Vitamin D, Proteinuria, Diabetic Nephropathy, and

Progression of CKD
Rajiv Agarwal
Indiana University School of Medicine and Richard L Roudebush VA Medical Center, Indianapolis, Indiana

Although the endocrine effects of vitamin D are widely recognized, somewhat less appreciated is that vitamin D may serve
paracrine functions through local activation by 1-␣-hydroxylase and thus maintain immunity, vascular function, cardiomyo-
cyte health, and abrogate inflammation and insulin resistance. In the kidney, vitamin D may be important for maintaining
podocyte health, preventing epithelial-to-mesenchymal transformation, and suppressing renin gene expression and inflam-
mation. Replacement with pharmacologic dosages of vitamin D receptor agonists (VDRA) in animal models of kidney disease
consistently show reduction in albuminuria, abrogation of glomerulosclerosis, glomerulomegaly, and glomerular inflamma-
tion, effects that may be independent of BP and parathyroid hormone, but the effects of VDRA in preventing tubulointerstitial
fibrosis and preventing the progression of kidney failure in these animal models are less clear. Emerging evidence in patients
with chronic kidney disease (CKD) show that vitamin D can reduce proteinuria or albuminuria even in the presence of
angiotensin-converting enzyme inhibition. In addition to reducing proteinuria, VDRA may reduce insulin resistance, BP, and
inflammation and preserve podocyte loss providing biologic plausibility to the notion that the use of VDRA may be associated
with salubrious outcomes in patients with diabetic nephropathy. Patients with CKD have a very high prevalence of deficiency
of 25-hydroxyvitamin D. Whether pharmacologic dosages of vitamin D instead of VDRA in patients with CKD can overcome
the paracrine and endocrine functions of this vitamin remains unknown. To demonstrate the putative benefits of native
vitamin D and VDRA among patients with CKD, randomized, controlled trials are needed.
Clin J Am Soc Nephrol 4: 1523–1528, 2009. doi: 10.2215/CJN.02010309

I
n 1978, a study published in The Lancet reported 18 pa-
tients who had advanced chronic kidney disease (CKD),
creatinine clearance of ⬍35 ml/min, and presence of renal
osteodystrophy and were treated with either vitamin D3 (4000
IU/d) or 1,25-dihydroxyvitamin D [1,25(OH)2D; 1 ␮g/d] along
with 500 mg of calcium after a 6-mo observation period (1). In
the group treated with 1,25(OH)2D, seven of eight patients
developed hypercalcemia that necessitated a reduction in dos-
age. The percentage fall in creatinine clearance was greater
during treatment than before treatment in all patients who
were on 1,25(OH)2D (P ⬍ 0.01) and in seven of nine patients on
vitamin D3 treatment (although the within group change here
was NS). The authors concluded that deterioration of renal
function was a major limitation of the clinical use of
1,25(OH)2D and vitamin D3 in nondialyzed patients with CKD.
Although the conclusions made by this important clinical
study were strong, evaluating the state-of-the-art science in
1978, ⬎30 yr later informs us that the dosage of 1,25(OH)2D
was rather high, the sample size too small, and the follow-up
period of 6 mo too short to provide reliable information
about the rates of progression of CKD in vitamin D–treated
Published online ahead of print. Publication date available at www.cjasn.org.
Correspondence: Dr. Rajiv Agarwal, Department of Medicine, Indiana University
School of Medicine, VAMC 111N, 1481 West 10th Street, Indianapolis, IN 46202.
Phone: 317-554-0000, ext. 2241; Fax: 317-554-0298; E-mail: ragarwal@iupui.edu
patients. Existing data seem to point to a salubrious effect of
vitamin D receptor agonists (VDRA) in animals with kidney
disease, and emerging evidence points to a similar benefit in
patients with CKD. The evolution of science of VDRA in
animal models of kidney disease and patients with CKD is
the subject of this review.
