Posttransplantation membranous nephropathy (MN) represents a rare complication of kidney transplantation that can be classified as recurrent or de novo. The clinical, pathologic, and immunogenetic ...characteristics of posttransplantation MN and the differences between de novo and recurrent MN are not well understood.
Multicenter case series.
We included 77 patients from 5 North American and European medical centers with post–kidney transplantation MN (27 de novo and 50 recurrent). Patients with MN in the native kidney who received kidney allografts but did not develop recurrent MN were used as nonrecurrent controls (n = 43). To improve understanding of posttransplantation MN, we compared de novo MN with recurrent MN and then contrasted recurrent MN with nonrecurrent controls.
Compared with recurrent MN, de novo MN was less likely to be classified as primary MN (OR, 0.04; P < 0.001) and had more concurrent antibody-mediated rejection (OR, 12.0; P < 0.001) and inferior allograft survival (HR for allograft failure, 3.2; P = 0.007). HLA-DQ2 and HLA-DR17 antigens were more common in recipients with recurrent MN compared with those with de novo MN; however, the frequency of these recipient antigens in recurrent MN was similar to that in nonrecurrent MN controls. Among the 93 kidney transplant recipients with native kidney failure attributed to MN, older recipient age (HR per each year older, 1.03; P = 0.02), recipient HLA-A3 antigen (HR, 2.5; P = 0.003), steroid-free immunosuppressive regimens (HR, 2.84; P < 0.001), and living related allograft (HR, 1.94; P = 0.03) were predictors of MN recurrence.
Retrospective case series, limited sample size due to rarity of the disease, nonstandardized nature of data collection and biopsies.
De novo and recurrent MN likely represent separate diseases. De novo MN is associated with humoral alloimmunity and guarded outcome. Potential predisposing factors for recurrent MN include recipients who are older, recipient HLA-A3 antigen, steroid-free immunosuppressive regimen, and living related donor kidney.
Genetic variation at the MYH9 locus is linked to the high incidence of focal segmental glomerulosclerosis (FSGS) and non-diabetic end-stage renal disease among African Americans. To further define ...risk alleles with FSGS we performed a genome-wide association analysis using more than one million single-nucleotide polymorphisms in 56 African-American and 61 European-American patients with biopsy-confirmed FSGS. Results were compared to 1641 European Americans and 1800 African Americans as unselected controls. While no association was observed in the cohort of European Americans, the case–control comparison of African Americans found variants within a 60kb region of chromosome 22 containing part of the APOL1 and MYH9 genes associated with increased risk of FSGS. This region spans different linkage disequilibrium blocks, and variants associating with disease within this region are in linkage disequilibrium with variants which have shown signals of natural selection. APOL1 is a strong candidate for a gene that has undergone recent natural selection and is known to be involved in the infection by Trypanosoma brucei, a parasite common in Africa that has recently adapted to infect human hosts. Further studies will be required to establish which variants are causally related to kidney disease, what mutations caused the selective sweep, and to ultimately determine if these are the same.
C3 glomerulopathy and idiopathic Ig-associated membranoproliferative GN are kidney diseases characterized by abnormal glomerular complement C3 deposition. These conditions are heterogeneous in ...outcome, but approximately 50% of patients develop kidney failure within 10 years.
To improve identification of patients with poor prognosis, we performed a detailed analysis of percutaneous kidney biopsies in a large cohort of patients. Using a validated histologic scoring system, we analyzed 156 native diagnostic kidney biopsies from a retrospective cohort of 123 patients with C3 glomerulopathy and 33 patients with Ig-associated membranoproliferative GN. We used linear regression, survival analysis, and Cox proportional hazards models to assess the relationship between histologic and clinical parameters with outcome.
Frequent biopsy features were mesangial expansion and hypercellularity, glomerular basement membrane double contours, and endocapillary hypercellularity. Multivariable analysis showed negative associations between eGFR and crescents, interstitial inflammation, and interstitial fibrosis/tubular atrophy. Proteinuria positively associated with endocapillary hypercellularity and glomerular basement membrane double contours. Analysis of second native biopsies did not demonstrate associations between immunosuppression treatment and improvement in histology. Using a composite outcome, risk of progression to kidney failure associated with eGFR and proteinuria at the time of biopsy, cellular/fibrocellular crescents, segmental sclerosis, and interstitial fibrosis/tubular atrophy scores.
Our detailed assessment of kidney biopsy data indicated that cellular/fibrocellular crescents and interstitial fibrosis/tubular atrophy scores were significant determinants of deterioration in kidney function.
Fibrillary and immunotactoid glomerulonephritis: Distinct entities with different clinical and pathologic features.
Controversy surrounds the relatedness of fibrillary glomerulonephritis (FGN) and ...immunotactoid glomerulonephritis (IT).
