Kidney nontumor

Renal allograft

Recurrent and de novo diseases



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Last staff update: 21 September 2022

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PubMed Search: Kidney recurrent de novo

Arzu Sağlam, M.D.
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Cite this page: Sağlam A. Recurrent and de novo diseases. PathologyOutlines.com website. https://www.pathologyoutlines.com/topic/kidneyrecurrentdenovo.html. Accessed December 6th, 2022.
Definition / general
  • Diseases that recur or develop de novo in the renal allograft
Essential features
  • Recurrent or de novo diseases can injure the renal allograft
  • Most native kidney diseases can recur or develop de novo in the allograft, including cardiovascular diseases / hypertension, diabetes, metabolic diseases, infectious diseases, drug toxicities, perfusion problems and cancer, in addition to de novo / recurrent primary glomerular diseases
  • Cause of end stage renal disease has to be known in order to differentiate recurrence from de novo disease
  • Morphology is similar to those in the native kidney but frequently has additional features related to allograft rejection or other complications of transplantation
  • Clinical course of the disease usually differs from those of the native kidney due to presence of iatrogenic immunosuppression
Terminology
  • Recurrent "name of disease entity" of the renal allograft: original disease that damaged the native kidney recurring in the allograft
  • De novo "name of disease entity" of the renal allograft: development of a new disease in the allograft, different than that which led to end stage renal disease
  • Unknown: when native kidney disease is not known
ICD coding
  • ICD-10: T86.19 - other complication of kidney transplant
Epidemiology
  • With improvement in treatment of rejection related complications, recurrent and de novo diseases have become a significant contributing factor to graft dysfunction (Transplantation 1999;68:635)
    • Today recurrent / de novo cardiovascular diseases and cancer are the most common cause of morbidity and mortality
  • Focal segmental glomerulosclerosis, IgA nephropathy, membranous glomerulonephritis and membranoproliferative glomerulonephritis are among the most common recurrent glomerular diseases that lead to graft loss (Nat Clin Pract Nephrol 2008;4:446)
  • True incidence of recurrent or de novo diseases has not been clearly established, predominantly due to complexity in initial classification of the primary disease leading to end stage kidney
  • Figures vary widely between studies and with regard to disease subtype; exact figures are hard to determine due to
    • Anonymity of primary cause of end stage renal disease
    • Possibility of subclinical disease going underdiagnosed where protocol biopsies are not performed (Nephrology (Carlton) 2014;19:6)
    • Possibility of newly developed disease being donor derived
    • Coexistence or morphological overlap of certain primary renal diseases and forms of rejection (World J Transplant 2017;7:285)
    • Differences in morphology of early recurrent / de novo disease (especially those observed in protocol biopsies of asymptomatic patients) from those of clinically symptomatic diseases in the native kidney (Kidney Int 2017;91:304)
    • Lower utilization of immunofluorescence and electron microscopy in transplant biopsies
  • Risk of recurrence of glomerular disease is higher in patients with living related transplantation (BMC Nephrol 2017;18:25)
    • Better HLA compatibility is also associated with increased risk of recurrence of glomerular disease but longterm outcome is better despite this drawback (Kidney Int 2018;93:482)
    • Estimated rates given, in a comprehensive review article, in relation to glomerular diseases can be seen in table 1 below (Nephrology (Carlton) 2014;19:6)
  • Individual disease entities
    • Membranous nephropathy
      • Recurrence rates vary (10 - 50%); recurrence usually takes place within the first year
      • Most cases of de novo membranous nephropathy develop after the first year
      • Detectable serum phospholipase A2 receptor before or at transplantation or reemergence after transplantation increases risk of recurrence
    • Focal segmental glomerulosclerosis
