have different intracellular distribution and ultrastructural features of inclusions, lack electron dense myeloid bodies and can detect by laboratory assays)
● Treatment with chloroquine, amiodarone or aminoglycosides (have similar myelin-like figures, Hum Pathol 2003;34:285)



Hereditary renal disease

Fibronectin glomerulopathy


Reviewers: Nikhil Sangle, M.D. (see Reviewers page)
Revised: 29 August 2012, last major update August 2012
Copyright: (c) 2003-2012, PathologyOutlines.com, Inc.

General
=========================================================================

● Massive fibronectin deposition in glomeruli due to autosomal dominant, non sex-linked disorder with 1q32 abnormality (Am J Hum Genet 1998;63:1724, OMIM #601894)
● Proteinuria, often nephrotic syndrome, microhematuria, hypertension and progressive loss of renal function
● May recur after renal transplant

Case reports
=========================================================================

● 3 year old boy with microhematuria and hypertension (Pediatr Nephrol 2002;17:363)
● 34 year old man with microhematuria and hypertension (Ultrastruct Pathol 2010;34:240)
● 41 year old man with nephrotic syndrome (Int J Clin Exp Pathol 2009;3:210)
Nephrol Dial Transplant 1998;13:2417

Micro description
=========================================================================

● Lobular accentuation of glomeruli with minimal hypercellularity (Nihon Jinzo Gakkai Shi 1999;41:49)
● Marked enlargement of mesangium and subendothelial space due to massive deposition of fibronectin and fibulin (PAS+, Congo red negative homogenous substance, Mod Pathol 2012;25:709), causing obliteration of capillary lumens

Micro images
=========================================================================


       
Various images

   
Recurrence in renal allograft


Massive mesangial expansion by intensely PAS+ deposits that were negative for silver and Congo red stains

Lobular accentuation of glomeruli

Trichrome stain

Fibronectin immunostain

Immunofluorescence
=========================================================================

● Strongly positive for plasma fibronectin (not cell-derived fibronectin), scanty immunoglobulin or complement deposition

Electron microscopy description
=========================================================================

● Fibronectin has dense granular appearance with 12-16 nm fibrils

Electron microscopy images
=========================================================================


       
Enlargement of glomerular basement membrane and massive mesangial electron-dense deposits



Hereditary renal disease

Glutaric acidemia type II


Reviewers: Nikhil Sangle, M.D. (see Reviewers page)
Revised: 29 August 2012, last major update August 2012
Copyright: (c) 2003-2012, PathologyOutlines.com, Inc.

General
=========================================================================

● Metabolic disorder due to deficiency of flavoprotein or its oxyreductase (Arch Pathol Lab Med 1988;112:1133)

Clinical features
=========================================================================

● Acidosis, non-ketotic hypoglycemia, hyperammonemia, dysmorphic facial features, urinary organic acidemia and “sweat sock” odor
● May have lipid accumulation in liver, heart and renal tubular epithelium
● May cause sudden death or an acute life-threatening event during first year of life (Mol Genet Metab 2008;93:36)

Case reports
=========================================================================

● 23 year old woman with adult onset presentation with myopathy (J Clin Neuromuscul Dis 2003;4:124)

Micro description
=========================================================================

● Subcortical renal glomerular cysts, renal medullary dysplasia

Electron microscopy description
=========================================================================

● Cytoplasmic, homogenous and moderately electron dense bodies with a limiting membrane (Arch Pathol Lab Med 1986;110:399)

Molecular description
=========================================================================

● Various mutations (Eur J Clin Invest 2002;32:707, Mol Genet Metab 2002;77:86)



Hereditary renal disease

Glycogen storage disease type I


Reviewers: Nikhil Sangle, M.D. (see Reviewers page)
Revised: 29 August 2012, last major update August 2012
Copyright: (c) 2003-2012, PathologyOutlines.com, Inc.

General
=========================================================================

● Autosomal recessive disorder caused by defects in the glucose-6-phosphatase complex
● Type IA: deficient activity in glucose-6-phosphatase-a (G6Pase) catalytic unit
● Type IB: defects in glucose-6-phosphate transporter protein (G6PC)
● Also G6Pase-β deficiency (Nat Rev Endocrinol 2010;6:676)

Clinical features
=========================================================================

● Fasting hypoglycemia, hyperuricemia, hyperlactatemia, hyperlipidemia
● Normal fertility, although high prevalence of irregular menstruation cycles and polycystic ovaries (J Inherit Metab Dis 2012;May 5 [Epub ahead of print])
● May have hypercalcemia (Turk J Pediatr 2012;54:35)
● Complications include life-threatening hypoglycemia and proteinuria progressing to renal failure (Clin J Am Soc Nephrol 2009;4:1741)

Treatment
=========================================================================

● Angiotensin type 1-receptor blockers (Clin Endocrinol (Oxf) 2005;63:19), lipid lowering drugs, dietary therapy (Intern Med 2010;49:1787)
● Possibly medium-chain triglycerides (Ann Nutr Metab 2010;56:225)

Electron microscopy description
=========================================================================

● Thickening, lamellation and glycogen deposition in glomerular basement membrane (Arch Pathol Lab Med 1988;112:271)



Hereditary renal disease

Hereditary onycho-osteodysplasia


Reviewers: Nikhil Sangle, M.D. (see Reviewers page)
Revised: 29 August 2012, last major update August 2012
Copyright: (c) 2003-2012, PathologyOutlines.com, Inc.

