vitamin-d-2 and Proteinuria

Paricalcitol, a selective activator of the vitamin D receptor (VDR), influences calcium and phosphorus homeostasis and bone metabolism. Whether paricalcitol reduces cardiovascular risk and protects renal function remains unclear. To systematically evaluate this in patients with chronic kidney disease (CKD), we conducted a meta-analysis of published randomized controlled trials (RCTs).. We searched MEDLINE, Embase, the Cochrane Library, and reference lists for RCTs comparing paricalcitol with placebo in stage 2-5 CKD (including pre-dialysis and renal replacement patients). The Cochrane quality assessment method was used to evaluate study quality. Results were summarized as risk ratios (RRs) for dichotomous outcomes or mean differences (MD) for continuous outcomes.. We included 21 studies comprising 1894 patients. Compared to placebo, paricalcitol reduced the risk of cardiovascular events (RR 0.55; 95% CI 0.35-0.87; p = 0.01), but the RR of hypercalcemia associated with paricalcitol was 6.50 (95% CI 3.21-13.15; p < 0.00001). Paricalcitol cannot significantly change systolic blood pressure and cardiac structure. Although proteinuria reduction was achieved more frequently with paricalcitol (RR 1.51; 95% CI 1.25-1.82; p < 0.0001), it did not significantly reduce proteinuria level compared to placebo. Paricalcitol could not protect renal function to delay CKD progression, since it reduced the glomerular filtration rate (MD -3.15; 95% CI -4.35--1.96; p < 0.0001) and elevated serum creatinine (MD 0.93; 95% CI 0.10-0.68; p = 0.008).. Paricalcitol reduces the risk of cardiovascular events in CKD patients but increases the risk of hypercalcemia and cannot improve cardiac structure. Meanwhile, it cannot significantly reduce proteinuria level or protect renal function.

Topics: Bone Density Conservation Agents; Cardiovascular Diseases; Ergocalciferols; Humans; Proteinuria; Renal Insufficiency, Chronic

Previous studies have demonstrated the safety and efficacy of using Paricalcitol for the treatment of secondary hyperparathyroidism (SHPT) in patients on dialysis. The aim of the current meta-analysis was to assess the safety and efficacy of Paricalcitol for the management of SHPT in patients with chronic kidney disease (CKD) not yet on dialysis. A secondary aim was to determine if sufficient data was available to assess the effect of Paricalcitol for the management of proteinuria.. A meta-analysis was conducted using the Cochrane Collaboration's RevMan 4.2 software.. Paricalcitol is effective in lowering PTH in patients with CKD not yet on dialysis and is also effective in lowering proteinuria in diabetic CKD patients. However, we uncovered a safety signal identifying an elevated calcium phosphate product and a trend towards the development of hypercalcemia. A phosphate elevation was not demonstrated because the target used in the clinical studies was a P > 5.5 mg/dl, a value appropriate for dialysis patients and not CKD patients.. Although Paricalcitol is effective in lowering PTH, we advise caution in the use of any active Vitamin D analogues in patients with CKD because of the potential risk of exacerbating vascular calcification.

Topics: Bone Density Conservation Agents; Ergocalciferols; Glomerular Filtration Rate; Humans; Hypercalcemia; Hyperparathyroidism, Secondary; Hyperphosphatemia; Kidney Failure, Chronic; Proteinuria; Randomized Controlled Trials as Topic; Risk; Treatment Outcome; Vitamin D

Proteinuria is the main predictor of chronic kidney disease progression. Drugs that block the renin-angiotensin-aldosterone (RAA) system reduce proteinuria and slow down the progression of the disease. However, their effect is suboptimal, and residual proteinuria persists as an important predictor of renal impairment. Vitamin D has pleiotropic effects that could have an impact on these parameters. In this study, we critically review the molecular and experimental bases that suggest an antiproteinuric effect of vitamin D receptor (VDR) activation and the available evidence on its antiproteinuric effect in clinical practice. In animal models, we have observed the antiproteinuric effect of VDR activation, which could be due to direct protective action on the podocyte or other pleiotropic effects that slow down RAA system activation, inflammation and fibrosis. Clinical trials have generally been conducted in patients with a vitamin D deficiency or insufficiency and the main trial (VITAL) did not demonstrate that paricalcitol improved the study's primary endpoint (decrease in the urine albumin to creatinine ratio). In this sense, the information available is insufficient to advise the use of native vitamin D or VDR activators as renoprotective antiproteinuric drugs beyond the experimental level. Two Spanish clinical trials and one Italian trial attempted to determine the effect of paricalcitol and vitamin D on residual proteinuria in various clinical circumstances (PALIFE, NEFROVID and PROCEED).