      • Recurrence rates vary: 30 - 80%, higher in pediatric patients and in patients with primary / idiopathic focal segmental glomerulosclerosis; lower in those with secondary or genetic focal segmental glomerulosclerosis in the native kidney (Pediatr Transplant 2010;14:314, Front Immunol 2019;10:1944)
      • Usually develops within the first 2 years posttransplant
      • Risk factors for recurrence are (Nephrol Dial Transplant 2006;21:1053, Transplant Proc 2007;39:737)
        • Childhood onset disease
        • Age < 15 years
        • Rapid progression from diagnosis to end stage renal disease
        • Presence of mesangial hypercellularity
        • Recurrence of focal segmental glomerulosclerosis in a previous allograft (risk of recurrence increases to 80 - 100%)
        • Presence or absence of nephrotic syndrome in presentation of native focal segmental glomerulosclerosis (Clin J Am Soc Nephrol 2021;16:1730)
        • Subclass of focal segmental glomerulosclerosis: primary / idiopathic, genetic and secondary; risk of recurrence being highest in primary / idiopathic focal segmental glomerulosclerosis
      • Focal segmental glomerulosclerosis may also develop / progress over time, in which case separation of recurrent versus de novo disease can be problematic
    • IgA nephropathy
      • IgA deposition is frequently encountered in the renal allograft and recurrence rates vary between 10 - 53% depending on whether protocol or indication biopsies are involved and the follow up period (Nephrology (Carlton) 2018;23:4, Front Immunol 2019;10:1944)
      • Risk of recurrence increases with time after transplant
      • Latent IgA deposition should be differentiated from IgA nephropathy
        • Latent IgA deposition: mesangial IgA deposition in an asymptomatic patient (no hematuria or proteinuria) established by protocol biopsies
        • IgA nephropathy: IgA deposition in a patient with urinary abnormalities
    • Membranoproliferative glomerulonephritis - immune complex mediated (BMC Nephrol 2016;17:7)
      • Polyclonal immunoglobulins
        • Recurrence risk is lower (30 - 35%)
        • Presents later, during the first 5 years
      • Monoclonal immunoglobulins
        • Recurrent disease is more common, 66%
        • Usually occurs within the first year
      • Risk of recurrence is correlated with
        • Living related donation: possible genetic background
        • Preemptive transplants
        • Low complement levels
        • Presence of monoclonal gammopathy
    • C3 glomerulopathy (World J Transplant 2016;6:632)
    • Thrombotic microangiopathy (Curr Opin Organ Transplant 2014;19:283, Transplant Rev (Orlando) 2018;32:58)
      • Most cases are due to development of de novo thrombotic microangiopathy
      • Risk of recurrence depends on etiology
        • Typical hemolytic uremic syndrome due to infections rarely recurs (Pediatr Nephrol 2002;17:809)
        • Recurrence is most common in atypical hemolytic uremic syndrome; overall recurrence is 60% and usually occurs during the first year posttransplant (Clin J Am Soc Nephrol 2006;1:88)
        • Risk of atypical hemolytic uremic syndrome changes in relation to genetic abnormality; i.e., risk of recurrence is 4 times higher in patients with mutations in complement genes (Am J Transplant 2013;13:663)
        • ADAMTS13 deficiency: if deficiency is genetic, disease can recur (BMC Nephrol 2013;14:156)
    • De novo immune complex glomerulonephritis, unclassified (Hum Pathol 2015;46:1521, Hum Pathol 2018;71:109)
      • Various immune complexes and complement components can be identified in the renal allograft with immunofluorescence
      • Although the majority of immune complex glomerulonephritis in the allograft have a correlate in the native kidney, some do not and are not readily classifiable
    • Cardiovascular diseases and posttransplant diabetes mellitus: a common cause of mortality and morbidity in kidney transplant recipients
    • Infectious diseases: especially opportunistic microorganisms
    • Cancer (Nat Rev Nephrol 2018;14:508)
      • Is the second most common cause of mortality and morbidity in kidney transplant recipients
      • Kidney transplant recipients have at least a twofold higher risk of developing or dying from cancer than the general population
      • Types with greatest risk increase are: Kaposi sarcoma, nonmelanoma skin cancers, lip cancer (> 10 times) and cancers with viral oncogenesis (posttransplant lymphoproliferative disorder and anogenital cancers)
Sites
  • Renal disease
Etiology / pathophysiology
Diagrams / tables