General
=========================================================================

● Uncommon, autosomal dominant disease due to point mutations in LMX1B gene at 9q34, also 17q21-22
● Also called nail-patella syndrome, Turner-Keiser syndrome, Fong’s syndrome, Osterreicher Syndrome
● Fingernail aplasia or dysplasia (especially first fingers), patellar absence or hypoplasia, subluxation of radial head and iliac horns

Clinical features
=========================================================================

● 1 per 50,000 live births
● Renal involvement in 30-55% (Pediatr Nephrol 2009;24:2345), usually asymptomatic proteinuria but may progress to renal failure

Case reports
=========================================================================

● 6 year old girl with normal renal imaging (Pediatr Dermatol 2010;27:95)
● 22 year old man presenting with renal failure (Pan Afr Med J 2011;9:31)

Treatment
=========================================================================

● Anti-proteinuric therapy (Nephrol Dial Transplant 2009;24:1335)

Treatment
=========================================================================

● Transplant if severe kidney disease

Micro description
=========================================================================

● Focal thickening of glomerular capillary walls, variable sclerotic glomeruli

Micro images
=========================================================================



"Moth-eaten" appearance of glomerular basement membrane

Electron microscopy description
=========================================================================

● Irregular thickening of glomerular basement membrane with moth eaten electron-lucent areas
● Also collagen-like fibers in electron lucent area and in mesangium

Electron microscopy images
=========================================================================


   
Thickening of glomerular basement membrane and foot process fusion

Molecular description
=========================================================================

● Various mutations (J Korean Med Sci 2009;24 Suppl:S82)
● LMX1B mutations in most cases (Genet Med 2010;12:431)



Hereditary renal disease

Infantile nephropathic cystinosis


Reviewers: Nikhil Sangle, M.D. (see Reviewers page)
Revised: 29 August 2012, last major update August 2012
Copyright: (c) 2003-2012, PathologyOutlines.com, Inc.

General
=========================================================================

● Autosomal recessive lysosomal storage disease causing corneal and kidney disease (Nephron 2001;89:50)
● Presents at 3–6 months with Fanconi’s syndrome (OMIM #219800)
● May progress to renal failure

Case reports
=========================================================================

● 2 year old girl (Sultan Qaboos Univ Med J 2011;11:503)

Case reports
=========================================================================

● 23 year old man with crystalline histiocytosis post-kidney transplant (Arch Pathol Lab Med 2002;126:1135)

Treatment
=========================================================================

● Kidney transplant (Srp Arh Celok Lek 2011;139:486)

Micro description
=========================================================================

● In renal allograft, dark cells are present in interstitium, rarely glomeruli or tubular lumina; darkness due to granular material in cytoplasm and nucleus and cytoplasmic inclusions of macrophages (Hum Pathol 1989;20:472)

Micro images
=========================================================================


                   
Various images

   
Left: interstitial deposition of rectangular refractile cystine crystals; right: multinucleated visceral epithelial cells


Immunohistochemical staining of control and cystinotic renal tissue

Electron microscopy images
=========================================================================


   
Prominent inclusions


Alterations in distal tubules, effacement of foot processes



Hereditary renal disease

Lecithin-cholesterol acyl transferase deficiency


Reviewers: Nikhil Sangle, M.D. (see Reviewers page)
Revised: 29 August 2012, last major update August 2012
Copyright: (c) 2003-2012, PathologyOutlines.com, Inc.

General
=========================================================================

● Lecithin cholesterol acyltransferase (LCAT) is crucial to maturation of high-density lipoprotein (HDL)
● Homozygosity causes deficiency of HDL-cholesterol (HDL-c); heterozygotes have half normal HDL-c levels
● Usually but not always due to mutations in coding sequence (Hum Mutat 2011;32:1290, Clin Nephrol 2011;76:323)
● Associated with nephrotic syndrome

Case reports
=========================================================================

● Two affected brothers (Mod Pathol 1991;4:331)

Treatment
=========================================================================

● Control of blood pressure and lifestyle measures to optimize non HDL lipoproteins (J Clin Lipidol 2011;5:493)

Micro description
=========================================================================

● Bubbly thickening of glomerular basement membrane in membranous pattern, mesangial sclerosis and foamy macrophages in capillaries and mesangium

Micro images
=========================================================================



Characterization of accumulated materials in glomeruli

Electron microscopy description
=========================================================================

● Small, solid, thread-like or lamellar dense structures in empty-appearing lacunae

Electron microscopy images
=========================================================================



Membrane-like deposits in glomerular lesions


Abnormalities with inclusion of lipid droplets

   
Glomerular lesions



Hereditary renal disease

Lipoprotein glomerulopathy


Reviewers: Nikhil Sangle, M.D. (see Reviewers page)
Revised: 30 August 2012, last major update August 2012
Copyright: (c) 2003-2012, PathologyOutlines.com, Inc.

General
=========================================================================

● Rare genetic disorder of lipid metabolism (Arch Pathol Lab Med 2010;134:279, Curr Opin Lipidol 2011;22:262)
● Various mutations; not all with mutations have glomerulopathy (Nephron Clin Pract 2010;114:c260)
● 2/3 male, often Japanese and wide age range (2 weeks to 69 years)
● Presents with heavy proteinuria, usually in adults
● 50% progress to renal failure
● Usually no systemic manifestations of hyperlipidemia

Treatment
=========================================================================

● Anti-lipidemic drugs (Clin Exp Nephrol 2010;14:619, Clin Exp Nephrol 2009;13:659); LDL-apheresis (J Med Case Rep 2009;3:9311) or immunoadsorption onto staphylococcal protein A for refractory cases (Nephrol Dial Transplant 2009;24:864)
● May recur in transplants

Micro description
=========================================================================

● Lipoprotein thrombi containing apolipoprotein apo E, usually E2

Micro images
=========================================================================


               
Lipoprotein thrombi

       
Dilated capillary lumina


Various lipid peroxidation-protein adducts

Electron microscopy description
=========================================================================

● Characteristic lamellar accumulations of variably sized lipid droplets

Electron microscopy images
=========================================================================


   
Lipid granules and concentrically laminated vacuoles


Glomerular capillary lumina filled with partially lamellated, finely vacuolated lipoprotein thrombi; mesangium is thickened by cell processes and increased matrix


Osmiophilic substances (arrows) are deposited in dilated subendothelial space



Hereditary renal disease

Ochronosis


Reviewers: Nikhil Sangle, M.D. (see Reviewers page)
Revised: 6 September 2012, last major update September 2012
Copyright: (c) 2003-2012, PathologyOutlines.com, Inc.

