Mira Varagunam

Bio: Mira Varagunam is an academic researcher from University of London. The author has contributed to research in topics: Kidney disease & Transplantation. The author has an hindex of 14, co-authored 15 publications receiving 1416 citations. Previous affiliations of Mira Varagunam include Queen Mary University of London.

Bicarbonate Supplementation Slows Progression of CKD and Improves Nutritional Status

Abstract: Bicarbonate supplementation preserves renal function in experimental chronic kidney disease (CKD), but whether the same benefit occurs in humans is unknown. Here, we randomly assigned 134 adult patients with CKD (creatinine clearance [CrCl] 15 to 30 ml/min per 1.73 m2) and serum bicarbonate 16 to 20 mmol/L to either supplementation with oral sodium bicarbonate or standard care for 2 yr. The primary end points were rate of CrCl decline, the proportion of patients with rapid decline of CrCl (>3 ml/min per 1.73 m2/yr), and ESRD (CrCl <10 ml/min). Secondary end points were dietary protein intake, normalized protein nitrogen appearance, serum albumin, and mid-arm muscle circumference. Compared with the control group, decline in CrCl was slower with bicarbonate supplementation (5.93 versus 1.88 ml/min 1.73 m2; P < 0.0001). Patients supplemented with bicarbonate were significantly less likely to experience rapid progression (9 versus 45%; relative risk 0.15; 95% confidence interval 0.06 to 0.40; P < 0.0001). Similarly, fewer patients supplemented with bicarbonate developed ESRD (6.5 versus 33%; relative risk 0.13; 95% confidence interval 0.04 to 0.40; P < 0.001). Nutritional parameters improved significantly with bicarbonate supplementation, which was well tolerated. This study demonstrates that bicarbonate supplementation slows the rate of progression of renal failure to ESRD and improves nutritional status among patients with CKD.

High glucose-induced oxidative stress causes apoptosis in proximal tubular epithelial cells and is mediated by multiple caspases

Abstract: Diabetic nephropathy is the leading cause of end-stage renal disease in the Western world. Poor glycemic control contributes to the development of diabetic nephropathy, but the mechanisms underlying high glucose-induced tissue injury are not fully understood. In the present study, the effect of high glucose on a proximal tubular epithelial cell (PTEC) line was investigated. Reactive oxygen species (ROS) were detected using the fluorescent probes dichlorofluorescein diacetate, dihydrorhodamine 123, and 2,3-diaminonapthalene. Peroxynitrite (ONOO-) generation and nitrite concentrations were increased after 24 h of high glucose treatment (P<0.05). LLC-PK1 cells exposed to high D-glucose (25 mM) for up to 48 h had increased DNA fragmentation (P<0.01), caspase-3 activity (P<0.001), and annexin-V staining (P<0.05) as well as decreased expression of XIAP when compared with controls (5 mM D-glucose). The ONOO- scavenger ebselen reduced DNA fragmentation and caspase-3 activity as well as the high glucose-induced nitrite production and DCF fluorescence. High glucose-induced DNA fragmentation was completely prevented by an inhibitor of caspase-3 (P<0.01) and a pan-caspase inhibitor (P<0.001). Caspase inhibition did not affect ROS generation. This study, in a PTEC line, demonstrates that high glucose causes the generation of ONOO-, leading to caspase-mediated apoptosis. Ebselen and a caspase-3 inhibitor provided significant protection against high glucose-mediated apoptosis, implicating ONOO- as a proapoptotic ROS in early diabetic nephropathy.

Pretransplant Donor-Specific Antibodies in Cytotoxic Negative Crossmatch Kidney Transplants: Are They Relevant?

