The challenge in diagnosing de novo minimal change disease after transplantation.

Abstract

A 24-year-old man with end-stage kidney disease (ESKD) secondary to renal coloboma syndrome received an en bloc kidney transplant from a 5-month-old donor. He was induced with thymoglobulin and discharged on tacrolimus, mycophenolate mofetil, and prednisone. Three months later, he was without complaint, had a creatinine of 1.4 mg/dL, and urine protein creatinine ratio (UPCR) of 5.7. He tested negative for hepatitis B, hepatitis C, and human immunodeficiency viruses. A kidney biopsy revealed immature-appearing glomeruli with moderate mesangial matrix expansion and focal mesangial hypercellularity. There was no interstitial inflammation and minimal interstitial fibrosis or tubular atrophy. Immunofluorescence examination was negative for immunoglobulins or complement deposits. Ultrastructural evaluation showed diffuse epithelial foot process effacement and podocyte injury. There were no electron dense deposits. Tubuloreticular inclusions were noted (Figure 1), because of which he underwent polymerase chain reaction testing for cytomegalovirus, BK virus and Epstein-Barr virus, all of which were negative. He was diagnosed to have de novo minimal change disease (MCD) and treated with prednisone 1 mg/kg daily and lisinopril 5 mg daily. Eight weeks later, his UPCR was 0.5, and prednisone was tapered over the next 2 months. His UPCR further decreased to 0.1. Twenty months after the diagnosis his UPCR is 0.1 and creatinine 0.9 mg/dL.FIGURE 1: Electron microscopic image showing diffuse epithelial foot process effacement (arrow) and tubuloreticular inclusions (arrowhead).Minimal change disease is characterized by the clinical picture of nephrotic syndrome without a reduction in glomerular filtration rate where a kidney biopsy shows normal glomeruli on light microscopy (or only minimal mesangial prominence), negative or low-level staining for C3, immunoglobulin M staining on immunofluorescence microscopy, and diffuse foot process effacement on electron microscopy.1 It was hypothesized to be caused by a secreted factor resulting from systemic T-cell dysfunction that damages the glomerular basement membrane.2 Some recent studies have suggested that podocyte expression of B7-1(CD-80) may cause MCD. Lipopolysaccharide-induced proteinuria is associated with podocyte B7-1 expression, and proteinuria is prevented in mice lacking B7-1.3 Urinary CD 80 is increased in humans with MCD when compared with those with other glomerular diseases and controls.4-6 Other recent studies have suggested that podocyte overexpression of angiopoietin-like 4 recapitulates many cardinal features of MCD.7 Diagnosing MCD in the renal allograft can be challenging because it has no distinguishing features, but is to be considered under certain circumstances. First, it has to be thought of in the appropriate clinical setting of nephrotic syndrome and a characteristic kidney biopsy as described above. Second, if the response to treatment of posttransplant MCD is similar to that in native disease, then one would predict a remission rate of 80% with high-dose steroids alone.8,9 Thus, sustained complete remission of proteinuria in the setting of minimal light microscopic findings argues strongly for a diagnosis of MCD. Third, MCD generally does not progress histologically and lead to ESKD. Appel et al8 showed that among 95 patients with MCD, only 4 progressed to ESKD and 3 of them had a repeat renal biopsy demonstrating focal segmental glomerulosclerosis (FSGS). The relationship between MCD and primary FSGS has remained controversial. Some have considered the two as a continuum of one disease whereas others consider them separate. The reason for the progression of MCD to FSGS has been assumed to be related to sampling error from a limited specimen containing superficial glomeruli where early changes of FSGS may not be seen. Separately, it is well recognized that FSGS has a high rate of recurrence after transplantation and early in its clinical course is histologically indistinguishable from MCD.10,11 Thus, it is important that the possibility of recurrent FSGS in the clinical scenario of heavy proteinuria after transplantation with minimal light microscopic findings be considered. The response rate of posttransplant MCD to high-dose steroids is unknown, but in the absence of data to the contrary, there is no reason to believe that it will respond differently from native kidney MCD. Focal segmental glomerulosclerosis, which rapidly recurs after a kidney transplantation, does not respond well to standard therapies. Only 63% of adults with recurrent FSGS who received plasmapheresis entered complete or partial remission.11 Focal segmental glomerulosclerosis is usually progressive in nonresponders, and a repeat biopsy is likely to show the classic light microscopic features of segmental sclerosis, eliminating MCD from further consideration. Perhaps patients with apparent FSGS defined only by early proteinuria and foot process effacement, who appear to respond readily to steroids, cytotoxic therapy, or plasmapheresis, may actually have MCD, especially if they do not have a history of FSGS. Corticosteroid therapy leads to complete remission in over 80% of adults with MCD.8,9 The optimal duration of therapy is unknown, though it is currently recommended to treat for 16 weeks before declaring a patient to have steroid resistance.12 Agents used in the treatment of steroid resistant MCD include cyclophosphamide, cyclosporine, tacrolimus and mycophenolate mofetil.12 Recent literature has reported on the use of abatacept, an inhibitor of B7-1, in the treatment of patients with FSGS and MCD. In some reports, partial or complete remission of proteinuria was seen in FSGS and MCD,13,14 whereas in others, abatacept had no impact on proteinuria.14,15 Zafarmand et al16 describe 5 cases of de novo MCD after transplant and review a further 9 cases in literature. They demonstrate that there is no specific primary renal disease that predisposes the graft to de novo MCD. Out of the 14 cases, 12 achieved remission of proteinuria (9 within a year). Of the remaining 2, 1 died of septic shock 2 months after onset of MCD, and the other achieved partial remission though the follow-up was for only 9 weeks. Follow-up of their 5 cases revealed that de novo MCD had no long-term adverse effect on the allograft. The true incidence of de novo MCD after kidney transplant is unknown and reportedly rare.17 This may be due to the routine exposure of transplant patients to immunosuppressive agents that are commonly used as therapeutic agents for MCD. We also believe that patients labeled as FSGS without its light microscopic features, who respond readily to steroids or plasmapheresis and do not progress to CKD, may have MCD rather than FSGS. Because the standard approach to posttransplant FSGS is plasmapheresis rather than high-dose steroids, some cases of true MCD may be missed. In patients without a clear diagnosis of FSGS in their native kidneys, whose posttransplant proteinuria is associated with normal glomerular filtration rate and minimal light microscopic findings, the diagnosis of MCD should be considered. Whether urinary CD80 can be used as a biomarker for the diagnosis of posttransplant MCD is not known.