Tenofovir use is associated with a reduction in calculated glomerular filtration rates in the Swiss HIV Cohort Study.

BACKGROUND: A growing number of case reports have described tenofovir (TDF)-related proximal renal tubulopathy and impaired calculated glomerular filtration rates (cGFR). We assessed TDF-associated changes in cGFR in a large observational HIV cohort. METHODS: We compared treatment-naive patients or patients with treatment interruptions > or = 12 months starting either a TDF-based combination antiretroviral therapy (cART) (n = 363) or a TDF-sparing regime (n = 715). The predefined primary endpoint was the time to a 10 ml/min reduction in cGFR, based on the Cockcroft-Gault equation, confirmed by a follow-up measurement at least 1 month later. In sensitivity analyses, secondary endpoints including calculations based on the modified diet in renal disease (MDRD) formula were considered. Endpoints were modelled using pre-specified covariates in a multiple Cox proportional hazards model. RESULTS: Two-year event-free probabilities were 0.65 (95% confidence interval [CI] 0.58-0.72) and 0.80 (95% CI 0.76-0.83) for patients starting TDF-containing or TDF-sparing cART, respectively. In the multiple Cox model, diabetes mellitus (hazard ratio [HR] = 2.34 [95% CI 1.24-4.42]), higher baseline cGFR (HR = 1.03 [95% CI 1.02-1.04] by 10 ml/min), TDF use (HR = 1.84 [95% CI 1.35-2.51]) and boosted protease inhibitor use (HR = 1.71 [95% CI 1.30-2.24]) significantly increased the risk for reaching the primary endpoint. Sensitivity analyses showed high consistency. CONCLUSION: There is consistent evidence for a significant reduction in cGFR associated with TDF use in HIV-infected patients. Our findings call for a strict monitoring of renal function in long-term TDF users with tests that distinguish between glomerular dysfunction and proximal renal tubulopathy, a known adverse effect of TDF.

Protein level expression of Toll-like receptors 2, 4 and 9 in renal disease.

Background. Toll-like receptors (TLR) recognize a variety of ligands, including pathogen-associated molecular patterns and link innate and adaptive immunity. Individual receptors can be up-regulated during infection and inflammation. We examined the expression of selected TLRs at the protein level in various types of renal disease.Methods. Frozen sections of renal biopsies were stained with monoclonal antibodies to TLR-2, -4 and -9.Results. Up-regulation of the three TLRs studied was seen, although the extent was modest. TLR-2- and -4-positive cells belonged to the population of infiltrating inflammatory cells; only in the case of TLR-9 were intrinsic glomerular cells positive in polyoma virus infection and haemolytic uraemic syndrome (HUS).Conclusions. Evidence for the involvement of the three TLRs tested in a variety of human renal diseases was found. These findings add to our understanding of the role of the innate immune system in kidney disease.

Determinants and burden of chronic kidney disease in the population-based CoLaus study: a cross-sectional analysis.

BACKGROUND: Chronic kidney disease (CKD) represents an increasing health burden. We present the population-based prevalence of CKD and compare the CKD Epidemiology collaboration (CKD-EPI) and modification of diet in renal disease (MDRD) equations to estimate the glomerular filtration rate, using the revised CKD classification with three albuminuria classes. We also explore factors associated with CKD. METHODS: The Swiss population-based, cross-sectional CoLaus study conducted in Lausanne (2003-2006) included 2810 men and 3111 women aged 35-75. CKD prevalence was assessed using CKD-EPI and MDRD equations and albuminuria estimated by the albumin-to-creatinine ratio in spot morning urine. Multivariate logistic regression was used to analyse determinants of CKD. RESULTS: Prevalence [95% confidence interval (CI)] of all stages CKD was 10.0% (9.2-10.8%) with CKD-EPI and 13.8% (12.9-14.6%) with MDRD. Using the revised CKD classification, the prevalence of low-, medium-, high- and very high-risk groups was 90.0, 8.46, 1.18 and 0.35% with CKD-EPI, respectively. With MDRD, the corresponding values were 86.24, 11.86, 1.55 and 0.35%. Using the revised classification, CKD-EPI systematically reclassified people in a lower risk category than MDRD. Age and obesity were more strongly associated with CKD in men [odds ratio (95% CI): 2.23(1.95; 2.56) per 10 years and 3.05(2.08;4.47), respectively] than in women [1.46 (1.29; 1.65) and 1.78 (1.30;2.44), respectively]. Hypertension, type 2 diabetes, serum homocysteine and uric acid were positively independently associated with CKD in men and women. CONCLUSIONS: One in 10 adults suffers from CKD in the population of Lausanne. CKD-EPI systematically reclassifies people in a lower CKD risk category than MDRD. Serum homocysteine and uric acid levels are associated with CKD independently of classical risk factors such as age, hypertension and diabetes.

