Exercise-induced lowering of chemerin is associated with reduced cardiometabolic risk and glucose-stimulated insulin secretion in older adults.

OBJECTIVE: To determine the effect of exercise on chemerin in relation to changes in fat loss, insulin action, and dyslipidemia in older adults. PARTICIPANTS: Thirty older (65.9±0.9yr) obese adults (BMI:34.5±0.7kg/m2). SETTING: Single-center, Cleveland Clinic. DESIGN: Prospective clinical trial. INTERVENTION: Twelve-weeks of exercise training (60minutes/day, 5day/week at ~85% HRmax). Subjects were instructed to maintain habitual nutrient intake. MEASUREMENTS: Plasma chemerin was analyzed using an enzyme-linked immunosorbent assay. Peripheral and hepatic insulin sensitivity was assessed using a euglycemic-hyperinsulinic clamp with glucose kinetics. First-phase and total glucose-stimulated insulin secretion (GSIS) was calculated from an oral glucose tolerance test. Fasting blood lipids (cholesterol, triglycerides), total/visceral fat (dual-x-ray absorptiometry and computerized tomography) and cardiorespiratory fitness (treadmill test) were also tested pre and post intervention. RESULTS: Exercise increased fitness and reduced total/visceral fat, blood lipids, and first-phase GSIS (P<0.05). Training also increased peripheral insulin sensitivity and lowered basal/insulin-related hepatic glucose production (P<0.01). The intervention reduced chemerin (87.1±6.0 vs. 78.1±5.8ng/ml; P=0.02), and the reduction correlated with decreased visceral fat (r=0.50, P=0.009), total body fat (r=0.42, P=0.02), cholesterol (r=0.38, P=0.04), triglycerides (r=0.36, P=0.05), and first-phase and total GSIS (r=0.39, P=0.03 and r=0.43, P=0.02, respectively). CONCLUSIONS: Lower chemerin appears to be an important hormone involved in cardiometabolic risk and GSIS reduction following exercise in older adults.

Association of metabolic syndrome with kidney function and histology in living kidney donors.

The selection of living kidney donors is based on a formal evaluation of the state of health. However, this spectrum of health includes subtle metabolic derangements that can cluster as metabolic syndrome. We studied the association of metabolic syndrome with kidney function and histology in 410 donors from 2005 to 2012, of whom 178 donors were systematically followed after donation since 2009. Metabolic syndrome was defined as per the NCEP ATPIII criteria, but using a BMI > 25 kg/m(2) instead of waist circumference. Following donation, donors received counseling on lifestyle modification. Metabolic syndrome was present in 50 (12.2%) donors. Donors with metabolic syndrome were more likely to have chronic histological changes on implant biopsies than donors with no metabolic syndrome (29.0% vs. 9.3%, p < 0.001). This finding was associated with impaired kidney function recovery following donation. At last follow-up, reversal of metabolic syndrome was observed in 57.1% of donors with predonation metabolic syndrome, while only 10.8% of donors developed de novo metabolic syndrome (p < 0.001). In conclusion, metabolic syndrome in donors is associated with chronic histological changes, and nephrectomy in these donors was associated with subsequent protracted recovery of kidney function. Importantly, weight loss led to improvement of most abnormalities that define metabolic syndrome.

Overweight, obesity and intentional weight loss in chronic kidney disease: NHANES 1999-2006.

OBJECTIVE: Obesity and chronic kidney disease (CKD) have emerged as major public health problems. We aimed to examine: (a) lifestyle and behavioral factors, (b) factors related to pursuing weight loss and (c) weight loss modalities pursued by CKD and non-CKD individuals who are overweight and obese. METHODS: Cross-sectional analysis of 10,971 overweight and obese adult participants in the National Health and Nutrition Examination Surveys conducted between 1999 and 2006. We examined the differences in lifestyle and behavioral factors between CKD and non-CKD participants and factors associated with pursuing weight loss using survey regression models. RESULTS: The total daily energy intake of the CKD population was lower than the non-CKD group (1987 kcal per day versus 2063 kcal per day, P=0.02) even after adjusting for relevant covariates. However, the percentage of energy derived from protein was similar between the groups. Sixty six percent of the CKD population did not meet the minimum recommended leisure time physical activity goals compared with 57% among non-CKD (P<0.001). Fifty percent of CKD participants pursued weight loss (vs fifty-five percent of non-CKD individuals, P=0.01), but the presence of CKD was not independently associated with the pursuit of weight loss in the multivariate model. Among participants pursuing weight loss, modalities including dietary interventions utilized by CKD and non-CKD participants were similar. Eight percent of CKD participants used medications to promote weight loss. CONCLUSIONS: Among the overweight and obese population, lifestyle and behavioral factors related to obesity and weight loss are similar between CKD and non-CKD participants. Insufficient data exist on the beneficial effects of intentional weight loss in CKD and these data show that a significant proportion of the CKD population use diets that may have high-protein content and medications to promote weight loss that may be harmful. Future clinical trials evaluating the efficacy and optimal modalities to treat obesity in the CKD population are warranted.

