Post Stroke Safinamide Treatment Attenuates Neurological Damage by Modulating Autophagy and Apoptosis in Experimental Model of Stroke in Rats.

Exploring and repurposing a drug have become a lower risk alternative. Safinamide, approved for Parkinson's disease, has shown neuroprotection in various animal models of neurological disorders. The present study aimed to explore the potential of safinamide in cerebral ischemia/reperfusion (I/R) in rats. Sprague-Dawley rats were used in middle cerebral artery occlusion model of stroke. The effective dose of safinamide was selected based on the results of neurobehavioral parameters and reduction in infarct size assessed 24 h post-reperfusion. For sub-acute study, the treatment with effective dose was extended for 3 days and effects on neurobehavioral parameters, infarct size (TTC staining and MRI), oxidative stress parameters (MDA, GSH, SOD, NOX-2), inflammatory cytokines (TNF-α, IL-1ß, IL-10), apoptosis (Bax, Bcl-2, cleaved caspase-3 expression, and TUNEL staining), and autophagy (pAMPK, Beclin-1, LC3-II expression) were studied. The results of dose selection study showed significant reduction (p < 0.05) in infarct size and improvement in neurobehavioral parameters with safinamide (80 mg/kg). In sub-acute study, safinamide showed significant (p < 0.05) improvement in motor coordination and infarct size reduction. Additionally, safinamide treatment significantly normalized altered redox homeostasis and inflammatory cytokine levels. However, no change was observed in expression of NOX-2 in I/R or safinamide treatment group when compared with sham. I/R induced deranged expression of apoptotic markers and increased TUNEL positive cells in cortex were significantly normalized with safinamide treatment. Further, safinamide significantly (p < 0.05) induced the expressions of autophagic proteins (Beclin-1 and LC3-II) in cortex. Overall, the results demonstrated neuroprotective potential of safinamide via anti-oxidant, anti-inflammatory, anti-apoptotic, and autophagy inducing properties. Thus, safinamide can be explored for repurposing in ischemic stroke after further exploration.

An interaction study of Ocimum sanctum L. and levetiracetam in pentylenetetrazole kindling model of epilepsy.

ETHNOPHARMACOLOGICAL RELEVANCE: Ocimum sanctum L. commonly known as tulsi (synonym of Ocimum tenuiflorum L.) is widely used in Ayurveda medicine and is having multitude neuromodulatory effect including the anticonvulsant effect in acute seizure models as per previous studies. In India, it is used for the treatment of epilepsy as traditional medicine. However, its role in chronic seizure model and interaction with newer antiepileptic drugs has not been investigated, which will enhance its translational value. AIM OF THE STUDY: Current study investigated the effect of Ocimum on chronic seizure model and its interaction with levetiracetam (LEV), a newer antiepileptic drug. MATERIALS AND METHODS: The adjuvant role of Ocimum sanctum hydroalcoholic extracts (OSHE) 1000 mg/kg along with LEV 300 mg/kg was studied in adult male Wistar rats with mean weight of 227.84 ± 21.68 g using pentylenetetrazole (30 mg/kg, i.p.) kindling (K) (with maximum 24 injections on alternate days and challenge on 7th-day). Along with seizure score, neurobehavioral, brain tissue oxidative stress and histopathology status were assessed. Pharmacokinetic interaction was assessed between LEV and OSHE after 14 days of drug treatment. RESULTS: K-LEV + OSHE had least seizure score during kindling and on the pentylenetetrazole-challenge test (p=0.031) than other kindling groups. Seizure protection was more in K-LEV + OSHE (85.72%) than others (K-LEV-42.86%, K-OSHE-42.86%, and K-Control-28.58%). Ocimum treated groups had better memory retention potential as evident from Morris water maze (MWM), passive avoidance test but not in an elevated plus maze test. Oxidative-stress was lower in Ocimum treated groups than K-Control group. As per histopathology, K-LEV + OSHE group had the least neuronal degeneration among kindling groups. There was no significant pharmacokinetic interaction between LEV and OSHE, except increased Tmax in LEV + OSHE group than LEV alone (p=0.009). CONCLUSIONS: Ocimum per se and combination with levetiracetam treatment exerted better seizure control, memory retention, oxidative stress reduction, and neuronal structure preservation than kindling control group. There was a very minimal drug interaction between Ocimum and LEV. So, Ocimum as an adjuvant to LEV may be shelpful in enhancing the antiepileptic effect and also in minimizing the adverse effects.