To better define their clinicopathologic features and outcome, we report the largest single center series of 67 cases biopsied from 1980 to 2001, including 61 FGN and 6 IT. FGN was defined by glomerular immune deposition of Congo red–negative randomly oriented fibrils of < 30 nm (mean, 20.1 ± 0.4 nm). IT was defined by glomerular deposition of hollow, stacked microtubules of ≥ 30 nm (mean, 38.2 ± 5.7 nm).
FGN comprised 0.6% of total native kidney biopsies and IT was tenfold more rare (0.06%). Deposits in FGN were immunoglobulin G (IgG) dominant and polyclonal in 96%. IgG subtype analysis in 19 FGN cases showed monotypic deposits in four (two IgG1 and two IgG4) and oligotypic deposits in 15 (all combined IgG1 and IgG4). In IT, deposits were IgG dominant in 83% and monoclonal in 67% (three IgG1κ and one IgG1λ). FGN patients were a mean age of 57 years, 92% were Caucasian, and 39% were male. At biopsy, FGN patients had the following clinical characteristics (mean, range): creatinine 3.1 mg/dL (0.5 to 14), proteinuria 6.5 g/day (0.8 to 25), 60% microhematuria, and 59% hypertension. Histologic patterns of FGN were diverse, including diffuse proliferative glomerulonephritis (DPGN) (nine cases), membranoproliferative glomerulonephritis (MPGN) (27 cases), mesangial proliferative/sclerosing (MES) (13), membranous glomerulonephritis (MGN) (four), and diffuse sclerosing (DS) (eight). The more proliferative (MPGN and DPGN) and sclerosing (DS) forms presented with a higher creatinine and greater proteinuria compared to MES and MGN. Median time to end-stage renal disease (ESRD) was 24.4 months for FGN and mean time to ESRD varied by histologic subtype: DS 7 months, DPGN 20 months, MPGN 44 months, compared to MES 80 months and MGN 87 months. There was no statistically significant effect of immunosuppressive therapy (given to 36% of FGN patients). By Cox regression (hazard ratio, confidence interval, P value), independent predictors of progression to ESRD were creatinine at biopsy 2.05 (1.55 to 2.72) P < 0.001 and severity of interstitial fibrosis 2.01 (1.05 to 3.85) P = 0.034. Although IT had similar presentation, histologic patterns, and outcome compared to FGN, it had a greater association with monoclonal gammopathy (P = 0.014), underlying lymphoproliferative disease (P = 0.020), and hypocomplementemia (P = 0.032).
FGN is an idiopathic condition characterized by polyclonal immune deposits with restricted gamma isotypes. Most patients present with significant renal insufficiency and have a poor outcome despite immunosuppressive therapy, and outcome correlates with histologic subtype. By contrast, IT often contains monoclonal IgG deposits and has a significant association with underlying dysproteinemia and hypocomplementemia. Differentiation of FGN from the much more rare entity IT appears justified on immunopathologic, ultrastructural, and clinical grounds.
The GFR slope has been evaluated as a surrogate end point for kidney failure in meta-analyses on a broad collection of randomized controlled trials (RCTs) in CKD. These analyses evaluate how ...accurately a treatment effect on GFR slope predicts a treatment effect on kidney failure. We sought to determine whether severity of CKD in the patient population modifies the performance of GFR slope.
We performed Bayesian meta-regression analyses on 66 CKD RCTs to evaluate associations between effects on GFR slope (the chronic slope and the total slope over 3 years, expressed as mean differences in ml/min per 1.73 m2/yr) and those of the clinical end point (doubling of serum creatinine, GFR <15 ml/min per 1.73 m2, or kidney failure, expressed as a log-hazard ratio), where models allow interaction with variables defining disease severity. We evaluated three measures (baseline GFR in 10 ml/min per 1.73 m2, baseline urine albumin-to-creatinine ratio UACR per doubling in mg/g, and CKD progression rate defined as the control arm chronic slope, in ml/min per 1.73 m2/yr) and defined strong evidence for modification when 95% posterior credible intervals for interaction terms excluded zero.
There was no evidence for modification by disease severity when evaluating 3-year total slope (95% credible intervals for the interaction slope: baseline GFR -0.05 to 0.03; baseline UACR -0.02 to 0.04; CKD progression rate -0.07 to 0.02). There was strong evidence for modification in evaluations of chronic slope (95% credible intervals: baseline GFR 0.02 to 0.11; baseline UACR -0.11 to -0.02; CKD progression rate 0.01 to 0.15).
These analyses indicate consistency of the performance of total slope over 3 years, which provides further evidence for its validity as a surrogate end point in RCTs representing varied CKD populations.