Cystatin C as a marker of early changes of renal function in Fabry nephropathy.

BACKGROUND: A sensitive, feasible and reproducible marker for renal function is necessary to evaluate the clinical efficacy of enzyme replacement therapy (ERT) in Fabry nephropathy. Serum creatinine has some limitations and cystatin C has been proposed, in other nephropathies, as a useful marker of renal function. The use of cystatin C as a marker of glomerular filtration rate (GFR) was investigated in Fabry patients receiving ERT. METHODS: Renal function was evaluated with serum creatinine, serum cystatin C and estimated GFR (through Modification of Diet in Renal Disease [MDRD], Cockcroft-Gault [C&G] and Hoek formulae) in 21 Fabry patients receiving ERT with agalsidase alfa for 3 years and in 13 Fabry patients receiving agalsidase alfa for 4 years. RESULTS: During years of ERT while serum creatinine remained stable, cystatin C values showed a significant, increasing trend right from the first year of ERT. CONCLUSIONS: In Fabry disease, cystatin C is a sensitive and reliable marker of renal function, and it should be taken into account when evaluating GFR trends during ERT.

Anemia and chronic kidney disease are potential risk factors for mortality in stroke patients: a historic cohort study.

BACKGROUND: Chronic kidney disease (CKD) is associated to a higher stroke risk. Anemia is a common consequence of CKD, and is also a possible risk factor for cerebrovascular diseases. The purpose of this study was to examine if anemia and CKD are independent risk factors for mortality after stroke. METHODS: This historic cohort study was based on a stroke registry and included patients treated for a first clinical stroke in the stroke unit of one academic hospital over a three-year period. Mortality predictors comprised demographic characteristics, CKD, glomerular filtration rate (GFR), anemia and other stroke risk factors. GFR was estimated by means of the simplified Modification of Diet in Renal Disease formula. Renal function was assessed according to the Kidney Disease Outcomes Quality Initiative (K/DOQI)-CKD classification in five groups. A value of hemoglobin < 120 g/L in women and < 130 g/L in men on admission defined anemia. Kaplan-Meier survival curves and Cox models were used to describe and analyze one-year survival. RESULTS: Among 890 adult stroke patients, the mean (Standard Deviation) calculated GFR was 64.3 (17.8) ml/min/1.73 m2 and 17% had anemia. Eighty-two (10%) patients died during the first year after discharge. Among those, 50 (61%) had K/DOQI CKD stages 3 to 5 and 32 (39%) stages 1 or 2 (p < 0.001). Anemia was associated with an increased risk of death one year after discharge (p < 0.001). After adjustment for other factors, a higher hemoglobin level was independently associated with decreased mortality one year after discharge [hazard ratio (95% CI) 0.98 (0.97-1.00)]. CONCLUSIONS: Both CKD and anemia are frequent among stroke patients and are potential risk factors for decreased one-year survival. The inclusion of patients with a first-ever clinical stroke only and the determination of anemia based on one single measure, on admission, constitute limitations to the external validity. We should investigate if an early detection and management of both CKD and anemia could improve survival in stroke patients.

Chronic NSAID use and long-term decline of renal function in a prospective rheumatoid arthritis cohort study.