Neuro-protective effect of monomethyl fumarate on ischemia reperfusion injury in rats: Role of Nrf2/HO1 pathway in peri-infarct region.

Post stroke recanalization has been associated with increased risk of oxidative stress. Stimulating endogenous antioxidant pathway by activation of nuclear factor erythroid-2-related factor-2 (Nrf2) plays a key role in neuronal defense against inflammation and oxidative stress in penumbra. Here, we explored whether monomethyl fumarate (MMF) could produce neuro-protection after ischemia/reperfusion (I/R) injury via Nrf2/HO1 activation. In male SD rats, middle cerebral artery was occluded for 90 min and confirmed using Laser Doppler flowmeter. MMF (10, 20 and 40 mg/kg) was administered in two divided doses at 30 min post ischemia and 5-10 min after reperfusion. After 24 h, effect on neurobehavioral parameters, infarct damage by TTC staining and MRI, oxidative stress and inflammatory cytokines were assessed. Expression studies of nuclear Nrf2 and cytoplasmic HO1 were performed in peri-infarct cortex and striatum; followed by dual immunofluorescence study to check the specific cell type. I/R induced neurobehavioral deficits and infarct damage were significantly (p < 0.05) attenuated by MMF (20 and 40 mg/kg). MMF, 20 mg/kg, significantly normalized I/R induced altered redox status and increased levels of TNF-α, IL-1ß in the ipsilateral cortex. MRI data showed significantly reduced infarct in cortex but not in striatum after MMF treatment. Expression of nuclear Nrf2 and cytoplasmic HO1 were significantly (p < 0.05) increased in peri-infarct cortex after treatment with MMF. Additionally, dual immunofluorescence showed increased Nrf2 expression in neurons and HO1 expression in neurons as well as astrocytes in peri-infarct cortex after MMF treatment. Our results show the neuro-protective potential of MMF probably by restricting the progression of damage from striatum to cortex through activation of Nrf2/HO1 pathway in peri-infarct cortex.

Posttransplant Lymphoproliferative Disorder: Experience from a Pediatric Nephrology Unit in North India.

Posttransplant lymphoproliferative disorder (PTLD) is reported in 1%-3% among pediatric renal allograft recipients. We report the experience of PTLD among pediatric renal allograft recipients at a pediatric nephrology center in North India. Four cases of PTLD were identified from among records of 95 pediatric renal allograft recipients over a period of 21 years. Constitutional and localizing symptoms were present in three patients each. The diagnosis was suggested on positron emission tomography in three patients and confirmed by histopathology in all. Sites affected included tonsils, cervical lymph nodes, duodenum, and para-aortic lymph nodes in one patient each. The lymphocytic infiltrate was polymorphic in three patients and monomorphic in one. Immunostaining suggested B-cell origin in all patients. There was evidence of Epstein-Barr virus infection in only one patient. The patients were successfully managed with reduction of immunosuppression (in all), rituximab (in 3), and excision of affected tissue (in 1). Over a follow-up period of 30-88 months, there were no episodes of disease recurrence or allograft rejection, and renal function was preserved.

Fluoride-associated ultrastructural changes and apoptosis in human renal tubule: a pilot study.

The susceptibility of the kidneys to fluoride toxicity can largely be attributed to its anatomy and function. As the filtrate moves along the complex tubular structure of each nephron, it is concentrated in the proximal and distal tubules and collecting duct. It has been frequently observed that the children suffering from renal impairments also have some symptoms of dental and skeletal fluorosis. The findings suggest that fluoride somehow interferes with renal anatomy and physiology, which may lead to renal pathogenesis. The aim of this study was to evaluate the fluoride-associated nephrotoxicity. A total of 156 patients with childhood nephrotic syndrome were screened and it was observed that 32 of them had significantly high levels ( p ≤ 0.05) of fluoride in urine (4.01 ± 1.83 ppm) and serum (0.1 ± 0.013 ppm). On the basis of urinary fluoride concentration, patients were divided into two groups, namely group 1 (G-1) ( n = 32) containing normal urine fluoride (0.61 ± 0.17 ppm) and group 2 (G-2) ( n = 32) having high urine fluoride concentration (4.01 ± 1.83 ppm). Age-matched healthy subjects ( n = 33) having normal levels of urinary fluoride (0.56 ± 0.15 ppm) were included in the study as control (group 0 (G-0)). Kidney biopsies were taken from G-1 and G-2 only, who were subjected to ultrastructural (transmission electron microscopy) and apoptotic (terminal deoxynucleotidyl transferase deoxyuridine triphosphate nick end labeling) analysis. Various subcellular ultrastructural changes including nuclear disintegration, chromosome condensation, cytoplasmic ground substance lysis, and endoplasmic reticulum blebbing were observed. Increased levels of apoptosis were observed in high fluoride group (G-2) compared to normal fluoride group (G-1). Various degrees of fluoride-associated damages to the architecture of tubular epithelia, such as cell swelling and lysis, cytoplasmic vacuolation, nuclear condensation, apoptosis, and necrosis, were observed.

