Active Vitamin D Treatment for Reduction of Residual Proteinuria: A Systematic Review

Despite renin-angiotensin-aldosterone system blockade, which retards progression of CKD by reducing proteinuria, many patients with CKD have residual proteinuria, an independent risk factor for disease progression. We aimed to address whether active vitamin D analogs reduce residual proteinuria. We systematically searched for trials published between 1950 and September of 2012 in the Medline, Embase, and Cochrane Library databases. All randomized controlled trials of vitamin D analogs in patients with CKD that reported an effect on proteinuria with sample size≥50 were selected. Mean differences of proteinuria change over time and odds ratios for reaching ≥15% proteinuria decrease from baseline to last measurement were synthesized under a random effects model. From 907 citations retrieved, six studies (four studies with paricalcitol and two studies with calcitriol) providing data for 688 patients were included in the meta-analysis. Most patients (84%) used an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker throughout the study. Active vitamin D analogs reduced proteinuria (weighted mean difference from baseline to last measurement was −16% [95% CI, −13% to −18%]) compared with controls (+6% [95% CI, 0% to +12%]; P<0.001). Proteinuria reduction was achieved more commonly in patients treated with an active vitamin D analog (204/390 patients) than control patients (86/298 patients; OR, 2.72 [95% CI, 1.82 to 4.07]; P<0.001). Thus, active vitamin D analogs may further reduce proteinuria in CKD patients in addition to current regimens. Future studies should address whether vitamin D therapy also retards progressive renal functional decline.CKD is a worldwide health burden, affecting about 15% of the Western adult population.¹ CKD is associated with premature death, cardiovascular disease, infection, and cancer, and it consumes disproportionate health care resources.^2–4 The mainstay of current CKD treatment is pharmacological blockade of the renin-angiotensin-aldosterone system (RAAS) by angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs). Although these drugs may retard progression of both renal and cardiovascular disease^5–9 partly through their capacity to reduce proteinuria,^10,11 progression to ESRD and cardiovascular complications cannot be prevented in many CKD patients.A recent single-level meta-analysis including over 2 million participants showed that albuminuria is independently associated with mortality and ESRD, regardless of age.¹² The amount of residual albuminuria/proteinuria under RAAS blockade is a strong predictor of both long-term renal disease progression^13,14 and cardiovascular complications,¹⁵ and an absent or blunted proteinuria response to the use of RAAS blockers is an especially strong predictor.¹⁶ The efficacy of RAAS blockade intensification in an attempt to further reduce residual proteinuria is, however, limited by side effects, such as hyperkalemia and hypotension.^17,18 Adjunctive therapies, which can offer the lowering of residual proteinuria but without these drawbacks, may improve renal and cardiovascular protection.Studies in animal models of CKD suggested that proteinuria, renal fibrosis, and renal function loss may be reduced by treatment with an active vitamin D analog not only as monotherapy but also when given as adjunctive therapy to conventional RAAS blockade.^19–21 In CKD patients, lower vitamin D concentrations have been associated with an increased risk of mortality,^22,23 cardiovascular complications,²⁴ and renal disease progression.²⁵ These findings have resulted in a number of small- to medium-sized prospective randomized controlled trials (RCTs) with the use of active vitamin D analogs targeting reduction of (residual) proteinuria in CKD patients. So far, results have been inconclusive, with studies reporting significant,^26–28 borderline significant,^29–31 or nonsignificant^32,33 effects. We performed a systematic review and meta-analysis of all available RCTs to address the effect of active vitamin D analogs on residual proteinuria in patients with CKD.