Hepatitis C-related membranoproliferative glomerulonephritis in the era of direct antiviral agents / Glomerulonefrite membranoproliferativa relacionada à hepatite C na era dos agentes antivirais diretos

Abstract Membranoproliferative glomerulonephritis (MPGN) is the most typical Hepatitis C virus (HCV)-associated glomerulopathy, and the available data about the utilization of direct-acting antivirals (DAA) in HCV-associated glomerulonephritis is inadequate. We evaluated the renal and viral response in two cases of HCV-related MPGN; the first caused by cryoglobulinemia while the second was cryoglobulin-negative. Both patients received immunosuppression besides DAA in different regimens. They achieved partial remission but remained immunosuppression-dependent for more than 6 months after DAA despite sustained virological response, which enabled safer but incomplete immunosuppression withdrawal. Both patients were tested for occult HCV in peripheral blood mononuclear cells and found to be negative. Hence, the treatment of HCV-related MPGN ought to be according to the clinical condition and the effects of drug therapy. It is important to consider that renal response can lag behind the virological response.

Resumo A glomerulonefrite membranoproliferativa (GNMP) é a glomerulopatia associada ao vírus mais típico da hepatite C (HCV), e os dados disponíveis sobre a utilização de antivirais de ação direta (AAD) na glomerulonefrite associada ao HCV são inadequados. Avaliamos a resposta renal e viral em dois casos de GNMP relacionados ao HCV; o primeiro causado por crioglobulinemia, enquanto o segundo era negativo para crioglobulina. Ambos os pacientes receberam imunossupressão além de AAD em diferentes esquemas terapêuticos. Eles alcançaram remissão parcial, mas permaneceram dependentes da imunossupressão por mais de 6 meses após os AAD, apesar da resposta virológica sustentada, que permitiu a retirada da imunossupressão mais segura, mas incompleta. Ambos os pacientes foram testados para HCV oculto em células mononucleares do sangue periférico e deram resultados negativos. Portanto, o tratamento do GNMP relacionado ao VHC deve ser de acordo com a condição clínica e os efeitos da terapia medicamentosa. É importante considerar que a resposta renal pode ficar aquém da resposta virológica.

Hepatitis C-related membranoproliferative glomerulonephritis in the era of direct antiviral agents.

Membranoproliferative glomerulonephritis (MPGN) is the most typical Hepatitis C virus (HCV)-associated glomerulopathy, and the available data about the utilization of direct-acting antivirals (DAA) in HCV-associated glomerulonephritis is inadequate. We evaluated the renal and viral response in two cases of HCV-related MPGN; the first caused by cryoglobulinemia while the second was cryoglobulin-negative. Both patients received immunosuppression besides DAA in different regimens. They achieved partial remission but remained immunosuppression-dependent for more than 6 months after DAA despite sustained virological response, which enabled safer but incomplete immunosuppression withdrawal. Both patients were tested for occult HCV in peripheral blood mononuclear cells and found to be negative. Hence, the treatment of HCV-related MPGN ought to be according to the clinical condition and the effects of drug therapy. It is important to consider that renal response can lag behind the virological response.

Chronic renal allograft dysfunction in Egyptian population: Histopathological and immunohistochemical study.

The chronic dysfunction stands as the most common cause of renal allograft loss. During the nineties of the past century, this condition was referred to as chronic allograft nephropathy (CAN). Since 2005, CAN has been assigned by the eighth Banff schema to four main categories via histopathological and immunohistochemical findings including chronic antibodymediated rejection (CAMR), chronic T-cell-mediated rejection (CTMR), chronic cyclosporine toxicity (CNITOX), and "interstitial fibrosis (IF)/tubular atrophy; not otherwise specified (NOS)" to eliminate the term CAN. We conducted a retrospective study of renal allograft cases with biopsy-proven chronic damage diagnosed at our nephropathology units, between January 2007 and September 2013, to assign them to the defined categories. Differences between groups were tested using one-way analysis of variance. The frequencies of the diagnostic categories were as follow: CNITOX (43.1%), CAMR (27.5%), CTMR (17.6%), and NOS (11.8%). The serum creatinine level, time posttransplant, and global sclerosis frequency were insignificant among the categories. Nine categorized cases showed transplant glomerulopathy; five of them were seen in association with CAMR. There was a positive relationship between the number of interstitial CD8 + T cells and the degree of IF in CTMR cases. Two cases showed combined features of CAMR and CTMR. Protocol renal allograft biopsy starting 3 months after transplantation with proper monitoring and adjustment of the calcineurin inhibitors level may reduce the potential risk of chronic damage in renal allograft.

Clinical characterization and NPHP1 mutations in nephronophthisis and associated ciliopathies: a single center experience.

