Post Renal Transplant Denovo Membranous Nephropathy

BACKGROUND:

Glomerulonephritis (GN) continues to be one of the main causes of end stage renal disease with an incidence of 10.5% to 38%.[1,2] Post transplant GN can be classified as recurrent, de novo and very rarely donor derived. A recurrent or de novo GN in the renal allograft is an important cause of allograft failure following renal transplantation.[3]

De novo/new-onset disease in a renal transplant is defined as the occurrence of a newly acquired non-rejection related pathologic process affecting the allograft, which differs from the recipient’s original kidney disease. The incidence of de novo GN is up to 10% at 15 years [4]

CASE PRESENTATION:

CASE 1:

A 32-year-old female with a history of rheumatoid arthritis and native kidney IgA nephropathy status post live related renal transplant one year ago was on regular OP follow up. She had 4 years history of IgA nephropathy and developed end stage renal disease in 3 years following initial diagnosis requiring hemodialysis before undergoing renal transplantation. Following transplant she was maintained on triple immunosuppressants. Her creatinine was within normal limits till 2 weeks back when her serum creatinine showed an increasing trend. Her urine routine showed 2+ proteinuria. Ultrasound transplant renal doppler was found to be normal. DSA was negative. In view of elevated serum tacrolimus level (more than 30ng/ml), Tacrolimus was stopped and she was switched to Everolimus. She underwent renal biopsy which showed membranous nephropathy with acute tubular injury.There were no features of rejection. PLA2R and NELL1 staining were found to be negative. She was started on angiotensin receptor blocker.

CASE 2:

A 39-year-old female with history of systemic hypertension, pulmonary tuberculosis and chronic kidney disease, was initiated on hemodialysis at the time of diagnosis. She underwent live related renal transplant with her husband as donor 6 months later and was on regular OP follow up. Her serum creatinine was found to be within normal limits. She presented with history of pedal edema and passing frothy urine for 2 months. She was found to have nephrotic range proteinuria.  Her urine PCR was 6.3 with a serum creatinine of 0.85 mg/dl. Her renal biopsy showed membranous nephropathy. There were no features of rejection, C4d was negative. PLA2R and NELL1 stains were found to be negative. She was started on ACE inhibitor.

DISCUSSION:

De novo membranous nephropathy (MN) is less common, in about 0.3–2.1% of adult transplant cases, where the native kidney diasease is not MN. There is a higher prevalence in pediatric renal transplant recipients. It can either be primary or secondary MN. The reported cases are primarily related to secondary causes which include viral infections, rejection, autoimmune disease, calcineurin inhibitors and thrombotic microangiopathy. [5,6]

The onset can be as early as 1 month post transplantation, with an interval range from 2 months to several years. The symptoms usually range from asymptomatic mild proteinuria and incidental biopsy findings to nephrotic range proteinuria and rapidly progressive GN. [7]

The exact pathogenic mechanism underlying de novo MN has not been clear. The association of chronic antibody-mediated rejection, positive peritubular capillary C4d staining, and donorspecific antibodies has been noted, particularly against HLA-DQ in many of the reported cases. The absence of PLA2R staining within the glomerular deposits suggests a possible link to an alloimmune response to an unknown tissue antigen [8,9]. There is a tendency for increased risk of de novo MN in HCV-positive patients, contributing toward lower graft survival [10]

In developing or early MN, the glomerular capillary wall changes may be minimal and not apparent by light microscopy (LM). Some degree of mesangial thickening and hypercellularity may be noted in about one-third of the cases. These cases are often discovered when a routine immunofluoresence(IF) and electron microscopy are performed on transplant kidney biopsies. A small proportion of cases may show evidence of antibody mediated rejection or early transplant glomerulopathy [11]. IF shows granular glomerular capillary wall staining for deposits of mainly polyclonal IgG and C3. In cases with antibody mediated rejection, there is positive linear C4d staining in the peritubular capillaries. This differs from primary MN by the lack of reactivity to PLA2R antibodies [9]. However, other potential forms of de novo MN (PLA2R, THSD7A, NELL-1, exostosin 1/exostosin 2, semaphorin 3B) could also be considered using specific antibodies that can help classify the underlying etiology [11]. Majority of PLA2R-positive and TSHD-positive cases display IgG4. A variable staining for IgG1 and IgG2 may also be observed along with some IgG4 in a proportion of cases showing other new antigens in MN [11]. The composition of the deposits may vary in case of infection or autoimmune etiology.