The effects of vitamin D on the bone and elsewhere can be
evaluated at the molecular level by examining knockout mice
and are reviewed by Bouillon et al. (2). Absence of a functional
vitamin D receptor (VDR) or its ligand, 25-hydroxyvitamin D-1
[25(OH)D1] ␣-hydroxylase (CYP27B1), in mice creates a bone
and growth plate phenotype that mimics severe vitamin D
deficiency. VDR rescue in the intestine restores a normal bone
and growth plate phenotype. Although the VDR is nearly ubiq-
uitously expressed and almost all cells respond to 1,25(OH)2D
exposure, the function of active vitamin D and its receptor is
not fully overlapping. For example, VDR-deficient mice but not
vitamin D- or 1 ␣-hydroxylase– deficient mice develop total
alopecia as is also seen in humans. The immune system of
VDR- or vitamin D– deficient mice shows increased sensitiv-
ity to autoimmune diseases such as inflammatory bowel
disease or type 1 diabetes after exposure to predisposing
factors. Although VDR-deficient mice do not have a sponta-
neous increase in cancer, they are more prone to oncogene-
or chemocarcinogen-induced tumors. They also develop
high renin hypertension, cardiac hypertrophy, and increased

Copyright © 2009 by the American Society of Nephrology ISSN: 1555-9041/409 –1523

1524 Clinical Journal of the American Society of Nephrology
thrombogenicity. Vitamin D deficiency in humans is associ-
ated with increased prevalence of diseases, as predicted by
the VDR null phenotype.
Animal Studies
Tian et al. (3) reviewed the mechanisms of salutary effects of
vitamin D on the kidney. The noncalcemic effects of VDRA
include vascular effects, immunomodulatory effects, anti-in-
flammatory effects, suppression of the renin-angiotensin sys-
tem (RAS), and effects on glucose homeostasis, which are dis-
cussed further.
Suppression of RAS
Seminal discoveries by Li et al. (4) demonstrated that vitamin
D is a potent negative endocrine regulator of the RAS and
works predominantly as a suppressor of renin biosynthesis (5).
Mice that lack the vitamin D receptor have elevated production
of renin and angiotensin II (AngII), leading to hypertension,
cardiac hypertrophy, and increased water intake. Vitamin D
repression of renin expression is independent of calcium me-
tabolism, the volume- and salt-sensing mechanisms, and the
AngII feedback regulation (4). In normal mice, vitamin D defi-
ciency stimulates renin expression, whereas injection of
1,25(OH)2D reduces renin synthesis (4). In cell cultures,
1,25(OH)2D directly suppresses renin gene transcription by a
VDR-dependent mechanism. Combined treatment of diabetic
mice with losartan and paricalcitol completely prevents albu-
minuria, restores glomerular filtration barrier structure, and
markedly reduces glomerulosclerosis (6). These beneficial ef-
fects are accompanied by blockade of intrarenal renin and
AngII accumulation induced by hyperglycemia and losartan.
These data demonstrate that inhibition of the RAS with com-
bination of vitamin D analogs and RAS inhibitors effectively
prevents renal injury in diabetic nephropathy. 1,25(OH)2D also
suppresses hyperglycemia-induced activation of the RAS and
TGF-␤ in mesangial and juxtaglomerular cells (7). TGF-␤ acti-
vates interstitial fibroblasts and induces tubular epithelial-to-
mesenchymal transition. Thus, by blocking TGF-␤, VDRA have
the potential to abrogate tubulointerstitial fibrosis. Taken to-
gether, these studies suggest that receptor-mediated vitamin D
actions in part via the RAS may provide renoprotection in
diabetic nephropathy.
Improvement in Insulin Resistance
Vitamin D deficiency has been linked with impaired glucose
metabolism, an established risk factor for cardiovascular dis-
ease (8). Because vitamin D is often deficient and its metabolism
substantially impaired in patients with CKD, absolute or func-
tional vitamin D deficiency may be particularly important in
these patients. Furthermore, impaired glucose metabolism is
common in CKD. De Boer (8) concluded in a recent review that
short-term studies on maintenance hemodialysis patients have
shown that vitamin D treatment improves insulin secretion and
sensitivity, but interventional studies on people without ESRD
have yielded mixed results. Improved glucose metabolism is
one potential mechanism through which vitamin D may exert
Clin J Am Soc Nephrol 4: 1523–1528, 2009
beneficial cardiovascular effects in patients with CKD, but fur-
ther research is needed.
