Kidney non-tumor

Stages of kidney development: pronephros (based on Wolffian duct, kidneys nonfunctional), mesonephros (appear at week 4, form nephron-like tubules but degenerate), metanephros (form at week 5, function by week 11)

Metanephric blastema: forms glomerulus, proximal convoluted tubules, loops of Henle, distal convoluted tubules, connective tissue of renal interstitium

Ureteric bud: forms cortical and medullary collecting tubules and medullary collecting ducts

Anatomy

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

11 cm long x 5-8 cm x 3 cm

Weighs 125-170 g in males, 115-155 g 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, 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, retroperitoneal

Glomeruli

Tuft-like vascular structure composed of lobules of specialized capillaries that arise from afferent arteriole and rejoin to drain into efferent arteriole

200 microns in diameter, 20% larger in juxtamedullary area

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

Glomerular basement membrane (GBM): normally 310-380 nm, composed of type IV collagen, laminin, polyanionic proteoglycans (mostly heparan sulfate), fibronectin, 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 noncollagenous (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

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: 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)

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

References: Mod Path 2002;15:988

Tubules and interstitium

Medullary rays: in cortex, contain cortical collecting tubules and loops of Henle of superficial nephrons

Renal columns of Bertin: cortical tissue extending into spaces between pyramids

Proximal tubules: long microvilli, numerous mitochondria and extensive intercellular interdigitations assist in reabsorption of sodium, water, proteins, glucose, potassium, phosphate, amino acids; vulnerable to toxins and ischemic damage

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 cells (nongranular cells that reside near afferent arteriole, macula densa and glomerulus and resemble mesangial cells); produces renin

Interstitium: contains fibroblast like cells and peritubular capillaries; expands due to edema and inflammation

Physiology of kidney

Filters 1700L of blood to 1L of urine per day

Excretes metabolic waste; regulates water, salt, pH; secretes renin, prostaglandins, erythropoietin

Nephron: glomerulus filters blood, filtrate 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, to calyx

Nephrons: production ceases at birth, are 1.3 million/kidney

Clearance: amount of plasma cleared of a substance per minute to appear in urine

Renal hormones

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

Renal disease-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:

Grossly visible hematuria, hypertension, azotemia, oliguria, mild edema, red blood cell casts, variable proteinuria

Associated with postinfectious, diffuse crescentic and membranoproliferative glomerulonephritis

Acute renal failure:

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

Azotemia:

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:

Azotemia progressing to uremia over a period of years

Stages of chronic renal failure: (1) diminished renal reserve (GFR 50% normal) with normal BUN/Cr, (2) renal insufficiency (azotemia, anemia, hypertension, polyuria, nocturia, (3) renal failure: GFR < 20% normal, kidneys cannot regulate volume of solutes and patient develops edema, metabolic acidosis and hypocalcemia, (4) end stage renal disease: GFR <5% normal

Represents the end stage of various renal diseases

Nephrotic syndrome:

Proteinuria > 3.5 g/day, hypoalbuminemia (serum level <3 g/dl), hyperlipidemia, lipiduria, severe edema (anasarca)

Due to derangement in glomerular capillary walls which leads to increased permeability to plasma proteins, causing massive proteinuria, hypoalbuminemia and generalized edema (pitting, periorbital and dependent edema)

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), congenital nephrotic syndrome

Rapidly progressive glomerulonephritis:

Acute glomerulonephritis with proteinuria and acute renal failure

Uremia:

Azotemia plus clinical signs/symptoms (gastroenteritis, peripheral neuropathy, fibrinous pericarditis, secondary hyperparathyroidism); associated with chronic renal failure

Tubular defects cause polyuria, nocturia, electrolyte disorders; due to diseases directly or indirectly affecting tubular function

Congenital anomalies

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

Absence of normal appearing proximal tubules

Associated with monochorionic twinning or renal hypoperfusion

References: Hum Path 1991;22:147; Hum Path 1986;17:1259

Agenesis

Bilateral agenesis is incompatible with life and is associated with pulmonary hypoplasia and limb defects

Incidence is 0.03% of newborns but 0.3% of stillborns

Unilateral renal agenesis is uncommon, not fatal

Compensatory hypertrophy in other kidney may cause glomerulosclerosis in adults

Case reports: associated with Klinefelter’s (47, XXY) syndrome (Archives 2004;128:e44)