General
=========================================================================

● Autosomal recessive disorder of increased urinary excretion of homogentisic acid (alkaptonuria), with deposition of “ochre-colored” (yellow) pigment in collagen-rich regions
● Occurs in 50% with alkaptonuria
● Due to disorder of homogentisic acid oxidase gene on chromosome 3q, an intermediate component in metabolism of tyrosine and phenylalanine, causing accumulation of benzoquinone acetic acid, which binds to collagen irreversibly
● Clinically black pigmentation of joints (arthritis with pigment deposition in cartilage and intervertebral disks), cardiovascular system (valvular calcifications and stenosis), kidney (black urine, pigmented stones) and skin (cutaneous pigmentation); also involvement of sclera of eye
● No effective treatment

Case reports
=========================================================================

● 66 year old woman with pigment in dura matter of brain (Arch Pathol Lab Med 2001;125:961)

Treatment
=========================================================================

● Preventive treatment with avoidance of topical phenols and diets low in tyrosine

Micro images
=========================================================================


Alkaptonuria ochronosis



Hereditary renal disease

Thin glomerular basement membrane disease / lesion


Reviewers: Nikhil Sangle, M.D. (see Reviewers page)
Revised: 30 August 2012, last major update August 2012
Copyright: (c) 2003-2012, PathologyOutlines.com, Inc.

General
=========================================================================

● Hereditary, often autosomal dominant disorder of thinning of lamina dense of glomerular basement membrane; normal renal function initially, but possibly late development of renal insufficiency or hypertension
● Also called benign familiar hematuria

Clinical features
=========================================================================

● 1-2% of general population (Arch Pathol Lab Med 2006;130:699), rare after age 50; 20-25% have isolated hematuria
● Asymptomatic, hematuria discovered on routine urinalysis; rarely gross hematuria; mild proteinuria in 60% (Pol J Pathol 2009;60:35)
● Normal renal function, excellent prognosis, but up to 30% develop late-onset renal insufficiency or hypertension
● Investigation of families and long term follow up recommended (Kidney Int 2010;78:1041, Nephrol Dial Transplant 2005;20:545)
● A diagnosis of exclusion

Pathogenesis
=========================================================================

● Associated with abnormalities in alpha 3 and alpha 4 genes for type IV collagen
● Rarely due to mutations in COL4A5 (Pediatr Nephrol 2010;25:545)
● Most patients are heterozygous; in homozygotes, resembles Alport’s disease and progresses to renal failure, even in women (Arch Pathol Lab Med 2009;133:224)

Micro description
=========================================================================

● Red blood cells in Bowman’s space and renal tubules, but otherwise normal (Arch Pathol Lab Med 1988;112:794)

Micro images
=========================================================================


   
Various images (scroll down)


Glomerulus shows no abnormalities on H&E


Strong staining for alpha 3-5, in comparison to Alport’s syndrome

Immunofluorescence
=========================================================================

● Strong linear glomerular basement membrane staining for alpha 3 and 4 protein (similar to normals, Arch Pathol Lab Med 2001;125:631), positive antibody staining to NC1 domain of glomerular basement membrane from patients with thin basement membrane disease
● Occasional IgM and IgG deposits

Electron microscopy description
=========================================================================

● Uniform thinning of lamina dense of glomerular basement membrane to 200 nm in > 50% of glomerular capillaries
● Some authors believe segmental thinning is sufficient for diagnosis (Arch Pathol Lab Med 2006;130:1533)
● Glomerular membrane occasionally ruptures
● No thickening, lamellation or inclusions of glomerular basement membrane

Electron microscopy images
=========================================================================


           
Various images


Diffusely thin glomerular basement membranes

Differential diagnosis
=========================================================================

Alport’s syndrome in women without typical clinical findings: thick glomerular basement membrane, lamellation, granular inclusions and loss of staining for alpha 3 and alpha 4 protein (Hum Pathol 2002;33:836)
● IgA nephropathy
● Non-specific GBM thinning is also seen in lupus nephritis and postinfectious glomerulonephritis



Infections / parasites

Abscess


Reviewer: Nikhil Sangle, M.D. (see Reviewers page)
Revised: 31 August 2012, last major update August 2012
Copyright: (c) 2003-2012, PathologyOutlines.com, Inc.

General
=========================================================================

● Due to ascending infection or hematogenous
Can occur in children without any GU abnormalities (Eur J Pediatr 2010;169:1423)
● See also acute pyelonephritis

Clinical features
=========================================================================

● High fever, chills, stomach pain, groin pain, weight loss, total malaise, clinical deterioration (Ned Tijdschr Geneeskd 2011;155:A3120)

Case reports
=========================================================================

● 5 year old boy with sickle cell anemia (Saudi J Kidney Dis Transpl 2009;20:282)
● 6 year old girl with E. coli abscess (Saudi J Kidney Dis Transpl 2011;22:1215)
● 38 year old HIV+ man with abscess containing Aspergillus fumigatus (Rev Iberoam Micol 2010;27:136)
● 66 year old man with Achromobacter denitrificans renal abscess (New Microbiol 2012;35:245)

Treatment
=========================================================================

● Antibiotics, drainage (Int Braz J Urol 2010;36:29), surgery is usually not needed (Rom J Intern Med 2011;;49:59)

Gross images
=========================================================================


           

           
Various images

Micro images
=========================================================================


   
Various images



Infections / parasites

Actinomycosis


Reviewers: Nikhil Sangle, M.D. (see Reviewers page)
Revised: 20 September 2012, last major update September 2012
Copyright: (c) 2003-2012, PathologyOutlines.com, Inc.

