Mira Varagunam

Bicarbonate supplementation slows progression of CKD and improves nutritional status.

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 m(2)) 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 m(2)/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 m(2); 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

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?

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 donor-specific antibodies (DSA) and 22 non-DSA. There were no cases of hyperacute rejection in any of the groups. Biopsy-proven 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; P<0.05). 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

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 survival in the SS recipient and FS or FF donor group as compared with the other three groups (SS recipient and donor, FS or FF recipient and SS donor, and FS or FF recipient and donor) were not significant: 0.90 (95% confidence interval [CI], 0.7 to 1.14; P=0.33), 0.87 (95% CI, 0.65 to 1.16; P=0.33), and 0.89 (95% CI, 0.65 to 1.23; P=0.48), respectively. The four groups had similar patient-survival rates and similar cumulative rates of acute rejection and allograft dysfunction, as assessed by means of serum creatinine levels. CONCLUSIONS Our results suggest that transplantation of FS or FF kidneys to SS recipients is not advantageous, possibly because chronic allograft nephropathy is a multifaceted disease involving the interplay of many biologic pathways.

High pre-transplant soluble CD30 levels are predictive of the grade of rejection.

In renal transplantation, serum soluble CD30 (sCD30) levels in graft recipients are associated with increased rejection and graft loss. We investigated whether pre‐transplant sCD30 concentrations are predictive of the grade of rejection. Pre‐transplant sera of 51 patients with tubulointerstitial rejection (TIR), 16 patients with vascular rejection (VR) and an age‐matched control group of 41 patients with no rejection (NR) were analyzed for sCD30. The transplant biopsies were immunostained for C4d. The median sCD30 level was significantly elevated in the group with VR (248 Units (U)/mL, range: 92–802) when compared with TIR (103 U/mL, range: 36–309, p < 0.001) and NR (179 U/mL, range: 70–343, p < 0.03). Moreover, patients with TIR had significantly lower sCD30 levels compared to NR. Based on C4d staining, a TH2 driven process, the median sCD30 levels were significantly raised in C4d+ patients compared with C4d− group (177 U/mL vs. 120 U/mL, p < 0.05). sCD30 levels measured at time of transplantation correlate with the grade of rejection. High pre‐transplant levels are associated with antibody‐mediated rejection which carries a poorer prognosis. sCD30 could be another tool to assess immunological risk prior to transplantation and enable a patient centered approach to immunosuppression.

The role of salt intake and salt sensitivity in the management of hypertension in South Asian people with chronic kidney disease: a randomised controlled trial

Background The effectiveness of salt restriction to lower blood pressure (BP) in Bangladeshi patients with chronic kidney disease (CKD) is uncertain. Objective To test the hypothesis that a tailored intervention intended to reduce salt intake in addition to standard care will achieve a greater reduction in BP in UK Bangladeshi patients with CKD than standard care alone. Design A randomised parallel-group controlled trial conducted over a 6 month period. Setting A tertiary renal unit based in acute care hospital in East London. Participants 56 adult participants of Bangladeshi origin with CKD and BP >130/80 mm Hg or on antihypertensive medication. Intervention Participants were randomly allocated to receive a tailored low-salt diet or the standard low-salt advice. BP medication, physical activity and weight were monitored. Main outcome measures The primary outcome was change in ambulatory BP. Adherence to dietary advice was assessed by measurement of 24 h urinary salt excretion. Results Of 56 participants randomised, six withdrew at the start of the study. During the study, one intervention group participant died, one control group participant moved to Bangladesh. Data were available for the primary endpoint on 48 participants. Compared with control group the intervention urinary sodium excretion fell from 260 mmol/d to 103 mmol/d (−131 to −76, p<0.001) at 6 months and resulted in mean (95% CI) falls in 24 h systolic/diastolic BP of −8 mm Hg (−11 to −5)/2 (−4 to −2) both p<0.001. Conclusions A tailored intervention can achieve moderate salt restriction in patients with CKD, resulting in clinically meaningful falls in BP independent of hypertensive medication. Trial Registration ClinicalTrials.gov NCT00702312.

Mild chronic kidney disease is an independent predictor of long-term mortality after emergency angiography and primary percutaneous intervention in patients with ST-elevation myocardial infarction