Vascular Effects
Somjen et al. (9) were the first to report an enzymatically
active 25(OH)D1 ␣-hydroxylase system in human vascular
smooth muscle cells, which could be upregulated by parathy-
roid hormone (PTH) and inhibited by exogenous vitamin D.
Emerging experimental data demonstrate important physio-
logic effects of vitamin D on factors that are protective for
vascular health (10).
Immunomodulating Effects
Vitamin D seems to regulate innate immunity through effects
on microbial recognition peptides such as Toll-like receptors
(TLRs) (11). TLRs are membrane-spanning receptors that rec-
ognize structurally conserved molecules derived from microbes
and activate immune responses. Mycobacterium tuberculosis
infection leads to increased 1 ␣-hydroxylase expression and
VDR upregulation in monocyte/macrophages in response to
activation by TLRs (12). Furthermore, macrophages can also
synthesize antimicrobial peptides such as cathelicidin, an effect
that is facilitated in the presence of 25(OH)D (13). In fact, it is
now being recognized that autocrine production of 1,25(OH)2D
might also be an important negative feedback mechanism to
deactivate innate and inflammatory responses of activated
macrophages (14).
In the kidney, vitamin D has similar immunomodulating
effects. For example, in vitro, 1,25(OH)2D attenuates TNF-␣–
induced monocyte chemoattractant protein 1 (MCP-1) expres-
sion by human proximal tubule cells (15). A synthetic VDRA,
paricalcitol, inhibits renal inflammation by promoting VDR-
mediated sequestration of NF-␬B signaling (16). Although cell
surface receptor–mediated, nongenomic pathways (17,18) are
described, the potent antiproliferative, prodifferentiative, and
immunomodulating activities (17,19,20) seem to be modulated
via vitamin D receptor– dependent genomic effects; the latter
seem to provide the biologic basis for salutary effects of VDRA
in patients with kidney disease.
Animal Models of Kidney Disease and Benefits of VDRA
Substantial number of studies point out the salutary effects of
VDRA in animals (Table 1). In aggregate there appears to be a
consistent reduction in albuminuria, abrogation of glomerulo-
sclerosis, glomerulomegaly and glomerular inflammation, ef-
fects that may be independent of BP and PTH. However, from
these studies the effects of VDRA in preventing tubulointersti-
tial fibrosis and preventing the progression of kidney failure
are less clear.
Human Studies
Vitamin D Deficiency in Patients with CKD
As renal function declines, serum levels of 1,25(OH)2D pro-
gressively decrease, leading to a vitamin D– deficient state (28).
Despite presence of adequate 25(OH)D, many patients with
CKD will have low serum levels of 1,25(OH)2D, which under-
lies the functional vitamin D deficiency in these patients. Some-
Table 1. Summary of studiesa
Reference Model Intervention Results

Schwarz et al., Subtotal nephrectomy 1,25(OH)2D Glomerular volume and glomerulosclerosis were less in treated animals.
1998 (21) with and without Albuminuria was 21% that of control animals. No effect on vascular
parathyroidectomy and tubulointerstitial sclerosis, systolic BP, or serum creatinine. Cell
proliferation was less. TGF-␤ expression in vessels and
tubulointerstitium was less. Effects were independent of PTH.
Makibayashi et al., Anti-Thy1 GN 22-Oxa-calcitriol or Less mesangial cell proliferation, less glomerulosclerosis, less
2001 (22) 1,25(OH)2D albuminuria at day 8. Reduced type 1 and IV collagens and ␣-smooth
Clin J Am Soc Nephrol 4: 1523–1528, 2009

muscle actin mRNA expression. TGF-␤ expression in glomeruli

reduced.
Panichi et al., 2001 Anti-Thy1 GN 1,25(OH)2D Proteinuria was 16% at day 7, and urinary IL-6 was significantly less
(23) compared with control animals. Decreased glomerular inflammation
(neutrophil, monocyte), glomerular size, and glomerular cell
proliferation. Creatinine at day 14 not statistically different from
control group.
