Original Investigation Oral Calcitriol for Reduction of Proteinuria in Patients With IgA Nephropathy: A Randomized Controlled Trial

Li-Jun Liu, MD, Ji-Cheng Lv, MD, Su-Fang Shi, MD, Yu-Qing Chen, MD, Hong Zhang, MD, PhD, and Hai-Yan Wang, MD
Background: Vitamin D has shown efcacy in the reduction of proteinuria in patients with chronic kidney disease. This study aimed to determine the effect of calcitriol on urinary protein excretion in patients with immunoglobulin A (IgA) nephropathy. Study Design: Open-label, nonplacebo-controlled, randomized study. Setting & Participants: 50 patients with IgA nephropathy were enrolled. The main criterion for inclusion was urinary protein excretion 0.8 g/d after renin-angiotensin systeminhibitor treatment for at least 3 months. Intervention: Patients were randomly assigned (1:1) to receive 2 doses (0.5 g) of calcitriol per week or no treatment for 48 weeks. Outcomes: The primary end point was to compare change in 24-hour urinary protein excretion from baseline to last measurement during treatment. Measurements: Every 8 weeks, there was measurement of 24-hour urinary protein excretion, serum calcium, serum phosphorus, serum creatinine, and intact parathyroid hormone. Results: Measurement of the primary end point showed changes in urinary protein excretion of 21% (from 1.29 to 1.58 g/24 h; 95% CI, 9% to 52%) in the control group and 19% (from 1.60 to 1.30 g/24 h; 95% CI, 42% to 4%) in the calcitriol-treated group. There was a signicant decrease in proteinuria in the calcitriol-treated group compared with the control group (difference between groups, 41%; 95% CI, 5%-79%; P 0.03). The secondary end point of achieving at least a 15% decrease in proteinuria was attained by 7 of 24 (29%) controls and 17 of 26 (65%) of those treated with calcitriol (P 0.02). No signicant differences were observed in decrease in estimated glomerular ltration rate and change in blood pressure between the 2 groups. The incidence of recorded adverse events was similar between the 2 groups. Limitations: Small and nonplacebo-controlled study. Conclusions: The addition of calcitriol to a renin-angiotensin system inhibitor resulted in a safe decrease in proteinuria in patients with IgA nephropathy. Am J Kidney Dis. 59(1):67-74. 2011 by the National Kidney Foundation, Inc. INDEX WORDS: Immunoglobulin A (IgA) nephropathy; proteinuria; calcitriol; renin-angiotensin system.

mmunoglobulin A (IgA) nephropathy is the most common form of primary glomerulonephritis globally.1 Several studies have indicated that a proportion (6%-43%) of patients with IgA nephropathy reach end-stage kidney disease within 10 years.2-4 Clinical risk factors for progression are identied as hypertension, proteinuria, decreased kidney function, and histologic lesions at presentation.2,3,5 Although there is no universally accepted optimal therapy for IgA nephropathy, currently established treatments include full renin-angiotensin system (RAS) inhibition and optimal blood pressure control for patients with proteinuria and/or hypertension. However, a substantial risk of progression remains even when these therapies are used.6-8 Corticosteroid treatment is controversial,9,10 and widespread use of this approach in clinical practice is limited by toxicity. Recent studies have shown broad-ranging activities of vitamin D that extend beyond the regulation of calcium and phosphorus metabolism mediated by the vitamin D receptor. These so-called noncalcemic activities include regulation of renal and cardiovascular functions and modulation of immune responses.11 Experimental data have indicated that vitamin D anaAm J Kidney Dis. 2012;59(1):67-74

logues mediate a decrease in albuminuria and slow the progression of kidney injury through activation of the vitamin D receptor in several animal models of kidney disease.12-14 The effects of vitamin D analogues are thought to target the nuclear factor B pathway and the RAS.15,16 The VITAL (Selective Vitamin D Receptor Activator [Paricalcitol] for Albuminuria Lowering) Study conducted by de Zeeuw et al17 investigated the effects

