Salwa S. Sheikh MD, FCAP, FASCPConsultant Pathologist

Dhahran Health Center, Saudi Aramco

• 43% - proteinuria >1g/24h• 13% - nephrotic range• Causes:

– Chronic allograft nephropathy /– Recurrent glomerulonephritis– Calcineurin-inhibitor toxicity

Kidney Transplant

• 3rd cause of renal allograft loss – 10 yrs• Cardiovascular morbidity & mortality• True prevalence –

– Pts losing allografts due to recurrent GN– Pts with recurrence & functioning grafts

Recurrent Glomerulonephritis

• Relatively small & variable• Short follow up post transplant

Limitations in Evaluating Epidemiology of Native & Recurrent GN

Studies

– Restrictive renal biopsies- 50% underlying dses- unknown in many ESRD pts

– Black pts-often labeled to have hypertensive nephrosclerosis

– Difficulty in determining the cause of native kidney dse when presenting at late stage

– Difficulty in determining primary vs secondary FSGS

Limitations in Evaluating Epidemiology of Native & Recurrent GN

Native Kidney Disease

– Lack of unified approach in diagnosis

– Non-uniform indications for biopsy• Protocol vs clinical renal dse• Not adequately classified –

EM / IF lacking

Limitations in Evaluating Epidemiology of Native & Recurrent GN

Indications for Post-transplantationRenal Biopsy

– Lack of histological features in early dse.

– Difficulty in differentiating GN from other causes.

– Difficulty in determining primary vs secondary.

Limitations in Evaluating Epidemiology of Native & Recurrent GN

Diagnosis of Post-transplant GN

Differential Diagnosis Of Recurrent Disease After Kidney TransplantationDe novo glomerulonephritis

Transplanted glomerulonephritis

Chronic rejection

Cyclosporine toxicity

Acute rejection

Allograft ischemia

Cytomegalovirus infection

Recurrent GN

• Prevalence of GN as cause of ESRD: 10-25%

• Prevalence of recurrent GN – 4%-20%• 2-5% - graft failure• Higher prevalence:

– Children– White population

Prevalence of Glomerulonephritis

– True recurrence– Transplant glomerulopathy with unknown

primary disease– De novo disease

Definition & ClassificationCLINICAL CLASSIFICATION

– Recurrence of primary GN – Recurrence of secondary GN – Recurrence of metabolic or systemic diseases– De novo diseases

Definition & ClassificationHISTOLOGICAL CLASSIFICATION

• Recurrence- first few weeks • De novo- usually after 1 yr post

transplantGLOMERULONEPHRITIS

% RECURRENCE

FSGS, idiopathic 20-30%IgAN 25%MPGN-I 25%MPGN-II 80-almost 100%Membranous GN 30%

Glomerulonephritis

• E Briganti, G Russ, J McNeil, R Atkins, S Chadban. Risk of renal allograft loss from recurrent glomerulonephritis. • N Engl J Med, 347(2): 103-109, 2002.

Analysis of Allograft Loss due to Recurrence of GN, AR, CR & Death

• E Briganti, G Russ, J McNeil, R Atkins, S Chadban. Risk of renal allograft loss from recurrent GN• N Engl J Med, 347(2): 103-109, 2002.

Analysis of Allograft Loss due to Recurrence of GN, According to GN Types

Cumulative Probability of Post-Transplant GN by Original Disease

Chailimpamontree, W. et al. Probability, Predictors, and Prognosis of Posttransplantation Glomerulonephritis. J Am Soc Nephrol 2009;20:843-851

Cumulative Probability of Post-Transplant GN by Histological Type

Chailimpamontree, W. et al. Probability, Predictors, and Prognosis of Posttransplantation Glomerulonephritis. J Am Soc Nephrol 2009;20:843-851

Cumulative Incidence of Recurrent Post-Transplant GN

Chailimpamontree, W. et al. Probability, Predictors, and Prognosis of Posttransplantation Glomerulonephritis. J Am Soc Nephrol 2009;20:843-851

Cumulative Incidence of De Novo Post-Transplant GN

Chailimpamontree, W. et al. Probability, Predictors, and Prognosis of Posttransplantation Glomerulonephritis. J Am Soc Nephrol 2009;20:843-851

Probability of Graft & Patient Survival with PTGN

Chailimpamontree, W. et al. Probability, Predictors, and Prognosis of Posttransplantation Glomerulonephritis. J Am Soc Nephrol 2009;20:843-851

Focal Segmental Glomerulosclerosis

Diagnosis FeaturesRecurrent FSGS Recurrent heavy proteinuria within 3 mo

Original disease caused renal failure <3yRejection Insidious onset of proteinuria

Feature of chronic rejection on biopsy, especially vascular sclerosis and glomerulopathy

Cyclosporine-related

Previous thrombotic microangiopathy affecting glomeruli

De novo FSGS Original disease not FSGSChronic rejection excluded

Other glomerulonephritis

Characteristics immunohistology and electron microscopy, especially in immunoglobulin A disease

DDX Of Segmental Glomerular Scars On Transplantat ion Biopsy

Etiological Classification of FSGS

• 7-10% in pts requiring transplant• FSGS recurs – 20%-30%• Recur 6-12m post transplant• Heavy proteinuria, hypertension, &/ loss of graft

function• Severe proteinuria in recurrent FSGS-

thromboembolic complications• Majority – nonhereditary- circulating permeability factor• Hereditary – mutations – NPHS2

FSGS

• Proteinuria onset within weeks (80% nephrotic)• Acute graft dysfunction• Histologic changes- 4-6 wks post transplant• EM- changes within days after proteinuria onset-

diffuse effacement of podocyte foot processes. • Recurrence- 20% - graft loss -5-10 yrs• Living related donor- avoided with prior allograft loss due to recurrent FSGS

FSGS

Risk Factor Recurrence rate, %Age <5y 50

Age <15y with progression to ESRD within 3y 80-100

First graft lost from FSGS 75-85Adults without risk factor 10-15

Risk Factors For Recurrent FSGS after Transplantation

Graft loss occurs in half of all patients with recurrent FSGS and nephrotic syndrome.