Marked variation of the association of ESRD duration before and after wait listing on kidney transplant outcomes.

Numerous studies report a strong association between pretransplant end-stage renal disease (ESRD) duration and diminished transplant outcomes. However, cumulative waiting time may reflect distinct phases and processes related to patients' physiological condition as well as pre-existing morbidity and access to care. The relative impact of pre- and postlisting ESRD durations on transplant outcomes is unknown. We examined the impact of these intervals from a national cohort of kidney transplant recipients from 1999 to 2008 (n = 112,249). Primary factors explaining prelisting ESRD duration were insurance and race, while primary factors explaining postlisting ESRD duration were blood type, PRA% and variation between centers. Extended time from ESRD to waitlisting had significant dose-response association with overall graft loss (AHR = 1.26 for deceased donors [DD], AHR = 1.32 for living donors [LD], p values < 0.001). Contrarily, time from waitlisting (after ESRD) to transplantation had negligible effects (p = 0.10[DD], p = 0.57[LD]). There were significant associations between pre- and postlisting ESRD time with posttransplant patient survival, however prelisting time had over sixfold greater effect. Prelisting ESRD time predominately explains the association of waiting time with transplant outcomes suggesting that factors associated with this interval should be prioritized for interventions and allocation policy. The degree to which the effect of prelisting ESRD time is a proxy for comorbid conditions, socioeconomic status or access to care requires further study.

Referral patterns of primary care physicians for chronic kidney disease in general population and geriatric patients.

BACKGROUND: Late referral of patients with chronic kidney disease (CKD) by primary care physicians (PCPs) is associated with poor outcomes. We sought to assess factors influencing PCPs referral patterns in the general population and in geriatric patients, and compared their perceptions to the referral patterns. METHODS: We retrospectively reviewed 268 patients with Stage 3 CKD (early referral) and 280 with Stage 4 CKD (appropriate referral) seen in renal clinic and compared them to 268 randomly selected non-referred Stage 4 CKD patients from primary care physicians office records. We also surveyed 400 regional PCPs on factors influencing their referral for CKD. RESULTS: Non-referred patients were significantly (p < 0.05) more likely to be over 65 years (OR: 3.5; 95% CI: 2.3 - 5.2), females (OR: 1.4; 95% CI: 1.0 - 2.0) and of non-white race (OR: 2.6; 95% CI: 1.5 - 4.5) after adjusting for relevant confounding variables. Charlson comorbidity index greater than 4 was associated with non-referral when the non-referral group was compared to the early referral group. Among geriatric patients, women and a higher comorbidity index were associated with non-referral. 25% of PCPs completed the survey and 62% PCPs were unfamiliar with K/DOQI referral guidelines. Age > 75 years, limited life expectancy, patient noncompliance or refusal to consider dialysis influenced PCPs decision to refer. CONCLUSIONS: Our study shows that elderly women, minorities and patients with multiple comorbidities are at risk for non-referral for CKD care. Educating PCPs on the appropriate referral of CKD patients, especially those at risk for late or non-referral to a nephrologist is warranted, as are trials assessing different educational strategies.

Anti-neutrophil cytoplasmic antibody associated crescentic IgA nephropathy in hematopoietic stem cell transplantation.