The knowledge of native kidney disease, routine urine analysis for proteinuria and hematuria and appropriate serologic testing are essential for a proper diagnosis of de novo diseases in renal transplants. A transplant renal biopsy subjected to LM, IF and EM is considered as the gold standard. The histologic findings might be modified due to immunosuppressive medication and other donor and recipient characteristics.

REFERENCES:

1. Allen P.J., Chadban S.J., Craig J.C., Lim W.H., Allen R.D.M., Clayton P.A., Teixeira-Pinto A., Wong G. Recurrent glomerulonephritis after kidney transplantation: Risk factors and allograft outcomes. Kidney Int. 2017;92:461–469. doi: 10.1016/j.kint.2017.03.015.
2. ByrneC,CaskeyF,Castledine C, Davenport A, Dawnay A,Fraser S, et al. UK renal registry: 20th annual report of the renal association. Nephron. (2018) 139(Suppl. 1):490958. doi: 10.1159/000490958
3. El-ZoghbyZM,StegallMD,LagerDJ,KremersWK,AmerH,GloorJM,etal. Identifying specific causes of kidney allograft loss. Am J Transplant. (2009) 9:527–35. doi: 10.1111/j.1600-6143.2008.02519
4. Ponticelli C, Moroni G, Glassock RJ. De novo glomerular diseases after renal transplantation. Clin J Am Soc Nephrol. 2014; 9(8): 147987.
5. Sethi S, Fervenza FC. Membranoproliferative glomerulonephritisa new look at an old entity. N Engl J Med. (2012) 366:1119–31. doi: 10.1056/NEJMra1108178 .
6. Sethi S, Fervenza FC. Standardized classification and reporting of glomerulonephritis. Nephrol Dial Transplant. (2019) 34:193–9. doi: 10.1093/ndt/gfy220
7. Ponticelli C, Glassock RJ. Posttransplant recurrence of primary glomerulonephritis. Clin J Am Soc Nephrol. (2010) 5:2363–72. doi: 10.2215/CJN.06720810
8. Batal I, Vasilescu ER, Dadhania DM, Adel AA, Husain SA, Avasare R, et al. Association of HLA typing and alloimmunity with posttransplantation membranous nephropathy:  a multicenter case series. Am J Kidney Dis. 2020; 76(3): 374–83.

9. Larsen CP, Walker PD. Phospholipase A2 receptor (PLA2R) staining is useful in the determination of de novo versus recurrent membranous glomerulopathy. Transplantation. 2013; 95(10): 1259–62.
10. Cruzado JM, Carrera M, Torras J, Grinyó JM. Hepatitis C virus infection and de novo glomerular lesions in renal allografts. Am J Transplant. 2001; 1: 171–8.
11. Wavamunno MD, O’Connell PJ, Vitalone M, Fung CL, Allen RD, Chapman JR, et al. Transplant glomerulopathy:  ultrastructural abnormalities occur early in longitudinal analysis of protocol biopsies. Am J Transplant. 2007; 7(12): 2757–68. 6 Royal V, Zee J, Li.

Dr. Yashilha D
Nephrology PG Resident
Kauvery Hospital, Chennai

Dr. R. Balasubramaniyam
Chief Nephrologist
Kauvery Hospital, Chennai

Dr. Balaji Kirushnan
Nephrologist
Kauvery Hospital, Chennai