Effect of resveratrol on sirtuins expression and cardiac complications in diabetes.

Sirtuins are the protein deacetylases, which are linked to metabolic diseases and aging. There are seven sirtuins present in cell, whose regulation in diabetic heart is yet to be explored. Resveratrol is a well-known activator of SIRT-1, but its effect on other sirtuins is not yet clear. In the present study, we focused to find out the expression and regulation of all sirtuins in diabetic heart with the effect of resveratrol administration on them. We have induced T1DM rat model using steptozotocin and T2DM rat model by feeding high fructose diet for a period of eight weeks and analyzed the myocardial changes. Resveratrol was administrated to both the models simultaneously. Increased oxidative stress and cardiac phenotype alterations shows the induction of cardiac abnormalities in both models. We have observed decreased SIRT-1 and increased SIRT-3 activity in the T2DM rat heart. Moreover, in case of T1DM, gene and protein expression of all sirtuins was down, except SIRT-2 whose protein levels were increased. Administration of resveratrol prevented the alteration in SIRT-1 in T2DM and SIRT-1, 2, 3 and SIRT-5 in T1DM rat heart. Altered level of protein acetylation was observed corresponding to the changes in sirtuins. In conclusion, sirtuins are perturbed in both types of diabetic heart and can be considered as druggable target for therapeutic intervention.

Understanding podocytopathy and its relevance to clinical nephrology.

Podocytopathies are the most common group of glomerular disorder leading to proteinuria. On the basis of pathophysiology, light microscopic and ultrastructural evaluation, the podocytopathies include minimal change disease, diffuse mesangial sclerosis, focal segmental glomerulosclerosis and collapsing glomerulopathy. The present review summarizes the basic etiopathogenesis of podocytopthies, highlights the common genetic and acquired factors in its causation, puts forth various diagnostic modalities and discusses the role of emerging agents or treatment.

A comparative study on renal biopsy before and after long-term calcineurin inhibitors therapy: an insight for pathogenesis of its toxicity.

Calcineurin inhibitors (CNIs) are effective immunosuppressive agents for the successful treatment of childhood steroid-resistant nephrotic syndrome (SRNS). Because these patients require long-term treatment, the identification of early markers of CNI-induced nephrotoxicity (CNIN) is imperative. The monitoring of CNI trough levels, serum creatinine, and glomerular filtration rate is not an accurate marker of CNIN. The present study has been undertaken to identify early markers of CNIN in SRNS patients. Twenty-four pediatric SRNS patients were included with paired renal biopsies, before initiation (time zero biopsy) and at least 1 year after CNI therapy (protocol renal biopsy) with standard dosage. Semiquantitative morphologic grading of the histologic features was done for assessing CNIN. Immunohistochemical markers for oxidative stress (nitrotyrosine [NT]), fibrogenic cytokine (transforming growth factor ß1 [TGF-ß1]), and endothelial injury (endothelial nitric oxide synthase [eNOS]) were evaluated. In addition, ultrastructural study was done to assess mitochondrial injury in endothelial and tubular epithelial cells. The protocol renal biopsies in comparison with time zero biopsies showed significant increase in glomerulosclerosis, juxtaglomerular apparatus hyperplasia, tubular atrophy, interstitial fibrosis, arteriolar hyalinosis, and smooth muscle vacuolization (P < .05 - P < .001). Significantly higher immunoexpression of eNOS (91.6%), NT (71%), and TGF-ß1 (87.5%) was noted in posttreatment biopsies. Mean mitochondrial injury grade among post-CNI cases in endothelial cells and proximal tubular cells was 2.28 and 1.4, whereas in pre-CNI, it was 0.28 and 0.27, respectively. We propose that immunohistochemical overexpression of NT, eNOS, and TGF-ß1 is an early marker of CNIN. Endothelial and proximal tubular mitochondrial injury may play an important role in the pathogenesis of CNIN.

