Histological grading in primary membranous nephropathy is essential for clinical management and predicts outcome of patients.

AIMS: Diagnosis of primary membranous nephropathy (PMN) is mainly based on immunofluorescence/immunohistochemistry findings. However, assessment of specific features on optical microscopy can help to estimate the severity of the disease, guide treatment and predict the response. The aim of this study was to identify, classify and grade the precise histological findings in PMN to predict renal function outcome and guide treatment. METHODS AND RESULTS: Histological parameters, including focal segmental sclerosis (FSGS), tubular atrophy (TA), interstitial fibrosis (IF) and vascular hyalinosis (VH), were re-evaluated in 752 patients with PMN. Their predictive value was estimated separately, and also in a combination score (FSTIV) graded from 0 to 4. Finally, the impact of histology was assessed in the response to immunosuppressive treatment. Mean age of patients was 53.3 (15-85) years and most presented with nephrotic syndrome. FSGS was present in 32% and VH in 51% of the patients, while TA and IF were graded as stage ≥1 in 52% and 51.4%, respectively. The follow-up period was 122.3 (112-376) months. FSGS, TA and IF and VH were associated with impaired renal function at diagnosis (P = 0.02, P < 0.0001, P = 0.001 and P = 0.02, respectively) and at the end of follow-up (P = 0.004, P < 0.0001, P < 0.0001 and P = 0.04, respectively). In multiple regression and binary logistic analysis, the presence of FSGS and degree of TA were the most significant parameters predicting renal function outcome, defined either by eGFR (end), FSGS (r = 0.6, P < 0.0001) and TA (r = 0.6, P < 0.0001), or by the endpoint of >50% eGFR reduction, FSGS (P = 0.001) and TA (P = 0.02). Also, patients presented with FSGS, IF, VH and/or with FSTIV > 1 could benefit from immunosuppression, regardless of clinical presentation. CONCLUSIONS: The presence and degree of four histological indices, FSGS, VH, TA and IF, assessed separately or in combination, and FSTIV score not only predict renal function outcome after long-term follow-up, but can also help in the choice of appropriate treatment. Decisions concerning immunosuppressive treatment can be guided by pathology regardless of clinical findings.

Novel and Founder Pathogenic Variants in X-Linked Alport Syndrome Families in Greece.

Alport syndrome (AS) is the most frequent monogenic inherited glomerulopathy and is also genetically and clinically heterogeneous. It is caused by semi-dominant pathogenic variants in the X-linked COL4A5 (NM_000495.5) gene or recessive variants in the COL4A3/COL4A4 (NM_000091.4/NM_000092.4) genes. The disease manifests in early childhood with persistent microhematuria and can progress to proteinuria and kidney failure in adolescence or early adulthood if left untreated. On biopsy, pathognomonic features include alternate thinning, thickening and lamellation of the glomerular basement membrane (GBM), in the presence of podocyte foot process effacement. Although previous studies indicate a prevalence of AS of about 1/50,000, a recent publication reported a predicted rate of pathogenic COL4A5 variants of 1/2320. We herewith present 98 patients (40 M/58 F) from 26 Greek families. We are selectively presenting the families segregating the X-linked form of AS with pathogenic variants in the COL4A5 gene. We found 21 different pathogenic variants, 12 novel: eight glycine and one proline substitutions in the collagenous domain, one cysteine substitution in the NC1 domain, two premature termination of translation codons, three splicing variants, one 5-bp insertion/frameshift variant, one indel-frameshift variant and four gross deletions. Notably, patients in six families we describe here and three families we reported previously, carried the COL4A5-p.G624D substitution, a founder defect encountered all over Europe which is hypomorphic with mostly milder symptomatology. Importantly, on several occasions, the correct genetic diagnosis reclassified patients as patients with AS, leading to termination of previous immunosuppressive/cyclosporine A therapy and a switch to angiotensin converting enzyme inhibitors (ACEi). With the understanding that all 98 patients span a wide range of ages from infancy to late adulthood, 15 patients (11 M/4 F) reached kidney failure and 11 (10 M/1 F) received a transplant. The prospects of avoiding lengthy diagnostic investigations and erroneous medications, and the advantage of delaying kidney failure with very early administration of renin-angiotensin-aldosterone system (RAAS) blockade, highlights the importance of timely documentation of AS by genetic diagnosis.

Efficacy of hemopoietic-stimulating factors in patients undergoing chronic hemodialysis.