General
=========================================================================

Actinomyces are anaerobic, gram-positive, non-acid fast filamentous bacteria that are normal flora in mouth, vagina, GI tract
● Cause chronic suppurative and granulomatous disease of cervico-facial, thoracic or abdominal region
● Sometimes called the most "misdiagnosed disease" because abscesses can mimic malignancy and may lead to unnecessary surgical resections (South Med J 2004;97:316, Am J Surg Pathol 2000;66:85)
Actinomyces israelii: usual cause of Actinomyces abscesses; also most common cause of disseminated actinomycosis, secondary to GI perforation (diverticulitis, appendicitis) or procedures, IUD, aspiration, poor oral hygiene / dental procedures

Case reports
=========================================================================

● 11 year old girl with 4 cm kidney tumor and multiple 1-2 mm lung nodules (Case of the Week #244)
● 39 year old man with sinus tracts (Radiology 2007;244:309)
● 46 year old woman with retroperitoneal mass (Infect Dis Obstet Gynecol 2011;2011:747059)
● 50 year old woman with solitary renal cyst (Indian J Urol 2008;24:416)
● 53 year old man with poor oral hygiene (Urol J 2010;7:80)
● 74 year old with coexisting renal vein thrombosis (Clin Nephrol 2012;77:156)

Treatment
=========================================================================

● Antibiotics; possibly nephrectomy

Gross images
=========================================================================



Actinomycosis of kidney

Micro description
=========================================================================

● Marked acute and chronic inflammation with occasional “sulfur granules”

Micro images
=========================================================================


   
11 year old girl

       
Retroperitoneal mass



Infections / parasites

Adenovirus


Reviewers: Nikhil Sangle, M.D. (see Reviewers page)
Revised: 1 September 2012, last major update September 2012
Copyright: (c) 2003-2012, PathologyOutlines.com, Inc.

General
=========================================================================

● May cause necrotizing tubulointerstitial nephritis with hemorrhagic cystitis or prostate involvement
● Associated with bone marrow or other transplant recipients (Transpl Infect Dis 2011;13:174, Am J Kidney Dis 2012;59:886, Am J Transplant 2011;11:1308) and chemotherapy
● Adenovirus activation after immunosuppression can lead to systemic infection and may trigger rejection or early graft loss (Transpl Infect Dis 2011;13:168)
● Adenovirus is also used as a vector for gene therapy (Transpl Immunol 2011;25:34)

Micro description
=========================================================================

● Hemorrhage and necrosis
● Tubulitis with intranuclear inclusion bodies; either smudge cells, Cowdry A intranuclear inclusions or full-type intranuclear-containing cells (Hum Pathol 1991;22:1225)

Micro images
=========================================================================


               
Various images

   
Adenovirus immunoperoxidase stain

Electron microscopy description
=========================================================================

● Intranuclear crystalline arrays of 75-80 nm viral particles



Infections / parasites

BK virus / polyomavirus


Reviewer: Nikhil Sangle, M.D. (see Reviewers page)
Revised: 1 September 2012, last major update September 2012
Copyright: (c) 2003-2012, PathologyOutlines.com, Inc.

General
=========================================================================

● Polyomaviruses are non-enveloped DNA viruses, 45 nm in diameter; members of papovavirus family, which also contain papillomavirus
● Polyomavirus BK is widely present in healthy individuals, but latent in kidneys, central nervous system and B cells
● Other polyoma viruses are JC (causes progressive multifocal leukencephalopathy) and SV40 (causes subclinical infections)
● JC and BK virus infection is very prevalent in the first 2 years after kidney transplant (J Res Med Sci 2011;16:916)
● Immunosuppression promotes reactivation of latent polyoma virus, leading to viral replication in renal tubular epithelial cells

Clinical features
=========================================================================

● BKV strain of polyoma virus may cause renal failure in AIDS patients, is reactivated in <8% of renal transplant patients with heavy immunosuppression or rarely in other immunosuppressed patients
● Rarely occurs in nonrenal solid organ transplantation (Am J Transplant 2010;10:2324)
● Diagnose by PCR (but variant strains may affect quantitation of viral load, J Clin Microbiol 2011;49:4072); urinary decoy cell detection (Transplantation 2011;92:1018) and immunostains (SV40 immunostain crossreacts with JCV)
● Increased risk with ureteral stenting (Transplant Proc 2011;43:2641)
● Associated with interstitial nephritis, infection of glomerular epithelial cells and crescents (minority of cases)
● JC virus strain of polyoma virus usually not associated with renal damage (Hum Pathol 2001;32:656), but present in renal tissue in 6% of AIDS patients (Mod Pathol 2003;16:35)

Case reports
=========================================================================

● 14 year old boy with AIDS and BK viral infection of lung and kidney causing diffuse alveolar damage and death (Am J Surg Pathol 2000;24:145)
● 31 year old IV drug user with AIDS and BK virus related renal failure (Arch Pathol Lab Med 1999;123:807)
● 53 year old with triple immunosuppressive therapy for transplant (Hum Pathol 2001;32:656)
● 62 year old man post-transplant for SLE induced renal disease (Arch Pathol Lab Med 2001;125:973)

Micro description
=========================================================================

In non-transplanted kidney:
● Interstitial inflammation, atrophic tubules with large and eosinophilic nuclei

In allograft kidney:
● Viral cytopathic effect with large, homogenous and purple intranuclear inclusions, primarily in tubular epithelium (Hum Pathol 2004;35:367)
● No necrosis (as seen in HSV), no perinuclear halo (as seen in CMV)
● Also ischemic glomerulopathy (62%), aneurysmal dilation of glomerular capillaries (28%) and mild increase in mesangial matrix (23%)
● Viral cytopathic effect in parietal Bowman’s capsule (29%, including using BK immunostains), crescents (12%) and glomerulonephritis (3%)

