Manisha Sahay

A Novel Hypoxia-Inducible Factor-Prolyl Hydroxylase Inhibitor (GSK1278863) for Anemia in CKD: A 28-Day, Phase 2A Randomized Trial.

BACKGROUNDnAnemia associated with chronic kidney disease (CKD) often requires treatment with recombinant human erythropoietin (EPO). Hypoxia-inducible factor-prolyl hydroxylase inhibitors (PHIs) stimulate endogenous EPO synthesis and induce effective erythropoiesis by non-EPO effects. GSK1278863 is an orally administered small-molecule PHI.nnnSTUDY DESIGNnMulticenter, single-blind, randomized, placebo-controlled, parallel-group study.nnnSETTING & PARTICIPANTSnAnemic non-dialysis-dependent patients with CKD stages 3-5 (CKD-3/4/5 group; n=70) and anemic hemodialysis patients with CKD stage 5D (CKD-5D group; n=37).nnnINTERVENTIONSnPatients with CKD-3/4/5 received placebo or GSK1278863 (10, 25, 50, or 100mg), and patients with CKD-5D received placebo or GSK1278863 (10 or 25mg) once daily for 28 days.nnnOUTCOMES & MEASUREMENTSnPrimary pharmacokinetic and pharmacodynamic (increase and response rates in achieving the target hemoglobin [Hb] concentration, plasma EPO concentrations, reticulocyte count, and others]) and safety and tolerability end points were obtained.nnnRESULTSnBoth CKD-3/4/5 and CKD-5D populations showed a dose-dependent increase in EPO concentrations and consequent increases in reticulocytes and Hb levels. Percentages of GSK1278863 participants with an Hb level increase > 1.0g/dL (CKD-3/4/5) and >0.5g/dL (CKD-5D) were 63% to 91% and 71% to 89%, respectively. Per-protocol-defined criteria, high rate of increase in Hb level, or high absolute Hb value was the main cause for withdrawal (CKD-3/4/5, 30%; CKD-5D, 22%). A dose-dependent decrease in hepcidin levels and increase in total and unsaturated iron binding were observed in all GSK1278863-treated patients.nnnLIMITATIONSnSparse pharmacokinetic sampling may have limited covariate characterization. EPO concentrations at the last pharmacodynamic sample (5-6 hours) postdose may not represent peak concentrations, which occurred 8 to 10 hours postdose in previous studies. Patients were not stratified by diabetes status, potentially confounding vascular endothelial growth factor and glucose analyses.nnnCONCLUSIONSnGSK1278863 induced an effective EPO response and stimulated non-EPO mechanisms for erythropoiesis in anemic non-dialysis-dependent and dialysis-dependent patients with CKD.

Leprosy in a renal transplant recipient: review of the literature

Abstract: A 52‐year‐old male underwent living‐related renal transplantation. He received prednisolone, azathioprine, and cyclosporine as immunosuppression protocol. Eleven years after transplantation, he developed pyrexia with multiple nodular lesions on his limbs, trunk, and face. Skin biopsy and smears showed the presence of numerous acid‐fast bacilli with 5% sulfuric acid indicative of Mycobacterium leprae. He was initiated on multidrug therapy (MDT) including dapsone, clofazimine, and rifampicin. After 2 years of MDT, he developed new multiple erythematous, tender subcutaneous nodules in crops over his face and upper limbs. Skin biopsies and histopathological examination confirmed the diagnosis of type 2 lepra reaction or erythema nodosa leprosum. He was managed with an increase in the dose of prednisolone and thalidomide. He was continued on MDT.

Renal disease in human immunodeficiency virus - Not just HIV-associated nephropathy

The aim of the study was to determine the various histopathological lesions in human immunodeficiency virus (HIV) patients with renal dysfunction and to establish clinicopathological correlation. Over a period of two years from January 2008 to March 2010, 27 HIV positive patients with renal dysfunction were subjected to renal biopsy. Of the 27 patients, 23 were males and four were females (85.2% males, 14.8% females). Mean age was 38.2 ± 10.36 (range 20 – 60) years. The probable mode of acquisition of HIV infection was sexual in 22 patients (81.5%). Thirteen patients (48%) had nephrotic proteinuria. The CD4 count ranged from 77 to 633/microliter. The kidneys were of normal size in 19 (70.4%) and bulky in eight (29.6%) patients. Thirteen patients required renal replacement therapy. Eleven patients had acute tubule-interstitial lesions (40.7%) while 15 (55.5%) had glomerular lesions. The various glomerular lesions were, focal segmental glomerulosclerosis in five, amyloidosis in three, diffuse proliferative GN in two, and membranoproliferative glomerulonephritis (GN), membranous GN, minimal change disease, diabetic nephropathy, crescentic GN, and thrombotic microangiopathy were seen in one each. None of the clinical or laboratory variables, except hypertension, was found to predict glomerular versus non-glomerular lesions on biopsy. In conclusion we show that a variety of glomerular and tubulointerstitial lesions can be seen on renal histology. Hence, renal biopsy is indicated in renal dysfunction associated with HIV for making proper diagnosis and therapy.

Renal histology in diabetic nephropathy: A novel perspective.