Anemia has been linked to increased mortality and morbidity in renal hemodialysis patients. Other risk factors that contribute to an adverse outcome include the variability of hemoglobin (Hb) levels and the decreased response to erythropoiesis-stimulating factors (ESFs). In this study we evaluated the effectiveness of four different ESFs (epoetin-A, epoetin-B, darbepoetin, and CERA), assessed the variability of Hb levels, and compared ESF dosages which contributed to the achievement of Hb levels in each individual patient with renal failure undergoing chronic hemodialysis maintenance. In conclusion, the four ESFs administered are equally effective in the treatment of anemia in renal hemodialysis patients and they do not influence in a different manner the variability of Hb. The administration of darbepoetin-A and CERA might possibly cause more patients to overshoot the target level of Hb.

Immunosuppressive regimens based on Cyclophospamide or Calcineurin inhibitors: Comparison of their effect in the long term outcome of Primary Membranous Nephropathy.

INTRODUCTION: Management of the Primary Membranous Nephropathy (PMN) usually involves administration of immunosuppressives. Cyclophosphamide (Cyclo) and Calcineurin Inhibitors (CNIs) are both widely used but only limited data exist to compare their efficacy in long term follow-up. AIM: The aim of the present study was to estimate and compare long term effects of Cyclo and CNIs in patients with PMN. PATIENTS-METHODS: Clinical data, histologic findings and long term outcome were retrospectively studied. The response to treatment and rate of relapse was compared between patients treated with CNIs or Cyclo based immunosuppressive regimens. RESULTS: Twenty three centers participated in the study, with 752 PMN patients (Mean age 53.4(14-87) yrs, M/F 467/285), followed for 10.1±5.7 years. All patients were initially treated with Renin Angiotensin Aldosterone System inhibitors (RAASi) for at least 6 months. Based on their response and tolerance to initial treatment, patients were divided into 3 groups, group I with spontaneous remission, who had no further treatment, group II, continued on RAASi only, and group III on RAASi+immunosuppression. Immunosuppressive regimes were mainly based on CNIs or Cyclo. Frequent relapses and failure to treatment were more common between patients who had started on CNIs (n = 381) compared to those initially treated with Cyclo (n = 110), relapse rate: 25.2% vs. 6.4%, p<0.0001, and no response rate: 22.5% vs. 13.6%, p = 0.04, respectively. CONCLUSIONS: Long term follow up showed that administration of Cyclo in PMN is followed by better preservation of renal function, increased response rate and less frequent relapses, compared to CNIs.

Predictive factors and therapeutic approach of renovascular disease: four years' follow-up.

BACKGROUND: There is no consensus about the renal function outcome after revascularization with stenting in atherosclerotic renovascular disease. In the present study, the outcome in BP control and renal function in patients with renovascular disease treated with percutaneous angioplasty and stent placement is compared with the outcome in patients with renovascular disease treated with medical treatment only. Additionally, the impact of oxidative stress and eosinophil count in peripheral blood as predictors of renal function deterioration in renovascular disease irrespective of treatment is investigated. METHODS: Eighty-two patients with renovascular disease were enrolled into a follow-up study (47.5+/-35.4 months). Thirty-six patients (group 1) underwent revascularization and stenting, and 46 patients (group 2) were on medical treatment only. In all patients, serum creatinine concentration, eosinophil count (EO) in peripheral blood, and estimation of oxidative stress with dROMs test were determined before and at the end of the follow-up. RESULTS: In revascularized patients (group 1), hypertension was cured in 11.1% and improved in 66.6%. Renal function improved in 30.5% and worsened in 36.2% of patients. In the medical treatment arm (group 2), hypertension improved in 71.4% of the patients. Renal function remained stable in 69.8% of patients and worsened in 30.2%. Cox regression analysis showed that higher levels of eosinophil count and higher levels of ROS, irrespectively of mode of treatment, were associated with renal function deterioration (i.e., serum creatinine increase more than 20% during follow-up). CONCLUSIONS: Revascularization was not superior to medical treatment in renal survival but had a greater positive impact on blood pressure control. Eosinophil count and oxidative stress were the stronger predictive factors for serum creatinine increase.

Calcium channels blockers and progression of kidney disease.

We aimed to compare regimens including calcium channel blockers (CCBs) to non-CCBs agents such as angiotensin-converting enzyme inhibitors (ACEIs) and/or angiotensin receptor blockers (ARBs) regarding progression in nondiabetic chronic kidney disease (CKD). There was no difference in reaching serum creatinine concentration (Cr) to more than 7 mg/dL and/or commencing dialysis. The CCB group compared to non-CCBs displayed a higher mean Cr (as well as a higher rate of increase) and proteinuria. Medication with CCBs and younger age were associated with adverse renal function outcome. It is concluded that CCBs are less effective than ACEIs or ARBs on preserving renal function and ameliorating proteinuria in nondiabetic CKD.