Protective effect of thymoquinone against high-fructose diet-induced metabolic syndrome in rats.

PURPOSE: Thymoquinone (TQ), a bioactive constituent of Nigella sativa (Linn.) seed, which is commonly used as a spice in Asian food, has been reported to possess a wide range of biological effects. The present study evaluated the effect of TQ on high-fructose diet (HFD)-induced metabolic syndrome (MetS) in male Wistar rats. METHODS: MetS was induced by 60% HFD over 42 days. TQ (25, 50 and 100 mg/kg, p.o. once daily) was administered along with HFD for 42 days. Pioglitazone (10 mg/kg, p.o. once daily) was used as a standard drug. Plasma glucose, triglycerides, total cholesterol and HDL-cholesterol were estimated on days 0 and 42. Change in blood pressure, oral glucose tolerance and insulin resistance were measured. Hepatic thiobarbituric acid reactive substances (TBARS), reduced glutathione (GSH), superoxide dismutase (SOD) and catalase levels were estimated as measures of hepatic oxidative stress. Hepatic mRNA of PPAR-α and PPAR-γ was also studied. RESULTS: TQ prevented the characteristic features of HFD-induced MetS, such as hyperglycaemia, hypertriglyceridemia, hypercholesterolaemia and elevated systolic blood pressure. TQ also prevented impaired glucose tolerance and insulin resistance. It also ameliorated HFD-induced increase in hepatic TBARS and depletion of SOD, catalase and GSH. TQ prevented reduction in hepatic mRNA of PPAR-α and PPAR-γ in HFD rats, and the effects were comparable to those of pioglitazone. CONCLUSIONS: This study demonstrates protective effect of TQ against HFD-induced MetS on rats which might have been mediated via PPAR mechanism.

Idiopathic collapsing glomerulopathy: A clinicopathologic analysis of 30 cases.

Collapsing glomerulopathy (CG) is a distinct clinicopathologic entity associated with various infections, medications and acute ischemia. There have been few scattered reports of CG from India. This study aimed at evaluating the clinicopathologic features of idiopathic CG in Indian patients with comparison between adult-onset and childhood CG. This study included all cases of idiopathic CG diagnosed over a period of 4 years (2006-2009). Appropriate clinical details and laboratory findings were retrieved. Renal biopsies were reviewed and detailed pathologic features assessed. Statistical analysis was performed to compare various features between adult-onset and childhood CG. Over these 4 years, 30 cases of idiopathic CG were diagnosed. Of these, 11 were children. Childhood CG cases had longer duration of symptoms and lower serum urea and creatinine levels compared with adult patients. In renal histology, tubular atrophy and interstitial fibrosis was frequent in our cases. Pediatric cases of CG showed a higher proportion of segmental glomerulosclerosis. On clinical follow-up, nine of the 30 patients progressed to end-stage renal disease and these included two pediatric patients. Idiopathic CG is a significant cause of renal dysfunction in both pediatric and adult patients. Childhood and adult-onset CG differ in few clinicopathologic features. Early and accurate diagnosis of CG is imperative for appropriate management of these patients.

Novel polymeric nanoparticles for intracellular delivery of peptide Cargos: antitumor efficacy of the BCL-2 conversion peptide NuBCP-9.

The preclinical development of peptidyl drugs for cancer treatment is hampered by their poor pharmacologic properties and cell penetrative capabilities in vivo. In this study, we report a nanoparticle-based formulation that overcomes these limitations, illustrating their utility in studies of the anticancer peptide NuBCP-9, which converts BCL-2 from a cell protector to a cell killer. NuBCP-9 was encapsulated in polymeric nanoparticles composed of a polyethylene glycol (PEG)-modified polylactic acid (PLA) diblock copolymer (NuBCP-9/PLA-PEG) or PEG-polypropylene glycol-PEG-modified PLA-tetrablock copolymer (NuBCP-9/PLA-PEG-PPG-PEG). We found that peptide encapsulation was enhanced by increasing the PEG chain length in the block copolymers. NuBCP-9 release from the nanoparticles was controlled by both PEG chain length and the PLA molecular weight, permitting time-release over sustained periods. Treatment of human cancer cells with these nanoparticles in vitro triggered apoptosis by NuBCP-9-mediated mechanism, with a potency similar to NuBCP-9 linked to a cell-penetrating poly-Arg peptide. Strikingly, in vivo administration of NuBCP-9/nanoparticles triggered complete regressions in the Ehrlich syngeneic mouse model of solid tumor. Our results illustrate an effective method for sustained delivery of anticancer peptides, highlighting the superior qualities of the novel PLA-PEG-PPG-PEG tetrablock copolymer formulation as a tool to target intracellular proteins.