Objective Moderate renal impairment (RI) with a glomerular filtration rate (GFR) <60 ml/min/1.73 m2 is known to predict survival. The authors investigated whether mild RI with an estimated GFR of 60–89 ml/min/1.73 m2 independently predicts survival in a contemporary population with ST segment elevation myocardial infarction (STEMI). Design This is a single-centre, observational, retrospective cohort study. Patients 601 patients with STEMI who underwent emergency catheter laboratory admission met the inclusion criteria for this study. Methods Estimated glomerular filtration rate (eGFR) was obtained by the Modified Diet in Renal Disease equation, and preprocedure renal function was subdivided into chronic kidney disease stages. Univariate and multivariate Cox regression analyses were performed to assess which of 17 patient or procedural variables were independent risk factors for death. Results Longitudinal data were collated for 576 patients (96.3%). Median follow-up time was 2.6 years. 30-day and long-term death rates were 5.7% and 12.5%, respectively. Following multivariable analysis, mild RI with an eGFR of 60–89 ml/min/1.73 m2 was a strong independent predictor of death, compared with an eGFR ≥90 ml/min/1.73 m2 (HR 2.79, 95% CI 1.98 to 3.92, p<0.001), and increasing chronic kidney disease stage was a strong predictor of death after both 30 days and long-term follow-up. An eGFR of 60–89 ml/min/1.73 m2 had a greater independent effect on short- and long-term mortality than the presence of diabetes mellitus (HR 2.0, 95% CI 1.2 to 3.33). Conclusion Mild RI (eGFR=60–89 ml/min/1.73 m2) on admission is strongly predictive of short- and long-term mortality in patients with STEMI admitted to the catheter laboratory. A redefined threshold of clinically significant impairment is now required (GFR<90 ml/min/1.73 m2).

Creatinine reduction ratio: a useful marker to identify medium and high-risk renal transplants.

Introduction. Delayed graft function (DGF) has a major impact on long-term renal transplant survival. However, it is a diagnosis made retrospectively with little opportunity to modify treatment protocols. A classification based on creatinine reduction ratio between days 1 and 2 (CRR2) suggests that patients with CRR2 less than or equal to 30% (nondialysis requiring DGF [ND-DGF]) have similar outcomes to those with dialysis-requiring delayed graft function (D-DGF). We retrospectively applied this definition in our cohort of patients to examine outcomes. Methods. We studied the association between CRR2 and graft outcomes in all 367 patients transplanted between 1996 and 2004 at our center. Patients were divided into the following three groups: IGF (immediate graft function; CRR2 >30%), D-DGF, and ND-DGF. Mean follow-up was 4.2 years. Results. IGF accounted for 36% of patients, D-DGF for 22%, and ND-DGF for 42%. CRR2 was inversely correlated with serum creatinine on days 7, 30, 90, and 365 (r ranging from −0.65 to −0.22, P<0.001). Graft survival at 5 years was 98% (IGF), 74% (D-DGF), and 89% (ND-DGF). There was a significant difference in graft survival between IGF and D-DGF (P<0.001) and IGF and ND-DGF (P=0.005). In a multivariate analysis adjusting for recipient age and sex, donor age and sex, and human leukocyte antigen mismatch, graft failure was 2.4 times more likely to occur in patients with D-DGF than those with ND-DGF(P=0.02). Conclusions. Our study shows CRR2 influences long-term graft outcomes. Unlike the original description, patients with ND-DGF carry an intermediate risk and perhaps should be considered on day 2 for alternative treatment protocols.

Prevalence of cognitive impairment in patients attending pre-dialysis clinic.

Approximately 20-30% of patients on renal replacement therapy (RRT) have cognitive impairment. Less is known about the prevalence of cognitive impairment in patients with advanced kidney disease awaiting the initiation of dialysis. Routine cognitive assessment was implemented in the pre-dialysis clinic, which enabled the Nephrologist and Pre-dialysis Nurse to identify those patients with impaired cognitive function and utilise this information to assess the suitability for self-care treatments, such as peritoneal dialysis, as well as to adapt information to meet their needs. Subsequently, a cross-sectional single-centre audit was undertaken to identify the prevalence of cognitive impairment in 132 consecutive new referrals to the pre-dialysis clinic using the Mini-mental State Examination (MMSE). Twenty percent (95% CI = 0.13, 0.27) were classified as cognitively impaired. Those with cognitive impairment were significantly older, and had lower eGFR and higher serum creatinine. It can be concluded that approximately 1 in 5 patients attending the pre-dialysis clinic has cognitive impairment, which may not be apparent on a routine clinical history. Cognitive function assessment is recommended for all, but particularly to the older patient, before advising on choice of dialysis modality or opting for conservative treatment.

A cross sectional study of consumer awareness of functional foods in Thessaloniki, Greece

Purpose – Increasing awareness of functional foods would have many health benefits such as reducing the incidence of non communicable diseases. The aim of this study is to investigate consumer awareness and consumption of functional foods in the city of Thessaloniki, Greece.Design/methodology/approach – A sample population of consumers was randomly selected outside popular supermarkets in the city of Thessaloniki (n=154). Trained interviewers conducted interviews and a questionnaire was completed by each participant. Socio‐demographic information and details of knowledge and consumption of functional foods were obtained. Data were analyzed using Stata.Findings – The analysis of the data showed that only 33 per cent of the consumers were aware of the term “functional foods”. Interestingly, the proportion of the sample population that knew about foods with health promoting factors was over 95 per cent. The term “functional food” was unfamiliar to the sample population. Over 70 per cent of the consumers surv...