The kidney biopsy in lupus nephritis: time to move beyond histology.

End-stage renal disease impairs functional status, diminishes quality of life and shortens lifespan. Despite recent improvements in survival of affected individuals in the USA, 50% of patients will die within 3 years of initiating hemodialysis [1]. Nephrologists, dialysis clinic providers, insurers and patients are all in need of therapeutic advances that can further impact mortality in this population. In the current era of growing emphasis on healthcare quality and safety and increasing attention to patient-centered outcomes, an ideal intervention is one that would safely improve clinical outcomes and have beneficial effects on the patients’ overall health and well-being. This framework has fostered renewed vigor in addressing a longstanding question about the management of hyperphosphatemia in the dialysis population: what is the ‘optimal’ serum phosphate? Large observational studies have repeatedly demonstrated a strong independent relationship between hyperphosphatemia and increased risk of mortality in patients undergoing dialysis treatment [2–4]. Experimental studies attest to the biological plausibility of these consistent epidemiologic findings. Phosphate excess has been implicated as a potent inducer of vascular calcification [5], which may contribute to increased rates of cardiovascular events and death through effects on arterial stiffness and left ventricular hypertrophy. However, randomized clinical trials evaluating the efficacy of lowering serum phosphate levels on reduction of mortality are lacking. Indeed, all phosphate binders in the USA have been approved solely on the basis of efficacy studies that demonstrated ability to reduce serum phosphate levels in hyperphosphatemic patients undergoing dialysis. In this evidence-free zone, several well-designed pharmacoepidemiologic studies employing propensity score methods to address confounding by indication have expanded our knowledge base [6–8]. In a prospective observational cohort study of 8610 incident hemodialysis patients in the USA, initiation of treatment with phosphate binders during the first 90 days on hemodialysis was independently associated with an 18–30% lower risk of subsequent 1-year all-cause mortality compared with no early treatment [6]. The results were unchanged in an analysis that matched treated and untreated patients on their baseline serum phosphate levels and propensity score of receiving phosphate binders. A subsequent study using data from the prevalent European dialysis population followed for 3 years yielded similar findings [7]. In this prospective cohort of 6797 patients, propensity score-adjusted analyses also demonstrated a significant association between phosphate binder use and lower all-cause and cardiovascular disease mortality. Importantly, with the exception for aluminum-based binders, there were no major differences in associations with mortality by phosphate binder class, with the hazard ratios (HR) ranging from 0.28 to 0.73. In contrast, a propensity score-matched analysis conducted in another USA cohort of incident dialysis patients found no significant association between use of calcium-based phosphate binders and 1-year survival (HR 0.89; 95% confidence interval [CI], 0.72–1.10) [8]. In this issue of Nephrology, Dialysis and Transplantation, Komaba and colleagues extend the existing data by reporting the findings from 2269 prevalent dialysis patients in Japan and by focusing on lanthanum carbonate as the pharmacological exposure variable. Similar to prior studies [6–8], the authors used rigorous statistical methodologies to address confounding. Uniquely, the data set captured information immediately prior to and during market introduction of lanthanum carbonate in Japan. This allowed the authors to study incident users of lanthanum carbonate, capture covariate information immediately prior to exposure and generate a sufficient number of matched treated and untreated individuals. As expected, compared with