Membranous glomerulonephritis and minimal change disease are the most common forms of glomerular diseases noted in patients with graft versus host disease after hematopoietic stem cell transplantation. Herein, we report a patient who developed anti-neutrophil cytoplasmic antibody associated crescentic IgA nephropathy within 3 months after autologous hematopoietic stem cell transplantation. He was treated with intravenous pulse steroids and monthly intravenous cyclophosphamide for 6 months followed by cyclophosphamide every 3 months and tapering dose of steroids. His proteinuria resolved and renal function remained stable. Two cases of crescentic IgA nephropathy have been reported in patients who underwent allogenic hematopoietic stem cell transplantation. The etiology of IgA nephropathy developing after hematopoietic stem cell transplantation is unclear and larger registry-based studies are needed to further explore this condition.

Choice of extracorporeal dialysis modality: can it be evidence based?

The incidence of end stage kidney disease is increasing worldwide and extracorporeal renal replacement techniques are widely used to treat these patients. Convective dialytic therapies such as hemodiafiltration are claimed to be superior to diffusive techniques such as hemodialysis given the higher clearance rates, hemodynamic stability and possibly reduced morbidity and mortality rates. Although observational studies have held this contention, randomized trials failed to do so. In this article, we present a case report and review available trial and systematic review evidence on the benefits-harms of various extracorporeal techniques. Both convective and diffusive clearance techniques were found to have similar all-cause mortality and hospitalization rates. Data on quality of life, dialysis related amyloidosis and procedure related outcomes such as hypotension have not been well studied. Most of the unbiased information, in the form of randomized trials, are only deriving from few and very small studies while large trials are lacking. Currently, there are three ongoing randomized clinical trials analyzing the efficacy of various extracorporeal techniques with focus on hard end points and their results will shed more light on this topic. Until then, since both convective and diffusive therapies have not been found to be different with respect to major patient-level outcomes but only some surrogates of uncertain clinical importance, the choice of renal replacement therapy should be based on other factors such as patients' preference, availability of dialysis centers and cost.

Haemoglobin and haematocrit targets for the anaemia of chronic kidney disease.

BACKGROUND: Anaemia affects 60% to 80% of patients with chronic kidney disease (CKD) reduces quality of life and is a risk factor for early death. Treatment options are blood transfusion, erythropoietin (EPO) and darbepoetin alfa. Recently higher haemoglobin (Hb) and haematocrit (HCT) targets have been widely advocated because of positive associations with improved survival and quality of life from observational studies. OBJECTIVES: To assess the benefits and harms of different Hb or HCT targets in CKD patients receiving any treatment for anaemia. SEARCH STRATEGY: We searched The Cochrane Renal Group's specialised register, Cochrane Central Register of Controlled Trials (CENTRAL, in The Cochrane Library) MEDLINE (from 1966), EMBASE (from 1980) and reference lists of retrieved articles. Date of most recent search: April 2006 SELECTION CRITERIA: Randomised controlled trials (RCTs) and quasi-RCTs comparing different Hb/HCT targets in patients with the anaemia of CKD. DATA COLLECTION AND ANALYSIS: Two reviewers independently assessed trial quality and extracted data. Statistical analyses were performed using the random effects model and results expressed as relative risks (RR) for dichotomous outcomes and weighted mean difference (MD) for continuous outcomes, with 95% confidence intervals (CI). MAIN RESULTS: Twenty two trials (3707 patients) were included. Hb > or = 133 g/L was not associated with a reduction in the risk of all-cause mortality compared with 120 g/L in dialysis and pre-dialysis patients. In pre-dialysis patients, there was a significantly lower end of treatment creatinine clearance with Hb < 120 g/L compared to > 130 g/L (MD -4.17, 95% CI -6.33 to -2.02) but no significant difference in the risk of end-stage kidney disease (ESKD) (RR 1.05, 95% CI 0.50 to 2.22). Lower Hb targets resulted in an increased risk for seizures (RR 5.25, 95% CI 1.13 to 24.34) and a reduced risk of hypertensive episodes (RR 0.50, 95% CI 0.33 to 0.76). There were no significant differences in the risk of vascular access thrombosis. AUTHORS' CONCLUSIONS: There was no significant difference in the risk of death for low (< 120 g/L) versus higher Hb targets (>133 g/L). Lower Hb targets were significantly associated with an increased risk for seizures but a reduced risk of hypertension. In general study quality was poor. There is a need for more adequately powered, well-designed and reported trials. Trials should be pragmatic, focusing on hard end-points (mortality, ESKD, major side effects) or outcomes which were previously not studied adequately (e.g. seizures, quality of life).