Images hosted on other servers:

Rates of recurrence and graft loss risk

Prevalence, risk of allograft failure, clinical predictors

Prognostic and predictive biomarkers

Proposed management options

Characteristics and differences

Clinical features
  • Diseases may recur / present subclinically and be diagnosed on protocol biopsies - histological and immunophenotypic recurrence / presentation
  • Clinical picture may be complicated due to accompanying rejection
  • Individual disease entities
Diagnosis
  • Similar to that of individual native kidney diseases; however, take into consideration indication of biopsy (protocol biopsy versus biopsy due to clinical symptoms) and accompanying alterations due to the effects of
    • Immunosuppressive agents (most notably calcineurin inhibitors)
    • Immunological injury
    • Posttransplant infections (especially viral)
    • Ischemia reperfusion injury
    • Hyperfiltration injury
Laboratory
  • Abnormalities in urine analysis: proteinuria, hematuria, leukocyturia
  • Abnormalities in serum creatinine, albumin and protein levels
  • No abnormal lab findings in early disease recurrence / de novo development (established via protocol biopsies)
Prognostic factors
Case reports
Treatment
Microscopic (histologic) description
  • Histology of early disease may be very subtle and different from that of typical findings one is used to seeing in native biopsies; strict adherence to diagnostic criteria can lead to delays in diagnosis
  • Membranous nephropathy (Clin Transplant 2016;30:1394)
    • Light microscopy: normal initially; development of basement membrane thickening, vacuolization and spikes later on
    • Immunofluorescence: peripheral granular IgG, C4d, kappa and lambda staining
    • Lack of phospholipase A2 receptor staining in de novo disease (Transplantation 2013;95:1259)
    • Electron microscopy: only small subepithelial deposits initially, may even be absent; formation of well-formed subepithelial deposits later during the disease course
    • De novo disease is more likely to have segmental distribution of immune deposits and accompanying mesangial hyperplasia / expansion
    • Changes in relation to accompanying allograft related complications may also be present
  • Focal segmental glomerulosclerosis (Adv Chronic Kidney Dis 2014;21:448, Clin Transplant 2011;25:6)
    • Light microscopy: may resemble minimal change disease initially, with development of segmental sclerosis later on
    • Recurrence is usually in the same morphological variant as that of the disease in the native kidney (J Am Soc Nephrol 2008;19:2219)
    • Perihilar and not otherwise specified focal segmental glomerulosclerosis variants are more common in de novo disease (Clin Transplant 2011;25:6)
    • Electron microscopy: ultrastructural findings of podocyte effacement can be seen very early (Transplantation 2012;93:1238)
    • In general, proteinuria precedes the histologic findings of focal segmental glomerulosclerosis seen by light microscopy
    • Changes in relation to accompanying allograft related complications may also be present (J Clin Diagn Res 2017;11:EC39)
  • IgA nephropathy
    • Light microscopy: near normal glomeruli to mesangial and endocapillary hypercellularity
    • Immunofluorescence: dominant IgA in the mesangium
    • Changes in relation to accompanying allograft related complications may also be present
  • Membranoproliferative glomerulonephritis - immune complex mediated
    • Early findings show sole mesangial proliferation without characteristic double contours of the glomerular capillary basement membrane
    • Typical findings can evolve rapidly as disease progresses
    • Changes in relation to accompanying allograft related complications may also be present
  • Alternative complement mediated membranoproliferative disease / C3 glomerulopathy (World J Transplant 2016;6:632)
    • Light microscopy: membranoproliferative pattern is common in C3 glomerulonephritis and chronic thrombotic microangiopathy
    • Immunofluorescence: isolated C3 deposition in C3 glomerulonephritis
    • Changes in relation to accompanying allograft related complications may also be present
  • Thrombotic microangiopathy (Curr Opin Organ Transplant 2014;19:283, Transplant Rev (Orlando) 2018;32:58)
    • Biopsy usually cannot identify the underlying cause (Curr Opin Organ Transplant 2014;19:283)
    • Light microscopy: thrombi within glomerular capillaries, arteries / arterioles
    • Bloodless glomeruli: glomerular capillary lumina occluded by endothelial swelling and amorphous material
    • Fragmented red blood cells within arterial / arteriolar walls or glomeruli
    • Severe mucoid intimal thickening of small arteries and arterioles
    • Concentric thickening of the small arteries / arterioles
    • Focal and segmental glomerular capillary thickening due to endothelial swelling (causing double contours)
    • Immunofluorescence: negative
    • Electron microscopy: subendothelial space expansion due to electron lucent material, new matrix formation and duplication of glomerular basement membranes
    • Chronic thrombotic microangiopathy has a membranoproliferative pattern of glomerular injury and resembles transplant glomerulopathy
      • Presence of donor specific antibodies, C4d staining in peritubular capillaries or microvascular inflammation represents chronic and active antibody mediated rejection, not chronic thrombotic microangiopathy
  • Diabetic nephropathy
    • Light microscopy: vascular changes predominate in recurrence; fewer mesangial nodules than in de novo disease (Transplantation 1996;62:632)
    • Immunofluorescence: negative
    • Changes in relation to accompanying allograft related complications may also be present
  • De novo immune complex glomerulonephritis, unclassified (Hum Pathol 2015;46:1521, Hum Pathol 2018;71:109)
    • Light microscopy: minimal mesangial expansion
    • Immunofluorescence: mesangial deposits of IgM or IgG
Microscopic (histologic) and immunofluorescence images