Nephronophthisis (NPHP) is a recessive disorder of the kidney that is the leading genetic cause of end-stage renal failure in children. Egypt is a country with a high rate of consanguineous marriages; yet, only a few studies have investigated the clinical and molecular characteristics of NPHP and related ciliopathies in the Egyptian population. We studied 20 children, from 17 independent families, fulfilling the clinical and the ultrasonographic criteria of NPHP. Analysis for a homozygous deletion of the NPHP1 gene was performed by polymerase chain reaction on the genomic DNA of all patients. Patients were best categorized as 75% juvenile NPHP, 5% infantile NPHP, and 20% Joubert syndrome-related disorders (JSRD). The mean age at diagnosis was 87.5 + 45.4 months, which was significantly late as compared with the age at onset of symptoms, 43.8 ± 29.7 months (P <0.01). Homozygous NPHP1 deletions were detected in six patients from five of 17 (29.4%) studied families. Our study demonstrates the clinical phenotype of NPHP and related disorders in Egyptian children. Also, we report that homozygous NPHP1 deletions account for 29.4% of NPHP in the studied families in this cohort, thereby confirming the diagnosis of type-1 NPHP. Moreover, our findings confirm that NPHP1 deletions can indeed be responsible for JSRD.

A five-year analysis of the incidence of glomerulonephritis at Cairo University Hospital-Egypt.

Our study aimed to obtain a comprehensive review of the incidence of biopsy-proven glomerulonephritis (GN) at the Cairo University Hospitals, Egypt, over the last five years. We analyzed the clinical and pathological data of all renal biopsy samples that were performed during the period from July 2003 to July 2008. Renal biopsy samples of 924 patients were referred for pathological assessment during the period of the study [437 male and 487 female patients; their mean age was 26.5 ± 14.6 years (range: 2.5-71 years)]. Focal segmental glomerulo-nephritis was the most frequent cause of primary GN (21.21%), followed by mesangial proliferative GN (18.93%), diffuse proliferative GN (13.96%), focal proliferative GN (12.77%) and membranous GN (10.93%). The results could be explained by the high incidence of lupus nephritis among the study subjects as well as the relatively young age of the study group.

Evaluation of renal gene expression of protein kinase C (PKC) isoforms in diabetic and nondiabetic proliferative glomerular diseases.

The protein kinase C (PKC) family consists of 13 members categorized as conventional or novel depending on whether diacylglycerol, calcium, or phosphatidylserine is required for activation. High glucose leads to activation of different forms of PKC across tissue types, thus determining the kind of diabetes-induced organ damage. PKC beta was reported to have a positive role in B-lymphocyte activity through activation of NF-kB, leading to various immune disorders. We examined renal expression of two PKC isoforms alpha and beta in renal biopsies of patients with diabetic nephropathy, lupus nephritis (LN) (Class 3-4), and mesangioproliferative glomerulonephritis (MPGN) to explore the role of each isoform in different glomerular diseases. PKC alpha and beta gene expression was studied by quantitative real-time reverse transcription-PCR in 20 patients with type 2 diabetes and proteinuria (serum creatinine 2.04 +/- 0.85 mg/dl, 24-h urinary protein 3.61 +/- 1.75 g, eGFR 37.85 +/- 17.89 ml/min/1.73 m2), 20 patients with proliferative LN (serum creatinine 1.67 +/- 1.50 mg/dl, 24-h urinary protein 4.46 +/- 5.01 g, eGFR 69.62 +/- 40.93 ml/min/1.73 m2), and 20 patients with MPGN (serum creatinine 3.32 +/- 2.79 mg/dl, 24-h urinary protein 4.65 +/- 4.11 g, eGFR 32.62 +/- 29.56 ml/min/1.73 m2). Normal tissues from the normal pole of four kidneys removed because of renal tumor served as controls. PKC á gene expression was significantly increased in diabetic kidneys compared to LN and MPGN (316.95 +/- 152.94 microg/ml vs. 185.97 +/- 32.13 and 195.46 +/- 46.45 microg/ml, p < 0.05). PKC â gene expression was significantly increased in the LN and MPGN groups compared to the diabetic nephropathy group (41.01 +/- 14.03 and 39.93 +/- 16.41 microg/ml, respectively, vs. 18.20 +/- 4.91 microg/ml, p < 0.05). Significant correlation was noted between the PKC alpha gene concentrations and proteinuria in diabetic patients. Renal expression of PKC alpha and beta genes in control tissues were significantly lower compared to diabetic kidneys, LN, and MPGN groups (32.31 +/- 0.36 and 4.67 +/- 2.41 microg/ml, respectively, p < 0.001). The study revealed enhanced renal gene expression of both PKC isoforms alpha and beta in diabetic kidney tissues, LN, and MPGN, but in different patterns. PKC alpha gene expression was significantly increased in diabetic patients with chronic kidney disease. The increased expression of the PKC beta gene in LN and MPGN highlights its role in regulation of the immune system. This may represent potential therapeutic targets for prevention of progressive kidney injury in diabetic and proliferative glomerular diseases.