De novo membranous nephropathy (MN) in kidney allografts. A peculiar form of alloimmune disease?

De novo membranous nephropathy (MN) is an uncommon complication of kidney transplantation, which shows histological findings similar to those seen in recurrent MN, but with some distinct differences. The clinical presentation may be variable, from asymptomatic to nephrotic proteinuria. The disease may run an indolent course or may have an accelerated course leading to allograft loss. De novo membranous nephropathy (MN) can develop in transplant recipients with viral hepatitis, Alport syndrome, ureteral obstruction, renal infarction, or in conjunction with recurrent IgA nephritis. Histologic signs of allograft rejection are often associated with or can antedate de novo MN. These findings suggest that donor‐specific antibodies and antibody‐mediated rejection might play a pathogenetic role in some patients with de novo MN. However, signs of rejection were absent in a number of cases, and in some instances the disease developed in recipients of “full house” HLA‐ matched kidneys. Thus, it seems possible that de novo MN is not because of allograft rejection per se, but is triggered by different injuries that can create an inflammatory environment, activate innate immunity, and expose hidden (cryptic) antigens, probably different from those observed to be involved in idiopathic MN. These events can lead to the production of circulating antibodies and in situ formation of immune complexes (IC) and the morphological lesion of MN.     

Preemptive Plasmapheresis and Recurrence of FSGS in High-Risk Renal Transplant Recipients

Recurrent focal segmental glomerulosclerosis (FSGS) following transplantation is ascribed to the presence of a circulating FSGS permeability factor (FSPF). Plasmapheresis (PP) can induce remission of proteinuria in recurrent FSGS. This study addressed the efficacy of pre-transplant PP in decreasing the incidence of recurrence in high-risk patients. Ten patients at high-risk for FSGS recurrence because of rapid progression to renal failure (n = 4) or prior transplant recurrence of FSGS (n = 6) underwent a course of 8 PP treatments in the peri-operative period. Recurrences were identified by proteinuria >3 g/day and confirmed by biopsy. Seven patients, including all 4 with first grafts and 3 of 6 with prior recurrence, were free of recurrence at follow-up (238-1258 days). Final serum creatinine in 8 patients with functioning kidneys averaged 1.53 mg/dL. FSGS recurred within 3 months in 3 patients, each of whom had lost prior transplants to recurrent FSGS. Two of these progressed to end-stage renal disease (ESRD) and the third has significant renal dysfunction. Based on inclusion criteria, recurrence rates of 60% were expected if no treatment was given. Therefore, PP may decrease the incidence of recurrent FSGS in high-risk patients. Definitive conclusions regarding optimal management can only be drawn from larger, randomized, controlled studies.     

Recurrence of IgA nephropathy in renal transplants

SUMMARY: The present article provides an update from the literature on the clinical significance of recurrent IgA disease in renal transplant patients, and it identifies possible reasons for the differences between the data that have been published. the clinical features of recurrent IgA nephropathy are described here, along with suggestions for the management of these patients.     

Treatment of symptomatic transplant glomerulopathy with rituximab

Kidney transplant glomerulopathy (TG) has a poor outcome as there are no known effective therapies. Therefore, we investigated whether rituximab therapy (RTx) could halt progression of established TG. Fourteen kidney-transplant patients (nine of whom were men), with median age of 54 (range: 30–74) years, of whom seven had biologic markers for HCV infection, underwent a kidney biopsy (KB) at 118 months post-transplant because of impaired allograft function, associated with albuminuria (95–13430 mg/day), within nephrotic-range albuminuria in seven patients. KBs showed no evidence of acute cellular rejection but showed TG. Donor-specific anti-HLA antibodies were present in six cases. When diagnosis of TG was made, patients were placed on rituximab therapy (RTx) (2–4 injections of 375 mg/m² week), and other concurrent immunosuppression treatments were not modified. By last follow up post-RTx (30 months), seven (50%) patients had lost their kidney within 6–26 months and the other seven had stable creatinine (182 vs. 161 μmol/l; NS), and albuminuria had decreased from 2660 to 500 mg/day ( P  = 0.03). There was prolonged B-cell lymphopenia (from 71 to 0/mm³) whereas immunoglobulin G, A, M levels remained stable, and four patients (28.5%) experienced severe infectious complications. We conclude that long-term RTx in kidney-transplant patients with TG is associated with allograft function/stabilization in 50% of cases.     

