In this retrospective study, treatment with alfacalcidol significantly reduced 24
hour albuminuria in a group of patients with CKD4-5, being treated for secondary hyperparathyroidism. The reduction was in the range of 8-12%, depending on the time frame analyzed. Patients with stable or no treatment with ACEi/ARBs had a greater decrease of 16%. The reduction in 24
hour albuminuria remained stable over time in an analysis of a subgroup of patients, where data were available for a longer observation period. No change was seen in the biochemical parameters of secondary hyperparathyroidism, although use of phosphate-binders did increase. Alfacalcidol-treatment did not significantly affect blood pressure, and loss of residual renal function was comparable to untreated patients.
Animal studies of VDRA-treatment in different experimental models of kidney failure support these clinical findings by consistently reporting reduction in albuminuria and also glomerulosclerosis [13
]. Proposed mechanisms include effects on the RAAS-system, as demonstrated by VDR-knockout mice having increased renin expression and thereby increased angiotensin II-production [19
]. Supportive of this, SNX-rats treated with VDRA show suppression of the biosynthesis of renin and angiotensin II [21
]. When vitamin D-treatment is combined with ACEi/ARBs, additional reno-protection has been demonstrated [18
]. Several other mechanisms may contribute: Reduced podocyte-damage with restoration of the glomerular filtration barrier [14
], reduced inflammatory response with inhibition of neutrophile and monocyte cell-accumulation and reduction in chemoattractants[15
], anti-proliferative effects[13
] and reduced oxidative stress [27
Our findings are in accordance with other clinical studies investigating the effects of VDRAs on proteinuria. Three randomized, placebo-controlled studies have used paricalcitol 1–2
μg/d as add-on-top treatment to stable RAAS-blockade with ACEi or ARBs. In a small RCT by Alborzi et al [7
], 24 patients with CKD 3 were treated with 1 or 2
μg/d paricalcitol or placebo for 1
month. A 46-48% reduction in 24
hour albuminuria with either dose was reported, with an increase of 35% in the placebo-group. There was a concomitant decrease in inflammation, measured as hsCRP, which was greater with the higher dose of paricalcitol (20% reduction with 1
μg/d, and 30% reduction with 2
μg/d) compared to 50% increase with placebo. Fishbane et al [8
] randomized 61 patients with CKD2-4 and proteinuria >400
mg/d to 1
μg/d paricalcitol or placebo. Half of these patients were diabetics and almost all in treatment with ACEi/ARBs (90.1%). With 1
μg/d of paricalcitol for 6
months there was a decrease in spot urine protein-creatinine ratio of 17.6% compared to an increase of 2.9% in controls. In the VITAL-study performed by de Zeeuw et al [9
], 281 patients with type 2 diabetes, nephropathy and stable ACEi/ARB-therapy, were randomized to 1 or 2
μg/d paricalcitol or placebo for 24
weeks. Most had macroalbuminuria (72%). Results were reported primarily as urinary albumin-to-creatinine ratio (UACR), but 24
hour urinary albumin was also available for a large subgroup (82%). There was a reduction in UACR in both treated arms (14% and 20%) and also in 24
hour urinary albumin (10% and 34%), but only the substantially greater reduction in the 2
μg/d arm reached statistical significance.
The amount of urinary protein excretion at baseline differed substantially in these studies - it was approximately twice as high in the study-population of Fishbane et al. (proteinuria 2.6-2.7
g/d), compared to the diabetics of the VITAL-study (albuminuria 1.0-1.1
g/d). Higher excretion of protein may be related to a higher level of renal inflammation – and anti-inflammatory and immuno-modulatory actions of VDRAs might explain why Fishbane et al. found a significant, and quite high, reduction in proteinuria with a 1
μg/d dose, while the 1
μg/d arm in the VITAL-study did not reach statistical significance. Also, VDRAs may reduce proteinuria
, as reported by Fishbane, more than albuminuria
, as reported by the VITAL-group, as some of the urinary proteins measured are of tubular origin and VDRAs reduce interstitial inflammation.
In our study, the dose of alfacalcidol was modest – on average 3.0 +/− 1.7
μg/weekly, or less than 0.5
μg/daily. Even so, there was a significant effect on 24
hour albuminuria similar to the 1
μg arm of the VITAL-study. The amount of albuminuria was generally high, on average 2.0
g/d, and our study-population was heterogeneous in underlying kidney diseases, comparable to Fishbanes study-population. We also found a tendency towards a greater decline in albuminuria with higher alfacalcidol-dose, but this did not reach statistical significance.
The primary goal of treatment for our patients was sHPT, and not changes in urinary protein excretion. Alborzi et al [7
] do not report baseline data of iPTH, but state, that they were unable to detect statistically significant reductions in PTH levels at 1
month. Fishbane et al [8
] report slightly elevated iPTH at baseline (7.8 pmol/l) without difference between groups, with a significant and stable decrease over 6
months (5.1 pmol/l) with paricalcitol-treatment. In the VITAL-study [9
], iPTH was higher at baseline (9.6-11 pmol/l), with a significant reduction of approximately 30% in both treated groups. Our patients differed from the abovementioned studies, in having a higher iPTH at baseline (26.7 pmol/L) and also more reduced kidney function, with mean eGFR < 20
Anti-proteinuric effects have been reported for the activated vitamin D hormone, calcitriol, as well. In an open-label study by Szeto et al [30
], ten patients with IgA nephropathy and persistent proteinuria despite RAAS-blockade received calcitriol 0.5
μg/twice weekly, which produced a 27.8% decrease in spot urine protein-creatinine ratio over 12
weeks. Similar results were reported in a recent and larger RCT (n = 50) by Liu et al [10
], where the same dose of calcitriol given over 48
weeks resulted in a 19% reduction in 24-hour urine protein excretion, with a between-group difference with placebo of 41%. Simultaneously, there was a decrease in serum TGF-β level.
Strenghts and limitations
The retrospective design is a weakness of this study. The observation period was relatively short and most of the observations were based on patients with only one urine collection after starting treatment in addition to the baseline collection. The antihypertensive treatment and use of ACEi/ARBs and diuretics were not controlled, but followed daily practice in our out-patient clinic, representing a confounding factor. Dosage of alfacalcidol was modest, and although the indication was treatment of sHPT, no overall change in relevant biohemical parameters could be detected. This shows an inconsistency in following guidelines during day to day practice.
Decrease in residual renal function reflects loss of nephron mass and might as such accompany a decrease in albuminuria, but in the present study the VDRA- group had unchanged albuminuria despite a loss of kidney function in the same range as the VDRA + group. Our primary endpoint, albuminuria, is a surrogate marker for progression of loss of kidney function. Recently, a clinical trial of renin inhibitor aliskiren, (ALTITUDE-trial) [31
] was closed, as it failed to demonstrate the anticipated beneficial effects on clinical endpoints (renal death, reaching end-stage renal disease and doubling of baseline serum creatinine clearance) despite achieving a greater reduction in proteinuria. It remains unknown whether VDRAs when used to reduce proteinuria might be beneficial in halting the progression of chronic kidney disease. Further prospective, randomized, placebo-controlled studies, investigating both changes in proteinuria, and clinically relevant renal endpoints are needed to clearify a possible role of VDRAs in the treatment of chronic kidney disease.
As alfacalcidol and phosphate binders were provided free of charge, the socio-economic status of patients as a bias was avoided.
To our knowledge, this is the first study to report the effects of alfacalcidol on proteinuria. This study supports experimental and clinical data that VDRAs have antiproteinuric actions, and suggests that this may be a class-effect.