Hirata et al., Subtotal nephrectomy 22-Oxa-calcitriol Albuminuria less (approximately 25% of controls at 8 wk); prevented
2002 (24) increases in serum creatinine and BUN; and reduced glomerular cell
number, volume, and sclerosis at 8 wk. ␤2-Microglobulin or NAG
levels were not affected.
Kuhlmann et al., Subtotal nephrectomy 1,25(OH)2D Albuminuria less, glomerular volume less, more podocytes, less
2003 (25) podocyte injury, less podocyte hypertrophy.
Tan et al., 2006 Obstructive Paricalcitol Reduced renal interstitial fibrosis, suppressed renal TGF-␤1 and its type
(26) nephropathy I receptor expression, restored vitamin D receptor abundance, and
inhibited cell proliferation and apoptosis. Paricalcitol also blocked
directly the EMT.
Freundlich et al., Subtotal nephrectomy Paricalcitol Glomerular and tubulointerstitial damage, hypertension, proteinuria,
2008 (27) and the deterioration of renal function were improved as a result of
decrease in angiotensinogen, renin, renin receptor, and vascular
endothelial growth factor mRNA levels in the remnant kidney by 30
to 50% with paricalcitol treatment.
Zhang et al., Diabetic VDR 1,25(OH)2D Diabetic VDR knockout mice developed more severe albuminuria and
2008 (7) knockout mice glomerulosclerosis as a result of increased glomerular basement
membrane thickening and podocyte effacement. In receptor knockout
mice, increased renin, angiotensinogen, TGF-␤, and connective tissue
growth factor accompanied the more severe renal injury.
Moving Points in Nephrology

a
1,25(OH)2D, 1,25-dihydroxyvitamin D; BUN, blood urea nitrogen; EMT, epithelial-to-mesenchymal transition; GN, glomerulonephritis; PTH, parathyroid hormone;
VDR, vitamin D receptor.
1525
1526 Clinical Journal of the American Society of Nephrology
what less commonly recognized is the high prevalence of nu-
tritional vitamin D deficiency, as determined by low 25(OH)D
concentrations in these patients. Thus, “absolute” vitamin D
deficiency is also common in patients with CKD. In 43 patients
with CKD spanning an estimated GFR (eGFR) range of 11 to
111 ml/min per 1.73 m2, Gonzalez et al. (29) reported vitamin D
deficiency as defined by a serum 25(OH)D level ⬍30 ng/ml in
86% of the patients. Possible explanations for this high preva-
lence of nutritional D deficiency in patients are reduced sun-
light exposure (e.g., in the elderly, the sick, dark-skinned peo-
ple, those who wear a veil for cultural reasons), losses of
vitamin D– binding protein in proteinuric states [25(OH)D is
lost in the urine bound to vitamin D– binding protein] and a
compromised endogenous synthesis of vitamin D from the skin
in the uremic state. It seems that increased removal of 25(OH)D
via nonrenal pathways may also play a role in causing a low
25(OH)D level. In fact, it is believed that the vast majority of
25(OH)D is used by the nonrenal tissues. Because monocytes
and macrophages express 1-␣ hydroxylase, it seems plausible
that apparent nutritional vitamin D deficiency could be a man-
ifestation of the inflammatory state in patients with CKD. In
this context, VDRA administration may lead to reduction in the
inflammatory state (30). Whether similar benefits can be real-
ized with vitamin D administration needs to be studied in
future trials. Endothelial cells can also rapidly induce 1-␣ hy-
droxylase activity in response to inflammatory cytokines and
may serve to deplete the stores of 25(OH)D (31). In one small
study, VDRA was unable to improve endothelial function, but
a larger study with vitamin D is warranted.
Vitamin D and Cohort Studies in CKD
In 15,068 adults who participated in the Third National
Health and Nutrition Examination Survey (NHANES III), de
Boer et al. (32) reported a stepwise increase in the prevalence of
albuminuria with decreasing quartiles of 25(OH)D concentra-
tion. After multivariate adjustment including region and season
of measurement and eGFR, relative risks for albuminuria by
decreasing quartile of vitamin D concentration were signifi-
cantly increased to 1.14, 1.22, and 1.37 in successive quartiles. In
the NHANES survey, 25(OH)D deficiency and eGFR both were
independently related to insulin resistance (33) as well as sev-
eral other cardiovascular risk factors, such as hypertension,
diabetes, obesity, and high serum triglyceride levels (34).