OBJECTIVES: Non-steroidal anti-inflammatory drugs (NSAIDs) may cause kidney damage. This study assessed the impact of prolonged NSAID exposure on renal function in a large rheumatoid arthritis (RA) patient cohort. METHODS: Renal function was prospectively followed between 1996 and 2007 in 4101 RA patients with multilevel mixed models for longitudinal data over a mean period of 3.2 years. Among the 2739 'NSAID users' were 1290 patients treated with cyclooxygenase type 2 selective NSAIDs, while 1362 subjects were 'NSAID naive'. Primary outcome was the estimated glomerular filtration rate according to the Cockroft-Gault formula (eGFRCG), and secondary the Modification of Diet in Renal Disease and Chronic Kidney Disease Epidemiology Collaboration formula equations and serum creatinine concentrations. In sensitivity analyses, NSAID dosing effects were compared for patients with NSAID registration in ≤/>50%, ≤/>80% or ≤/>90% of assessments. FINDINGS: In patients with baseline eGFRCG >30 mL/min, eGFRCG evolved without significant differences over time between 'NSAID users' (mean change in eGFRCG -0.87 mL/min/year, 95% CI -1.15 to -0.59) and 'NSAID naive' (-0.67 mL/min/year, 95% CI -1.26 to -0.09, p=0.63). In a multivariate Cox regression analysis adjusted for significant confounders age, sex, body mass index, arterial hypertension, heart disease and for other insignificant factors, NSAIDs were an independent predictor for accelerated renal function decline only in patients with advanced baseline renal impairment (eGFRCG <30 mL/min). Analyses with secondary outcomes and sensitivity analyses confirmed these results. CONCLUSIONS: NSAIDs had no negative impact on renal function estimates but in patients with advanced renal impairment.

Assessment of adult formulas for glomerular filtration rate estimation in children.

BACKGROUND: Estimated glomerular filtration rate (eGFR) is an important diagnostic instrument in clinical practice. The National Kidney Foundation-Kidney Disease Quality Initiative (NKF-KDOQI) guidelines do not recommend using formulas developed for adults to estimate GFR in children; however, studies confirming these recommendations are scarce. The aim of our study was to evaluate the accuracy of the new Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formula, the Modification of Diet in Renal Disease (MDRD) formula, and the Cockcroft-Gault formula in children with various stages of chronic kidney disease (CKD). METHODS: A total of 550 inulin clearance (iGFR) measurements for 391 children were analyzed. The cohort was divided into three groups: group 1, with iGFR >90 ml/min/1.73 m(2); group 2, with iGFR between 60 and 90 ml/min/1.73 m(2); group 3, with iGFR of <60 ml/min/1.73 m(2). RESULTS: All formulas overestimate iGFR with a significant bias (p < 0.001), present poor accuracies, and have poor Spearman correlations. For an accuracy of 10 %, only 11, 6, and 27 % of the eGFRs are accurate when using the MDRD, CKD-EPI, and Cockcroft-Gault formulas, respectively. For an accuracy of 30 %, these formulas do not reach the NKF-KDOQI guidelines for validation, with only 25, 20, and 70 % of the eGFRs, respectively, being accurate. CONCLUSIONS: Based on our results, the performances of all of these formulas are unreliable for eGFR in children across all CKD stages and cannot therefore be applied in the pediatric population group.

Estimation de la fonction rénale par l'equation MDRD: intérêt et limites pour l'adaptation des doses de médicaments [Renal function estimation by MDRD equation: interest and limitations for drug dosing].

The MDRD (Modification of diet in renal disease) equation enables glomerular filtration rate (GFR) estimation from serum creatinine only. Thus, the laboratory can report an estimated GFR (eGFR) with each serum creatinine assessment, increasing therefore the recognition of renal failure. Predictive performance of MDRD equation is better for GFR < 60 ml/min/1,73 m2. A normal or near-normal renal function is often underestimated by this equation. Overall, MDRD provides more reliable estimations of renal function than the Cockcroft-Gault (C-G) formula, but both lack precision. MDRD is not superior to C-G for drug dosing. Being adjusted to 1,73 m2, MDRD eGFR has to be back adjusted to the patient's body surface area for drug dosing. Besides, C-G has the advantage of a greater simplicity and a longer use.

Is there an age cutoff to apply adult formulas for GFR estimation in children?