Diabetic nephropathy (DN) is the leading cause of end-stage renal disease all over the world. India has a high incidence and prevalence of diabetes and >30% have nephropathy. Recently, a histological classification has been proposed. This study analyzed the renal histology in 114 diabetic patients with renal dysfunction. Nearly 75% of patients had DN. Fifty five (63.95%) were males. Mean duration of diabetes was 7.04 ± 4.9 years. Mean serum creatinine in study group was 5.2 ± 2.9 mg/dl, with mean estimated glomerular filtration rate of 23.43 ± 21.48 ml/min/1.732 m2. Forty eight patients (55.81%) had diabetic retinopathy (DR); prevalence of DR was more in patients who had diabetes for > 10 years than patients who had diabetes for <6 years (P = 0.022). The most common histological class was Class IV observed in 37 (43.02. %) cases, Class III DN in 24 (27.90%) cases, Class IIa and Class IIb in 11 (12.79%) cases each and Class I DN in 3 (3.48%) cases. Higher histological class was associated with higher proteinuria, lower glomerular filtration rate (P < 0.001) and was more likely to be associated with retinopathy (P = 0.012) and hypertension (P = 0.0003) but did not correlate with duration of diabetes (P = 0.85). There was a poor correlation between retinopathy and DN. Biopsy helps to stage the renal lesions in diabetics with renal dysfunction.

Focal and segmental glomerulosclerosis: does prognosis vary with the variants?

Focal and segmental glomerulosclerosis (FSGS) is a clinicopathological entity. The following five FSGS variants: Collapsing, cellular, glomerular tip, peri-hilar and not otherwise specified (NOS) are recognized, which may have prognostic value. The aim of this study was to highlight the clinical course and outcome in the different pathological variants of FSGS and to evaluate the predictive risk factors of end-stage renal disease (ESRD). It was a retrospective analysis of biopsy-proven primary FSGS patients who presented over a period of three years. The data were collected from the clinical and biopsy records of the Nephrology Unit. There were 116 patients with biopsy-proven FSGS. The frequency of occurrence of FSGS among all cases of the nephrotic syndrome seen in our unit was 35.47%. NOS was the most common pathological variant (62.2%), followed by peri-hilar (11.2%), cellular (9.4%) and glomerular tip (7.7%), and the least common variant was collapsing (4.3%). Majority of patients with collapsing, NOS and glomerular tip variants had nephrotic range proteinuria. However, the amount of proteinuria was highest in the glomerular tip and collapsing variants. A higher percentage of patients with the collapsing and cellular variants had renal failure at the time of presentation. A higher rate of tubular and interstitial changes was seen in the collapsing and cellular variants. The collapsing and cellular variants showed lower response rate and higher rates of ESRD, while the glomerular tip lesion had the highest remission rate and the lowest rate of ESRD. Poor prognostic factors for ESRD in FSGS were initial renal insufficiency, severe tubulo-interstitial change, initial nonresponsiveness to steroids and collapsing histopathological variant. Our study suggests that histopathological classification of FSGS is of paramount importance in the management and in predicting the prognosis.

Renal cortical necrosis in tropics

The aim of this study is to review cases of renal cortical necrosis (RCN) that were seen on renal biopsy at our center over a period of seven years. All renal biopsy records over seven years at the Osmania General Hospital were reviewed to identify patients with histologically proven RCN. The demographic, clinical, laboratory investigations and follow-up data were noted. There were a total of 105 patients with RCN. The mean age was 28.13 ± 12.40 years. Forty-one cases (39.04%) resulted from obstetric complications. The most common histology type of RCN was patchy cortical necrosis in 65 patients (62%). All patients required dialysis, and the mean duration of dialysis was 3 ± 1 weeks. Thirty-three (31.42%) patients progressed to end-stage kidney disease while three patients underwent renal transplantation. Ten (9.5%) patients succumbed to acute kidney injury. The remaining patients recovered sufficient renal function and were dialysis-independent till the last follow-up. RCN is an important cause of chronic kidney disease. Obstetric complications are the leading cause of RCN in our setting. An early renal biopsy, especially in cases of anuric renal failure, helps in establishing the diagnosis.

Indian chronic kidney disease study: Design and methods.

The rate and factors that influence progression of chronic kidney disease (CKD) in developing countries like India are unknown. A pan‐country prospective, observational cohort study is needed to address these knowledge gaps.

Low renin hypertension

Low renin hypertension is an important and often underdiagnosed cause of hypertension. It may be associated with high aldosterone levels as in Conns syndrome or low aldosterone levels as in Liddle syndrome, and syndrome of apparent mineralocorticoid excess, glucocorticoid remediable hypertension etc. Some forms of essential hypertension are also associated with low renin levels. Hypokalemia may be an important finding in low renin hypertension. The aldosterone to renin ratio helps in correct diagnosis. The treatment varies with etiology hence an accurate diagnosis is essential. Aldosterone antagonists play an important role in medical management of some varieties of low renin hypertension.

An unusual case of nephrotic syndrome.

Nephrotic syndrome can be rarely due to inherited disorders of enzymes. One such variety is lecithin cholesterol acyltransferase deficiency. It leads to accumulation of unesterified cholesterol in the eye and other organs. We report a case of nephrotic syndrome with cloudy cornea and hypocholesterolemia with foam cells and lipid deposits on renal biopsy. Awareness about this rare disease may help in the early institution of specific measures to prevent progression to end-stage renal disease.

Maternal drugs and neonatal renal failure

Maternal use of drugs during pregnancy may cause irreversible renal failure in the newborn. This report highlights the adverse effect of telmisartan during the last trimester of pregnancy. The neonate presented with oliguric renal failure and the renal histology showed proximal tubular dysgenesis.