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Calcitriol; Clinical Trials as Topic; Cost-Benefit Analysis; Diabetic Nephropathies; Disease Models, Animal; Disease Progression; Drug Evaluation, Preclinical; Ergocalciferols; Gene Expression Regulation; Humans; Kidney Diseases; Mice; Mice, Knockout; Multicenter Studies as Topic; Myocytes, Smooth Muscle; Phosphates; Podocytes; Proteinuria; Rats; Receptors, Calcitriol; Renal Dialysis; Renin-Angiotensin System; Vitamin D

Observational data indicate that newer vitamin D compounds such as paricalcitol can suppress serum intact parathyroid hormone (iPTH) and reduce proteinuria in patients with CKD. To systematically evaluate the efficacy and safety of paricalcitol for CKD, we conducted a meta-analysis of the published randomized controlled trials (RCTs).. MEDLINE, Embase, the Cochrane Library, and article reference lists were searched for RCTs that compared paricalcitol with placebo in the treatment of patients with stage 2-5 CKD. The quality of the studies was evaluated using the Jadad method. The results are summarized as risk ratios (RRs) for dichotomous outcomes or mean differences for continuous outcomes.. Nine studies (832 patients) were included. Compared with placebo, paricalcitol suppressed serum iPTH (RR, 6.37; 95% confidence interval [95% CI], 4.64-8.74; P<0.001) and reduced proteinuria (RR, 1.68; 95% CI, 1.25-2.25; P<0.001). Compared with the control group, the RR for hypercalcemia associated with paricalcitol use was 2.25 (95% CI, 0.81-6.26; P=0.12). Patients receiving paricalcitol therapy did not have an increased risk of endocrine system and cardiovascular system adverse effects (RR, 1.07; 95% CI, 0.84-1.36; P=0.58).. We confirm that paricalcitol suppresses iPTH and lowers proteinuria in patients with stage 2-5 CKD without an increased risk of adverse events. A trend toward increased hypercalcemia did not reach statistical significance, but may be clinically relevant. A randomized trial is needed to determine if paricalcitol affects the development of ESRD or mortality.

Topics: Biomarkers; Chi-Square Distribution; Chronic Disease; Ergocalciferols; Evidence-Based Medicine; Humans; Hypercalcemia; Hyperparathyroidism, Secondary; Kidney Diseases; Odds Ratio; Parathyroid Hormone; Proteinuria; Randomized Controlled Trials as Topic; Risk Assessment; Risk Factors; Severity of Illness Index; Treatment Outcome

Proteinuria after kidney transplantation is accompanied by an increased risk of graft failure. In this single-center, placebo-controlled, double-blind trial we studied whether vitamin D receptor activator paricalcitol might reduce proteinuria. Patients with urinary protein-to-creatinine ratio (UPCR) ≥20 mg/mmol despite optimization of the renin angiotensin aldosterone system (RAAS) blockade were randomly assigned to receive 24 weeks' treatment with 2 μg/day paricalcitol or placebo. Primary endpoint was change in UPCR, and main secondary endpoints were change in urinary albumin-to-creatinine ratio (UACR) and 24-h proteinuria. Analysis was by intention to treat. One hundred and sixty-eight patients undergo randomization, and 83 were allocated to paricalcitol, and 85 to placebo. Compared with baseline, UPCR declined in the paricalcitol group (-39%, 95% CI -45 to -31) but not in the placebo group (21%, 95% CI 9 to 35), with a between group difference of -49% (95% CI -57 to -41; P < 0.001). UACR and 24-h proteinuria decreased only on paricalcitol therapy and significantly differed between groups at end-of-treatment (P < 0.001). Paricalcitol was well tolerated but incidence of mild hypercalcemia was higher than in placebo. In conclusion, addition of 2 μg/day paricalcitol lowers residual proteinuria in kidney transplant recipients. Long-term studies are needed to determine if the reduction in proteinuria improves transplant outcomes (ClinicalTrials.gov, number NCT01436747).

