Idiopathic nephrotic syndrome comprises several podocyte diseases of unknown origin that affect the glomerular podocyte, which controls the permeability of the filtration barrier in the kidney to proteins. It is characterized by the daily loss of more than 3 g of protein in urine and the lack of inflammatory lesions or cell infiltration. We found that the abundance of c-mip (c-maf inducing protein) was increased in the podocytes of patients with various acquired idiopathic nephrotic syndromes in which the podocyte is the main target of injury. Mice engineered to have excessive c-mip in podocytes developed proteinuria without morphological alterations, inflammatory lesions, or cell infiltration. Excessive c-mip blocked podocyte signaling by preventing the interaction of the slit diaphragm transmembrane protein nephrin with the tyrosine kinase Fyn, thereby decreasing phosphorylation of nephrin in vitro and in vivo. Moreover, c-mip inhibited interactions between Fyn and the cytoskeletal regulator N-WASP (neural Wiskott-Aldrich syndrome protein) and between the adaptor protein Nck and nephrin, potentially accounting for cytoskeletal disorganization and the effacement of foot processes seen in idiopathic nephrotic syndromes. The intravenous injection of small interfering RNA targeting c-mip prevented lipopolysaccharide-induced proteinuria in mice. Together, these results identify c-mip as a key component in the molecular pathogenesis of acquired podocyte diseases.

This study showed that OPcR rejections portend a poor outcome irrespective of the Banff score. Our data strongly support the hypothesis that a humoral component participated in the graft injuries. Altogether, the data suggest that OPcR rejection might represent a late and attenuated variant of acute humoral rejection that should be classified separately from ACR.

This study confirms the benefit to identify in the future clinical or biological predictive risk factors for NS recurrence after renal transplantation. It also indicates that donor age is a reliable risk factor for recurrence in adult recipients and suggests for the first time a possible opposite relationship between recurrent FSGS and acute rejection.

Acute graft pyelonephritis is a common complication in renal transplant recipients. The consequences of this complication on kidney allograft survival remain controversial. Bacterial infection is likely to activate the immune system, potentially leading to acute or chronic rejection. Here, we report for the first time two documented cases of acute rejection occurring shortly after acute graft pyelonephritis, suggesting that pyelonephritis can initiate acute rejection. The immunologic process leading to the alloimmune response is discussed. These reports suggest that acute rejection should be questioned in case of atypical graft outcome in the context of acute graft pyelonephritis.

We studied 92 patients with transplant glomerulopathy to develop a prognostic index based on the risk factors for allograft failure within five years of diagnosis (Development cohort). During 60 months (median) follow up, 64 patients developed allograft failure. A chronic-inflammation score generated by combining Banff ci, ct and ti scores, serum creatinine and proteinuria at biopsy, were independent risk factors for allograft failure. Based on the Cox model, we developed a prognostic index and classified patients into risk groups. Compared to the low risk group (median allograft survival over 60 months from diagnosis), patients in the medium risk group had a hazard ratio of 2.83 (median survival 25 months), while those in the high risk group had a hazard ratio of 5.96 (median survival 3.7 months). We next evaluated the performance of the prognostic index in an independent external cohort of 47 patients with transplant glomerulopathy (Validation cohort). The hazard ratios were 2.18 (median survival 19 months) and 16.27 (median survival 1.6 months), respectively, for patients in the medium and high risk groups, compared to the low risk group (median survival 47 months). Our prognostic index model did well in measures of discrimination and calibration. Thus, risk stratification of transplant glomerulopathy based on our prognostic index may provide informative insight for both the patient and physician regarding prognosis and treatment.

We report the occurrence of chronic kidney disease after living-related kidney transplant involving monozygotic twin brothers of Afro-Caribbean origin who were both heterozygous for the G1 and G2 APOL1 kidney disease risk alleles. A 21 year-old black man with endstage kidney disease of unknown aetiology received a kidney from his monozygotic twin brother (confirmed by microsatellite analysis). Thirty months after transplantation, the patient presented proteinuria and decreased eGFR with typical focal segmental glomerulosclerosis lesions on the graft biopsy. He received steroid therapy, but progressed to kidney failure 5 years later. The twin brother displayed normal kidney function without proteinuria at the time of transplant; however, 7 years later, he exhibited decreased estimated GFR (40 ml/min/1.73m) and proteinuria (2.5 g/day). APOL1 genotyping of revealed that both donor and recipient were heterozygous for the G1 and G2 alleles. This unique case is in stark contrast to expectations for identical twin transplantation and suggests a role for APOL1 polymorphisms in both the donor and recipient.

BackgroundThe association between sarcoidosis and glomerular diseases has not been extensively investigated in a large series and the potential features of this uncommon association remain to be determined.MethodsWe retrospectively identified 26 patients with biopsy-proven glomerular lesions that occurred in a sarcoidosis context. Potential remission of glomerular disease and sarcoidosis under specific treatment (steroid and/or immunosuppressive agents) was recorded for all patients. Demographic, clinical and biological characteristics were assessed at the time of kidney biopsy for each patient. Therapeutic data were analyzed for all patients.ResultsGlomerular disease occurred after the diagnosis of sarcoidosis in 11 of 26 cases (42%) (mean delay of 9.7 years). In six patients (23%), the glomerulopathy preceded the sarcoidosis diagnosis (mean delay 8 years). In the last nine patients (35%), both conditions occurred simultaneously. The most frequent glomerular disease occurring in sarcoidosis patients was membranous nephropathy in eleven cases. Other glomerular lesions included IgA nephropathy in six cases, focal segmental glomerulosclerosis in four patients, minimal change nephrotic syndrome for three patients and proliferative lupus nephritis in two patients. Granulomatous interstitial nephritis was associated with glomerular disease in six patients and was exclusively found in patients in whom the both disease occurred simultaneously. In nine patients with simultaneous glomerular and sarcoidosis diseases, we observed a strong dissociation between glomerular disease and sarcoidosis in terms of steroid responsiveness. At the end of the follow-up (mean of 8.4 years), six patients had reached end-stage renal disease and three patients had died.ConclusionsA wide spectrum of glomerular lesions is associated with sarcoidosis. The close temporal relationship observed in some patients suggests common causative molecular mechanisms of glomerular injury but complete remission of both diseases in response to exclusive steroid therapy is infrequent.

The interpretation of cellular infiltrate from renal transplant recipients with borderline (BL) changes is still a challenging problem. To analyze the immune phenotype of such infiltrate, we quantified the mRNA expression of Foxp3 and interleukinL-10 and granzyme B (GB) in 15 kidney biopsies with BL changes. Controls were patients presenting type IA acute rejection and nonrejecting patients. Only levels of GB mRNA correlated significantly with response to antirejection therapy. Levels of Foxp3 mRNA in BL changes were intermediate between type IA acute rejection and nonrejecting controls. To determine the balance of alloagressive to graft-protecting T cells, we quantified the Foxp3/GB ratio. BL changes T cells infiltrate expressed a significantly higher Foxp3/GB ratio than that in IA acute rejection. These results suggest that T cell infiltrate from BL change exhibit a tolerogenic rather than a cytotoxic phenotype.