Kamal Sud

A Randomized, Controlled Trial of Steroids and Cyclophosphamide in Adults with Nephrotic Syndrome Caused by Idiopathic Membranous Nephropathy

Idiopathic membranous nephropathy (IMN) is the most common cause of nephrotic syndrome in adults. Universal consensus regarding the need for and the modality of therapy has not been formed because of a lack of controlled trials of sufficient size, quality, and duration. This study compared the effect of a 6-mo course of alternating prednisolone and cyclophosphamide with supportive treatment in adults with nephrotic syndrome caused by IMN on doubling of serum creatinine, development of ESRD, and quality of life in a randomized, controlled trial. Patients were followed up for 10 yr. Data were analyzed on an intention-to-treat basis. A total of 93 patients completed the study. Of the 47 patients who received the experimental protocol, 34 achieved remission (15 complete and 19 partial), compared with 16 (five complete, 11 partial) of 46 in the control group (P < 0.0001). The 10-yr dialysis-free survival was 89 and 65% (P = 0.016), and the likelihood of survival without death, dialysis, and doubling of serum creatinine were 79 and 44% (P = 0.0006) in the two groups. Treated patients exhibited significantly lower prevalence of edema, hypertension, hypoalbuminemia, hyperlipidemia that required therapy, angiotensin-converting enzyme inhibitor/angiotensin II receptor blocker use, and better quality of life on follow-up. The incidence of infections was similar in the two groups. In conclusion, untreated IMN with nephrotic syndrome is associated with a high risk for deterioration of renal function. A 6-mo regimen of cyclophosphamide and steroids induces remissions in a high proportion, arrests progression of renal insufficiency, and improves quality of life.

Common variants of inflammatory cytokine genes are associated with risk of nephropathy in type 2 diabetes among Asian Indians.

Background Inflammatory cytokine genes have been proposed as good candidate genes for conferring susceptibility to diabetic nephropathy. In the present study, we examined the combined effect of multiple alleles of pro inflammatory cytokine genes for determining the risk of nephropathy in type 2 diabetic patients. Methodology/Principal Findings Eight single nucleotide polymorphisms (SNPs) of pro-inflammatory cytokine genes (CCL2, TGFB1, IL8, CCR5, and MMP9) were genotyped in two independently ascertained type 2 diabetic cohorts with (DN) and without nephropathy (DM); consisting of patients from North India (n = 495) and South India (n = 188). Genotyping was carried out using PCR, allele specific oligonucleotide-PCR (ASO-PCR), PCR-RFLP and TaqMan allelic discrimination assays and the gene–gene interaction among genetic variants were determined by multi dimensional reduction (MDR) software. Serum high sensitive CRP (hs-CRP) levels were measured by ELISA. The hs-CRP levels were significantly higher in DN as compared to the DM group (p<0.05). The CCL2, IL8, CCR5 and MMP9 polymorphisms were found to be associated with the risk of diabetic nephropathy. Frequency of CCL2 II, IL8 -251AA, CCR5 59029AA and MMP9 279Gln/Gln genotypes were significantly higher in DN than in DM group (p<0.05) and associated with an increased risk of nephropathy in both North and South Indian cohorts. CCR5 DD and IL8 -251AA genotypes were more prevalent in North Indian DN group only. The co-occurrence of risk associated genotypes (II, -2518GG (CCL2), DD (CCR5) and 279Gln/Gln (MMP9) conferred a tenfold increased risk of nephropathy among type 2 diabetics (p<0.0002). Conclusion The present study highlights that common variants of inflammatory cytokine genes exert a modest effect on risk of DN and a combination of risk alleles confer a substantial increased risk of nephropathy in type 2 diabetes among Asian Indians.

ACE variants interact with the RAS pathway to confer risk and protection against type 2 diabetic nephropathy.