Duplication of ureters

Occurs in <1% of individuals

Usually asymptomatic; may be associated with obstruction

Ectopic (displaced) kidneys

Usually at pelvic brim, may have kinking of ureters

Horseshoe kidney

1/500 autopsies, 90% are fused at lower pole

Associated with obstruction

Hypoplasia

Failure of kidney to develop to normal size without scarring

Usually unilateral, with a reduced number of pyramids (6 or less)

Oligomeganephronia: a type of hypoplasia with a small kidney but hypertrophied nephrons

PRIMARY GLOMERULAR DISEASES

Biopsy-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

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

Must carefully evaluate glomeruli, tubules, interstitium, vessels

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 Path 2002;15:988)

Immunofixation: best performed on unfixed, frozen sections; examine for IgG, IgM, IgA, C3, C1q, C4, fibrin, kappa, 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, fibrin

EM: 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

Frozen section: requested to determine adequacy (% sclerotic glomeruli) in donor kidney for transplant

Transplant biopsies: performed to assess rejection

References: Mod Path 2004;17:1555

Glomerular disease-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.

Micro:

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

Pathogenesis of glomerular injury

Usually immune mediated via antibody deposition, cell-mediated injury or activation of alternative complement pathway

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

Micro: injured epithelial cells have vacuoles, retract and detach from basement membrane, lose foot processes

Immunofluorescence patterns: 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 Path 2002;15:988)

C1q nephropathy

Rare; causes proteinuria that responds poorly to steroids

Teenagers and young adults, higher incidence among blacks and males

Slow progression to renal failure

Micro: variable mesangial hypercellularity with increase in mesangial matrix; variable segmental glomerulopathy

Immunofluorescence: prominent mesangial C1q deposition; also IgG, IgM, IgA and C3

EM: mesangial immune complex deposits

DD: lupus nephritis (may have prominent deposition of C1q, C3, immunoglobulins)

Chronic glomerulonephritis

An end stage disease due to progression of various types of glomerulonephritis; occasionally is no prior history of kidney disease

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 decreases as glomeruli disappear

Gross: symmetrically small kidneys with thin granular cortex and increased peripelvic fat

Micro: glomerulosclerosis, tubular atrophy and thyroidization, interstitial fibrosis and lymphocytic inflammation; arterial and arteriolar sclerosis

Congenital nephrotic syndrome

Heterogenous conditions with nephrotic syndrome in first 3 months of life

No response to steroids or immunosuppressive therapy

Treatment: renal transplant

DD: membranous glomerulonephritis (associated with congenital syphilis, mercury poisoning), toxoplasmosis, HIV, malaria, CMV, minimal change glomerulopathy

References: OMIM #600995

Finnish type

Autosomal recessive

Occurs in 1 per 10,000 newborns in Finland, lower incidence elsewhere

1.5% of cases of nephrotic syndrome in childhood

Nephrin protein at 19q13.1, normally at slit diaphragm of glomerular podocyte, is missing in patients with Finnish-type syndrome of gene mutations

Can diagnose in utero via genetic testing

Heavy proteinuria in utero

At birth, large placentas, proteinuria, edema, infections, premature birth, mild facial/limb abnormalities, poor development

Disease progresses to death without kidney transplant; dramatic improvement with transplant, but 20% have recurrence of nephrotic syndrome

Micro: proximal and distal tubular ectasia with flattening of tubular epithelium, microcysts, glomerulosclerosis, immature glomeruli

Immunofluorescence: nonspecific IgM and C3 in mesangium and capillaries

EM: obliteration of foot processes

References: OMIM #256300

Diffuse mesangial sclerosis

Early onset of severe proteinuria (within first 6 months of life), with rapid progression to end stage renal disease by age 3 years

May be associated with Denys-Drash syndrome (nephrotic syndrome, male pseudohermaphroditism, Wilms’ tumor) or be isolated

Normal placenta, no premature births, but is associated with cataracts and corneal clouding, aniridia, microencephaly, mental retardation, hypertelorism

Does not recur after transplantation

Micro: diffuse mesangial sclerosis; tubular atrophy and interstitial fibrosis

Immunofluorescence: mesangial deposits of IgM, C3, C1q

EM: obliteration of foot processes, basement membrane thickening, increase in mesangial matrix