From the Renal Division, Peking University First Hospital, Institute of Nephrology, Peking University, Key Laboratory of Renal Disease, Ministry of Health of China, Beijing, PR China. Received May 5, 2011. Accepted in revised form September 5, 2011. Originally published online October 24, 2011. Trial registration: ClinicalTrials.gov; study number: NCT00862693. Address correspondence to Hong Zhang, MD, PhD, Renal Division, Peking University First Hospital, Peking University Institute of Nephrology, Key Laboratory of Renal Disease, Ministry of Health of China, Beijing 100034, PR China. E-mail: hongzh@bjmu.edu.cn 2011 by the National Kidney Foundation, Inc. 0272-6386/$36.00 doi:10.1053/j.ajkd.2011.09.014
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of selective vitamin D receptor activation by paricalcitol for a decrease in albuminuria in patients with type 2 diabetes. This study showed that the addition of 2 g/d of paricalcitol to RAS inhibition safely decreased residual albuminuria in patients with diabetic kidney disease and resulted in a benecial decrease in residual renal risk in patients with diabetes.17 However, the effects of this strategy in patients with IgA nephropathy are unknown. A previous small (n 10) noncontrolled trial reported that twiceweekly oral doses of calcitriol produced a modest antiproteinuric effect that was accompanied by a decrease in serum transforming growth factor (TGF).18 However, the study design and small sample size used render the data inconclusive, and the efcacy of vitamin D or its analogues in patients with IgA nephropathy remains to be investigated in a large randomized controlled trial. In this study, a randomized trial was carried out to investigate the efcacy of calcitriol in the reduction of proteinuria in patients with IgA nephropathy who were receiving stable treatment with an angiotensinconverting enzyme (ACE) inhibitor and/or angiotensin receptor blocker (ARB). Furthermore, the effects of calcitriol on estimated glomerular ltration rate (eGFR) and blood pressure were examined.

proteinuria. The calcitriol dose was maintained in the absence of adverse effects and a corrected serum calcium level 2.45 mmol/L. However, the calcitriol dose was immediately decreased or discontinued if corrected serum calcium level was 2.45 mmol/L. Adjustment for iPTH level was permitted according to the standard therapy guideline. In this study, no calcitriol dosage adjustments were required in response to iPTH level uctuation. During the course of study, neither the ACE-inhibitor nor the ARB dose was changed. In the event of a requirement for intensication of blood pressure therapy, other antihypertensive treatments were initiated or increased in dose.

End Points
The difference in change in proteinuria between the baseline measurement and last study evaluation (48 weeks in study completers) between the 2 groups was predened as the primary end point. Secondary efcacy measures were recorded from baseline to the last measurement during treatment and included the proportion of patients achieving at least a 15% decrease in proteinuria, an end point used in prior studies.20 Mean change in eGFR and blood pressure was recorded as an additional efcacy measure. Proteinuria was determined by the pyrogallol redmolybdate method.

Statistical Analysis
The intention-to-treat data set included all randomly assigned patients who received at least one study treatment and had at least one postrandomization follow-up visit. The last value for patients who did not reach the nal visit was carried forward for calculation. All patients received at least a single dose of study medication (calcitriol) and were included in the analysis as described. Continuous variables are reported as mean standard deviation. Categorical variables are reported in terms of frequency and percentage. The primary end point was comparison of change in proteinuria between the baseline measurement and last evaluation between the 2 groups. Absolute proteinuria changes were calculated by using the last measurement of 24-hour protein excretion minus the baseline measurement of proteinuria. The percentage of change in proteinuria was calculated by dividing the change in absolute proteinuria by the baseline measurement of proteinuria. The difference in changes between 2 groups was analyzed by t test. Changes in proteinuria over time between the 2 groups also were compared using analysis of variance for repeated measures. Analysis of variance and repeated-measures analyses also were used to analyze change from baseline in other continuous efcacy variables. Treatment group differences in response rates were assessed using Fisher exact test. Differences in the incidence of adverse events between treatment groups and other categorical variables were assessed using Fisher exact test. We calculated that a total sample size of 44 patients was needed for at least 80% power to detect an absolute difference in proteinuria of protein excretion of 0.3 0.5 g/d from baseline to last measurement during treatment between the calcitriol treatment group and control group at a 2-sided signicance level of 0.05.20 A 10% dropout rate was considered and a total of 50 patients was needed. All statistical analyses were conducted using SAS, version 8.2 (www.sas.com), at a signicance level of P 0.05.