Genetic predisposition has been proposed to be a major determinant in the development of renal complications of diabetes. Among candidate genes examined for susceptibility to diabetic nephropathy, angiotensin-converting enzyme (ACE) gene has been found to be associated with pathogenesis and progression of diabetic nephropathy. However, the role of other renin-angiotensin system (RAS) polymorphisms and their possible interactions with different ACE I/D genotypes are less clearly defined. Recent studies also show that ACE haplotypes may be better predictors to disease susceptibility. Thus, in the present study, we evaluated the association of ACE haplotypes and the interactions of ACE, angiotensinogen (AGT), and angiotensin II receptor type I (AGTR1) gene polymorphisms with DNP in Asian Indians. We genotyped seven variants of the RAS pathway genes (ACE, AGT, and AGTR1) in type 2 diabetic cohorts without nephropathy (DM) and with nephropathy (DNP), using allele-specific oligonucleotide-PCR, and PCR-restriction fragment length polymorphism assays. We studied the interaction of these variants with each other and ACE I/D polymorphism. Frequency of ACE D allele and DD genotype (ACE I/D) was significantly higher in DNP (p < 0.005) and was associated with increased risk of nephropathy. The frequency of T allele, MT/TT genotypes (AGT: M235T), and C allele 1166CC genotype (AGTR1: A1166C) was higher and associated with increased risk of DNP (235T, p < 0.0001; 235TT/MT, p < 0.01; 1166C, p < 0.007; 1166CC, p < 0.0001). The ACE locus revealed a near doubling in the prevalence of T-D-G risk haplotype (odds ratio, 1.76) in DNP (0.13) compared to DM (0.08; p < 0.02). ACE haplotypes carrying the I allele were associated with a lower risk of DNP (C-I-A, p < 0.04; C-I-G, p < 0.008). ACE ID/DD genotypes in combination with ACE rs4311, rs4343, and AGT rs699 mutant genotypes increased the risk of DNP development fourfold (p < 0.01). This study provides the first evidence for a disease haplotype for DNP at the ACE locus in Asian Indians. The study further indicates that ACE D allele individually and in interaction with other RAS single-nucleotide polymorphisms significantly increases the risk of nephropathy in type 2 diabetic patients of Asian Indian origin.

The Utility of 1‐ and 3‐Month Protocol Biopsies on Renal Allograft Function: A Randomized Controlled Study

Identification of pathological events in the renal allograft using protocol biopsies at predetermined time intervals may yield useful information and improve outcomes. We examined the influence of decisions taken on the basis of 1‐ and 3‐month protocol biopsies findings on 1‐year renal allograft function in a prospective randomized study. Out of 102 living‐donor allograft recipients, 52 were randomized to undergo protocol biopsies and 50 controls had only indicated biopsies. All acute rejection (AR) episodes (clinical and subclinical) were treated. Calcineurin inhibitor (CNI) dose adjustments were made on clinical judgment. Baseline recipient and donor characteristics, immunosuppressive drug usage, HLA matches and 2‐h cyclosporine levels were similar in both groups. At 1 and 3 months, protocol biopsies revealed borderline (BL) changes in 11.5% and 14% patients, AR in 17.3% and 12% and chronic allograft nephropathy (CAN) in 3.8% and 10%. The incidence of clinically evident AR episodes was similar in the two groups, but biopsy group had lower serum creatinine at 6 months (p = 0.0003) and 1 year (p < 0.0001). The renal functions were similar in those with normal histology and BL changes. Protocol biopsies are helpful in detecting subclinical histological changes in the graft and improving short‐term renal allograft function.

Predictors of mortality in acute renal failure in a developing country : A prospective study

Acute renal failure (ARF) occurs in wide range of conditions, making the evaluation of its prognosis a difficult task. Data regarding prognostic factors in ARF in a general population in developing countries are scarce. The objective of the study was to describe predictors of mortality in ARF that are relevant in the developing world. This prospective study was carried out over a one-year period; all hospitalized adults with ARF were included in the study. Predictors of mortality studied included causes of ARF, pre-existing diseases, and severity as well as complications of ARF. Of 33,301 patients admitted during the study period, 294 (0.88%) were either admitted with or developed ARF after hospitalization. Mean age was 43.9 ± 16.9 (18–86 yrs). Sepsis was the most common cause (63.26%). Pre-existing diseases like cardiovascular disease (CVSD), respiratory system disease (RSD), central nervous system disease (CNSD), hypertension, diabetet mellitus (DM), and malignancy were significantly higher in elderly as compared to younger patients. On univariate analysis sepsis, hypoperfusion as a cause of ARF and hospital-acquired ARF were associated with higher mortality. Pre-existing diseases viz. RSD, CVSD, CNSD, and DM had higher mortality. Among the severity and complications of ARF, oliguria, bleeding and infection during the course of ARF and critical illness were predictors of poor outcome. Age >60 yrs was associated with significantly higher mortality. However, on multivariate analysis, only critical illness (odds ratio 37.3), age > 60 years (odds ratio of 5.6), and sepsis as cause of ARF (odds ratio of 2.6) were found to be independent predictors of mortality.