References: OMIM #256370

Diffuse mesangial hypercellularity with nephrotic syndrome

2-10% of renal biopsies from patients with idiopathic nephrotic syndrome

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: mild mesangial hypercellularity

Immunofluorescence: IgM, variable C3

EM: obliteration of foot processes, sparse mesangial deposits

Fibrillary glomerulonephritis

Deposition of extracellular nonamyloid fibrillary material in glomeruli and tubular basement membranes (“nephropathy” better term than glomerulonephritis)

Rare, <1% of renal biopsies

More common in whites and females

Patients present with heavy proteinuria, hematuria, and systemic hypertension

50% eventually develop end-stage kidney disease within 2 to 4 years from diagnosis

Associated with membranoproliferative glomerulonephritis

7% also have lymphoproliferative disorders

No evidence of extrarenal fibrillary deposits

Features overlap with hepatitis C virus induced cryoglobulinemic glomerulonephritis

Not a disease, but the morphologic expression of a diverse group of diseases incompletely defined (Hum Path 2001;32:660)

Diagnosis: based on ultrastructural (EM) findings; some authors require exclusion of cryoglobulins

Case reports: crescentic glomerulonephritis with linear IgG staining (Archives 2001;125:534), polyclonal gammopathy but IgG1 deposits (Mod Path 1998;11:103)

Micro: mesangial expansion with PAS-positive material, diffuse thickening of the glomerular basement membrane; variable proliferative lesions, 25% have crescents

Negative stains: Congo red, thioflavin T

Immunofluorescence: deposition of IgG4, C3, kappa and lambda light chains

EM: randomly arranged non-amyloid fibrils in the mesangium and glomerular capillary walls, 18-22 nm thick vs. 10 nm for amyloid and 30-50 nm thick and organized for immunotactoid glomerulopathy; usually extensive effacement of epithelial foot processes

References: AJSP 1991;15:632

Focal proliferative and necrotizing glomerulonephritis

Only parts of some glomeruli affected; proliferative, not sclerotic; also necrosis and fibrin deposition

Microscopic to gross hematuria, 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

Focal and segmental glomerulosclerosis

A histologic pattern of glomerulosclerosis (some glomeruli, part of capillary tuft) associated with heavy proteinuria and progressive renal failure

In normal adults ages 55 or less at autopsy, glomerulosclerosis affects <3% of glomeruli (Archives 1989;113:1253)

Primary (idiopathic) form: causes 10% of nephrotic syndrome in children (usually <5 years), 20% in adults (20-39 years); associated with hematuria, hypertension, nonselective proteinuria; rarely is familial

Secondary forms: heroin addiction, HIV, IgA nephropathy, renal ablation nephropathy, unilateral renal agenesis, hypertension, sickle cell disease, morbid obesity, obstruction, reflux, congenital (associated with 19q13 or nephrin alterations), glycogen storage disease, congenital heart disease, healed focal proliferative and necrotizing glomerulonephritis; have 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.

Micro: focal and segmental glomerulosclerosis and mesangial sclerosis in lobules that appear to adhere to Bowman’s capsule (begins in corticomedullary region), hyaline deposits and 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

Immunofluorescence: IgM and C3 in sclerotic segments

EM: epithelial cell detachment from glomerular basement membrane; extensive foot process obliteration (even in non-sclerotic glomeruli), mesangial sclerosis with increased matrix, collapsed glomerular loops

Special form in IV drug abuse and AIDS

Rapid progression to end stage renal failure in AIDS (3-4 months) and IV drug abuse (2-4 years)

Note: HIV also causes acute renal failure, postinfectious, membranous or membranoproliferative glomerulonephritis (Hum Path 1987;18:1293)

Micro: 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, interstitial inflammatory infiltrate (primarily activated T cells)

EM: tubuloreticular structures in endothelium (non specific for infection), induced by interferon alpha

References: Hum Path 1988;19:1060 (tubuloreticular inclusions)

Collapsing glomerulopathy

Resembles special form 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

Aggressive variant of focal segmental glomerulosclerosis

Similar changes in renal allografts

May be due to altered hemodynamics

Process may have different origin in renal allografts (Hum Path 2002;33:437)

Micro: 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, lymphocytic infiltrate

Immunofluorescence: segmental IgM and C3

Glomerular tip lesion

Appears to have similar response to therapy as classic type

Micro: 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

Idiopathic nodular glomerulosclerosis
Resembles nodular diabetic glomerulosclerosis, but in nondiabetic patients

