The Role of Paricalcitol in Chronic Kidney Disease
Figure 3: Change in Urinary Albumin-to-creatinine Ratio from Baseline to Last Measurement During Treatment (A); Change in Urinary Albumin-to-creatinine Ratio Over Time During Treatment and Withdrawal (B)
AB
10 15
-15 -10 -5 0 5
-35 -30 -25 -20
p= 0.071 Placebo
Combined paricalcitol
p= 0.023 1 µg
p= 0.053 2 µg
paricalcitol paricalcitol Placebo UACR = urinary albumin-to-creatinine ratio.
A: Error bars represent 95 % confidence intervals; p-values are for the comparison of paricalcitol versus placebo. B: Error bars represent 95 % confidence intervals. Reproduced with permission from de Zeeuw et al., 2010.112
intervene in the RAAS, such as angiotensin-converting enzyme (ACE) inhibitors, can reduce proteinuria and retard both cardiovascular and renal morbidity and mortality.101,102
(and therefore residual cardiovascular and renal risk) can be high in patients receiving treatment and new therapeutic strategies are needed to further reduce this residual risk.103
A multivariate analysis of CKD patients found that lower serum vitamin D concentrations strongly correlated with an increased risk of proteinuria.4
Knockout of the VDR in diabetic mice was associated with severe proteinuria and in preclinical models that mimic various stages of CKD, paricalcitol reduced proteinuria and slowed the progression of kidney injury.104–106
The mechanisms responsible for these renoprotective effects of paricalcitol are not yet elucidated, but vitamin D is known to be a negative endocrine regulator of the RAAS. Indeed, in experimental models of CKD, paricalcitol was shown to suppress the renal RAAS, inhibit renal inflammation and have anti-proliferative effects.105,107,108
The anti-proteinuric effects of paricalcitol have also been demonstrated in a number of small or post-hoc studies involving CKD patients. In one such post-hoc analysis of a randomised trial evaluating the PTH suppressive effects of oral paricalcitol in patients with stage 3 and 4 CKD, the paricalcitol-treated patient subgroup had greater reductions in proteinuria compared with placebo, with and without concomitant blockade of the RAAS.109
found that oral paricalcitol significantly reduced proteinuria compared with placebo in patients with CKD.110,111
In a short-term study, 24 patients
were randomly allocated to three groups to receive placebo, 1 μg or 2 μg paricalcitol orally for one month.111
After this period there was a
significant reduction in proteinuria: the treatment:baseline ratio of 24-hour albumin excretion rate was 1.35 (p=0.01) for placebo, 0.52 (p<0.001) for 1 μg paricalcitol and 0.54 (p=0.01) with a 2 μg dose of paricalcitol. The effect on proteinuria was independent of haemodynamic changes or PTH suppression and residual effects were noted a month after treatment was stopped.
These encouraging findings were subsequently validated in a large, randomised, placebo-controlled, double-blind trial involving 281
EUROPEAN NEPHROLOGY
Figure 4: Kaplan-Meier Analysis of Survival with Paricalcitol or Calcitriol
However, residual proteinuria
100 90 80 70 60 50 40 30 20 10 0
05 10 15 Paricalcitol Reproduced with permission from Teng et al., 2003.16
patients, which aimed to prospectively test the effectiveness of paricalcitol for the reduction of residual albuminuria in patients with type 2 diabetic nephropathy who were receiving stable treatment with ACE inhibitors or angiotensin receptor blockers.112
Patients were Subsequent prospective randomised trials
randomised to receive 24 weeks’ treatment with either placebo, 1 μg/day paricalcitol, or 2 μg/day paricalcitol. The percentage increase in geometric mean urinary albumin-to-creatinine ratio from baseline to last measurement during treatment was significantly higher in the 2 μg paricalcitol group compared with placebo (18 % reduction in proteinuria, p=0·053) (see Figure 3).112
Paricalcitol as an Immunomodulator Systemic inflammatory processes are common in patients with CKD and are a major predictor of poor clinical outcome in this setting.113 Evidence suggests that pro-inflammatory cytokines play a central role in the genesis of both cachexia and cardiovascular disease in CKD 5D.113,114
Vitamin D is known to have a role as an immunomodulator targeting various immune cells, including monocytes, macrophages, dendritic cells, T- and B-lymphocytes,115
and vitamin D deficiency is 87 20 Months Calcitriol 25 30 35
10 20 30 40
-40 -30 -20 -10 0
Treatment phase Withdrawal phase
4
8
12
16 Time (weeks) 1 µg paricalcitol 2 µg paricalcitol
20
24
+30 Days
+60
p<0.001
40
Chang in UACR (%)
Chang in UACR (%)
Survival (%)
Page 1 |
Page 2 |
Page 3 |
Page 4 |
Page 5 |
Page 6 |
Page 7 |
Page 8 |
Page 9 |
Page 10 |
Page 11 |
Page 12 |
Page 13 |
Page 14 |
Page 15 |
Page 16 |
Page 17 |
Page 18 |
Page 19 |
Page 20 |
Page 21 |
Page 22 |
Page 23 |
Page 24 |
Page 25 |
Page 26 |
Page 27 |
Page 28 |
Page 29 |
Page 30 |
Page 31 |
Page 32 |
Page 33 |
Page 34 |
Page 35 |
Page 36 |
Page 37 |
Page 38 |
Page 39 |
Page 40 |
Page 41 |
Page 42 |
Page 43 |
Page 44 |
Page 45 |
Page 46 |
Page 47 |
Page 48 |
Page 49 |
Page 50 |
Page 51 |
Page 52 |
Page 53 |
Page 54 |
Page 55 |
Page 56 |
Page 57 |
Page 58 |
Page 59 |
Page 60 |
Page 61 |
Page 62 |
Page 63 |
Page 64 |
Page 65 |
Page 66 |
Page 67 |
Page 68 |
Page 69 |
Page 70 |
Page 71 |
Page 72 |
Page 73 |
Page 74 |
Page 75 |
Page 76 |
Page 77 |
Page 78 |
Page 79 |
Page 80 |
Page 81 |
Page 82 |
Page 83 |
Page 84 |
Page 85 |
Page 86 |
Page 87 |
Page 88 |
Page 89 |
Page 90 |
Page 91 |
Page 92