Glomerulonephritis is the major cause of proteinuria in renal transplant recipients: histopathologic findings of renal allografts with proteinuria

The proteinuria in renal allograft recipients has been regarded as a sign of poor prognosis. The causes of post-transplant proteinuria include chronic rejection, chronic transplant glomerulopathy, glomerulonephritis (GN), acute rejection, and cyclosporine nephrotoxicity. Among them, chronic rejection is known to be most frequent. We analyzed the histopathologic findings of renal allograft biopsies in 197 Korean recipients with proteinuria. Among them, 26 patients developed proteinuria over 500 mg/d. All patients received baseline immunosuppression with cyclosporine. From 26 patients with post-transplant proteinuria, 29 biopsies were performed and their histologic diagnoses were immunoglobulin A nephropathy (IgAN) in 17, IgAN combined with chronic allograft nephropathy in 1, focal segmental glomerulosclerosis in 2, crescentic GN in 1, membranous GN in 1, diabetic nephropathy in 1, acute tubulointerstitial nephritis in 1, and chronic rejection in 3 biopsies. The remaining two biopsies showed nonspecific findings. The most common cause of post-transplant proteinuria was IgAN (62% of biopsies). The incidence of chronic rejection was relatively low and predominant cyclosporine-associated changes were not observed. In conclusion, our data suggest that the main causes of post-transplant proteinuria in Korea are primary glomerulonephritides rather than chronic rejection or cyclosporine nephrotoxicity, and the kidney allograft biopsies from patients with proteinuria should be handled as native kidney.     

Clinical Features and Histology of Apolipoprotein L1-Associated Nephropathy in the FSGS Clinical Trial

Genetic variants in apolipoprotein L1 (APOL1) confer risk for kidney disease. We sought to better define the phenotype of APOL1-associated nephropathy. The FSGS Clinical Trial involved 138 children and young adults who were randomized to cyclosporin or mycophenolate mofetil plus pulse oral dexamethasone with a primary outcome of proteinuria remission. DNA was available from 94 subjects who were genotyped for APOL1 renal risk variants, with two risk alleles comprising the risk genotype. Two APOL1 risk alleles were present in 27 subjects, of whom four subjects did not self-identify as African American, and 23 of 32 (72%) self-identified African Americans. Individuals with the APOL1 risk genotype tended to present at an older age and had significantly lower baseline eGFR, more segmental glomerulosclerosis and total glomerulosclerosis, and more tubular atrophy/interstitial fibrosis. There were differences in renal histology, particularly more collapsing variants in those with the risk genotype (P=0.02), although this association was confounded by age. APOL1 risk genotype did not affect response to either treatment regimen. Individuals with the risk genotype were more likely to progress to ESRD (P<0.01). In conclusion, APOL1 risk genotypes are common in African-American subjects with primary FSGS and may also be present in individuals who do not self-identify as African American. APOL1 risk status is associated with lower kidney function, more glomerulosclerosis and interstitial fibrosis, and greater propensity to progress to ESRD. The APOL1 risk genotype did not influence proteinuria responses to cyclosporin or mycophenolate mofetil/dexamethasone.     

Recurrence of Scedosporium Apiospermum Infection Following Renal Re-Transplantation

Immunosuppression for organ transplantation results in increased susceptibility to opportunistic infections including fungal, such as Scedosporium apiospermum. Even though many reported cases of this infection had both local and systemic manifestations, majority of the systemic infections had a fatal outcome. We report a case of a 50-year-old Caucasian male with lymphocutaneous and presumed pulmonary Scedosporium infection 4 years after renal transplantation that was successfully treated with voriconazole and discontinuation of immunosuppression. He received a second transplant 3 years later in the absence of clinical evidence of S. apiospermum infection. Unfortunately, 4 months after transplantation he developed recurrence of the same infection localizing to the soft tissues. Presently this infection is under control with surgical excision and voriconazole therapy. To our knowledge this is the first reported case of recurrent S. apiospermum infection in a renal transplant recipient. We suggest prophylactic antifungal therapy in all re-transplants with this infection.     