Mean age 68 years, 74% white, 78% men

Typically presents with renal insufficiency (83%, mean serum creatinine of 2.4 mg/dL), proteinuria > 3g/day (70%), nephrotic syndrome (22%)

Associated with hypertension (96%), smoking (91%, mean 53 pack-years), hypercholesterolemia (90%), extrarenal vascular disease (44%)

A diagnosis of exclusion

Poor prognostic factors for end stage renal disease: continued smoking, lack of angiotensin II blockage, degree of arteriosclerosis

Micro: prominent diffuse and nodular mesangial sclerosis, glomerular basement membrane thickening, arteriosclerosis and arteriolosclerosis; also neovascularization of glomeruli

Positive stains: CD34 highlights increased number of vascular channels within glomeruli compared with normal controls

References: Hum Path 2002;33:826

IgA nephropathy (Berger’s disease)

A type of diffuse mesangioproliferative glomerulonephritis (also Henoch-Schonlein purpura, SLE, IgM nephropathy, resolving stage of postinfectious glomerulonephritis)

IgA in mesangium and elevated serum IgA

Most common form of primary glomerulonephritis worldwide; causing 10% of cases of end stage renal failure in many countries

Common at ages 10-29 years, usually males, who present with gross or microscopic hematuria after respiratory infection, but no systemic disease

More common in southern Europe, Asia, Native Americans

Slowly progressive: 25%-50% have renal failure at 20 years; recurs in 20-60% of allografts

IgA immune complexes are deposited in mesangium, activate alternative complement pathway

IgA deposits also present in Henoch-Schonlein purpura; diseases may be related

Secondary disease: associated with gluten enteropathy (celiac disease), liver disease, dermatitis herpetiformis (Archives 1983;107:324)

Poor prognosis: prominent arteriolar hyalinization, older age, heavy proteinuria, hypertension

Case reports: death due to pulmonary hemorrhage (Archives 1994;118:542)

Micro: 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

Immunofluorescence: IgA, often IgG and C3 in mesangium; IgA also in capillaries of dermis, lung, liver, intestine

EM: electron dense deposits in mesangium of all glomeruli

DD: mesangial IgA deposition associated with obstructive jaundice (Hum Path 1987;18:1149)

Immunotactoid glomerulopathy

Rare, <1% of renal biopsies

More common in whites and females

Patients have monoclonal immunoglobulin deposition in glomeruli and may have circulating paraproteins

Related to fibrillary glomerulonephritis, but different fibril size and arrangement

May overlap with hepatitis C virus-induced cryoglobulinemic glomerulonephritis

Associated with nephrotic syndrome

33% of patients with (vs. 7% without) circulating or urinary paraproteins have lymphoproliferative disorders

Poor long term survival

Diagnosis: based on EM findings

Case reports: 59 year old woman with proteinuria, immunotactoid glomerulopathy, heavy chain disease and follicular lymphoma (Archives 2004;128:689)

Micro: mesangial widening and occasional hypercellularity, capillary wall thickening; 25% have crescents

Negative stains: Congo red, thioflavin T

Immunofluorescence: variable IgG, C3; occasional IgM, IgA

EM: extracellular, nonamyloid deposits 30-50 nm wide, focally arranged in parallel arrays and with a visible lumen (microtubules), usually within mesangium but also involving basement membrane

Membranoproliferative glomerulonephritis

Also called hypocomplementemic (C3), lobular or mesangiocapillary / mesangiopathic glomerulonephritis

Alterations in basement membrane and proliferation of mesangial cells

Intermittent remissions but overall downhill course

Not a pure entity, as type I and II appear to have different etiologies

Type I: CLASSICAL (2/3)

5% of cases of glomerulonephritis affecting children and young adults

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

Secondary disease occurs with chronic immune complex disorders (SLE, hepatitis B/C, HIV, schistosomiasis), alpha-1-antitrypsin deficiency, malignancies

May cause high rates of non-diabetic end stage renal disease in Navajo Indians in US (Archives 1989;113:158)

Micro: 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

Immunofluorescence: lumpy bumpy (granular) for C3, IgG, early complement (C1q, C4)

EM: subendothelial and mesangial electron-dense deposits, increased mesangial matrix, mesangialization of capillary loops, foot process fusion

Type II: DENSE DEPOSIT (1/3)