Micro images
=========================================================================


           

           

               
Various images


Figure 1: tubulointerstitial nephritis with lymphocytes and enlarged tubular epithelial cells
Figure 2: tubular cells have large smudged nuclei and basophilic chromatin
Figure 3: EM shows distinct intranuclear inclusion; 4: inclusion consists of crystalline arrays of nonenveloped, round, electron-dense particles, mean 45 nm in diameter, in loose crystalline lattices


Electron microscopy images
=========================================================================



Tubular cell with numerous viral particles (inset: anti-SV40 antibody)

Differential diagnosis
=========================================================================

● Rejection
● Other infection



Infections / parasites

CMV


Reviewers: Nikhil Sangle, M.D. (see Reviewers page)
Revised: 1 September 2012, last major update September 2012
Copyright: (c) 2003-2012, PathologyOutlines.com, Inc.

General
=========================================================================

● Viral infection associated with renal transplants, due to immunosuppression

General
=========================================================================

● May be associated with other viral infections
● Controversial if associated with graft rejection (Nephrol Dial Transplant 2012;27:435)
● In UK, CMV mismatch does not appear to affect patient and graft survival in renal transplant recipients (Transplantation 2009;88:77)
● Symptomatic primary CMV infections are commonly detected after cessation of valganciclovir prophylaxis (Am J Transplant 2010;10:2026, Nephrol Dial Transplant 2009;24:316)
● Recommended to use quantitative PCR rather than serology to monitor CMV infection in pre- and post-transplantation patients (Egypt J Immunol 2010;17:41)

Micro description
=========================================================================

● Large tubular cells with enlarged basophilic nuclei with inclusions and perinuclear halo
● Also tubular injury

Micro images
=========================================================================


               
Enlarged renal tubular epithelial cells with enlarged basophilic nuclei with inclusions and tubular injury

               
Round and discrete intranuclear inclusion surrounded by a white thin halo

       
Various images

Electron microscopy description
=========================================================================

● Cytoplasmic virus has bulls-eye appearance



Infections / parasites

Coccidioidomycosis


Reviewers: Nikhil Sangle, M.D. (see Reviewers page)
Revised: 1 September 2012, last major update September 2012
Copyright: (c) 2003-2012, PathologyOutlines.com, Inc.

See also Lung-nontumor chapter

General
=========================================================================

● Very rare in kidney
● Causes considerable morbidity and mortality in renal transplant recipients at various sites, often as the result of reactivated infection (Transplantation 2007;83:1182, Am J Transplant 2006;6:340)

Micro images
=========================================================================


   
Various images

Virtual images
=========================================================================



Coccidioidomycosis of kidney



Infections / parasites

Dioctophyma renale


Reviewers: Nikhil Sangle, M.D. (see Reviewers page)
Revised: 1 September 2012, last major update September 2012
Copyright: (c) 2003-2012, PathologyOutlines.com, Inc.

General
=========================================================================

● Also called giant kidney worm
● Found in dogs, minks, cats, other fish-eating mammals
● Adult worms live in renal pelvis, their eggs incite a granulomatous response
● Adult worms progressively destroy renal parenchyma until only kidney and worm remain

Case reports
=========================================================================

● 47 year old farmer in Australia (Am J Surg Pathol 1983;7:281)
● 50 year old Chinese man with cyst in upper kidney (Am J Surg Pathol 1986;10:508)
● 51 year old woman with fatal bilateral dioctophymatosis (J Parasitol 2010;96:1152)

Gross description
=========================================================================

● Hemorrhagic cyst, often thick walled

Gross images
=========================================================================



Kidney and worms

Micro description
=========================================================================

● Cyst wall composed of granulomatous tissue with eggs and cross striations of parasites
● Eggs have birefringent striated double wall

Micro images
=========================================================================


   
Left: various images; right: eggs (arrows) and granulomatous response

Differential diagnosis
=========================================================================

● Liesegang rings (Diagn Cytopathol 1990;6:197)



Infections / parasites

Escherichia coli


Reviewer: Nikhil Sangle, M.D. (see Reviewers page)
Revised: 6 September 2012, last major update September 2012
Copyright: (c) 2003-2012, PathologyOutlines.com, Inc.

See also HUS/TTP

General
=========================================================================

● Variants producing Shiga toxin are contaminants of food and water, cause diarrheal prodrome followed by more severe disease of the kidneys and CNS symptoms, referred to as diarrhea-associated hemolytic uremic syndrome (Toxins (Basel) 2010;2:2769)
● Uropathogenic Escherichia coli is causative agent in most urinary tract infections, including pyelonephritis, which may cause acute renal failure in healthy individuals and renal transplant patients (Int J Nephrol 2012;2012:681473)
● May adhere to and invade kidney epithelial cells (Braz J Med Biol Res 2012;45:417)
● Causes pyelonephritis associated with renal transplants; men are more at risk, TMP/SMZ prophylaxis is protective (Clin J Am Soc Nephrol 2010;5:1290)
● Drug resistance is emerging (Antimicrob Agents Chemother 2010;54:546)

Case reports
=========================================================================

● 6 year old girl with renal abscess (Saudi J Kidney Dis Transpl 2011;22:1215)
● Unilateral emphysematous pyelonephritis due to infected ruptured cyst in diabetic patient with polycystic kidney disease (G Ital Nefrol 2011;28:85)
● Cases of transplant-associated transmission (MMWR Morb Mortal Wkly Rep 2010;59:1642)



Infections / parasites

Hantavirus


Reviewer: Nikhil Sangle, M.D. (see Reviewers page)
Revised: 1 September 2012, last major update September 2012
Copyright: (c) 2003-2012, PathologyOutlines.com, Inc.