BACKGROUND: Estimation of glomerular filtration rate (eGFR) using a common formula for both adult and pediatric populations is challenging. Using inulin clearances (iGFRs), this study aims to investigate the existence of a precise age cutoff beyond which the Modification of Diet in Renal Disease (MDRD), the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI), or the Cockroft-Gault (CG) formulas, can be applied with acceptable precision. Performance of the new Schwartz formula according to age is also evaluated. METHOD: We compared 503 iGFRs for 503 children aged between 33 months and 18 years to eGFRs. To define the most precise age cutoff value for each formula, a circular binary segmentation method analyzing the formulas' bias values according to the children's ages was performed. Bias was defined by the difference between iGFRs and eGFRs. To validate the identified cutoff, 30% accuracy was calculated. RESULTS: For MDRD, CKD-EPI and CG, the best age cutoff was ≥14.3, ≥14.2 and ≤10.8 years, respectively. The lowest mean bias and highest accuracy were -17.11 and 64.7% for MDRD, 27.4 and 51% for CKD-EPI, and 8.31 and 77.2% for CG. The Schwartz formula showed the best performance below the age of 10.9 years. CONCLUSION: For the MDRD and CKD-EPI formulas, the mean bias values decreased with increasing child age and these formulas were more accurate beyond an age cutoff of 14.3 and 14.2 years, respectively. For the CG and Schwartz formulas, the lowest mean bias values and the best accuracies were below an age cutoff of 10.8 and 10.9 years, respectively. Nevertheless, the accuracies of the formulas were still below the National Kidney Foundation Kidney Disease Outcomes Quality Initiative target to be validated in these age groups and, therefore, none of these formulas can be used to estimate GFR in children and adolescent populations.

Scoring system for renal pathology in Fabry disease: report of the international study group of fabry nephropathy (ISGFN).

BACKGROUND: In Fabry nephropathy, alpha-galactosidase deficiency leads to accumulation of glycosphingolipids in all kidney cell types, proteinuria and progressive loss of kidney function. METHODS: An international working group of nephrologists from 11 Fabry centres identified adult Fabry patients, and pathologists scored histologic changes on renal biopsies. A standardized scoring system was developed with a modified Delphi technique assessing 59 Fabry nephropathy cases. Each case was scored independently of clinical information by at least three pathologists with an average final score reported. RESULTS: We assessed 35 males (mean age 36.4 years) and 24 females (43.9 years) who mostly had clinically mild Fabry nephropathy. The average serum creatinine was 1.3 mg/dl (114.9 micromol/l); estimated glomerular filtration rate was 81.7 ml/min/1.73 m(2) and urine protein to creatinine ratio was 1.08 g/g (122.0 mg/mmol). Males had greater podocyte vacuolization on light microscopy (mean score) and glycosphingolipid inclusions on semi-thin sections than females. Males also had significantly more proximal tubule, peritubular capillary and vascular intimal inclusions. Arteriolar hyalinosis was similar, but females had significantly more arterial hyalinosis. Chronic kidney disease stage correlated with arterial and glomerular sclerosis scores. Significant changes, including segmental and global sclerosis, and interstitial fibrosis were seen even in patients with stage 1-2 chronic kidney disease with minimal proteinuria. CONCLUSIONS: The development of a standardized scoring system of both disease-specific lesions, i.e. lipid deposition related, and general lesions of progression, i.e. fibrosis and sclerosis, showed a spectrum of histologic appearances even in early clinical stage of Fabry nephropathy. These findings support the role of kidney biopsy in the baseline evaluation of Fabry nephropathy, even with mild clinical disease. The scoring system will be useful for longitudinal assessment of prognosis and responses to therapy for Fabry nephropathy.

Pioglitazone improves fat distribution, the adipokine profile and hepatic insulin sensitivity in non-diabetic end-stage renal disease subjects on maintenance dialysis: a randomized cross-over pilot study.

BACKGROUND: Fat redistribution, increased inflammation and insulin resistance are prevalent in non-diabetic subjects treated with maintenance dialysis. The aim of this study was to test whether pioglitazone, a powerful insulin sensitizer, alters body fat distribution and adipokine secretion in these subjects and whether it is associated with improved insulin sensitivity. TRIAL DESIGN: This was a double blind cross-over study with 16 weeks of pioglitazone 45 mg vs placebo involving 12 subjects. METHODS: At the end of each phase, body composition (anthropometric measurements, dual energy X-ray absorptometry (DEXA), abdominal CT), hepatic and muscle insulin sensitivity (2-step hyperinsulinemic euglycemic clamp with 2H2-glucose) were measured and fasting blood adipokines and cardiometabolic risk markers were monitored. RESULTS: Four months treatment with pioglitazone had no effect on total body weight or total fat but decreased the visceral/sub-cutaneous adipose tissue ratio by 16% and decreased the leptin/adiponectin (L/A) ratio from 3.63×10-3 to 0.76×10-3. This was associated with a 20% increase in hepatic insulin sensitivity without changes in muscle insulin sensitivity, a 12% increase in HDL cholesterol and a 50% decrease in CRP. CONCLUSIONS/LIMITATIONS: Pioglitazone significantly changes the visceral-subcutaneous fat distribution and plasma L/A ratio in non diabetic subjects on maintenance dialysis. This was associated with improved hepatic insulin sensitivity and a reduction of cardio-metabolic risk markers. Whether these effects may improve the outcome of non diabetic end-stage renal disease subjects on maintenance dialysis still needs further evaluation. TRIAL REGISTRATION: ClinicalTrial.gov NCT01253928.