Therapeutic efficacy of poly (lactic-co-glycolic acid) nanoparticles encapsulated ivermectin (nano-ivermectin) against brugian filariasis in experimental rodent model.

The present study reports on the antifilarial activity of poly (lactic-co-glycolic acid) nanoparticles encapsulated ivermectin (nano-IVM) against human lymphatic filariid Brugia malayi in rodent host Mastomys coucha. Nano-IVM was prepared and optimized by nanoprecipitation method. The selected nano-IVM (F5) showed a uniform spherical shape with 96 nm diameter and 74.12 % entrapment efficiency, and when used at a suboptimal dose of 100 µg/kg body weight, completely eliminated filarial parasites from systemic circulation on 60 days post-infection in animals inflicted with B. malayi. In contrast, the coadministration of nano-IVM (F5) along with standard filaricide diethylcarbamazine (DEC) was found to be competent enough to suppress microfilarial stage of parasites and successfully eliminated microfilaria at 45 days posttreatment. However, the free form of both the drugs alone or in combination was unable to impart such suppression and followed by recurrence of the infection. Interestingly, nano-IVM (F5) was also found to be effective against adult stage parasites causing 36.67 % worm mortality and 75.89 % in combination with DEC; however, female sterilization remain almost similar. Thus, the combination of entrapped IVM with DEC exhibited enhanced microfilaricidal and marginally better macrofilaricidal efficacy than any of the single formulation or drugs combination.

Diagnostic dilemma in histopathology report following robot assisted laparoscopic prostatectomy: tumour 'hide and seek'.

INTRODUCTION: Widespread PSA (prostate specific antigen) screening has resulted in stage migration of prostate cancer. Smaller tumor volumes are being detected in radical prostatectomy specimens. This has coincided with increasing reports about the 'vanishing cancer phenomenon.' AIMS: To analyse the cases of robot assisted laparoscopic prostatectomy (RALP) at our institute in which the pre operative prostate biopsy was positive for adenocarcinoma but no tumor could be identified in the final histopathology, and to review the literature for possible reasons for such a phenomenon. MATERIALS AND METHODS: Nine patients were identified out of a total of 184 cases of RALP in which the final histopathology did not correlate with the initial biopsy report. The initial biopsy slides as well as the final histopathology slides were reviewed by a second pathologist. The specimens were processed in entirety and additional sections were taken until no tissue was left. RESULTS: Two patients had cancer diagnosed on TURP (transurethral resection of prostate) chips, while the remaining patients had undergone TRUS biopsy for elevated PSA. The final histopathological diagnosis was benign prostatic hyperplasia in two patients, chronic prostatitis in four patients, and acute florid prostatitis in one patient, granulomatous prostatitis with glandulostromal hyperplasia in one patient and TCC (transitional cell carcinoma) of prostate in one patient. CONCLUSION: Most cases of pT0 are due to inability of routine histopathological analysis to identify minute tumor focus. Urologists need to be aware of this in view of the potential medico legal implications.

Basics of kidney biopsy: A nephrologist's perspective.

The introduction of the kidney biopsy is one of the major events in the history of nephrology. Primary indications of kidney biopsy are glomerular hematuria/proteinuria with or without renal dysfunction and unexplained renal failure. Kidney biopsy is usually performed in prone position but in certain situations, supine and lateral positions may be required. Biopsy needles have changed with times from Vim-Silverman needle to Tru-cut needle to spring-loaded automatic gun. The procedure has also changed from blind bedside kidney biopsy to ultrasound marking to real-time ultrasound guidance to rarely computerized tomography guidance and laparoscopic and open biopsy. In very specific situations, transjugular kidney biopsy may be required. Most of the centers do kidney biopsy on short 1-day admission, whereas some take it as an outdoor procedure. For critical interpretation of kidney biopsy, adequate sample and clinical information are mandatory. Tissue needs to be stained with multiple stains for delineation of various components of kidney tissue. Many consider that electron microscopy (EM) is a must for all kidney biopsies, but facilities for EM are limited even in big centers. Sophisticated tests such as immunohistochemistry and in-situ hybridization are useful adjuncts for definitive diagnosis in certain situations.