General
=========================================================================

● Rodent RNA virus that causes hemorrhagic fever with renal and pulmonary syndrome (Arch Pathol Lab Med 2003;127:30)

Clinical features
=========================================================================

● Often presents with fever (acute flu-like febrile illness), thrombocytopenia (with hemorrhage), acute renal injury (sudden and extreme albuminuria, renal failure, Int Urol Nephrol 2012;44:1185)
● Renal disease typically only occurs in non-US cases, severity depends on causative agent (severe - Dobrava-Belgrade and Hantaan; moderate - Seoul; mild - Puumala virus, Nephrology (Carlton) 2010;15:340, Nephrol Dial Transplant 2010;25:2997)
● Overall mortality rate is 7%
● Proteinuria and increased systolic blood pressure persist up to 6 years after acute episode (Nephron Clin Pract 2009;112:c115)
● Caused significant mortality during Korean War (formerly known as Korean hemorrhagic fever)
● Infects glomeruli and tubules; infection causes breakdown of cell-to-cell contacts (J Virol 2011;85:9811)

Case reports
=========================================================================

● 30 year old man with uncommonly severe infection with Puumala strain (J Am Soc Nephrol 2008;19:1653)
● 31 year old man in Tbilisi, Georgia (Emerg Infect Dis 2009;15:1489)

Micro images
=========================================================================


               
Various images

   
Immunohistochemistry



Infections / parasites

Microsporidiosis


Reviewer: Nikhil Sangle, M.D. (see Reviewers page)
Revised: 1 September 2012, last major update September 2012
Copyright: (c) 2003-2012, PathologyOutlines.com, Inc.

General
=========================================================================

● Emerging pathogens causing life-threatening infections in organ transplant recipients
● Can cause peristent diarrhea (J Clin Microbiol 2011;49:1301) or fever of unknown origin (Transpl Infect Dis 2009;11:83)

Case reports
=========================================================================

● 45 year old woman with living related donor transplant on high-dose steroids for acute rejection (Arch Pathol Lab Med 2003;127:e224)

Micro images
=========================================================================



Interstitial inflammation and tubular damage


Spores in urine sample


Figure 1: Intra- and extracellular small spherical structures with dense neutrophilic infiltrates
Figure 2: EM shows spherical organisms with vacuoles and membrane bound granular material
Figure 3: spores from conjunctival scrapings
Figure 4: punctate areas of necrosis in brain at autopsy




Infections / parasites

Tuberculosis


Reviewer: Nikhil Sangle, M.D. (see Reviewers page)
Revised: 1 September 2012, last major update September 2012
Copyright: (c) 2003-2012, PathologyOutlines.com, Inc.

General
=========================================================================

● Each year, 9 million new cases of TB, causing 1.5 million annual deaths (WHO: Global Tuberculosis Control 2011)
● GU tract is #2 most common site of infection after lungs

Clinical features
=========================================================================

● Renal involvement may be indolent, may not become apparent until 20+ years from detection of primary infection
● Urogenital TB is associated with unilateral non-functioning kidney in 27% of cases, with renal failure present in 7% (Int J Urol 2008;15:827)
● In chronic kidney disease of all causes, one study from India demonstrated a 4% incidence of TB, which was usually tuberculin skin test negative (Clin Nephrol 2007;67:217)
● In immunocompromised patients, urogenital TB usually has systemic symptoms, dissemination, multiple renal foci (Int Urol Nephrol 2009;41:327)

Case reports
=========================================================================

● 20 year old man (Am J Trop Med Hyg 2011;84:843)
● 29 year old man with renal hydronephrosis (Case of the Week #128)
● 33 year old man presenting with end stage renal disease secondary to renal TB (Rev Inst Med Trop Sao Paulo 2012;54:57
● 38 year old man with negative PPD and repeatedly negative AFB tests (Proc (Bayl Univ Med Cent) 2012;25:236)

Radiologic images
=========================================================================



Renal tuberculosis

Gross description
=========================================================================

● Multiple cavities filled with yellow friable necrotic material

Gross images
=========================================================================


   

       
Renal tuberculosis

Micro description
=========================================================================

● Extensive caseous necrosis, with occasional granulomas composed of epithelioid cells and Langhans giant cells with surrounding lymphocytes
● Very early granulomas might not show caseation
● The interface of viable cells and caseous necrosis is where acid-fast bacilli (AFB) are most found

Micro images
=========================================================================


               
Various images

       
Miliary tuberculosis - kidney

Differential diagnosis
=========================================================================

● Xanthogranulomatous pyelonephritis: different clinical picture, AFB negative, although AFB may be difficult to detect even in TB patients; TB PCR and AcuProbe are more sensitive (Int J Urol 2006;13:67)
● Occasionally fungal infections and sarcoidosis can cause non-caseating epithelioid cell granulomas



Drug related toxicity

Adefovir nephrotoxicity


Reviewers: Nikhil Sangle, M.D. (see Reviewers page)
Revised: 2 September 2012, last major update September 2012
Copyright: (c) 2003-2012, PathologyOutlines.com, Inc.

General
=========================================================================

● Antiretroviral agent used for HIV
● 10 mg daily dose may be associated with hypophosphatemia, elevated creatinine level and Fanconi syndrome, due to reversible proximal tubular toxicity (Expert Opin Drug Saf 2011;10:809, Am J Ther 2011 Apr 23 [Epub ahead of print])
● Causes severe acute degenerative changes in proximal tubules, possibly mediated by focal deficiency of cytochrome C oxidase (Hum Pathol 2001;32:734)

Case reports
=========================================================================

● 47 year old man taking 10 mg/day adefovir for chronic Hepatitis B who developed Fanconi syndrome (Gut Liver 2010;4:389)

Electron microscopy description
=========================================================================

● Proximal tubular mitochondria are enlarged, dysmorphic and disoriented with reduced cristae



Drug related toxicity

Analgesic nephropathy


Reviewer: Nikhil Sangle, M.D. (see Reviewers page)
Revised: 2 September 2012, last major update September 2012
Copyright: (c) 2003-2012, PathologyOutlines.com, Inc.

