Vitamin D analogues to target residual proteinuria: potential impact on cardiorenal outcomes

Abstract

Residual proteinuria, the amount of proteinuria that remains during optimally dosed renin-angiotensin-aldosterone system (RAAS) blockade, is an independent risk factor for progressive renal function loss and cardiovascular complications in chronic kidney disease (CKD) patients. Dual RAAS blockade may reduce residual proteinuria but without translating into improved cardiorenal outcomes at least in diabetic nephropathy; rather, dual RAAS blockade may increase the risk of adverse events. These findings have challenged the concept of residual proteinuria as an absolute treatment target. Therefore, new strategies must be explored to address whether by further reduction of residual proteinuria using interventions not primarily targeting the RAAS benefit in terms of cardiorenal risk reduction would accrue. Both clinical and experimental intervention studies have demonstrated that vitamin D can reduce residual proteinuria through both RAAS-dependent and RAAS-independent pathways. Future research should prospectively explore vitamin D treatment as an adjunct to RAAS blockade in an interventional trial exploring clinically relevant cardiorenal end points.

Vitamin D (25 ( OH) D ) in patients with chronic kidney disease stages 2-5

“…Another study was made in patients with CKD stages 3 and 4 and with vitamin D values over 23 ng/mL and a stable GFR, they managed an adequate response to cholecalciferol in a course of 5 years follow up (considered for the suppression of PTH levels and to obtain vitamin D levels between 40 and 60 ng/mL) 43. An additional benefit from cholecalciferol in this population was the reduction in albuminuria even in patients with diabetic nephropathy 25,44; this is likely due to the intervention of pathways dependent or independent of blocking the renin-angiotensin-aldosterone system 45.…”

Optimal management of bone mineral disorders in chronic kidney disease and end stage renal disease

“…Suggesting that endothelial dysfunction is at least partially reversible in CKD patients and vitamin D supplementation may yet exert favorable effects on the cardiovascular system, two trials identified improvement in endothelial function with paricalcitol use [14, 15]. Consistent with prior studies suggesting that vitamin D can reduce proteinuria both through RASS-dependent and RAAS-independent pathways [17], Molina et al [18] identified a significant decrease in proteinuria in CKD patients treated with cholecalciferol for 6 months. Thus, despite a number of negative trials with vitamin D supplementation, recent data indicate possible benefit on endothelial dysfunction and albuminuria.…”

Heparanase: another renal player controlled by vitamin D

“…The conviction that these general activities of vitamin D may be of paramount importance is supported by epidemiological studies showing a strong association between low vitamin D levels and a higher risk of cardiovascular, infectious, autoimmune and neurodegenerative disorders, diabetes and cancer, both in healthy people and in patients with chronic kidney disease (CKD) [4,5]. Interventional studies also support this impression, and supplementation with vitamin D and its analogues seems to be associated with a lower mortality [5].Interestingly, supplementation with vitamin D and its analogues may have kidney-protecting effects too, as suggested by a decrease in urinary protein levels [6]. Proteinuria is the most powerful predictor of unfavourable outcome in most forms of CKD, and its reduction is considered to be a surrogate endpoint in trials investigating the effects of experimental drugs on the progression of CKD to end-stage renal disease (ESRD) [7].…”

“…Interestingly, supplementation with vitamin D and its analogues may have kidney-protecting effects too, as suggested by a decrease in urinary protein levels [6]. Proteinuria is the most powerful predictor of unfavourable outcome in most forms of CKD, and its reduction is considered to be a surrogate endpoint in trials investigating the effects of experimental drugs on the progression of CKD to end-stage renal disease (ESRD) [7].…”

“…In animal models, the inhibitory effect of vitamin D on the TGFβ/SMAD pathway can control renal fibrosis [6], but further studies are needed to establish whether this occurs through heparanase. Should this prove to be the case, it will be of enormous relevance to the treatment of non-proteinuric or minimally-proteinuric kidney disorders too, which have a similarly dismal prognosis and are virtually orphan conditions when it comes to specific therapies (autosomal-dominant polycystic kidney disease or ischaemic nephropathy, to name just two).…”