The short-term impact of protocol biopsies in a live-related renal transplant program using tacrolimus based immunosuppression.

The aim of the study was to assess the impact of protocol biopsies in a live-related renal transplant program using tacrolimus-based immunosuppression in the short term. Eighty-three live-related transplant recipients were randomly allocated to protocol biopsy group (Group I, n = 40) and a control group (Group II, n = 43). Other immunosuppressants in these groups consisted of either mycophenolate mofetil or azathioprine and steroids. Protocol biopsies were conducted in biopsy group at 1, 6, and 12 months post-transplant. The non-biopsy group was followed by serial serum creatinine and biopsies in them were conducted as and when clinically indicated. Both groups were analyzed at 12 months with respect to graft function and survival. The two groups were similar with respect to age, number of dialysis pre-operatively, tacrolimus levels, induction therapy, donor age, and donor glomerular filtration rate. Forty protocol biopsies were conducted at 1 month, 31 at 6 months, and 26 at 12 months. The prevalence of sub-clinical rejection at 1, 6, and 12 months in these biopsies was 17.5%, 11.2%, and 10.3%, respectively. The prevalence of calcineurin inhibitor toxicity during same period was 15%, 15.5%, and 14.4%, respectively. The cumulative rejection rate in Group I and Group II at 12-month follow-up was 10.3% and 11.3% (P = 0.78), respectively, and cumulative calcineurin inhibitor toxicity at 12 months was 14.4% and 9.3% (P = 0.59), respectively, were not statistically significant. There was no difference in graft survival and function at 1 year. Protocol biopsies have a limited role in a well-matched renal transplant program with tacrolimus-based immunosuppression in the short term. However, the long-term impact of protocol biopsies needs further evaluation.

Study of CC chemokine receptor 5 in renal allograft rejection.

Allospecific recruitment of T cells is primary to the pathogenesis of renal transplant rejection. Chemokines and their receptors inducing a Th1 cytokine response play a central role in this recruitment. Renal allograft biopsies of 28 patients with acute cellular rejection and 10 protocol biopsies (controls) were examined in accordance with Banff grading 2007 schema. Immunohistochemistry for CD3 and CC chemokine receptor 5 (CCR5) in sequential sections was performed and quantitatively assessed in the glomeruli, tubules, and interstitium. Histopathologic and clinical correlations were carried out. CD3- and CCR5-positive cells were observed in significantly higher numbers in rejection cases than in controls (P = 0.010). A larger proportion of CCR5-positive cells were noted in the foci of tubulitis compared to the interstitial infiltrates and glomeruli in all cases, and it correlated with the grade of cellular rejection (P = 0.010). A greater number of CCR5-positive cells were seen in early rejection (<6 months posttransplant) compared to late rejection. No clinical correlation with serum creatinine levels was found. CCR5-positive cells represent the alloaggressive subset of T cells in ACR, and their numbers correlate with rejection severity. CCR5 may be used as a marker of early acute rejection and may be an important target for future antirejection therapies.

HIV associated renal disease: a pilot study from north India.