Topics: Adult; Aged; Albuminuria; Angiotensin-Converting Enzyme Inhibitors; Bone Density Conservation Agents; Cohort Studies; Creatinine; Double-Blind Method; Ergocalciferols; Female; Graft Survival; Humans; Kidney Function Tests; Kidney Transplantation; Male; Middle Aged; Phenotype; Proteinuria; Renal Insufficiency; Renin-Angiotensin System; Treatment Outcome

In stable renal transplant recipients with hyperparathyroidism, previous studies have indicated that vitamin D agonist treatment might have anti-proteinuric effects. Animal studies indicate possible anti-fibrotic and anti-inflammatory effects. Early introduction of paricalcitol in de novo renal transplant recipients might reduce proteinuria and prevent progressive allograft fibrosis. We performed a single-center, prospective, randomized, open-label trial investigating effects of paricalcitol 2 μg/day added to standard care. Participants were included 8 weeks after engraftment and followed for 44 weeks. Primary end point was change in spot urine albumin/creatinine ratio. Exploratory microarray analyses of kidney biopsies at study end investigated potential effects on gene expression. Secondary end points included change in glomerular filtration rate (GFR), pulse wave velocity (PWV), and endothelial function measured by peripheral arterial tonometry as reactive hyperemia index (RHI). Seventy-seven de novo transplanted kidney allograft recipients were included, 37 receiving paricalcitol. Paricalcitol treatment lowered PTH levels (P = 0.01) but did not significantly reduce albuminuria (P = 0.76), change vascular parameters (PWV; P = 0.98, RHI; P = 0.33), or influence GFR (P = 0.57). Allograft gene expression was not influenced. To summarize, in newly transplanted renal allograft recipients, paricalcitol reduced PTH and was well tolerated without negatively affecting kidney function. Paricalcitol did not significantly reduce/prevent albuminuria, improve parameters of vascular health, or influence allograft gene expression.

Topics: Administration, Oral; Animals; Ergocalciferols; Gene Expression; Glomerular Filtration Rate; Humans; Hyperemia; Hyperparathyroidism; Kidney; Kidney Transplantation; Parathyroid Hormone; Prospective Studies; Proteinuria; Pulse Wave Analysis; Receptors, Calcitriol

KDOQI guideline suggests that nutritional vitamin D should be supplemented in chronic kidney disease (CKD) patients who have vitamin D insufficiency/deficiency. However, there are scarce data regarding the additional benefit of active vitamin D supplement in CKD patients who were receiving nutritional vitamin D supplement. This study was conducted to explore the effect of adding active vitamin D to nutritional vitamin D supplement on proteinuria and kidney function in CKD with vitamin D insufficiency/deficiency.. This double-blind, randomized placebo-controlled trial was performed to answer the above question. Sixty-eight patients with CKD stage 3-4, urine protein to creatinine ratio (UPCR) > 1 g/g, and serum 25OH-D level < 30 ng/mL were enrolled. Patients were randomly assigned to receive 12-week treatment with oral ergocalciferol plus placebo (n = 36) or oral ergocalciferol plus calcitriol (n = 32).. The mean baseline values of UPCR of both groups were comparable (3.6 ± 3.8 g/g in combined group and 3.5 ± 3.0 g/g in ergocalciferol group). Following 12-week treatment, there were significant reductions in UPCR from baseline in both groups (2.3 ± 2.1 g/g in combined group and 2.4 ± 2.0 g/g in ergocalciferol group). The percentage reductions in UPCR of both groups were not significantly different. The mean eGFR and blood pressure did not differ between baseline and 12-week follow-up and between both groups. No severe hypercalcemia or serious side effects were noted in both groups.. The proteinuria lowering effect of ergocalciferol in CKD patients with vitamin D deficiency was demonstrated. Additional calcitriol supplement did not have more effects on proteinuria.. (Thai Clinical Trials Registry (TCTR) 20140929002 ). Date of registration: September 27, 2014.

