The Renin-Angiotensin system is a major mediator of progressive renal injury In CKD and drugs that target the RAS have been shown to slow the progression of glomerulosclerosis, tubulointerstitial fibrosis and proteinuria. However, the effects of even maximal doses of ACEi/ARB are limited, in part due to the compensatory rise in renin levels due to the disruption of feedback inhibition. Last, week, the Lancet published the results of the VITAL study which was designed to see whether treatment with paricalcitol added to RAS-blockade could reduce albuminuria in patients with diabetic nephropathy.
So, why Vit D? Vit D is a negative endocrine regulator of the RAS. Mice lacking the vitamin D receptor constitutively express high levels of renin and angiotensin and develop more severe glomerulosclerosis than wild-type mice in an animal model of diabetes. Vit D therapy has been shown to decrease inflammation, expression of renin mRNA and reduce fibrosis in mouse models.
In observational studies in humans, low Vit D levels have been associated with increased systolic BP, a higher risk for cardiovascular disease and increased proteinuria in CKD. A number of small studies have suggested that treatment with activated Vit D can reduce blood pressure and proteinuria.
In this study, the authors took 281 patients with diabetic nephropathy who were on a stable dose of ACEi/ARB and treated them for 24 weeks with control, 1mcg paricalcitol or 2mcg paricalcitol. The primary endpoint was mean change in UACR over the length of the study and the secondary endpoints were mean change in 24hr albumin excretion and the percentage of patients achieving a 15% decrease in albuminuria.
At the end of the study, there was a significant fall in 24h albumin excretion in the 2mcg group but not in the 1mcg group. There was also a decrease in mean UACR in the 2mcg group but this did not quite reach significance. Interestingly, when the patients were stratified by 24h Na excretion, only those with a Na excretion of >178mmol/day had a significant fall in albuminuria. eGFR also decreased in the 2mcg group relative to controls. eGFR, albuminuria and BP returned to baseline within a few weeks of stopping the study drug.
The authors concluded that paricalcitol at 2mcg daily reduced albuminuria in patients with T2DM and was well tolerated. However, I’m not so sure about this. There were 3 deaths in the 2mcg group vs. none in the other two groups although none were attributed to the study drug. 15 patients on the study drug (11 on 2mcg) had to withdraw due to adverse events against 2 in the placebo group. Finally, only 58% of patients on 2mcg managed to stay on this dose throughout. The rest had to reduce the dose to 3 times weekly because of hypoparathyroidism. There was no breakdown at the end as to whether the patients on a reduced dose had less or more protein and the results were not stratified by baseline Vit D levels so it is difficult to know from this study if these patients in particular would benefit from Vit D therapy.
Overall, this is an interesting study that suggests that Vit D might be a potential addition to the drugs we use to treat diabetic nephropathy but I can’t say that I would change my practice yet based on this study alone.