BACKGROUND & OBJECTIVES: HIV/AIDS patients may have renal involvement also, however, Indian data are sparse. The present study was done to find the spectrum of renal diseases in HIV/AIDS patients in north India. METHODS: In this prospective pilot study, HIV positive patients aged >18 yr were screened for renal involvement [serum creatinine >1.5 mg% and/or significant proteinuria (>500 mg /day)]. Patients who were positive on screening were followed up prospectively and underwent kidney biopsy if indicated. RESULTS: A total of 526 patients were screened, of these, 91 (17.3%) were found to have renal involvement. Group A (Treatment naοve) comprised 392 patients who were not on antiretroviral treatment (ART) and group B (patients on ART) comprised 134 patients. More patients (74/392, 18.9%) in group A had renal involvement as compared to patients in group B (17/134, 12.7%). Of the 91 patients with renal involvement, 26 were followed up and underwent kidney biopsy. Thirteen patients had only proteinuria and another 13 had renal dysfunction with or without proteinuria. Most common histological diagnosis was mesangioproliferative glomerulonephritis (mes PGN) (10/26). Two patients had collapsing FSGS (focal segmental glomerulosclerosis) and three patients had immune complex glomerulonephritis. Seven patients had acute kidney injury, whom six totally recovered from their renal function. All patients with mesPGN tolerated angiotensin converting enzyme (ACE) inhibitors well. There was mixed response of collapsing FSGS to steroids. Both patients with MPGN (membranoproliferative glomerulonephritis) did well on low dose of steroid and ART. INTERPRETATION & CONCLUSIONS: Renal involvement was found to be common in HIV positive patients (17.3%). A low occurrence of renal involvement found in patients already on ART suggests some renoprotective effect of ART. Our preliminary results showed that collapsing FSGS was not rare in Indian HIV positive population, but classical HIV associated nephropathy was not seen. Longitudinal studies with robust study design and large sample size need to be done to confirm the findings.

Calcineurin inhibitor induced nephrotoxicity in steroid resistant nephrotic syndrome.

Prolonged therapy with calcineurin inhibitors (CNI) is effective in patients with difficult nephrotic syndrome. However, information on prevalence and risk factors for nephrotoxicity in children with steroid-resistant nephrotic syndrome is limited. This retrospective observational study was conducted on 40 patients with steroid-resistant nephrotic syndrome treated with cyclosporine (CyA) (n = 28) or tacrolimus (n = 12) for more than 2 years. Nephrotoxicity was defined by the presence of striped fibrosis involving ≥10% of the interstitium or nodular hyalinosis in more than one arteriole. Ten additional parameters were graded semi-quantitatively. Continuous data are presented as median and interquartile range (IQR). The median (IQR) age at onset of nephrotic syndrome and CNI therapy were 30 (21-45) and 49.5 (40-102.5) months. A second renal biopsy, following 30 (26-35) months of CNI therapy, showed histological toxicity in 10 (25%) patients. Toxicity was seen in 7 and 3 patients receiving CyA and tacrolimus, respectively, and 5 patients each with minimal change and focal segmental glomerulosclerosis. Therapy with CNI was associated with significant increases in scores for global glomerulosclerosis, tubular atrophy, interstitial fibrosis, nonnodular arteriolar hyalinosis (P < -0.001 for all), arteriolar smooth-muscle vacuolization (P = -0.02), juxtaglomerular hyperplasia (P = -0.002), and tubular microcalcinosis (P = -0.06). Risk factors for nephrotoxicity were initial resistance (OR 9; 95% CI 1.0-80.1; P = -0.049); dose of CyA (OR 9.2; 95% CI 1.1-74.6; P = -0.037); duration of heavy proteinuria (OR 1.2; 95% CI 1.0-1.4; P = -0.023); and hypertension during therapy (OR 6; 95% CI 1.3-28.3; P = -0.023). Following prolonged CNI therapy, one in four biopsies show features of toxicity. Prolonged duration of heavy proteinuria, hypertension, initial steroid resistance and high CyA dose predict the occurrence of nephrotoxicity.

Plasma cell-rich acute rejection of the renal allograft: A distinctive morphologic form of acute rejection?

This study was aimed at evaluating the clinicopathologic features of plasma cell-rich acute rejection (PCAR) of renal allograft and comparing them with acute cellular rejection (ACR), non-plasma cell-rich type. During a 2-year period, eight renal allograft biopsies were diagnosed as PCAR (plasma cells >10% of interstitial infiltrate). For comparison, 14 biopsies with ACR were included in the study. Detailed pretransplant data, serum creatinine at presentation, and other clinical features of all these cases were noted. Renal biopsy slides were reviewed and relevant immunohistochemistry performed for characterization of plasma cell infiltrate. The age range and duration of transplantation to diagnosis of acute rejection were comparable in both the groups. Histologically, the proportion of interstitial plasma cells, mean interstitial inflammation, and tubulitis score were higher in the PCAR group compared with cases with ACR. A significant difference was found in the outcome at last follow-up, being worse in patients with PCAR. This study shows that PCAR portends a poor outcome compared with ACR, with comparable Banff grade of rejection. Due to its rarity and recent description, nephrologists and renal pathologists need to be aware of this entity.