METHODS
Study Participants
Patients with biopsy-conrmed IgA nephropathy were enrolled from the IgA follow-up team in Peking University Institute of Nephrology. Patients 18 years and older with persistent proteinuria with protein excretion 0.8 g/d after optimal blood pressure control and full RAS inhibition for at least 3 months (in 3 consecutive samples monthly, and the last value was used as baseline calculation), eGFR (calculated by using the 4-variable MDRD [Modication of Diet in Renal Disease] Study equation19) 15 mL/min/1.73 m2, and serum calcium levels 2.45 mmol/L were eligible for inclusion. Patients receiving treatment with corticosteroids or other immune suppressant drugs and those with other severe coexisting diseases, such as chronic liver disease, myocardial infarction, cerebrovascular accident, or malignant hypertension, were excluded. The study protocol was approved by an independent ethics committee at Peking University First Hospital, and written informed consent was obtained from all patients.

Treatment Regimen
This was an open-label randomized controlled trial of calcitriol in patients with biopsy-conrmed IgA nephropathy. The randomization sequence was computer generated by the statistician and preserved in a sealed envelope. Randomization was carried out by nontrial-associated staff. Patients in the study were assigned (1:1) to calcitriol or no treatment for 48 weeks. Patients received calcitriol (F. Hoffmann-La Roche, Ltd, Swiss, www.roche. com.cn), 0.5 g, 2 times per week with at least 3 days between 2 doses. Patients were asked to report their pill consumption for evaluation of treatment adherence. Patients were recalled every 8 weeks for clinical evaluation and measurement of serum intact parathyroid hormone (iPTH), calcium, phosphorus, creatinine, and
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RESULTS
Demographic Data Of 164 patients screened for eligibility, 50 were enrolled. All patients nished at least one visit after baseline. Four of these patients completed only 2-5 study visits. Three women became pregnant during the study period, and one of these women (in the calcitriol-treated group) discontinued treatment. All 3
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Calcitriol in IgA Nephropathy

Figure 1. Patient prole.

patients discontinued ACE-inhibitor and ARB treatment after conrmation of the pregnancy. These 7 patients were included in the analysis (Fig 1). Baseline demographic, clinical, and biochemical characteristics and concomitant treatments were balanced between the treatment and control groups (Table 1). This study did not include patients with diabetes mellitus, although there was a higher proportional rate of patients treated with a combination of ACE inhibitors and ARBs compared with the former study.17 The 2 groups were matched with respect to histologic ndings (Table 1) according to Haas grading.21 All patients enrolled in this study received at least one study treatment and had at least one postrandomization follow-up visit. Therefore, all patients were included in the intention-to-treat analysis. Two patients were lost to follow-up in the calcitriol-treated group, and one patient, in the control group (Fig 1). Proteinuria and Other Clinical Parameters Individual changes in proteinuria from baseline to last evaluation in the 2 groups are shown in Fig 2. Measurement of the primary end point showed changes in urinary protein excretion of 21% (from 1.29 to 1.58 g/24 h; 95% condence interval [CI], 9% to 52%) in the control group and 19% (from 1.60 to 1.30 g/24 h; 95% CI, 42% to 4%) in the calcitriol-treated group. There was a signicant decrease in proteinuria in the calcitriol-treated group compared with the control group (difference between groups, 41%; 95% CI, 5%-79%; P 0.03; Table 2). The relative difference in change in proteinuria between the 2
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groups also was signicant (protein excretion, 0.59; 95% CI, 0.06-1.11 g/24 h; P 0.02). In the analysis of variance for repeated measurement, there was no signicant difference in proteinuria between the 2 groups (P 0.8), and there was no signicant time effect (P 0.9) or time and treatment interaction effect (P 0.1). In the secondary efcacy analysis, a 15% decrease in proteinuria occurred less frequently in controls (7 of 24; 29.2%) than in calcitriol-treated patients (17 of 26; 65.4%; P 0.02). eGFR decreased from baseline to the last evaluation in the calcitriol-treated group (change, 3.2; 95% CI, 8.13 to 1.73 mL/min/1.73 m2) compared with a slight increase in the control group (change, 0.03; 95% CI, 4.87 to 4.93 mL/min/1.73 m2). No signicant difference was detected between mean eGFR from baseline to the last evaluation in either group or change in eGFR between the 2 groups (P 0.6). There was no signicant change in mean systolic and diastolic blood pressures throughout the course of study in either treatment group. Mean blood pressures at baseline were 118/74 16/11 mm Hg in the control group and 117/77 13/10 mm Hg in the calcitrioltreated group. At the last evaluation, mean blood pressures were 116/72 13/9 mm Hg in the placebo group and 117/76 16/11 mm Hg in the calcitrioltreated group. Mean number of antihypertensive drugs and mean dose per patient were not signicantly different between the 2 groups at baseline, and there were no signicant differences at the last evaluation. Mean iPTH level increased slightly from 36.7 20.2 pg/mL at baseline to 40.2 34.8 pg/mL (P 0.7) at last measurement in the placebo group and
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Table 1. Patient Characteristics at Baseline
Control Group (n 24) Calcitriol Group (n 26) P