Dense deposits in glomerular basement membrane

Familial or associated with partial lipodystrophy (loss of subcutaneous fat from fat and upper body)

Apparent activation of alternative complement pathway

60-70% have antibody to 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, Bruch’s membrane of retina

Micro: similar to type I, but less prominent cellular proliferation; strongly PAS+, eosinophilic, refractile and ribbon-like thickening of glomerular basement membrane, also basement membrane of Bowman’s capsule and tubules

Immunofluorescence: linear or double contoured C3 and properdin staining of glomerular capillary walls and bright nodular or ringlike reaction in mesangium, NOT in dense deposits; usually no immunoglobulins

EM: dense deposits in lamina densa of glomerular basement membrane, Bowman's capsule, spleen, causes long ribbon of hazy material; also nodular deposits of similar material in mesangium

References: Mod Path 2002;15:988

Type III: MIXED (rare)

Two morphologic subtypes that are clinically similar to each other and to type I membranous glomerulonephritis

Type III-Burkholder variant

Combined features of type I membranoproliferative glomerulonephritis and membranous glomerulonephritis

EM: subendothelial and subepithelial deposits and mesangial interposition associated with basement membrane spikes

Type III-Anders variant

Hybrid of type I and II membranoproliferative glomerulonephritis

EM: massive accumulation of deposits within basement membrane with membranous disruption, highlighted by silver stain

Membranous glomerulonephritis

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

75% of adult and 20% of childhood cases are idiopathic autoimmune disease linked to HLA, caused by antibodies to a renal autoantigen

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, angiofollicular lymph node hyperplasia (Archives 1979;103:591)

Proteinuria may be due to C5b-C9 (MAC complex of complement)

With progression, get membrane thickening, narrow capillary lumina, mesangial sclerosis, glomerulosclerosis

Proximal convoluted tubules contain hyaline droplets, reflecting protein reabsorption

Rarely tubulointerstitial nephritis due to anti-tubular basement membranes, usually progressive to end stage renal failure, usually affects male children

Hepatitis B cases resemble lupus nephritis class V, but are HepB+ and lack SLE’s extrarenal manifestations and autoantibodies (Mod Path 2000;13:166)

Clinical course: 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); variable course of disease makes it difficult to evaluate therapy; EM stages II-IV below have similar prognosis

Micro: early-normal; later-uniform diffuse capillary wall thickening without hypercellularity, without mesangial sclerosis, without inflammatory cells

Immunofluorescence: granular diffuse peripheral deposits, usually IgG and C3, also C5b-C9, occasionally IgM or IgA

EM stages:

Stage I: Scattered subepithelial electron dense deposits, normal glomeruli by light microscopy

Stage II: Spike and dome; deposits (dome) covered by glomerular basement membrane material (spikes); extensive obliteration of foot processes

Stage III: Deposits become intramembranous as spikes close over immune deposits

Stage IV: Dissolution of deposits (by macrophages, mesangial cells) with rarefaction and irregular glomerular basement membrane thickening; associated with severe tubular atrophy and vascular sclerosis

References: Mod Path 2002;15:988

Minimal change glomerulopathy

Also called minimal change disease, nil disease, lipoid necrosis, foot process disease

Causes 80% of cases of nephrotic syndrome in children (usually ages 2-6), 20% in adults

Extensive foot process "fusion" appears to be due to epithelial injury with loss of glomerular anionic charge

"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

Associated with respiratory infections, immunizations, lead or mercury ingestion, allergies, acute interstitial nephritis, Hodgkin’s lymphoma; in elderly, associated with NSAIDs

Clinical: nephrotic syndrome, selective for albumin, often with severe edema or proteinuria, but with minimal microscopic glomerular alterations and usually no hypertension, no hematuria, no azotemia

Note: minimal change disease, diffuse mesangial hypercellularity and focal and segmental glomerulosclerosis may be a continuum of the same disease.