Contributed by Arzu Sağlam, M.D.
Membranous nephropathy in allograft

Membranous nephropathy in allograft

IgG deposition, immunofluorescence

IgG deposition,
immunofluorescence

Recurrent Focal segmental glomerulosclerosis in allograft

Recurrent focal
segmental
glomerulosclerosis
in allograft

IgA nephropathy in allograft

IgA nephropathy in allograft

Mesangial IgA deposition, immunofluorescence

Mesangial IgA
deposition,
immunofluorescence


IgA nephropathy in allograft

IgA nephropathy in allograft

Mesangial IgA deposition, immunofluorescence

Mesangial IgA
deposition,
immunofluorescence

Recurrent amyloidosis in allograft

Recurrent amyloidosis in allograft

Recurrent amyloidosis in allograft, Congo stain polarized microscopy

Recurrent amyloidosis
in allograft, Congo
stain polarized
microscopy

Nonspecific IgM deposition, immunofluorescence

Nonspecific IgM
deposition,
immunofluorescence

Immunofluorescence description
  • See disease specific descriptions above
Positive stains
  • See disease specific descriptions above
Electron microscopy description
  • See disease specific descriptions above
Genetics
  • Genetic forms of focal segmental glomerulosclerosis have very low risk of recurrence, therefore, genetic testing may be considered in children and those adult onset focal segmental glomerulosclerosis patients where cause of focal segmental glomerulosclerosis is uncertain, especially if there is a family history
    • Screening of the donors for patients undergoing live related donor transplantation may also be considered in these circumstances (Transplant Proc 2019;51:3077)
  • Some studies suggest a genetic link between HLA antigens and risk of membranous nephropathy recurrence (N Engl J Med 2011;364:616, Kidney Int 2021;99:671, Kidney Int 2021;100:243)
  • Increased risk of recurrence of atypical hemolytic uremic syndrome (HUS) in patients with mutations in complement factor genes and complement regulatory factor genes, therefore genetic complement testing is recommended for all atypical HUS patients undergoing transplant (Am J Transplant 2013;13:663)
Videos