Age (y) Sex (M:F) Weight (kg) Height (cm) Systolic blood pressure (mm Hg) Diastolic blood pressure (mm Hg) Urine protein excretion (g/24 h) Serum creatinine (mol/L) eGFR (mL/min/1.73 m2) Albumin (g/dL) Serum calcium (mmol/L) Serum phosphorus (mmol/L) iPTH (pg/mL) 1,25-Dihydroxyvitamin D (pmol/L) Histologic grading score (Haas) Grade 1 Grade 2 Grade 3 Grade 4 Grade 5 25-Hydroxyvitamin D (nmol/L) Antihypertensive drugs ACEi ARB Combination of ACEi & ARB Calcium channel blocker Metoprolol Diuretic Hydrochlorothiazide Spironolactone Statin

36.3 10.2 13:11 72.6 19.5 167.7 8.3 118.3 16.5 73.8 11.3 1.15 (1.01-1.57) 103.3 34.5 78.0 28.2 4.30 0.34 2.29 0.07 1.12 0.16 36.71 20.19 44.9 15.1 3 0 8 11 2 30.2 6.3 12 (50.0) 21 (87.5) 10 (41.7) 5 (20.8) 3 (12.5) 10 (41.7) 5 (20.8) 5 (20.8) 4 (16.7)

35.6 10.8 16:10 69.7 18.7 167.9 10.0 117.1 12.7 76.7 9.9 1.44 (1.14-1.93) 104.8 42.7 83.1 35.8 4.15 0.38 2.25 0.10 1.14 0.17 37.79 19.71 48.4 15.0 1 0 12 11 2 27.5 7.3 11 (42.3) 23 (88.5) 7 (30.8) 4 (15.4) 2 (7.69) 5 (19.2) 4 (15.4) 1 (3.85) 3 (11.5)

0.8 0.8 0.6 0.9 0.8 0.3 0.08 0.9 0.6 0.2 0.1 0.7 0.9 0.4 0.3 NA 0.4 0.9 0.9 0.2 0.8 0.7 0.4 0.9 0.9 0.2 0.9 0.2 0.9

Note: Continuous data are shown as mean standard deviation or mean (95% condence interval); categorical variables, as number or number (percentage). Conversion factors for units: serum creatinine in mol/L to mg/dL, 0.0113; eGFR in mL/min/1.73 m2 to mL/s/1.73 m2, 0.01667; albumin in g/dL to g/L, 10; phosphorus in mmol/L to mg/dL, 3.1. No conversion necessary for iPTH in pg/mL and ng/L. Abbreviations: ACEi, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker; eGFR, estimated glomerular ltration rate; iPTH, intact parathyroid hormone; NA, not applicable.