Abstract: Background. The corresponding antigens of alloantibodies identified in patients awaiting kidney transplantation are often listed as unacceptable for transplantation. The use of solid phase testing, being more sensitive and accurate than conventional complement-dependent cytotoxicity (CDC) assays, has resulted in increased identification of alloantibodies. We aimed to study the clinical importance of alloantibodies defined solely by solid phase techniques. Methods. All patients transplanted between 1999 and 2001 at our center with available day-of-transplant sera (D0) were included (121 patients). All had negative CDC crossmatches. Results. Thirty-eight patients (31%) had detectable alloantibodies using high-definition assays with 16 having donorspecific antibodies (DSA) and 22 non-DSA. There were no cases of hyperacute rejection in any of the groups. Biopsyproven acute rejection rates in the DSA and non-DSA were similar to the unsensitized group. Delayed graft function and 1-year graft survival rates were also similar for the three groups as were median 1-year serum creatinine levels. Multivariate analysis, however, showed that DSA were associated with an increased relative risk of longer-term graft failure (relative risk, 6.5; P0.05). Conclusions. These data show that in the context of a CDC-negative crossmatch, the presence of D0 DSA has little impact on any early graft parameters. DSA, however, are associated with poorer longer-term graft outcomes in kidney transplantation.

C3 polymorphisms and allograft outcome in renal transplantation.

Abstract: Background Complement activation plays a role in the development of chronic allograft nephropathy, a common cause of late allograft loss. The role of two complement component 3 (C3) allotypes, called C3F (fast) and C3S (slow) on the basis of their electrophoretic motility, in the long-term outcome of renal allografts remains controversial. Methods We selected a random sample of 1147 donor and recipient pairs from the Collaborative Transplant Study DNA bank, and their DNA specimens were genotyped for the C3F and C3S alleles. The genotyping results were analyzed according to allograft outcome. Transplants were divided into four groups, according to the recipient and donor genotypes: SS recipient and FS or FF donor (the standard for comparison, since this combination has been reported to have the best outcome), SS recipient and donor, FS or FF recipient and SS donor, and FS or FF recipient and donor. Results Baseline characteristics of the four transplant groups were similar. The hazard ratios for allograft ...

Nitric Oxide and Peroxynitrite in Health and Disease

Abstract: The discovery that mammalian cells have the ability to synthesize the free radical nitric oxide (NO) has stimulated an extraordinary impetus for scientific research in all the fields of biology and medicine. Since its early description as an endothelial-derived relaxing factor, NO has emerged as a fundamental signaling device regulating virtually every critical cellular function, as well as a potent mediator of cellular damage in a wide range of conditions. Recent evidence indicates that most of the cytotoxicity attributed to NO is rather due to peroxynitrite, produced from the diffusion-controlled reaction between NO and another free radical, the superoxide anion. Peroxynitrite interacts with lipids, DNA, and proteins via direct oxidative reactions or via indirect, radical-mediated mechanisms. These reactions trigger cellular responses ranging from subtle modulations of cell signaling to overwhelming oxidative injury, committing cells to necrosis or apoptosis. In vivo, peroxynitrite generation represents a crucial pathogenic mechanism in conditions such as stroke, myocardial infarction, chronic heart failure, diabetes, circulatory shock, chronic inflammatory diseases, cancer, and neurodegenerative disorders. Hence, novel pharmacological strategies aimed at removing peroxynitrite might represent powerful therapeutic tools in the future. Evidence supporting these novel roles of NO and peroxynitrite is presented in detail in this review.

