Prediction of CKD Progression and Cardiovascular Events Using Albuminuria and Pulse Wave Velocity.

INTRODUCTION: Chronic kidney disease (CKD) is associated with cardiovascular disease (CVD) and death. Albuminuria is an established risk factor, but additional biomarkers predicting CKD progression or CVD are needed. Arterial stiffness is an easily measurable parameter that has been associated with CVD and mortality. We evaluated the ability of carotid-femoral pulse wave velocity (PWV) and urine albumin-creatinine (UAC) ratio to predict CKD progression, cardiovascular events, and mortality in a cohort of CKD patients. METHODS: In CKD stage 3-5 patients, PWV and UAC were measured at baseline. CKD progression was defined as 50% decline in estimated glomerular filtration rate (eGFR), initiation of dialysis, or renal transplantation. A composite endpoint was defined as CKD progression, myocardial infarction, stroke, or death. Endpoints were analyzed using Cox regression analysis adjusted for possible confounders. RESULTS: We included 181 patients (median age 69 [interquartile range 60-75] years, 67% males) with a mean eGFR of 37 ± 12 mL/min/1.73 m2 and UAC 52 (5-472) mg/g. Mean PWV was 10.6 m/s. Median follow-up until first event was 4 (3-6) years with 44 and 89 patients reaching a CKD progression or composite endpoint, respectively. UAC (g/g) significantly predicted both CKD progression (HR 1.5 [1.2; 1.8]) and composite endpoints (HR 1.4 [1.1; 1.7]) in adjusted Cox regression. In contrast, PWV (m/s) was not associated with neither CKD progression (HR 0.99 [0.84; 1.18]) nor the composite endpoint (HR 1.03 [0.92; 1.15]). CONCLUSION: In an aging CKD population, UAC predicted both CKD progression and a composite endpoint of CKD progression, cardiovascular events, or death, while PWV did not.

Megalin dependent urinary cystatin C excretion in ischemic kidney injury in rats.

BACKGROUND: Cystatin C, a marker of kidney injury, is freely filtered in the glomeruli and reabsorbed by the proximal tubules. Megalin and cubilin are endocytic receptors essential for reabsorption of most filtered proteins. This study examines the role of these receptors for the uptake and excretion of cystatin C and explores the effect of renal ischemia/reperfusion injury on renal cystatin C uptake and excretion in a rat model. METHODS: Binding of cystatin C to megalin and cubilin was analyzed by surface plasmon resonance analysis. ELISA and/or immunoblotting and immunohistochemistry were used to study the urinary excretion and tubular uptake of endogenous cystatin C in mice. Furthermore, renal uptake and urinary excretion of cystatin C was investigated in rats exposed to ischemia/reperfusion injury. RESULTS: A high affinity binding of cystatin C to megalin and cubilin was identified. Megalin deficient mice revealed an increased urinary excretion of cystatin C associated with defective uptake by endocytosis. In rats exposed to ischemia/reperfusion injury urinary cystatin C excretion was increased and associated with a focal decrease in proximal tubule endocytosis with no apparent change in megalin expression. CONCLUSIONS: Megalin is essential for the normal tubular recovery of endogenous cystatin C. The increase in urinary cystatin C excretion after ischemia/reperfusion injury is associated with decreased tubular uptake but not with reduced megalin expression.

Comparison of bone and renal effects in HIV-infected adults switching to abacavir or tenofovir based therapy in a randomized trial.

INTRODUCTION: Our objective was to compare the bone and renal effects among HIV-infected patients randomized to abacavir or tenofovir-based combination anti-retroviral therapy. METHODS: In an open-label randomized trial, HIV-infected patients were randomized to switch from zidovudine/lamivudine (AZT/3TC) to abacavir/lamivudine (ABC/3TC) or tenofovir/emtricitabine (TDF/FTC). We measured bone mass density (BMD) and bone turnover biomarkers (osteocalcin, osteocalcin, procollagen type 1 N-terminal propeptide (P1NP), alkaline phosphatase, type I collagen cross-linked C-telopeptide (CTx), and osteoprotegerin). We assessed renal function by estimated creatinine clearance, plasma cystatin C, and urinary levels of creatinine, albumin, cystatin C, and neutrophil gelatinase-associated lipocalin (NGAL). The changes from baseline in BMD and renal and bone biomarkers were compared across study arms. RESULTS: Of 40 included patients, 35 completed 48 weeks of randomized therapy and follow up. BMD was measured in 33, 26, and 27 patients at baseline, week 24, and week 48, respectively. In TDF/FTC-treated patients we observed significant reductions from baseline in hip and lumbar spine BMD at week 24 (-1.8% and -2.5%) and week 48 (-2.1% and -2.1%), whereas BMD was stable in patients in the ABC/3TC arm. The changes from baseline in BMD were significantly different between study arms. All bone turnover biomarkers except osteoprotegerin increased in the TDF/FTC arm compared with the ABC/3TC arm, but early changes did not predict subsequent loss of BMD. Renal function parameters were similar between study arms although a small increase in NGAL was detected among TDF-treated patients. CONCLUSION: Switching to TDF/FTC-based therapy led to decreases in BMD and increases in bone turnover markers compared with ABC/3TC-based treatment. No major difference in renal function was observed. TRIAL REGISTRATION: Clinicaltrials.gov NCT00647244.