Treatment of idiopathic membranoproliferative glomerulonephritis with mycophenolate mofetil and steroids.

BACKGROUND: Treatment of adults with idiopathic membranoproliferative glomerulonephritis (IMPGN) is often unrewarding with approximately 60% of patients progressing to end-stage renal failure within 10 years. Although children with IMPGN may respond to steroid therapy, there is no significant benefit to treating adult IMPGN patients with immunosuppression. METHODS: Outcome measures in five patients with IMPGN who were treated with oral prednisolone and mycophenolate mofetil (MMF) (treatment group) were compared with six patients with IMPGN who did not receive immunosuppression (control group). RESULTS: There was no significant difference between either group in baseline clinical characteristics or systolic and diastolic blood pressure during observation. In the treatment group, there was a significant reduction in proteinuria from a baseline of 5.09 to 1.97 g/24 h (P = 0.003) at 6 months, 1.96 g/24 h (P = 0.003) at 12 months and 2.59 g/24 h (P = 0.015) at 18 months. There was no significant change in proteinuria over 18 months in the control group. Serum creatinine concentration and creatinine clearance did not change significantly over 18 months in the treatment group. In the control group, there were significant changes in serum creatinine and creatinine clearance over 18 months [baseline 103 to 159 micromol/l (P = 0.004) and baseline 108 to 67 ml/min (P > 0.001), respectively] when compared to baseline, although the differences were not significant when the two groups were compared directly. CONCLUSIONS: This preliminary study suggests that in the short term, the combination of MMF and prednisolone can significantly reduce proteinuria and may preserve renal function in patients with IMPGN.     

Renal transplant outcomes in primary FSGS compared with other recipients and risk factors for recurrence: A national review of the Irish Transplant Registry

Introduction

Primary focal segmental glomerular sclerosis (p‐FSGS) is commonly complicated by recurrence (r‐FSGS) post‐transplantation. Our objective was to describe Irish outcomes for transplantation after end‐stage renal disease (ESRD) due to p‐FSGS, specifically rates of, and treatments for, r‐FSGS.

Patients and Methods

Irish patients with biopsy‐proven FSGS were identified from the Irish National Kidney Transplant database (1982‐2015). Medical record review was performed to identify predictors of r‐FSGS and treatments for r‐FSGS. Transplant outcomes were compared to outcomes in all renal transplants performed during the same time period using registry data. Demographic and clinical predictors of r‐FSGS were identified. Statistical analysis was performed using Stata (version 13, College Station, TX, USA).

Results

Thirty‐eight transplant recipients had biopsy‐proven p‐FSGS, 16 received a second transplant. A total of 3846 transplants formed the comparator group. r‐FSGS complicated 60.5% (23/38) of first transplants. Eighty‐six percent (10/12) of patients with previous r‐FSGS developed recurrent disease after further transplantation. Patients with p‐FSGS receiving a first renal transplant had higher rate of graft failure than those with another cause of ESRD (HR 1.9, 95% CI 1.152‐3.139). Sixteen patients received immunotherapy for r‐FSGS; 12 (86%) had at least partial response, but two (14%) developed significant complications.

Discussion

We demonstrate high rates of r‐FSGS and describe modest success from with treatments for r‐FSGS.     

A randomized,controlled double-blind study comparing the efficacy and safety of dose-ranging voclosporin with placebo in achieving remission in patients with active lupus nephritis

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De novo membranoproliferative glomerulonephritis III in a renal transplant patient: case report and review of the literature

Idiopathic membranoproliferative glomerulonephritis (MPGN) is a rare cause of renal failure with a cumulative incidence of 0.3% of all ESRD and 4% of all primary glomerulonephritis for types I and II. Membranoproliferative glomerulonephritis type III is more uncommon and idiopathic de novo MPGN III in a renal transplant patient has not been reported. We present the case of a 57-year old white female patient with a diagnosis of lithium toxicity as cause of end stage renal disease (ESRD) who developed MPGN III in her allograft 6 years after a renal transplant. Despite treatment, she progressed to ESRD within four and a half years from the time of diagnosis.     