A Predictive Model for Progression of Chronic Kidney Disease to Kidney Failure

Abstract: Context Chronic kidney disease (CKD) is common. Kidney disease severity can be classified by estimated glomerular filtration rate (GFR) and albuminuria, but more accurate information regarding risk for progression to kidney failure is required for clinical decisions about testing, treatment, and referral. Objective To develop and validate predictive models for progression of CKD. Design, Setting, and Participants Development and validation of prediction models using demographic, clinical, and laboratory data from 2 independent Canadian cohorts of patients with CKD stages 3 to 5 (estimated GFR, 10-59 mL/min/1.73 m 2 ) who were referred to nephrologists between April 1, 2001, and December 31, 2008. Models were developed using Cox proportional hazards regression methods and evaluated using C statistics and integrated discrimination improvement for discrimination, calibration plots and Akaike Information Criterion for goodness of fit, and net reclassification improvement (NRI) at 1, 3, and 5 years. Main Outcome Measure Kidney failure, defined as need for dialysis or preemptive kidney transplantation. Results The development and validation cohorts included 3449 patients (386 with kidney failure [11%]) and 4942 patients (1177 with kidney failure [24%]), respectively. The most accurate model included age, sex, estimated GFR, albuminuria, serum calcium, serum phosphate, serum bicarbonate, and serum albumin (C statistic, 0.917; 95% confidence interval [CI], 0.901-0.933 in the development cohort and 0.841; 95% CI, 0.825-0.857 in the validation cohort). In the validation cohort, this model was more accurate than a simpler model that included age, sex, estimated GFR, and albuminuria (integrated discrimination improvement, 3.2%; 95% CI, 2.4%-4.2%; calibration [Nam and D’Agostino χ 2 statistic, 19 vs 32]; and reclassification for CKD stage 3 [NRI, 8.0%; 95% CI, 2.1%-13.9%] and for CKD stage 4 [NRI, 4.1%; 95% CI, −0.5% to 8.8%]). Conclusion A model using routinely obtained laboratory tests can accurately predict progression to kidney failure in patients with CKD stages 3 to 5.

Epidemiology of chronic kidney disease in children

Abstract: In the past 30 years there have been major improvements in the care of children with chronic kidney disease (CKD). However, most of the available epidemiological data stem from end-stage renal disease (ESRD) registries and information on the earlier stages of pediatric CKD is still limited. The median reported incidence of renal replacement therapy (RRT) in children aged 0–19 years across the world in 2008 was 9 per million of the age-related population (4–18 years). The prevalence of RRT in 2008 ranged from 18 to 100 per million of the age-related population. Congenital disorders, including congenital anomalies of the kidney and urinary tract (CAKUT) and hereditary nephropathies, are responsible for about two thirds of all cases of CKD in developed countries, while acquired causes predominate in developing countries. Children with congenital disorders experience a slower progression of CKD than those with glomerulonephritis, resulting in a lower proportion of CAKUT in the ESRD population compared with less advanced stages of CKD. Most children with ESRD start on dialysis and then receive a transplant. While the survival rate of children with ERSD has improved, it remains about 30 times lower than that of healthy peers. Children now mainly die of cardiovascular causes and infection rather than from renal failure.

Preexisting Donor-Specific HLA Antibodies Predict Outcome in Kidney Transplantation

Abstract: The clinical importance of preexisting HLA antibodies at the time of transplantation, identified by contemporary techniques, is not well understood. We conducted an observational study analyzing the association between preexisting donor-specific HLA antibodies (HLA-DSA) and incidence of acute antibody-mediated rejection (AMR) and survival of patients and grafts among 402 consecutive deceased-donor kidney transplant recipients. We detected HLA-DSA using Luminex single-antigen assays on the peak reactive and current sera. All patients had a negative lymphocytotoxic cross-match test on the day of transplantation. We found that 8-year graft survival was significantly worse (61%) among patients with preexisting HLA-DSA compared with both sensitized patients without HLA-DSA (93%) and nonsensitized patients (84%). Peak HLA-DSA Luminex mean fluorescence intensity (MFI) predicted AMR better than current HLA-DSA MFI (P = 0.028). As MFI of the highest ranked HLA-DSA detected on peak serum increased, graft survival decreased and the relative risk for AMR increased: Patients with MFI >6000 had >100-fold higher risk for AMR than patients with MFI <465 (relative risk 113; 95% confidence interval 31 to 414). The presence of HLA-DSA did not associate with patient survival. In conclusion, the risk for both AMR and graft loss directly correlates with peak HLA-DSA strength. Quantification of HLA antibodies allows stratification of immunologic risk, which should help guide selection of acceptable grafts for sensitized patients.