General
=========================================================================

● Bilateral chronic renal disease due to excessive intake of analgesics, with papillary necrosis (tips of medullary pyramids) and later chronic tubulointerstitial nephritis
● Disorder appears to be limited to phenacetin containing analgesics (Nephrol Dial Transplant 2009;24:1253)

Clinical features
=========================================================================

● High rates in Australia (Clin J Am Soc Nephrol 2008;3:768), southeast USA
● Due to red blood cell damage from phenacetin metabolites in numerous products: phenacetin plus aspirin, caffeine, acetaminophen (a metabolite of phenacetin) or codeine
● 80% women; also people with chronic pain, factory workers
● 50% have co-existing urinary tract infection
● Anemia, renal stones and inability to concentrate urine
● May have gross hematuria or renal colic due to sloughing of necrotic papillae
Complication: papillary urothelial carcinoma of renal pelvis

Other causes of papillary necrosis:
● Diabetes mellitus: 75% women, usually 10+ years of disease, 80% have urinary tract infection, all papillae affected similarly
● Obstruction: 90% male, 90% have infection, frequent calcification
● Sickle cell disease: M=F, few papillae affected

Case reports
=========================================================================

● 55 year old businessman with chronic osteoarthritis and end stage renal disease (Niger J Clin Pract 2012;15:231)

Gross description
=========================================================================

● Depressed cortex due to cortical atrophy overlying necrotic papillae
● Papillae show varying stages of necrosis and sloughing

Micro description
=========================================================================

Early: papillae have patchy necrosis
Later: papillae are diffusely necrotic with ghost tubules and dystrophic calcification; renal columns of Berlin are usually spared from tubular atrophy; small vessels have basement membrane thickening

Micro images
=========================================================================


   
Various images



Drug related toxicity

Chloroquine toxicity


Reviewers: Nikhil Sangle, M.D. (see Reviewers page)
Revised: 2 September 2012, last major update September 2012
Copyright: (c) 2003-2012, PathologyOutlines.com, Inc.

General
=========================================================================

● Chloroquine used for malaria prophylaxis and treatment; also for rheumatoid arthritis, systemic/discoid lupus erythematosus, other connective tissue disorders (eMedicine)

Case reports
=========================================================================

● 46 year old woman with Sjogren's syndrome (Hum Pathol 2003;34:285)
● 56 year old woman with rheumatoid arthritis (Mod Pathol 2005;18:733)



Drug related toxicity

Cyclosporin A toxicity


Reviewer: Nikhil Sangle, M.D. (see Reviewers page)
Revised: 2 September 2012, last major update September 2012
Copyright: (c) 2003-2012, PathologyOutlines.com, Inc.

General
=========================================================================

● Anticalcineurins (cyclosporine A and tacrolimus) were discovered in late 70's; constitute a basic component of all immunosuppressive protocols to control transplant rejection for solid organ graft recipients
● Nephrotoxicity is major concern (Clin J Am Soc Nephrol 2009;4:481)
● Nephrotoxic, hepatotoxic and neurotoxic
● Also causes gingival hyperplasia, hypertrichosis and lymphoma
● Nephrotoxicity is dose related, occurs in 3%

Functional toxicity
=========================================================================

● Mild decrease in renal function and increase in serum creatinine, hypertension in 50%, reversible if dosage lowered and no morphologic changes in kidney
● Toxicity due to alteration in intrarenal hemodynamics (vasoconstrictive phenomenon)

Acute tubular toxicity
=========================================================================

● Similar to functional toxicity but more severe
● Microscopic changes include vacuoles in proximal tubules (due to dilated endoplasmic reticulum with giant mitochondria, large lysosomes) and microcalcifications
● Also arteriolar smooth muscle cell degeneration, endothelial cell swelling, intimal thickening, variable hyaline or mucoid deposits which narrow lumen
● Dose dependent and reversible

Thrombotic microangiopathy
=========================================================================

● Resembles hemolytic uremic syndrome
● Occurs days to weeks after transplantation
● Glomeruli and vessels show thrombotic microangiopathy with platelet and fibrin thrombi and minimal inflammatory infiltrate
● Poor prognosis
● In one study, most common cause was antibody mediated rejection, not cyclosporine toxicity (Am J Transplant 2010;10:1804)

Chronic toxicity
=========================================================================

● Hypertension and slow progression to renal failure
● Arterioles show nodular or diffuse hyalinosis of vessel walls or mucoid thickening of intima, leading to luminal narrowing
● Also diffuse interstitial fibrosis and tubular atrophy
● Early glomerular changes are aggregates of platelets and fibrin
● Late changes are focal and segmental glomerulosclerosis or global scarring
● Changes are irreversible

Micro images
=========================================================================



Various images

           
Expression of P-glycoprotein, endothelin1, RANTES, MCP1 mRNA (ISH)

   
Allograft treated with cyclosporine A


Classic features of calcineurin inhibitor toxicity (cyclosporine and tacrolimus)



Drug related toxicity

Gold therapy


Reviewer: Nikhil Sangle, M.D. (see Reviewers page)
Revised: 2 September 2012, last major update September 2012
Copyright: (c) 2003-2012, PathologyOutlines.com, Inc.