Actionable genetic findings have implications for care of patients with kidney disease, and genetic testing is an emerging tool in nephrology practice. However, there are scarce data regarding best ...practices for return of results and clinical application of actionable genetic findings for kidney patients.
We developed a return of results workflow in collaborations with clinicians for the retrospective recontact of adult nephrology patients who had been recruited into a biobank research study for exome sequencing and were identified to have medically actionable genetic findings.
Using this workflow, we attempted to recontact a diverse pilot cohort of 104 nephrology research participants with actionable genetic findings, encompassing 34 different monogenic etiologies of nephropathy and five single-gene disorders recommended by the American College of Medical Genetics and Genomics for return as medically actionable secondary findings. We successfully recontacted 64 (62%) participants and returned results to 41 (39%) individuals. In each case, the genetic diagnosis had meaningful implications for the patients' nephrology care. Through implementation efforts and qualitative interviews with providers, we identified over 20 key challenges associated with returning results to study participants, and found that physician knowledge gaps in genomics was a recurrent theme. We iteratively addressed these challenges to yield an optimized workflow, which included standardized consultation notes with tailored management recommendations, monthly educational conferences on core topics in genomics, and a curated list of expert clinicians for patients requiring extranephrologic referrals.
Developing the infrastructure to support return of genetic results in nephrology was resource-intensive, but presented potential opportunities for improving patient care.
This article contains a podcast at https://www.asn-online.org/media/podcast/CJASN/2020_04_16_12481019.mp3.
Approximately 50% of patients with fibrillary glomerulonephritis (GN) progress to end-stage renal disease (ESRD) within 2 years of diagnosis, and no standard therapy exists. The data on rituximab ...therapy for fibrillary GN are limited and have inconsistent outcomes. Here, we report the largest case series to date using rituximab for fibrillary GN.
Retrospective chart reviews were conducted on 12 patients with fibrillary GN who were treated with rituximab (1 g i.v. × 2 doses or 375 mg/m(2) × 4 doses) at the Center for Glomerular Diseases at Columbia University Medical Center. Non-progression of disease was defined as stable/improved serum creatinine (SCr) with a minimum of 1 year of follow-up.
The median SCr was 2.1 (range 0.7-2.7) mg/dL, median estimated glomerular filtration rate (eGFR) 39 (range 21-98) mL/min/1.73 m(2) and median proteinuria 4497 (range 210-7542) mg/day at the time of rituximab initiation. Four patients had received immunosuppression before rituximab, and nine received immunosuppression after rituximab, with four receiving a second rituximab course. Four of 12 patients were non-progressors, 3 of 12 had progressive renal dysfunction without reaching ESRD, and 5 patients reached ESRD. The median follow-up for patients who did not reach ESRD was 38 (range 14-76) months after rituximab treatment. Non-progressors had lower SCr values, higher eGFRs and shorter median duration from diagnosis to treatment than progressors. No serious adverse events were noted.
Rituximab therapy was associated with non-progression of renal disease in 4 of 12 patients. At the time of treatment, these non-progressors had better renal function and shorter time from diagnosis to treatment than progressors.
A renewed interest in the role of complement in the pathogenesis of glomerular diseases has improved our understanding of their basic, underlying physiology. All 3 complement pathways-classical, ...lectin, and alternative-have been implicated in glomerular lesions both rare (e.g., dense deposit disease) and common (e.g., IgA nephropathy). Here we review the basic function of these pathways and highlight, with a disease-specific focus, how activation can lead to glomerular injury. We end by exploring the promise of complement-targeted therapies as disease-specific interventions for glomerular diseases.
Recurrence of the original kidney disease after renal transplantation is an increasingly recognized cause of allograft loss. Idiopathic membranous nephropathy (iMN) is a common cause of proteinuria ...that may progress to ESRD. It is known that iMN may recur after kidney transplantation, causing proteinuria, allograft dysfunction, and allograft loss. Limited data regarding the frequency and treatment of recurrent iMN are available.
In this single-center study, all patients who had iMN and were receiving a first kidney transplant were included. We retrospectively assessed the incidence of biopsy-confirmed recurrent iMN and compared clinical characteristics of patients with and without recurrence. In addition, the effect of treatment with rituximab on proteinuria and renal allograft function in patients with recurrent iMN was examined
The incidence of recurrent iMN was 44%, and recurrences occurred at a median time of 13.6 months after transplantation. Two patterns of recurrence were identified: Early and late. No predictors of recurrence or disease progression could be identified. Treatment with rituximab was effective in four of four patients in stabilizing or reducing proteinuria and stabilizing renal function.
Recurrence of iMN is common even in the era of modern immunosuppression. Rituximab seems to be a valuable treatment option for these patients, although lager studies are needed to confirm our data.
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