Case reports: intravascular B cell lymphoma of kidney associated with minimal change disease (Hum Path 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

May develop nephrocalcinosis due to hypercalciuria from chronic furosemide use (Hum Path 2000;31:1363)

Micro: normal glomeruli, tubules have lipid droplets due to reabsorption of lipoproteins that leak from glomeruli ("lipoid nephrosis")

Positive stains: albumin in proximal tubular epithelial cells

Immunofluorescence: negative

EM: extensive foot process effacement (foot processes retract into cell bodies, not actually fusion); microvillous transformation of epithelial cells, cyst formation

DD: focal and segmental glomerulosclerosis (tubular atrophy and interstitial scarring)

Post-infectious glomerulonephritis

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

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, meningococci, other bacteria

Similar process occurs in response to endogenous antigen in SLE

Post-streptococcal disease is decreasing in US, where post-Staphylococcal aureus infection is more frequent, but is common elsewhere

Children age 6-10: 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, hypertension

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, crescentic glomerulonephritis

Adults: may have atypical presentation with sudden hypertension, edema, elevated BUN; 60% recover, others develop rapidly progressive glomerulonephritis

Laboratory (children and adults): high antistreptococcal antibody titers, low C3 (due to consumption)

Micro: glomeruli are globally and diffusely enlarged and hypercellular due to neutrophils and macrophages and proliferation of mesangial and endothelial cells; swelling of endothelial cells and presence of inflammatory cells obstructs capillary lumina; returns to normal within months

Immunofluorescence: lumpy-bumpy (granular) deposition of IgG, IgM and C3 in peripheral glomerular loops; also properdin; no C1q or C4

EM: subepithelial humps (finely granular, dome-shaped, electron dense, representing immune complex deposits), obliteration of epithelial cell foot processes

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 Path 2003;34:3)

Rapidly progressive (crescentic) glomerulonephritis

Also called extracapillary proliferative glomerulonephritis, because cell proliferation is primarily in Bowman’s space

Crescents are end result of damage to glomerular basement membrane or Bowman's capsule; due to deposition of fibrin, epithelial cells and inflammatory cells; may have various causes

Crescents affect 50% of glomerular circumference, 70% of glomeruli

Rapid, usually irreversible loss of renal function associated with severe oliguria and hematuria, unresponsive to steroids

Symptoms of nephritic syndrome, nephrotic syndrome and renal failure

Causes death within weeks if untreated

Case reports: after Hepatitis B infection (Mod Path 1992;5:262)

Gross: enlarged, pale kidneys with cortical petechial hemorrhages

Micro: crescents in glomeruli are proliferation of parietal epithelium of Bowman’s capsule with macrophages, neutrophils, lymphocytes, fibrin, collagen; also see glomerular capillary collapse, atrophic tubules, interstitial inflammation

EM: wrinkling and focal disruptions in glomerular basement membrane

DD: 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%)

Goodpasture’s syndrome: antibody to alpha 3 chain of type 4 collagen (part of noncollagenous 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, 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: coexisting vasculitis (Archives 1980;104:300)

Micro: hypercellular glomeruli, crescents, variable neutrophils, no/rare intracapillary cell proliferation

Immunofluorescence: diffuse linear staining of glomerular basement membrane, IgG > IgM, also C3 and focal fibrin in capillary loops

EM: no deposits; fibrin at glomerular basement membrane breaks

DD (based on clinical presentation): microscopic polyarteritis, Wegener’s granulomatosis; similar immunofluorescent findings in diabetic nephropathy, SLE

TYPE 2: Immune complex crescentic glomerulonephritis (35%)

Immune complex deposition with complement activation due to postinfectious glomerulonephritis, types I and II membranoproliferative glomerulonephritis, cryoglobulinemic glomerulonephritis, SLE, IgA nephropathy, Henoch-Schonlein purpura, idiopathic

Usually children

Must treat underlying disease; plasmapheresis NOT helpful

Micro: 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)

EM: immune complex deposits as subepithelial humps or mesangial deposits, fibrin at glomerular basement membrane breaks

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

No anti-glomerular basement membrane antibodies, no immune complexes

Usually elderly

Either limited to kidney or associated with clinical vasculitis (Wegener’s granulomatosis, microscopic polyarteritis)

Often have serum C-ANCA (against proteinase 3; associated with Wegener’s) or P-ANCA (against myeloperoxidase; in those without extrarenal vasculitis); those with microscopic polyarteritis have either

Better prognosis than type 1

Micro: resembles type 1

Immunofluorescence: Ig negative, possibly C3 and fibrin/fibrinogen with crescents

EM: same as type 1 (no deposits, fibrin at glomerular basement membrane breaks)