General
=========================================================================

Gold salts may cause interstitial nephritis or nephrotic syndrome with gold deposits present within tubular epithelium, interstitial macrophages and free within renal interstitium
● Gold treatment may be continued for short periods under close supervision despite moderate proteinuria without causing permanent renal damage (Br J Rheumatol 1989;28:53)

Case reports
=========================================================================

● Due to gold salts for rheumatoid arthritis (Arch Pathol Lab Med 1983;107:258, Arch Pathol Lab Med 1977;101:635)

Treatment
=========================================================================

● Cessation of gold therapy

Immunofluorescence
=========================================================================

● May have IgG or C3 deposits in granular pattern in glomerular basement membrane, due to unknown immune complex (Arch Pathol Lab Med 1981;105:373)



Drug related toxicity

Indinavir nephropathy


Reviewers: Nikhil Sangle, M.D. (see Reviewers page)
Revised: 2 September 2012, last major update September 2012
Copyright: (c) 2003-2012, PathologyOutlines.com, Inc.

General
=========================================================================

● Protease inhibitor used to treat HIV, strongly associated with direct nephrotoxicity (Adv Chronic Kidney Dis 2010;17:72)
● May cause tubulointerstitial nephritis due to intratubular precipitation of indinavir crystals, with damage to tubular epithelial cells and histiocytic reaction
● Tolerance may be higher in those from sub-Saharan Africa versus US / Europe (AIDS Res Hum Retroviruses 2007;23:62)
● May resemble tuberculosis (Braz J Infect Dis 2008;12:99)

Case reports
=========================================================================

● 49 year old man with HIV and indinavir-induced nephrolithiasis 3 years after discontinuing indinavir (Int Urol Nephrol 2011;43:571)

Treatment
=========================================================================

● Dose reduction (Eur J Clin Pharmacol 2007;63:901), discontinuation, urine acidification, early insertion of bilateral double-J ureteral stents (Int Urol Nephrol 2007;39:743)

Micro images
=========================================================================


               
Biopsy findings


Crystal induced tubular injury

           
Indinavir crystals in urinary sediment

Electron microscopy images
=========================================================================



Granulomatous giant cell reaction with crystals within lumen



Drug related toxicity

NSAID associated nephropathy


Reviewers: Nikhil Sangle, M.D. (see Reviewers page)
Revised: 3 September 2012, last major update September 2012
Copyright: (c) 2003-2012, PathologyOutlines.com, Inc.

See also Analgesic nephropathy

General
=========================================================================

● NSAIDs rarely cause acute renal failure due to inhibition of vasodilatory prostaglandins
● May cause an acute hypersensitivity interstitial nephritis, acute interstitial nephritis and minimal change disease together, or membranous glomerulonephritis

Clinical features
=========================================================================

● Particularly affects newborns and elderly (Eur Rev Med Pharmacol Sci 2011;15:1461, Am J Med 2007;120:280e1)
● Increased risk of acute renal failure in volume depleted children (Arch Dis Child 2007;92:524, Ned Tijdschr Geneeskd 2006;150:1861)

Micro images
=========================================================================



Minimal change glomerulopathy


Renal cortical necrosis in mildly dehydrated 13 year old girl receiving diclofenac sodium for Crohn's disease



Drug related toxicity

Oxycodone nephropathy


Reviewer: Nikhil Sangle, M.D. (see Reviewers page)
Revised: 3 September 2012, last major update September 2012
Copyright: (c) 2003-2012, PathologyOutlines.com, Inc.

General
=========================================================================

● Intravenous injection of suppositories containing oxycodone may cause granulomatous glomerulonephritis and subsequent renal failure (Hum Pathol 1998;29:1246)
● May also cause widespread tubulointerstitial involvement, with fibrillar deposits in glomeruli and tubular basement membranes (Hum Pathol 2002;33:783)

Clinical features
=========================================================================

● Oxycodone can accumulate during chronic renal failure (South Med J 2007;100:212)
● Elderly may have higher levels due to altered pharmacokinetics (Drugs Aging 2011;28:41)

Positive stains
=========================================================================

● PAS

Negative stains
=========================================================================

● Congo red, silver



Drug related toxicity

Tacrolimus (FK506) toxicity


Reviewer: Nikhil Sangle, M.D. (see Reviewers page)
Revised: 3 September 2012, last major update September 2012
Copyright: (c) 2003-2012, PathologyOutlines.com, Inc.

See also Cyclosporine A toxicity

General
=========================================================================

● Immunosuppressive drug used frequently in renal transplants, effect may be mediated by binding to FKBP12, a cytosolic protein
● FKBP12/FK506 binds to and inactivates calcineurin (a serine / threonine phosphatase), which inhibits calcium and calmodulin dependent B and T cell responses by blocking NFAT-mediated transcription

Clinical features
=========================================================================

● Systemic levels of tacrolimus, if kept within a relatively narrow target window, may not be associated with nephrotoxicity (Transplant Proc 2009;41:3393)
● The presence of rejection does not rule out Tacrolimus or Cyclosporine toxicity
● Red cell exchange transfusion may be useful for severe toxicity (Pediatr Nephrol 2011;26:2245)
● Although mechanism of action is similar to cyclosporine A, mechanisms causing nephrotoxicity may differ (J Proteomics 2011;75:677)

Treatment
=========================================================================

● Reduce dosage

Micro description
=========================================================================

● Toxicity (in 1%) is similar to cyclosporin A at level of renal vascular endothelium, leading to fibrin thrombi in glomerular capillaries and afferent arterioles (Am J Surg Pathol 1996;20:306, Am J Surg Pathol 1993;17:60)
● May also cause arteriolar hyalinosis and splitting / reduplication of glomerular basement membrane

Micro images
=========================================================================


           

           

                   
Various images

Electron microscopy images
=========================================================================



Tubular vacuoles represent dilatations of endoplasmic reticulum and lysosomal elements

End of Kidney non tumor > Superpage part 1


This information is intended for physicians and related personnel, who understand that medical information is often imperfect, and must be interpreted in the context of a patient's clinical data using reasonable medical judgment. This website should not be used as a substitute for the advice of a licensed physician.

All information on this website is protected by copyright of PathologyOutlines.com, Inc. Information from third parties may also be protected by copyright. Please contact us at copyrightPathOut@gmail.com with any questions (click here for other contact information).