Treatment of Parvovirus B-19 (PV B-19) Infection Allows for Successful Kidney Transplantation Without Disease Recurrence

Parvovirus B 19 (PV-B19) has emerged as a cause of glomerulopathy in native and transplanted kidneys. Disease recurrence is less well described. The clinical and pathological spectrum of PV-B19 infection can be quite variable and therefore easily missed. There are no data regarding the safety of transplantation in PV-B19-infected patients. We diagnosed a kidney transplant patient with recurrent PV-B19 infection and collapsing glomerulopathy (CG) on renal biopsy. Retrospective analysis of stored serum showed that PV-B19 DNA was present prior to the transplant. The patient was treated with intravenous immunoglobulin (IVIG), and eventually the virus was successfully eradicated after allograft loss and discontinuation of immunosuppressive medications. The patient subsequently received her fourth kidney transplant. Polymerase chain reaction (PCR) for PV-B19 DNA was negative on multiple occasions for approximately 1 year prior to her transplant. The patient is now 22 months post transplantation, quarterly serum PCRs continue to be negative for PV-B19 DNA despite reinstitution of immunosuppressive therapy. The patient's renal function remains stable with a serum creatinine of 0.9 mg/dL and a serum albumin of 4.2 g/dL. Successful diagnosis and treatment of PV-B19 viremia appears to allow for successful transplantation without evidence of disease recurrence. Since PV-B19 can cause significant morbidity post transplant, it is important to screen potential transplant candidates at risk for PV-B19 infection pre transplant. Careful surveillance post transplantation is necessary to identify disease recurrence so that early treatment can be initiated.     

Individualized scheme of immunoadsorption for the recurrence of idiopathic focal segmental glomerulosclerosis in the graft: a single center experience

Abstract

Objectives: To explore the role of immunoadsorption (IA) for the treatment of idiopathic focal segmental glomerulosclerosis (FSGS) recurrence in the renal allograft, if applied in a personalized manner. Methods: We studied patients with end-stage renal disease (ESRD) due to idiopathic FSGS, transplanted between 2001 and 2010. Patients with FSGS recurrence were treated with daily sessions of IA for the first week, followed by an every other day scheme and then individualized tapering until discontinuation. Complete remission was defined as a reduction of 24-h proteinuria to ≤0.5?g/day and partial remission as a reduction of 24-h proteinuria to 50% or more from baseline. Results: Of the 18 renal transplant recipients with ESRD due to idiopathic FSGS, 12 (66.7%) experienced disease recurrence in a mean time of 0.75 months post-transplantation (KTx), with a mean proteinuria of 8.9?g/day at the time of recurrence. The mean recipient age was 30.8 years; the mean donor age was 47.4 years, while living related donors provided the allograft in seven cases. Four of the patients received therapy with rituximab in addition to IA. During a mean time of follow-up of 48.3 months, seven patients (58.3%) achieved complete remission, and five (41.7%) partial remission. At the end of follow-up, eight patients (66.7%) had functioning grafts, being in sustained remission, in contrast to four patients (33.3%), who ended up in ESRD because of FSGS recurrence. Conclusions: IA was shown efficacious in a small series of patients with recurrent FSGS in the graft. Renal function remained stable in eight of the 12 patients with FSGS recurrence.     

Use of the urinary protein creatinine index to assess proteinuria in renal transplant patients.