CT in the Evaluation of Complicated Autosomal Dominant Polycystic Kidney Disease

Purpose: We retrospectively reviewed the CT findings in 24 cases of autosomal dominant polycystic kidney disease (ADPKD) to assess the role of CT in the diagnostic work-up of patients with complicated ADPKD. Material and Methods: Twenty-four patients with ADPKD underwent unenhanced and contrast-enhanced CT for flank pain, haematuria, or fever. The images were retrospectively reviewed for presence of complicated cysts, their morphological features and associated findings in the perinephric space/retroperitoneum. Results: Cyst haemorrhage was present in all patients, seen as high-density cysts, which were mostly bilateral. Most of these cysts had sharply outlined contours, sharp interfaces with adjacent renal parenchyma, imperceptible walls, and homogeneous density, and did not enhance following i.v. contrast administration. However, a few haemorrhagic cysts (9 cysts in 6 patients) showed inhomogeneous density (n = 7), dependent layering of high-density blood leading to fluid-fluid level (n = 2), and contour irregularity (n = 3). CT revealed presence of cyst infection in 6 cases; the involved cysts were larger (average size 4.2 cm) than adjacent cysts, had only a mildly increased or near water density, and showed wall thickening and enhancement. Other findings included air within the infected cyst (n = 1), thickening and enhancement of peri- and paranephric fasciae (n = 5), and abscesses in the posterior paranephric space and adjoining psoas muscle (n = 2). In 2 other patients, although CT suggested cyst infection because of presence of wall enhancement, diagnostic needle aspiration revealed only sterile haemorrhagic fluid. In 1 case, CT revealed a soft tissue density enhancing mass in one of the cysts; this proved to be a renal cell carcinoma by fine-needle biopsy. Calculi were observed in 7 patients, and cyst wall calcification in 11 cases. Conclusion: A combination of unenhanced and contrast-enhanced CT allows correct diagnosis and differentiation amongst the various complications affecting patients with ADPKD. However, in a small subgroup of patients, it may not be possible to differentiate between haemorrhage and infection; such cases require diagnostic needle aspiration for diagnosis.

Tests for Latent Tuberculosis in People With ESRD: A Systematic Review.

BACKGROUND The relative diagnostic accuracy of interferon γ release assays (IGRAs; based on ELISA [enzyme-linked immunosorbent assay] or ELISPOT [enzyme-linked immunosorbent spot], ie, the QuantiFERON and T-SPOT.TB tests, respectively) and the tuberculin skin test (TST) for latent tuberculosis (TB) infection in people with end-stage kidney disease is uncertain and national guidelines for their use are inconsistent. STUDY DESIGN Systematic review. SELECTION CRITERIA FOR STUDIES Evaluated performance of tests for latent TB with clinical risk-factor assessment. SETTING & POPULATION People with end-stage kidney disease (chronic kidney disease stage 5 [eGFR <15] or kidney transplant recipients). No limits on setting. INDEX TESTS ELISA- or ELISPOT-based IGRAs, TST, assays to detect antimycobacterial antibodies, and flow cytometry-based tests. OUTCOMES Odds of test positivity with clinical risk factor for latent TB, expressed as ORs and relative ORs (RORs). RESULTS 47 studies (6,828 participants) were included, but only 30 studies (4,546 participants) contained sufficient data to contribute to meta-analysis. Studies were predominately in the dialysis population (23/30; 3,700 participants) in countries with low to moderate TB prevalence (0.0-50.0 cases/10(5) persons). BCG vaccination rate was variable (2.7%-100.0%). 9 studies compared IGRAs with the TST directly, 17 studies evaluated the TST only, and the other 4 studies evaluated other tests. Compared to a positive TST result, a positive ELISA-based IGRA result was associated more strongly with radiologic evidence of past TB (ROR, 4.29; 95% CI, 1.83-10.3; P = 0.001) and contact with active TB (ROR, 3.36; 95% CI, 1.61-7.01; P = 0.001). Compared to a negative TST result, a negative ELISA-based IGRA result was associated more strongly with BCG vaccination (ROR, 0.30; 95% CI, 0.14-0.63; P = 0.002). There were insufficient data to compare performance of the ELISPOT-based IGRA with the TST or ELISA-based IGRA. LIMITATIONS 17 of 47 included studies (36.2%) did not contain sufficient data to contribute to meta-analysis. CONCLUSIONS Compared to the TST, the ELISA-based IGRA was associated more strongly with risk factors for latent TB in end-stage kidney disease.

CT of liver cysts in patients with autosomal dominant polycystic kidney disease.