Hereditary nephritis

Alport’s syndrome

Also called hereditary nephritis

Nephritis, subtle nerve deafness (55%, apparent in adults) and eye disorders in 15-30% (anterior lens dislocation, posterior cataracts, corneal dystrophy) due to defects in collagen IV synthesis affecting basement membranes

Incidence of 1 per 5-10,000 in US

The cause of end stage renal failure in 2.5% of children and 0.3% of adults in US

Ages 5-20 years, usually males, with gross or microscopic hematuria, red blood cell casts, often mild proteinuria, progressive loss of renal function; more likely to progress to renal failure in males

Rate of progression to end stage renal disease and deafness are mutation dependent, and each kindred reported has different mutations

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

Pathogenesis: X linked form (80%) due to mutations in alpha 5 gene at Xq22 coding collagen type IV, a component of glomerular basement membrane which interferes with its suprastructure, reducing production of alpha 3 (Goodpasture’s antigen) and alpha 4; some X linked patients also have diffuse leiomyomatosis

Also autosomal recessive (mutations in collagen type IV alpha 3 or alpha 4 genes, males and females have similar prognosis), and possibly autosomal dominant forms

Screening: segmental glomerular basement membrane staining is suggestive

Case reports: development of anti-glomerular and anti-tubular basement membrane antibodies after renal transplant (Archives 1994;118:728)

Treatment: kidney transplant; 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

Micro: early - segmental proliferation or sclerosis of glomeruli, increased mesangial matrix; may see fetal type glomeruli, foam cells in glomeruli or tubules; late - glomerulosclerosis, tubular atrophy

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)

EM: irregular thickening and thinning of glomerular basement membrane with splitting and lamination of lamina densa and granular inclusions; children and women may have only thin glomerular basement membranes without other alterations

DD: resolving stages of membranous glomerulonephritis, familial thin glomerular basement membrane (GBM) disease (positive staining with anti-GBM antibodies, negative in Alport’s syndrome)

References: Hum Path 2002;33:836; Hum Path 1998;29:404 (alpha5 staining in X linked female patients); article about Dr. Alport

Bartter’s syndrome

Rare, <150 cases reported

Hypokalemia, metabolic alkalosis, hyperaldosteronism, growth retardation, normal blood pressure but with blunted pressor response to exogenous angiotensin II; also polyuria, impairment of concentrating ability, increased renin, angiotensin II and prostaglandins

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; also associated with salt wasting and volume depletion, causing renin secretion and increased serum angiotensin II and aldosterone, further stimulating potassium and acid secretion, causing hypokalemia and acidosis; lack of NaCl reabsorption is associated with lack of calcium reabsorption

Neonatal type: more severe, presents with polyhydramnios due to intrauterine polyuria; also high urinary calcium, nephrocalcinosis, severe failure to thrive, marked growth retardation

Classic type: develops during first months or years with failure to thrive, dehydration, growth retardation, at most mild hypercalciuria, no significant nephrocalcinosis

Treatment: difficult, large doses of oral KCl with spironolactone, possibly ACE inhibitors, indomethacin

Micro: hyperplasia of juxtaglomerular apparatus

EM: epithelioid cells associated with afferent and sometimes efferent arterioles, with prominent Golgi complexes and secretory granules, some rhomboidal; also immature glomeruli in children, nephrocalcinosis

DD: high dose loop diuretics, conditions causing severe GI potassium chloride loss (have low chloride levels)

Collagen type III glomerulopathy

Also called primary glomerular fibrosis, collagenofibrotic glomerulopathy

Autosomal recessive and sporadic, due to deposition of type III collagen, normally absent in kidneys

Either gender, variable age

Children present with increasing proteinuria and nephrotic syndrome, hypertension, progressive renal failure, and possibly hemolytic uremic syndrome

Adults have indolent course

Micro: diffuse increase in mesangial matrix, generalized widening of glomerular capillary walls

Immunofluorescence: strong anti-collagen type III staining in capillary loops and mesangium (normally absent in kidneys); negative or focal IgM deposition

EM: large accumulation of collagen fibrils in subendothelial glomerular basement membrane and mesangial matrix

DD: hereditary onycho-osteodysplasia (has ultrastructural similarities)

References: Pediatr Nephrol 1993;7:354

Fabry’s disease

Also called alpha-galactosidase A deficiency, angiokeratoma corporis diffusum universale