Angiotensin converting enzyme inhibitors and angiotensin II receptor antagonists for preventing the progression of diabetic kidney disease.

BACKGROUND: Angiotensin converting enzyme inhibitors (ACEi) and angiotensin II receptor antagonists (AIIRA) are considered to be equally effective for patients with diabetic kidney disease (DKD), but renal and not mortality outcomes have usually been considered. OBJECTIVES: To evaluate the benefits and harms ACEi and AIIRA in patients with DKD. SEARCH STRATEGY: We searched MEDLINE (1966 to December 2005), EMBASE (1980 to December 2005), the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library issue 4 2005) and contacted known investigators. SELECTION CRITERIA: Studies comparing ACEi or AIIRA with placebo or each other in patients with DKD were included. DATA COLLECTION AND ANALYSIS: Two authors independently assessed trial quality and extracted data. Statistical analyses were performed using the random effects model and results expressed as relative risk (RR) with 95% confidence intervals (CI). Heterogeneity among studies was explored using the Cochran Q statistic and the I(2) test, subgroup analyses and random effects metaregression. MAIN RESULTS: Fifty studies (13,215 patients) were identified. Thirty eight compared ACEi with placebo, five compared AIIRA with placebo and seven compared ACEi and AIIRA directly. There was no significant difference in the risk of all-cause mortality for ACEi versus placebo (RR 0.91, 95% CI 0.71 to 1.17) and AIIRA versus placebo (RR 0.99, 95% CI 0.85 to 1.17). A subgroup analysis of studies using full-dose ACEi versus studies using half or less than half the maximum tolerable dose of ACEi showed a significant reduction in the risk of all-cause mortality with the use of full-dose ACEi (RR 0.78, 95% CI 0.61 to 0.98). Baseline mortality rates were similar in the ACEi and AIIRA studies. The effects of ACEi and AIIRA on renal outcomes (ESKD, doubling of creatinine, prevention of progression of micro- to macroalbuminuria, remission of micro- to normoalbuminuria) were similarly beneficial. Reliable estimates of effect of ACEi versus AIIRA could not be obtained from the three studies in which they were compared directly because of their small sample size. AUTHORS' CONCLUSIONS: Although the survival benefits of ACEi are known for patients with DKD, the relative effects on survival of ACEi with AIIRA are unknown due to the lack of adequate direct comparison studies. In placebo controlled studies, only ACEi (at the maximum tolerable dose, but not lower so-called renal doses) were found to significantly reduce the risk of all-cause mortality. Renal and toxicity profiles of these two classes of agents were not significantly different.

Tacrolimus-associated hypomagnesemia in renal transplant recipients.

BACKGROUND: Since hypomagnesemia occurs frequently in tacrolimus treated patients, we studied the correlation between renal magnesium wasting and tacrolimus blood levels in renal transplant patients. METHODS: Serum magnesium, fractional excretion of magnesium (FEMg), and 24-hour urinary excretion of magnesium were measured in 41 transplant patients and 10 healthy volunteers for correlation with tacrolimus level. RESULTS: Of tacrolimus-treated patients, 43% displayed hypomagnesemia. FEMg (7.42+/-3.59% versus 1.88+/-0.43%) and 24-hour urinary excretion (112.36+/-51.43 mg/dL versus 6.7+/-2.79 mg/dL) were significantly higher among tacrolimus-treated patients than controls. Magnesium replacement did not influence FEMg or 24-hour urinary magnesium excretion. Tacrolimus level was the best predictor of 24-hour urinary magnesium excretion and FEMg. Serum magnesium levels correlated inversely with tacrolimus concentrations and creatinine clearance. CONCLUSION: Hypomagnesemia in renal transplant recipients results from renal magnesium wasting. Tacrolimus levels and renal function impact on the excess renal magnesium excretion. Studies of longer duration are warranted to assess the long-term effects of this early posttransplant hypomagnesemia.

Antimicrobial agents and catheter-related interventions to prevent peritonitis in peritoneal dialysis: Using evidence in the context of clinical practice.