decreased slightly from 37.8 19.7 to 35.9 21.4 pg/mL (P 0.8) in the calcitriol-treated group. There was no signicant difference between mean iPTH levels measured at baseline to the last evaluation between the 2 groups (P 0.6). Serum calcium level increased slightly in both the calcitriol-treated (from 2.25 0.10 to 2.27 0.09 mmol/L) and the control group (from 2.29 0.07 to 2.30 0.08 mmol/L). However, there were no signicant differences in either serum calcium or phosphorus levels from baseline to last evaluation in either group or between the 2 groups. Adverse Effects The incidence of adverse events was similar in the 2 groups (P 0.6). Nine adverse events (9/24; 37.5%) were reported in the control group (Table 3).
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These included upper respiratory tract infection (n 3), urinary tract infection (n 1), paronychia (n 1), diarrhea (n 1), liver function disorder (n 1), hyperkalemia (n 1), and joint pain (n 1). Seven adverse events (7/26; 26.9%) were reported in the calcitriol-treated group (Table 3). These included upper respiratory tract infection (n 4), rash (n 1), and gout (n 1). No serious adverse events were reported in the control group. One patient in the calcitriol-treated group was admitted to the hospital after acute onset of renal calculus with serum calcium level in the reference range. The patient recovered after conservative treatment and discontinued calcitriol treatment. No hypercalcemia was reported. None of the adverse events reported was thought to be related to study medications, with the exception of the renal calculus.
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Figure 2. Absolute and relative change in urinary protein excretion (g/24 h) and serum calcium and phosphorus levels in the 2 study groups from baseline to 48 weeks. Error bars represent standard deviation.

DISCUSSION In this randomized controlled trial of 50 patients, it was observed that treatment with 2 doses (0.5 g) of calcitriol per week (with at least 3 days between 2 doses) for 48 weeks decreased proteinuria in patients
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with IgA nephropathy who were on stable doses of ACE inhibitors and/or ARBs, even in patients with dual inhibition of the RAS by a combination of ACE inhibitors and ARBs. Furthermore, this study showed that patients treated with calcitriol had a substantially
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Table 2. Comparison of Change in Proteinuria From Baseline to 48 Weeks Between Randomized Groups
Treatment Group Control Group Difference (95% CI) P

24-h urine protein excretion No. of patients Baseline (g/24 h) Last measurement (g/24 h) Change in proteinuria (g/24 h) Percentage change (%) No. with 15% reduction in proteinuria

26 1.60 1.30 0.30 19 17 (65.4)

24 1.29 1.58 0.29 21 7 (29.2)

0.32 (0.04 to 0.67) 0.28 (0.83 to 0.27) 0.59 (0.06 to 1.11) 41 (5 to 79)

0.08 0.3 0.02 0.03 0.02

Note: Except where indicated, data are mean values or number (percentage). Difference is absolute value of the difference between 2 groups. Abbreviation: CI, condence interval.

greater likelihood of a response rate in proteinuria decrease than controls. A decrease in proteinuria 15% was measured in 65.4% (17/26) of patients in the calcitriol-treated group compared with 29.2% (7/24) in the control group. The drug generally was safe and well tolerated during the study period. Early observational studies of vitamin D supplementation in patients have indicated the capacity of activators of the vitamin D receptor to decrease proteinuria in a number of chronic kidney diseases.18,22,23 Fishbane et al20 described a study of 61 patients with proteinuric kidney disease randomly assigned to receive 1 g/d of paricalcitol or placebo. After 6 months, changes in protein excretion from baseline to the last evaluation were 2.9% for controls and 17.6% for the paricalcitol group (P 0.04). The VITAL Study conducted by de Zeeuw et al17 was a placebocontrolled double-blind trial of 281 patients with type 2 diabetes and albuminuria who were receiving conventional RAS blockade. These patients were treated with placebo or paricalcitol (1 or 2 g/d) for 24 weeks. The antiproteinuric effect of treatment with 2 g/d of paricalcitol was shown by a 18% decrease
Table 3. Adverse Events in the Treatment Period
Control Group (n 24) Treatment Group (n 26)

Any event Infection Upper respiratory tract Urinary tract infection Paronychia Diarrhea Liver function disorder Hyperkalemia Joint pain Rash Gout Renal calculus

9 (37.5) 3 (12.5) 1 (4.2) 1 (4.2) 1 (4.2) 1 (4.2) 1 (4.2) 1 (4.2) 0 (0) 0 (0) 0 (0)

7 (26.9) 4 (15.4) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 1 (4.2) 1 (4.2) 1 (4.2)