X linked (Xq22.1) recessive lysosomal storage disease that affects 1 per 40,000

Highly penetrant in hemizygous males with symptoms at infancy or childhood; later age of presentation in heterozygous females, who usually have more variable severity due to variable lyonization of X chromosome and may have normal leukocyte alpha-galactosidase A activity

Due to 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 symptoms include angiokeratomas on skin of abdomen, buttocks, lips, genitalia, upper thighs; also hematuria and proteinuria progressing to renal failure, corneal dystrophy, recurrent shooting pains in legs

Death due to renal, cardiac or cerebrovascular disease at age 40+

Case reports: atypical variant, limited to heart or kidney abnormalities, diagnosed by renal biopsy for proteinuria (Archives 1996;120:86), 42 year old woman with persistent proteinuria (Archives 1985;109:89), atypical variant with accumulation in heart, not kidney or liver (Hum Path 1990;21:1067),

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 and immunostains for ceramide trihexoside; in women, must perform DNA mutation analysis of alpha-galactosidase A gene to exclude carrier state

Treatment: recombinant human alpha-galactosidase A replacement therapy

Micro (kidney): enlarged and vacuolated visceral epithelium, parietal epithelium, mesangial cells, endothelial cells, vascular smooth muscle, distal tubular cells; narrowing and thrombosis of arteries and arterioles

Positive stains: PAS, oil red O, Sudan black, Luxol fast blue (stain glycolipid and phospholipid-like material)

Immunofluorescence: negative

EM: 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; also urine sediment (Archives 1981;105:361)

DD (foam cell change): Gaucher’s disease, gangliosidoses, fucosidosis, mucopolysaccharidoses (all have different intracellular distribution and ultrastructural features of inclusions, can detect by laboratory assays), treatment with chloroquine, amiodarone or aminoglycosides (have similar myelin-like figures, Hum Path 2003;34:285)

References: Archives 1980;104:17

Fibronectin glomerulopathy

Massive fibronectin deposition in glomeruli

Autosomal dominant, non sex linked, due to 1q32 abnormality (Am J Hum Genet 1998;63:1724)

Proteinuria, often nephrotic syndrome, microhematuria, hypertension, progressive loss of renal function

May recur after renal transplant

Micro: lobular accentuation of glomeruli with minimal hypercellularity; marked enlargement of mesangium and subendothelial space due to massive deposition of fibronectin (PAS+, Congo red negative homogenous substance)

Immunofluorescence: strongly positive for fibronectin, scanty immunoglobulin or complement deposition

EM: fibronectin has dense granular appearance with 12-16 nm fibrils

References: OMIM %601894

Glutaric acidemia type II

Metabolic disorder due to deficiency of flavoprotein or its oxyreductase

Acidosis, nonketotic hypoglycemia, hyperammonemia, dysmorphic facial features, urinary organic acidemia, “sweat sock” odor

May have lipid accumulation in liver, heart and renal tubular epithelium

Micro: subcortical renal glomerular cysts, renal medullary dysplasia

EM: cytoplasmic, homogenous, moderately electron dense bodies with a limiting membrane

References: Archives 1986;110:399, Archives 1988;112:1133

Glycogen storage disease

Type I: thickening, lamellation and glycogen deposition in glomerular basement membrane

References: Archives 1988;112:271

Hereditary onycho-osteodysplasia

Also called nail-patella syndrome, Turner-Keiser syndrome, Fog’s syndrome

1 per 50,000 live births

Uncommon, autosomal dominant

Fingernail aplasia or dysplasia (especially first fingers), patellar absence or hypoplasia, subluxation of radial head and iliac horns

Renal involvement in 30-55%, usually asymptomatic proteinuria but may progress to renal failure

Due to point mutations in LMX1B gene at 9q34, also 17q21-22

Treatment: transplant if severe kidney disease

Micro: focal thickening of glomerular capillary walls, variable sclerotic glomeruli

EM: irregular thickening of glomerular basement membrane with moth eaten electron-lucent areas; also collagen-like fibers in electron lucent area and in mesangium

Infantile nephropathic cystinosis

Lysosomal storage disease causing kidney disease

Case reports: crystalline histiocytosis in patient post-kidney transplant (Archives 2002;126:1135), in renal allograft, dark cells present in interstitium, rarely glomeruli or tubular lumina, due to dark, granular material in cytoplasm, nucleus and cytoplasmic inclusions of macrophages (Hum Path 1989;20:472)

Treatment: kidney transplant