Case #34 - HacettepePathology

Sample pathology report
  • Kidney, allograft biopsy:
    • Recurrent focal segmental glomerulosclerosis (see comment)
    • No significant deposition on immunofluorescence microscopy. No evidence of T cell or antibody mediated rejection. Interstitial fibrosis / tubular atrophy absent. Arterial intimal fibrosis (mild).
    • Microscopic description: Serial sectioning shows 26 glomeruli, one of which is globally sclerotic. 2 glomeruli with segmental sclerosis are identified; these segments display obliteration of the capillary tuft and adhesion to the Bowman membrane, accompanied by hyalinosis, lipid vacuoles and hypertrophy of the parietal epithelial cells. Other glomeruli appear close to normal by light microscopy. Endocapillary or extracapillary proliferation, necrosis, intracapillary inflammatory cells (g0), intracapillary thrombi or double contouring of the capillary walls are absent (cg0). Interstitium shows multifocal edema and minimal inflammatory infiltrate comprising < 10% of the nonscarred cortical parenchyma (i0). No significant tubulitis or peritubullary capillaritis is seen (t0, ptc0). Narrow foci of IFTA can be identified, comprising less than 10% of the cortical parenchyma with scattered mononuclear cells (i-IFTA0, ci0, ct0). Immunohistochemical staining for C4d and SV40 is negative. Arteries display mild intimal fibrosis (cv1). Intimal arteritis is not identified (v0).
    • Immunofluorescence microscopy: 3 glomeruli observed
      • Anti IgG Ab: No deposits
      • Anti IgA Ab: No deposits
      • Anti IgM Ab: Segmental peripheral 1+ granular staining (interpreted as nonspecific)
      • Anti C3 Ab: No glomerular deposits, blush segmental reactivity on walls of arterioles
      • Anti C1q Ab: No deposits
      • Anti kappa Ab: No glomerular deposits, 2+ staining of tubular casts
      • Anti lambda Ab: No glomerular deposits, 2+ staining of tubular casts
    • Comment: Biopsy findings are consistent with recurrent focal glomerulosclerosis in this patient biopsied due to proteinuria during the early posttransplant period. There is no evidence of accompanying T cell or antibody mediated rejection or significant chronic tubulointerstitial damage. Vascular sclerosis is most probably donor related.
Differential diagnosis
  • De novo versus recurrence:
    • Differentiation of late recurrence versus development of de novo disease may be challenging
    • In glomerular diseases early onset (< 1 - 2 years after transplant) favors recurrent disease
  • Antibody mediated rejection (ABMR) may have similar morphology with:
    • Immune complex mediated glomerular disease with membranoproliferative pattern of injury:
      • Can resemble chronic active ABMR
      • Immunofluorescence findings of immunoglobulins or complement deposition provides evidence for immune complex or complement mediated disease
    • Acute and chronic thrombotic microangiopathy:
      • Can resemble active and chronic active ABMR, respectively
      • Negative immunofluorescence
      • Absence of microvascular inflammation, C4d staining in peritubular capillaries and donor specific antibodies
    • Presence of microvascular inflammation (transplant glomerulitis, peritubular capillaritis and transplant glomerulopathy), C4d staining in peritubular capillaries, presence of donor specific antibodies in the serum and lack of glomerular immune complex deposition by immunofluorescence are characteristics of antibody mediated rejection
  • Donor transmitted glomerular diseases:
Additional references
Board review style question #1
Which patient group below is at an increased risk of developing antiglomerular basement membrane glomerulonephritis following transplant?

  1. Patients with Alport syndrome
  2. Patients with diabetic nephropathy
  3. Patients with IgA nephropathy
  4. Patients with membranous glomerulonephritis
  5. Patients with primary oxalosis
Board review style answer #1
A. Patients with Alport syndrome. Patients with Alport syndrome lack α3, α4 or α5 chains of collagen IV after transplantation the α3, α4 or α5 chains of collagen IV of the donor kidney are recognized as foreign by the host immune system, which results in development of antibodies against these components and antiglomerular basement membrane glomerulonephritis.

Comment Here

Reference: Recurrent and de novo diseases
Board review style question #2

Above is a photomicrograph of the renal allograph biopsy of a patient who has been transplanted 3 weeks ago. The patient has a clinical history of hemolytic uremic syndrome due to infection. Immunohistochemistry reveals presence of peritubular and glomerular C4d staining. Which of the following differential diagnostic entities is the most likely diagnosis?

  1. Active antibody mediated rejection
  2. Acute calcineurin inhibitor toxicity
  3. Recurrent C3 glomerulopathy
  4. Recurrent hemolytic uremic syndrome
  5. Recurrent membranoproliferative glomerulonephritis
Board review style answer #2
A. Active antibody mediated rejection. The photomicrograph shows thrombotic microangiopathy; although almost all the mentioned entities enter the differential diagnosis, the presence of C4d staining initially points to active antibody mediated rejection; furthermore, hemolytic uremic syndrome due to infections typically does not recur.

Comment Here

Reference: Recurrent and de novo diseases
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