High one year mortality in adults with sickle cell disease and end-stage renal disease.

Adequate pre-dialysis care reduces mortality among end-stage renal disease (ESRD) patients. We tested the hypothesis that individuals with ESRD due to sickle cell disease (SCD-ESRD) receiving pre-ESRD care have lower mortality compared to individuals without pre-ESRD care. We examined the association between mortality and pre-ESRD care in incident SCD-ESRD patients who started haemodialysis between 1 June, 2005 and 31 May, 2009 using data provided by the Centers for Medicare and Medicaid Services (CMS). SCD-ESRD was reported for 410 (0·1%) of 442 017 patients. One year after starting dialysis, 108 (26·3%) patients with incident ESRD attributed to SCD died; the hazard ratio (HR) for mortality among patients with SCD-ESRD compared to those without SCD as the primary cause of renal failure was 2·80 (95% confidence interval [CI] 2·31-3·38). Patients with SCD-ESRD receiving pre-dialysis nephrology care had a lower death rate than those with SCD-ESRD who did not receive pre-dialysis nephrology care (HR = 0·67, 95% CI 0·45-0·99). The one-year mortality rate following an ESRD diagnosis was almost three times higher in individuals with SCD when compared to those without SCD but with ESRD and could be attenuated by pre-dialysis nephrology care.

PTH and 1.25 vitamin D response to a low-calcium diet is associated with bone mineral density in renal stone formers.

BACKGROUND: Renal calcium stones and hypercalciuria are associated with a reduced bone mineral density (BMD). Therefore, the effect of changes in calcium homeostasis is of interest for both stones and bones. We hypothesized that the response of calciuria, parathyroid hormone (PTH) and 1.25 vitamin D to changes in dietary calcium might be related to BMD. METHODS: A single-centre prospective interventional study of 94 hyper- and non-hypercalciuric calcium stone formers consecutively retrieved from our stone clinic. The patients were investigated on a free-choice diet, a low-calcium diet, while fasting and after an oral calcium load. Patient groups were defined according to lumbar BMD (z-score) obtained by dual X-ray absorptiometry (group 1: z-score <-0.5, n = 30; group 2: z-score -0.5-0.5, n = 36; group 3: z-score >0.5, n = 28). The effect of the dietary interventions on calciuria, 1.25 vitamin D and PTH in relation to BMD was measured. RESULTS: An inverse relationship between BMD and calciuria was observed on all four calcium intakes (P = 0.009). On a free-choice diet, 1.25 vitamin D and PTH levels were identical in the three patient groups. However, the relative responses of 1.25 vitamin D and PTH to the low-calcium diet were opposite in the three groups with the highest increase of 1.25 vitamin D in group 1 and the lowest in group 3, whereas PTH increase was most pronounced in group 3 and least in group 1. CONCLUSION: Calcium stone formers with a low lumbar BMD exhibit a blunted response of PTH release and an apparently overshooting production of 1.25 vitamin D following a low-calcium diet.

Diabète et insuffisance rénate terminate. Evolution en huit ans dans le canton de Vaud [Diabetes and end stage renal disease. Eight year progression in the Canton de Vaud, Switzerland].

Diabetic nephropathy is the first cause of endstage renal disease. The demographic expansion, the increase in the incidence of diabetes and the prolonged survival rates explain the steep increase observed these last 30 years. In the United States, improved treatment has brought to a decline in the incidence of end-stage renal disease in the diabetic population since the mid nineties. We examined the change in prevalence of diabetics on dialysis from 2001 and 2009 in the Canton de Vaud, Switzerland. The prevalence of diabetics on dialysis increased from 18% to 31% in dialysis centers and increased from 1.1/1000 to 1.9/1000 in the diabetic population. These are strong indicators that efforts are needed to improve the renal outcome of patients with diabetic nephropathy.