Note: Values shown as number (percentage). 72

(P 0.053) in urinary albumin-creatinine ratio compared with placebo and a 15% decrease in the combined group (1 and 2 g/d) versus placebo in 24-hour urinary albumin excretion (P 0.07). However, the exact effects of vitamin D or its analogues in patients with IgA nephropathy (nondiabetic nephropathy) are undened. This randomized controlled study provides evidence of the effect of calcitriol treatment in patients with IgA nephropathy. Vitamin D and its analogues appear to mediate antiproteinuric effects through activation of the vitamin D receptor by several mechanisms. Experimental studies have shown that vitamin D acts as a strong negative endocrine regulator of the RAS and functions mainly to suppress renin production.15,24 Therefore, the effects on RAS inhibition represent an important target in the treatment of IgA nephropathy. Furthermore, vitamin D has been shown to exert immunomodulatory effects. In vitro, 1,25-hydroxyvitamin D was observed to attenuate tumor necrosis factor and induced monocyte chemoattractant protein expression by human proximal tubule cells.25 The renoprotective effects of vitamin D and its analogues also are mediated by suppression of antiproliferative effects, antibrotic effects, and prodifferentiative and immunomodulatory activities either alone or in combination.12,26,27 Furthermore, vitamin D and its analogues suppressed TGF and decreased glomerulosclerosis in animal models with or without diabetes.12 Suppression of TGF by vitamin D in vivo also has been shown in a clinical study.18 Vitamin D receptor activation also inhibits renal inammation by promoting vitamin D receptormediated sequestration of nuclear factor B signaling.16,28 Increased proteinuria is associated with rapid loss of kidney function. Therefore, approaches aimed at the reduction of proteinuria represent an important target in the treatment of renal proteinuric disease.29 Thus, it can be hypothesized that the antiproteinuric effects of calcitriol are associated with those of renal protective drugs, such as ACE inhibitors or ARBs.
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Patients treated with calcitriol in this study showed a slight decrease in eGFR and an increase in serum creatinine level, although these changes did not reach statistical signicance. It can be speculated that the manifestation of a modest decrease in eGFR is caused by an effect on creatinine metabolism that has been reported previously with calcitriol30 rather than a loss of kidney function. The decrease in eGFR resulting from vitamin D treatment was in accordance with a former clinical study.17 Therefore, well-dened end points such as end-stage kidney disease or death are required for verication of the renoprotective effects of calcitriol in clinical trials. It should be noted that the interpretation of data obtained in this study is limited by the small sample size, use of proteinuria as a surrogate marker of progression, and short follow-up in addition to the absence of ambulatory blood pressure and 24-hour sodium excretion measurements. The latter is important to the effect of the RAS inhibition treatment in patients with renal disease. However, in this center, patients are educated regularly regarding sodium intake and other nutritional materials. In post hoc analysis, the VITAL Study found a greater decrease in albuminuria with paricalcitol when dietary sodium intake was high.17 We do not have data for sodium excretion in our participants and cannot comment on the potential effect of sodium intake on calcitriol effects in IgA nephropathy. The maximum tolerated dose of calcitriol was not established by titration in this study, and the dose used was relatively low. Previous studies have shown that a higher dose of vitamin D or its analogue has a more pronounced antiproteinuric effect.17,23 However, a former study from Hong Kong showed an effective decrease in proteinuria by the same low dosage of calcitriol used in this study, although one patient developed transient hypercalcemia. Furthermore, most patients enrolled in our study had normal kidney function, in contrast to other studies that included a high proportion of patients with decreased kidney function.17,20,23 Therefore, it was believed that the calcitriol dose used in this study was tolerated well and sufcient to achieve the effect of a decrease in proteinuria. Further studies are required to investigate the optimal dose of calcitriol for the treatment of patients with IgA nephropathy. An additional limitation is that because of the exclusion of patients using corticosteroids, those with high-grade proteinuria were excluded because most are prescribed corticosteroids according to local practice. In conclusion, oral calcitriol therapy (2 doses of 0.5 g/wk) has a modest but signicant antiproteinuric effect in patients with IgA nephropathy and persistent proteinuria despite ACE-inhibitor and/or ARB therapy.
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Additional studies are required to conrm the renalprotective effect of calcitriol in patients with IgA nephropathy.

ACKNOWLEDGEMENTS
Support: None. Financial Disclosure: The authors declare that they have no relevant nancial interests.

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