– Childhood onset ( recurrence as high as 50%)– Recurrence of FSGS in prior allograft – Rapid progression (within 3yrs)– White race– Diffuse Mesangial hypercellularity (native)– Sirolimus therapy (de novo) – Graft failure - <20 yrs age – 24% of living

related donors & 11% of cadavaric grafts

FSGS Risk factors for clinically relevant recurrence

• Collapsing FSGS:– Majority - De novo– Higher rate of graft loss

• Secondary & familial FSGS:– Do not recur

FSGS

• Prophylactic plasmapheresis – more effective in preventing recurrence than after transplant

• Children – majority respond • Adults – less effective

FSGS

Plasmapheresis

• Usually- 1yr post transplant• In association with arteriolar hyalinosis• Negative independent predictor of graft

survival• Calcineurin-inhibitor toxicity• Sirolimus

De Novo FSGS

• Overall frequency – 10%-30%• Graft loss – 50% of these pts• Recurrence within 1-2 wks – severe proteinuria• Histology – identical, early cases – EM, IF

Membranous Glomerulonephritis

• Risk factors (Not conclusive) :– Early recurrence & Massive proteinuria-

progress rapidly to graft failure– HLA – Hepatitis B & C, autoimmune dse e.g.

SLE. – Malignancy - lymphoma

Membranous Glomerulonephritis

• Recurrence - 80% - almost 100%• As early as 12 d after surgery• Crescent formation- negative correlation

with graft survival

Membranoproliferative Glomerulonephritis- Type Il ( Dense Deposit Dse)

• Type I- Idiopathic / hepatitis C virus, cryoglobulinemia.

• Recurrence: 36% in HCV +ve, 4% HCV –ve pts• Recurrence as early as 2 wks• 20-50% of pts, proteinuria, usually within 4 yrs• Graft failure – 10-50%

Membranoproliferative Glomerulonephritis- Type I

• Recurrence – 20%-60%• Frequency increases over time • 13% of recurrent cases – recurrence related

allograft dysfunction in 5 yrs• Allograft loss from recurrence – 45%-70%

IgA Nephropathy

• Predictors of clinically relevant recurrence:– Function of time post

transplantation– Young age– Living related – higher risk

of recurrence & graft deterioration

IgA Nephropathy

• Recurrence rate – variable– SLE – 2%-10%– Wegener’s granulomatosis

– 17%– Anti-GBM -Recurrence -

<5% (Anti-GBM titers -ve for 6-12m prior to transplant)

– De novo anti-GBM in Alport dse

Systemic Diseases

How to follow pts with underlying GN after transplant ??

• Obtain exact diagnosis of primary dse wherever possible

• Native kidney biopsy - when not contraindicated

• Closely follow pts. peri- & post-operatively- abnormal lab findings- aggressive work up

• Urinalysis/ visit• Early diagnosis - Biopsy – EM, IF

Recommendations

Investigating Recurrent Disease After Kidney TransplantationRenal biopsy with immunofluorescence and electron microscopy

Cyclosporin A level

Urine microscopy and culture

24-h urine protein

Renal ultrasonogtraphy

Anti-glomerular basement membrane autoantibody and antineutrophil cytoplasm antibody

Cytomegalovirus serology and viral antigen detection

Hepatitis C virus serology and RNA detection

Investigating Recurrent Disease After Kidney Transplantation

Bilateral Pretransplant Native Nephrectomy

• Third cause of allograft loss at 10 yrs• With increasing graft survival- increase risk

of recurrence• Bilateral nephrectomy prior to transplant

does not prevent recurrence

Conclusion

• No specific therapy – except for FSGS • Living related donors – particular attention

– LRD - restricted e.g. FSGS– LRD - discouraged in repeat transplant (rate of

recurrence =>80%)

Conclusion

• B Ianyi. A primer on recurrent and de novo glomerulonephritis in renal allografts. Nat Clin Pract Nephrol, 4(8): 446-457, 2008.

• J Floege. Recurrent glomerulonephritis following renal transplantation. Nephrol Dial Transplant, 18: 1260-1265, 2003.

• E Briganti, G Russ, J McNeil, R Atkins, S Chadban. Risk of renal allograft loss from recurrent glomerulonephritis. N Engl J Med, 347(2): 103-109, 2002.

• S Chadban. Glomerulonephritis recurrence in the renal graft. J Am Soc Nephrol, 12: 394-402, 2001.

• W Chailimpamontree, et al. probability, predictors, and prognosis of posttransplantation glomerulonephritis. J Am Soc Nephrol. 20: 843-851, 2009.

• W Golgert, G Appel, S Hariharan. recurrent glomeruonephritis after renal transplantation: An unsolved problem. Clin J Am Soc Nephrol, 3: 800-807, 2008.

• B Choy, T Chan, K Lai. Recurrent glomerulonephritis after kidney transplantation. Am J Transplant, 6(11): 2535-1542, 2006.

• W Couser. Recurent glomerulonephritis in the renal allograft: an update of selected areas. Exp Clin Transplant, 3(1): 283-288, 2005.

• K Joshi, R Nada, M Minz, V Sakhuja. Recurrent glomerulopathy in the renal allograft.

References