Warfarin-related nephropathy occurs in patients with and without chronic kidney disease and is associated with an increased mortality rate

An acute increase in the international normalized ratio (INR; a comparison of prothrombin time to monitor the effects of warfarin) over 3 in patients with chronic kidney disease (CKD) is often associated with an unexplained acute increase in serum creatinine (SC) and an accelerated progression of CKD. Kidney biopsy in a subset of these patients showed obstruction of the renal tubule by red blood cell casts, and this appears to be the dominant mechanism of the acute kidney injury. We termed this warfarin-related nephropathy (WRN), and previously reported cases of WRN only in patients with CKD. We now assess whether this occurs in patients without CKD, its risk factors, and consequences. In 15,258 patients who initiated warfarin therapy during a 5-year period, 4006 had an INR over 3 and SC measured at the same time; however, the large data set precluded individual patient clinical assessment. A presumptive diagnosis of WRN was made if the SC increased by over 0.3mg/dl within 1 week after the INR exceeded 3 with no record of hemorrhage. WRN occurred in 20.5% of the entire cohort, 33.0% of the CKD cohort, and 16.5% of the no-CKD cohort. Other risk factors included age, diabetes mellitus, hypertension, and cardiovascular disease. The 1-year mortality was 31.1% with compared with 18.9% without WRN, an increased risk of 65%. Thus, WRN may be a common complication of warfarin therapy in high-risk patients and CKD doubles this risk. The mechanisms of these risks are unclear

Creatinine Fluctuation in Patients With Lupus Nephritis: Considerations for Clinical Trial Endpoints.

Lupus nephritis (LN) is a common manifestation of systemic lupus erythematosus (SLE) and a major driver of morbidity and mortality. Proliferative forms of LN are typically managed with immunosuppressive therapy, with the aim of attenuating renal inflammation and preserving kidney function.1 Unfortunately, despite several clinical trials of LN conducted over the past 30 to 40 years, none has translated into new Food and Drug Administration (FDA)−approved therapies. Multiple issues in clinical trial design likely contributed to these negative outcomes, such as confounding background medications (especially high-dose glucocorticoids), trial duration, and the choice of trial endpoints. Most trials incorporated composite endpoints to define clinical response based on proteinuria and kidney function. Kidney function was generally assessed as a change in estimated glomerular filtration rate or serum creatinine (sCr) as compared to the patients’ values at trial entry.2 Thresholds were then chosen to define the extent of the clinical response (complete, partial, or no response). However, evidence supporting these thresholds is not robust. For example, most studies used a proteinuria cutoff of <0.3 to 0.5 g/d to describe complete response; however, a post hoc analysis of 2 large LN trials demonstrated that proteinuria levels of <0.7 to 0.8 g/d after 1 year of treatment predicted favorable long-term kidney outcomes, suggesting that a less stringent proteinuria cutoff may be reasonable. Similarly, an sCr value <15% above baseline has often been required for complete response in LN trials.S1−S5 However, day-to-day variations in sCr measurements are routinely observed in clinical practice in patients with and without chronic kidney disease, even when measured within a 24-hour period.3 To determine a threshold of kidney function that accounts for expected day-to-day variations, we investigated the fluctuation of sCr in a cohort of patients with LN who were complete renal responders. [...

Markers of kidney tubule function and risk of cardiovascular disease events and mortality in the SPRINT trial

AimsBiomarkers of kidney tubule injury, inflammation and fibrosis have been studied extensively and established as risk markers of adverse kidney and cardiovascular disease (CVD) outcomes. However, associations of markers of kidney tubular function with adverse clinical events have not been well studied, especially in persons with chronic kidney disease (CKD).Methods and resultsUsing a sample of 2377 persons with CKD at the baseline Systolic Blood Pressure Intervention Trial (SPRINT) visit, we evaluated the association of three urine tubular function markers, alpha-1 microglobulin (α1m), beta-2 microglobulin (β2m), and uromodulin, with a composite CVD endpoint (myocardial infarction, acute coronary syndrome, stroke, acute decompensated heart failure, or death from cardiovascular causes) and mortality using Cox proportional hazards regression, adjusted for baseline estimated glomerular filtration rate (eGFR), albuminuria, and CVD risk factors. In unadjusted analysis, over a median follow-up of 3.8 years, α1m and β2m had positive associations with composite CVD events and mortality, whereas uromodulin had an inverse association with risk for both outcomes. In multivariable analysis including eGFR and albuminuria, a two-fold higher baseline concentration of α1m was associated with higher risk of CVD [hazard ratio (HR) 1.25; 95% confidence interval (CI): 1.10-1.45] and mortality (HR 1.25; 95% CI: 1.10-1.46), whereas β2m had no association with either outcome. A two-fold higher uromodulin concentration was associated with lower CVD risk (HR 0.79; 95% CI: 0.68-0.90) but not mortality (HR 0.86; 95% CI: 0.73-1.01) after adjusting for similar confounders.ConclusionAmong non-diabetic persons with CKD, biomarkers of tubular function are associated with CVD events and mortality independent of glomerular function and albuminuria

The Benefits of Intensive Versus Standard Blood Pressure Treatment According to Fine Particulate Matter Air Pollution Exposure A Post Hoc Analysis of SPRINT

Fine particulate matter <2.5 µm (PM 2.5 ) air pollution is implicated in global mortality, especially from cardiovascular causes. A large body of evidence suggests a link between PM 2.5 and elevation in blood pressure (BP), with the latter implicated as a potential mediator of cardiovascular events. We sought to determine if the outcomes of intensive BP lowering (systolic BP <120 mm Hg) on cardiovascular events are modified by PM 2.5 exposure in the SPRINT (Systolic BP Intervention Trial). We linked annual PM 2.5 exposure estimates derived from an integrated model to subjects participating in SPRINT. We evaluated the effect of intensive BP lowering by PM 2.5 exposure on the primary outcome in SPRINT using cox-proportional hazard models. A total of 9286 participants were linked to PM 2.5 levels (mean age 68±9 years). Intensive BP-lowering decreased risk of the primary outcome more among patients exposed to higher PM 2.5 ( P interaction =0.047). The estimate for lowering of primary outcome was numerically lower in the highest than in the lower quintiles. The benefits of intensive BP-lowering were larger among patients chronically exposed to PM 2.5 levels above US National Ambient Air Quality Standards of 12 µg/m 3 (hazard ratio, 0.47 [95% CI, 0.29–0.74]) compared with those living in cleaner locations (hazard ratio, 0.81 [95% CI, 0.68–0.97]), P interaction =0.037. This exploratory nonprespecified post hoc analysis of SPRINT suggests that the benefits of intensive BP lowering on the primary outcome was greater in patients exposed to higher PM 2.5 , suggesting that the magnitude of benefit may depend upon the magnitude of antecedent PM 2.5 exposure