BACKGROUND: Peritonitis still represents a common and major complication of peritoneal dialysis. The broader adoption of several strategies, including antimicrobial and catheter related interventions, has been advocated to prevent or reduce the risk of peritonitis in peritoneal dialysis. METHODS: In this article we start with the presentation of a clinical case where concern exists about the strategies for preventing peritoneal dialysis peritonitis. We then look at the available evidence in the form of systematic reviews of randomized trials and individual randomized trials of interventions to prevent peritonitis in peritoneal dialysis. A summary of the evidence is provided and then put in context with the clinical case scenario. RESULTS: Nineteen eligible trials (1949 patients) of antimicrobial agents and 37 (2822 patients) of catheter related interventions to prevent peritonitis in peritoneal dialysis were identified. Nasal mupirocin compared with placebo significantly reduced the exit-site and tunnel infection rate (1 trial, 2716 patient months, RR 0.58, 95% CI 0.40 to 0.85) but not peritonitis rate (1 trial, 2716 patient months, RR 0.84, 95% CI 0.44 to 1.60). As for antimicrobial strategies, perioperative intravenous antibiotics compared with no treatment significantly reduced the risk of early peritonitis (4 trials, 335 patients, RR 0.35, 95% CI 0.15 to 0.80) but not exit site and tunnel infection (3 trials, 114 patients, RR 0.32, 95% CI 0.02 to 4.81). As for catheter related strategies, Y-set and twin-bag systems were superior to conventional spike systems (7 trials, 485 patients, RR 0.64, 95% CI 0.53 to 0.77) and no other catheter-related intervention was demonstrated to prevent peritonitis in PD. CONCLUSIONS: Evidence exists to support the use of perioperative intravenous antibiotic prophylaxis at the time of catheter placement, the twin-bag and Y-set system, as well as prophylaxis with mupirocin in Staphylococcus aureus nasal carriers. Despite lack of evidence, several other agents are used and recommended in major international guidelines, which is reasonable but requires further investigation.

HMG CoA reductase inhibitors (statins) for dialysis patients.

BACKGROUND: Cardiovascular disease accounts for more than half the number of deaths among dialysis patients. The role of HMG CoA reductase inhibitors (statins) in the treatment of hyperlipidemia in dialysis patients is unclear and their safety has not been established. OBJECTIVES: To assess the benefits and harms of statins in peritoneal dialysis (PD) and hemodialysis patients (HD). SEARCH STRATEGY: We searched MEDLINE (1966-July 2003), EMBASE (1980-July 2003), the Cochrane Central Register of Controlled trials (CENTRAL, in The Cochrane Library - issue 2, 2004), the Cochrane Renal Group's specialized register (April 2004) and handsearched reference lists of textbooks, articles and scientific proceedings. SELECTION CRITERIA: Randomized controlled trials (RCTs) and quasi-RCTs comparing statins with placebo, no treatment or other statins in dialysis patients. DATA COLLECTION AND ANALYSIS: Two reviewers independently assessed trial quality and extracted data. Statistical analyses were performed using the random effects model after testing for heterogeneity. The results were expressed as weighted mean difference (WMD) for continuous outcomes and relative risk (RR) for dichotomous outcomes with 95% confidence intervals (CI). MAIN RESULTS: Six studies involving 357 participants were identified - three studies had both continuous ambulatory peritoneal dialysis (CAPD) and HD participants, two included only HD participants and one study only included CAPD participants. Studies were all of short duration and morbidity and mortality were not assessed. Average total cholesterol decreased significantly with statins compared to placebo in all dialysis patients (WMD -53.70 mg/dL (1.40 mmol/L), 95% CI -66.95 to -40.54). Similarly, average LDL cholesterol decreased significantly with statins in comparison to placebo in all patients (WMD -55.40 mg/dL (1.44 mmol/L), 95% CI -69.90 to -40.90) as did average triglycerides (-33.72 mg/dL (0.37 mmol/L), 95% CI -54.16 to -13.28). There was a significant increase in average HDL cholesterol levels (WMD 4.84 mg/dL (0.13 mmol/L), 95% CI 0.28 to 9.40) with statins compared to placebo in HD but not in CAPD patients. One trial compared statins to the hypolidemic agent probucol and found no significant differences between the two treatment groups. REVIEWERS' CONCLUSIONS: Statins used for 12 weeks decreased cholesterol levels in dialysis patients similar to the general population. Included studies were of short duration and therefore the efficacy of statins in decreasing the cardiovascular, cerebrovascular events and mortality rates is still unclear. The safety of statins needs to be addressed in the current ongoing clinical trials.