The use of 24-h urine protein collections for the assessment of proteinuria in renal transplant patients has been compared with the protein creatinine index (PCI) obtained from spot urine samples. Paired data from 148 patients showed a correlation of 0.77 (P less than 0.001) between 24-h protein excretion and the PCI. A PCI of 750 identified proteinuria of greater than 1.0 g/24 h with a sensitivity of 89% and a specificity of 93%. The predictive value of a positive test was 81% and that of a negative test 96%. Similar performance was observed for the detection of proteinuria of differing severities ranging from 0.5 g/24 h to 2.0 g/24 h. The use of spot testing was popular with both patients and staff, and reduced the sample handling cost to 15% of that of 24-h urine collection. We recommend that PCI be adopted as the standard outpatient test for the assessment of proteinuria following renal transplantation.     

The relationship between proteinuria and allograft survival in patients with transplant glomerulopathy: a retrospective single-center cohort study

Proteinuria and transplant glomerulopathy (TG) are common in kidney transplantation. To date, there is limited knowledge regarding proteinuria in different types of TG and its relationship to allograft survival. A retrospective cohort analysis of TG patients from indication biopsies was performed to investigate the relationship of proteinuria, histology, and graft survival. One hundred and seven (57.5%) out of 186 TG patients lost their grafts with a median survival of 14 [95% confidence interval (CI) 10–22] months after diagnosis. Proteinuria ≥1 g/24 h at the time of biopsy was detected in 87 patients (46.8%) and the median of proteinuria was 0.89 (range 0.05–6.90) g/24 h. TG patients with proteinuria ≥1 g/24 h had worse 5-year graft survival (29.9% vs. 53.5%, P = 0.001) compared with proteinuria <1 g/24 h. Proteinuria was associated with graft loss in univariable Cox regression [hazard ratio (HR) 1.25, 95% CI, 1.11–1.41, P < 0.001], and in multivariable analysis (adjusted HR 1.26, 95% CI 1.11–1.42, P < 0.001) independent of other risk factors including creatinine at biopsy, positive C4d, history of rejection, and Banff lesion score mesangial matrix expansion. In this cohort of TG patients, proteinuria at indication biopsy is common and associated with a higher proportion of graft loss.     

Angiotensin-converting enzyme inhibition in experimental in-situ immune complex glomerulonephritis: influence on renal function, proteinuria, and morphology

BACKGROUND: Converting enzyme inhibition (CEI) ameliorates progressive lossof function in non-immune-mediated renal diseases and experimentalhypertension. Little, however, is known on the potential roleof CEI in established experimental chronic glomerular immuneinjury. We therefore studied the effect of the CEI ramiprilon renal function and morphology in a model of immune mediatedglomerular injury. METHODS: The immune complex glomerulonephritis was induced in uninephrectomizedrats by intrarenal perfusion with the cationized antigen followedby an intravenous application of the antibody. This diseaseis characterized by the development of progressive albuminuriaand a nephrotic syndrome (albuminuria: immune complex glomerulonephritis342±58, control 76±18 mg/24 h; P<0.001). TheCEI by ramipril, dissolved in the drinking water, was given28 weeks after induction of the disease and treatment was continuedfor 12 weeks. RESULTS: In these experiments ramipril significantly reduced albuminexcretion (immune complex glomerulonephritis+CEI 109±16mg/24 h; P<0.01) when compared with untreated nephritic rats.Ramipril, however, did not significantly change inulin clearances(immune complex glomerulonephritis 224±67, immune complexglomerulonephritis+CEI 278±48 µ1/min/100 g bw).Glomerular structural damage expressed as glomerular damageindex was significantly greater in rats with immune complexglomerulonephritis when compared with controls (immune complexglomerulonephritis 0.91±0.13; control 0.60±0.08;P<0.05), but was uneffected by the treatment with the CEI(immune complex glomerulonephritis+CEI 1.02±0.26; control+CEI0.63±0.11). CONCLUSIONS: These data demonstrate that ramipril reduced albuminuna in amodel of immune complex glomerulonephritis; however, it failedto alter GFR and glomerular damage index. The study suggeststhat ramipril ameliorates proteinuria independently of obviousglomerular histological changes. The reduction of proteinuriais, however, associated with a significant decrease in filtrationfraction and therefore is at least partially haemodynamicallymediated.