Zehnder et al. (15) measured vitamin D metabolites, markers of
inflammation and gene expression, in 174 patients with a vari-
ety of kidney diseases. Urinary MCP-1 and renal macrophage
infiltration each were inversely correlated with serum
1,25(OH)2D levels. Higher levels of 25(OH)D were also associ-
ated with lower inflammation. Patients with acute renal inflam-
mation had a significant increase in urinary and kidney MCP-1,
macrophage infiltration, and macrophage and renal epithelial
1-␣ hydroxylase (CYP27B1) expression but significantly lower
levels of serum 1,25(OH)2D in comparison with patients with
chronic ischemic disease despite similar levels of renal damage.
Thus, decreased serum vitamin D metabolites and activation of
the paracrine/autocrine vitamin D system are important corre-
lates of inflammation in patients with CKD. London et al. (35)
Clin J Am Soc Nephrol 4: 1523–1528, 2009
reported that 25(OH)D as well as its active metabolite
1,25(OH)2D is directly associated with endothelial function and
inversely with arterial calcifications in patients with CKD.
Taken together, it seems that 25(OH)D deficiency in patients
with CKD is associated with worse risk factors (albuminuria,
insulin resistance, inflammation, hypertension, dyslipidemia,
and endothelial dysfunction) for progression of kidney disease.
The presence of vitamin D deficiency is associated with in-
cident cardiovascular disease in the general population (36).
Because risk factors for cardiovascular and kidney disease by
and large overlap, it is possible that cardiovascular and renal
benefits may accrue in patients with CKD. In fact, several
studies of patients who had CKD and were not on dialysis
supported the presence of a salutary effect of vitamin D. In an
Italian cohort, Ravani et al. (37) found that 25(OH)D plasma
concentration was an independent inverse predictor of disease
progression and death in patients with stages 2 through 5 CKD
after multivariate adjustment. Shoben et al. (38) reported that
oral calcitriol use was associated with lower mortality in non-
dialysis US veterans with CKD. After multivariate adjustment
including eGFR and baseline levels of PTH, calcium, and phos-
phorous, oral calcitriol use was associated with a 26% lower
risk for death and a 20% lower risk for death or dialysis. The
association of calcitriol with improved survival was not statis-
tically different across baseline PTH levels, although calcitriol
use was associated with a greater risk for hypercalcemia. In
another cohort of US veterans with CKD, Kovesdy et al. (39)
reported that the incidence rate ratios for mortality and com-
bined death and dialysis initiation were significantly lower in
patients who were treated with calcitriol. Treatment with cal-
citriol was also associated with a trend toward a lower inci-
dence of dialysis.
It remains that neither cross-sectional nor longitudinal stud-
ies can prove a cause-and-effect relationship between use of
VDRA and outcomes. Randomized trials are needed.
Randomized Trials of VDRA in Patients with CKD
At least three clinical trials have evaluated the use of VDRA
in patients who had CKD and were not on renal replacement
therapy. In the first study, Agarwal et al. (40) reported reduc-
tion in proteinuria detected semiquantitatively by dipstick us-
ing an automated analysis in patients who had stages 3 and 4
CKD with secondary hyperparathyroidism and participated in
three randomized, controlled trials of oral paricalcitol. In that
post hoc analysis, reduction in dipstick proteinuria occurred in
the face of the frequent use of agents that block the RAS.
Although previous studies reported that dipstick proteinuria is
a good predictor of spot urine protein/creatinine ratios, an
obvious limitation of that study was the method of detection of
proteinuria (automated dipstick versus spot urinary protein/
creatinine or albumin/creatinine ratio).
