Kidney nontumor
Diseases of renal allograft
Recurrent and de novo diseases

Editorial Board Member: Nicole K. Andeen, M.D.
Editor-in-Chief: Debra Zynger, M.D.

Topic Completed: 25 July 2019

Revised: 25 July 2019

Copyright: 2019, PathologyOutlines.com, Inc.

PubMed Search: Kidney[TI] recurrent de novo

Page views in 2019 to date: 125
Cite this page: Sağlam A. Recurrent and de novo diseases. PathologyOutlines.com website. http://www.pathologyoutlines.com/topic/kidneyrecurrentdenovo.html. Accessed October 22nd, 2019.
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 in the allograft, including hypertension, diabetes, metabolic disease and drug toxicities, perfusion problems or de novo / recurrent primary glomerular diseases
  • Cause of end stage renal disease has to be known in order to diagnose recurrence
  • 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 because of 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
Epidemiology
  • With improvement in treatment, recurrent and de novo diseases have become a significant contributing factor to graft dysfunction (Transplantation 1999;68:635)
  • Focal segmental glomerulosclerosis, IgA nephropathy, membranous glomerulonephritis and membranoproliferative glomerulonephritis are among the most common glomerular recurrent 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
  • Figures vary widely between studies and with regard to disease subtype; exact figures are hard to determine due to:
    • Unknown primary cause of end stage renal disease
    • May be subclinical and underdiagnosed where protocol biopsies are not performed (Nephrology (Carlton) 2014;19:6)
    • Possibility of donor derived disease
    • Some primary renal diseases and forms of rejection may have similar morphology or coexist (World J Transplant 2017;7:285)
    • Morphology of early recurrent / de novo disease, especially in protocol biopsies of asymptomatic patients, may be different from that in clinically symptomatic diseases in the native kidney (Kidney Int 2017;91:304)
    • Lower utilization of immunofluorescence and electron microscopy in transplant biopsies
  • 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
    • Focal segmental glomerulosclerosis
      • Recurrence rates vary: 30 - 50%, higher in pediatric patients (Pediatr Transplant 2010;14:314)
      • 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
      • 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 followup period (Nephrology (Carlton) 2018;23:4)
      • 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 related (BMC Nephrol 2016;17:7)
      • Recurrent disease is common, 45%
      • 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
    • Complement related membranoproliferative disease / 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 de novo thrombotic microangiopathy development
      • 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 the CFH gene or carriers of the hybrid gene between CFH / CFHR1 (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
  • Estimated rates given in a comprehensive review article in relation to glomerular diseases (Nephrology (Carlton) 2014;19:6, see table below)
Etiology / pathophysiology
Diagrams / tables

Images hosted on other servers:

Rates of recurrence and graft loss risk

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
  • Abnormalities in serum creatinine, albumin and protein levels
  • No abnormal lab findings in early recurrence / de novo development (established via protocol biopsies)
Prognostic factors
Case reports
Treatment
Microscopic (histologic) description
  • Membranous nephropathy (Clin Transplant 2016;30:1394)
    • Light microscopy: normal initially; later development of thickening, basement membrane vacuolization and spikes
    • 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: small subepithelial deposits initially; later formation of well formed subepithelial deposits
    • 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
    • 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
  • Complement related 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) images

Contributed by Arzu Sağlam, M.D.

Membranous glomerulopathy and acute rejection

Recurrent FSGS (JMS stain)

IgA glomerulopathy

Immunofluorescence images

Contributed by Arzu Sağlam, M.D.

IgG

Mesangial IgA deposits

Positive stains
  • See disease specific descriptions above
Electron microscopy description
  • See disease specific descriptions above
Differential diagnosis
Board review question #1
Which patient group below is at an increased risk of developing antiglomerular basement membrane antibody 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 answer #1
A. Patients with Alport syndrome

Reference: Recurrent and de novo diseases

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Board review question #2
Which of the following is not associated with increased risk of disease recurrence or de novo disease development in renal transplant patients?

  1. Advanced age at transplantation
  2. Persistence of original inciting agents related to renal disease in the native kidney
  3. Poor blood pressure control in a patient with hypertension
  4. Poor diabetic control in a diabetic patient
  5. Transplantation of pediatric kidney into adult
Board review answer #2
A. Advanced age at transplantation

Reference: Recurrent and de novo diseases

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Board review question #3
Which of the following statements in relation to recurrent / de novo diseases of the renal allograft is incorrect?

  1. De novo membranous nephropathy is more likely to have segmental distribution of immune deposits and accompanying mesangial hyperplasia / expansion
  2. De novo thrombotic microangiopathy development can be associated with use of calcineurin inhibitors
  3. Hemolytic uremic syndrome due to infections typically recurs
  4. IgG4 subtype is dominant in recurrent membranous nephropathy
  5. In recurrent diabetic nephropathy, vascular changes predominate and fewer nodules are present in comparison to de novo disease
Board review answer #3
C. Hemolytic uremic syndrome due to infections typically recurs

Reference: Recurrent and de novo diseases

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