Purpose: The purpose of this study was to illustrate the CT appearances of liver cysts in patients with autosomal dominant polycystic kidney disease (ADPKD). Material and Methods: Contrast-enhanced CT images of 24 patients with ADPKD were retrospectively evaluated for the presence, number, size and distribution of liver cysts. An attempt was made to categorize these cysts into peribiliary cysts (located adjacent to larger portal triads or in the hepatic hilum) and intrahepatic cysts (within the liver parenchyma but not in contact with larger portal triads). When it was not possible to definitely categorize the cysts into either type, the cysts were labeled as indeterminate. Results: Liver cysts were seen in 13 (54%) patients. Intrahepatic cysts were seen in 12 patients, and were mainly peripheral in location with sizes ranging from less than 10 mm to 8 cm. Peribiliary cysts were seen in all 13 patients and were usually less than 10 mm in size. These cysts were seen as discrete cysts (8 patients), a string of cysts (10 patients), or as a tubular structure paralleling the portal vessels, mimicking biliary dilatation (11 patients). Twelve patients also showed indeterminate cysts which defied definite categorization into either type; two common causes of confusion included large (more than 10 mm) discrete cysts in the hilar region and the presence of a vessel adjacent to peripheral cysts. Conclusion: Liver cysts in patients with ADPKD show a wide variety of appearances on CT. Familiarity with these findings is essential to avoid confusion with other abnormalities.

Acute peritoneal dialysis in neonates: comparison of two types of peritoneal access

Abstract A total of 23 sessions of peritoneal dialysis (PD) were given to 20 neonates with acute renal failure. Intravenous cannula (Biovalve 14G Vygon) was used for PD access in 13 procedures and guide wire-inserted femoral vein catheter (Medcomp-pediatric) in 10 procedures. Intraperitoneal bleed was seen in 1 procedure each in both groups. Dialysate leak and catheter blockade were more common with intravenous cannula [3 (23.1%), 8 (61.5%)] than guide wire-inserted femoral vein catheter [1 (10%), 4 (40%), P-NS]. Due to repeated catheter blockade, 5 (38.4%) PD sessions could not be completed with intravenous cannula and had to be prematurely closed; this complication was not seen with guide wire-inserted femoral vein catheter (P<0.05). Percentage reduction of serum creatinine per PD session was significantly higher in neonates being dialyzed with guide wire-inserted femoral vein catheter (51.7%±8.5%) than those dialyzed with intravenous cannula (38.3%±5.2%). Incidence of peritonitis was not significantly different [2 (15.4%) vs. 1 (10%)]. To conclude, for an effective PD in neonates, guide wire-inserted femoral vein catheter is safe and is associated with fewer access-related problems.

The association between peritoneal dialysis modality and peritonitis.

BACKGROUND AND OBJECTIVES There is conflicting evidence comparing peritonitis rates among patients treated with continuous ambulatory peritoneal dialysis (CAPD) or automated peritoneal dialysis (APD). This study aims to clarify the relationship between peritoneal dialysis (PD) modality (APD versus CAPD) and the risk of developing PD-associated peritonitis. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS This study examined the association between PD modality (APD versus CAPD) and the risks, microbiology, and clinical outcomes of PD-associated peritonitis in 6959 incident Australian PD patients between October 1, 2003, and December 31, 2011, using data from the Australia and New Zealand Dialysis and Transplant Registry. Median follow-up time was 1.9 years. RESULTS Patients receiving APD were younger (60 versus 64 years) and had fewer comorbidities. There was no association between PD modality and time to first peritonitis episode (adjusted hazard ratio [HR] for APD versus CAPD, 0.98; 95% confidence interval [95% CI], 0.91 to 1.07; P=0.71). However, there was a lower hazard of developing Gram-positive peritonitis with APD than CAPD, which reached borderline significance (HR, 0.90; 95% CI, 0.80 to 1.00; P=0.05). No statistically significant difference was found in the risk of hospitalizations (odds ratio, 1.12; 95% CI, 0.93 to 1.35; P=0.22), but there was a nonsignificant higher likelihood of 30-day mortality (odds ratio, 1.33; 95% CI, 0.93 to 1.88; P=0.11) at the time of the first episode of peritonitis for patients receiving APD. For all peritonitis episodes (including subsequent episodes of peritonitis), APD was associated with lower rates of culture-negative peritonitis (incidence rate ratio [IRR], 0.81; 95% CI, 0.69 to 0.94; P=0.002) and higher rates of gram-negative peritonitis (IRR, 1.28; 95% CI, 1.13 to 1.46; P=0.01). CONCLUSIONS PD modality was not associated with a higher likelihood of developing peritonitis. However, APD was associated with a borderline reduction in the likelihood of a first episode of Gram-positive peritonitis compared with CAPD, and with lower rates of culture-negative peritonitis and higher rates of Gram-negative peritonitis. Peritonitis outcomes were comparable between both modalities.