Extending these findings, Alborzi et al. (30) reported a pro-
spective pilot trial of 24 patients who had CKD (two patients
stage 2, remaining stage 3) and were randomly allocated in a
double-blind manner to three equal groups to receive 0, 1, or 2
␮g of paricalcitol, a vitamin D analog, orally for 1 mo. At 1 mo,
treatment/baseline ratio of high-sensitivity C-reactive protein
Clin J Am Soc Nephrol 4: 1523–1528, 2009
was 1.5 (95% confidence interval [CI] 1.1 to 2.1; P ⫽ 0.02) with
placebo, 0.8 (95% CI 0.3 to 1.9; P ⫽ 0.62) with 1-␮g dosage, and
0.5 (95% CI 0.3 to 0.9; P ⫽ 0. 03) with 2-␮g dosage of paricalcitol.
At 1 mo, treatment/baseline ratio of 24-h albumin excretion
rate was 1.35 (95% CI 1.08 to 1.69; P ⫽ 0.01) with placebo, 0.52
(95% CI 0.40 to 0.69; P ⬍ 0.001) with 1-␮g dosage, and 0.54 (95%
CI 0.35 to 0.83; P ⫽ 0. 01) with 2-␮g dosage (P ⬍ 0.001 for
between-group changes). No differences were observed in
iothalamate clearance, flow-mediated dilation (a measure of
endothelial function), 24-h ambulatory BP, or PTH with treat-
ment or upon washout. The limitations of that trial include the
small sample size and the limited duration of exposure to VDR
activator. Furthermore, all patients had low 25(OH)D defi-
ciency in that study; whether nutritional replacement could
have improved albuminuria or inflammation remains un-
known. That study therefore cannot provide definite answers
to questions of the clinical use of paricalcitol for renal protec-
tion; however, it seems from that study that paricalcitol-in-
duced reduction in albuminuria and inflammation may be
mediated independent of its effects on hemodynamics or PTH
suppression.
In an uncontrolled trial, reported from Hong Kong, 10 pa-
tients with biopsy-proven IgA nephropathy and persistent pro-
teinuria despite angiotensin-converting enzyme inhibition and
AngII receptor blockade were treated with 0.5 ␮g calcitriol
twice weekly for 12 wk (41). After calcitriol treatment, there
was a significant overall decrease in urine protein-creatinine
ratio from 1.98 ⫾ 0.74 to 1.48 ⫾ 0.81 g/g (P ⫽ 0.007) during the
first 6 wk that persisted throughout the study period. No
significant change in BP or renal function was noted. There was
a simultaneous decrease in serum TGF-␤ level, and percentage
of decrease in serum TGF-␤ level significantly correlated with
percentage of change in proteinuria (Spearman r ⫽ 0.643; P ⫽
0.02).
Whether VDRA should be used to reduce the rate of progres-
sion of CKD cannot be answered by the studies discussed
herein; larger trials are required. Lowering of albuminuria or
proteinuria in these trials, however, occurred without changes
in BP even when recorded by ambulatory BP monitoring, rais-
ing the notion that improvement in kidney disease conferred by
the use of these drugs may occur via nonhemodynamic path-
ways.
Future Directions
Randomized, controlled trials with paricalcitol are under
way to demonstrate whether paricalcitol will have antipro-
teinuric or cardioprotective effects in patients with CKD. In
one such trial, reduction in albuminuria from baseline to 24
wk is the primary end point (ClinicalTrials.gov identifier
NCT00421733), whereas, in another, the change in left ventric-
ular mass index assessed by cardiac magnetic resonance imag-
ing over 48 wk is the primary end point (ClinicalTrials.gov
identifier NCT00497146). The Vitamin D Receptor Activator
(Paricalcitol) in Albuminuria Lowering (VITAL) study has ran-
domly assigned 282 patients with diabetes in a double-blind,
multicenter trial to placebo or 1 or 2 ␮g of paricalcitol taken
once daily in patients with eGFR between 15 and 90 ml/min
Moving Points in Nephrology 1527
per 1.73 m2 and urine albumin/creatinine concentration be-
tween 100 and 3000 mg/d on average of three morning void
specimen. All patients have to be on a stable dosage of angio-
tensin-converting enzyme inhibitor or angiotensin receptor
blocker and have reasonable control of BP and blood glucose to
participate. Results are awaited. Each of these trials, conducted
with patients with CKD, should provide better evidence (or
lack thereof) for cardiovascular and renal protection.
Disclosures
Consultant, speaker bureau, and grant support from Abbott.
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