Topics: Aged; Blood Pressure; Calcitriol; Creatinine; Double-Blind Method; Drug Therapy, Combination; Ergocalciferols; Female; Glomerular Filtration Rate; Humans; Male; Middle Aged; Proteinuria; Renal Insufficiency, Chronic; Severity of Illness Index; Thailand; Treatment Outcome; Vitamin D; Vitamin D Deficiency; Vitamins

Secondary hyperparathyroidism contributes to post-transplant CKD mineral and bone disorder. Paricalcitol, a selective vitamin D receptor activator, decreased serum parathyroid hormone levels and proteinuria in patients with secondary hyperparathyroidism. This single-center, prospective, randomized, crossover, open-label study compared the effect of 6-month treatment with paricalcitol (1 μg/d for 3 months and then uptitrated to 2 µg/d if tolerated) or nonparicalcitol therapy on serum parathyroid hormone levels (primary outcome), mineral metabolism, and proteinuria in 43 consenting recipients of renal transplants with secondary hyperparathyroidism. Participants were randomized 1:1 according to a computer-generated sequence. Compared with baseline, median (interquartile range) serum parathyroid hormone levels significantly declined on paricalcitol from 115.6 (94.8-152.0) to 63.3 (52.0-79.7) pg/ml (P<0.001) but not on nonparicalcitol therapy. At 6 months, levels significantly differed between treatments (P<0.001 by analysis of covariance). Serum bone-specific alkaline phosphatase and osteocalcin decreased on paricalcitol therapy only and significantly differed between treatments at 6 months (P<0.001 for all comparisons). At 6 months, urinary deoxypyridinoline-to-creatinine ratio and 24-hour proteinuria level decreased only on paricalcitol (P<0.05). L3 and L4 vertebral mineral bone density, assessed by dual-energy x-ray absorption, significantly improved with paricalcitol at 6 months (P<0.05 for both densities). Paricalcitol was well tolerated. Overall, 6-month paricalcitol supplementation reduced parathyroid hormone levels and proteinuria, attenuated bone remodeling and mineral loss, and reduced eGFR in renal transplant recipients with secondary hyperparathyroidism. Long-term studies are needed to monitor directly measured GFR, ensure that the bone remodeling and mineral effects are sustained, and determine if the reduction in proteinuria improves renal and cardiovascular outcomes.

Topics: Adult; Bone Density; Bone Density Conservation Agents; Bone Remodeling; Calcium; Creatinine; Cross-Over Studies; Ergocalciferols; Female; Humans; Hyperparathyroidism, Secondary; Kidney Transplantation; Male; Middle Aged; Parathyroid Hormone; Phosphates; Postoperative Complications; Prospective Studies; Proteinuria; Vitamin D

Existing treatment of proteinuria is not sufficient to halt the chronic kidney disease (CKD) epidemic. Therefore the aim of our study was to evaluate the effect of paricalcitol on proteinuria in non-dialysis CKD patients with secondary hyperparathyroidism treated according to Kidney Disease: Improving Global Outcomes (KDIGO) guidelines. Forty-one non-dialysis CKD patients with secondary hyperparathyroidism (iPTH >65 pg/mL), serum calcium <2.6 mmol/L, serum phosphate <1.8 mmol/L and proteinuria (>150 mg/day) were treated with paricalcitol 1 μg/day. Most were treated for 6 months, with the exception of three patients having iPTH <30 pg/mL after 3 months, in whom therapy was stopped. All patients were followed for 6 months. 24-h ambulatory blood pressure (24hABP) monitoring was performed at 0 and 6 months. Fixed doses of ACE inhibitors and/or ARBs and/or statins were kept for 3 months before and during the study. Forty-one patients (30 men, 11 women; age 62.44 ± 11.93 years) with different primary causes of CKD were enrolled in the study. Urinary albumin/creatinine ratio (UACR), 24-h urinary albuminuria (24hUA) and 24-h urinary quantitative proteinuria (24hUQP) were measured. Values at 0 and 6 months of these parameters were log-transformed for statistical analysis. After treatment with paricalcitol, statistically significant reduction (paired t-test) in 24hUA (P < 0.011) and 24hUQP (P < 0.0001) were found. The reduction of UACR was not significant (P = 0.074). In the observational period no statistically significant reduction in 24hABP was found. Treatment with 1 μg paricalcitol daily according to clinical practice in non-dialysis CKD patients with secondary hyperparathyroidism and proteinuria significantly reduces 24hUA and 24hUQP without significant change in 24hABP.

Topics: Adult; Aged; Aged, 80 and over; Albuminuria; Blood Pressure; Blood Pressure Monitoring, Ambulatory; Bone Density Conservation Agents; Creatinine; Ergocalciferols; Female; Follow-Up Studies; Humans; Hyperparathyroidism, Secondary; Male; Middle Aged; Practice Guidelines as Topic; Proteinuria; Renal Insufficiency, Chronic; Time Factors

Vitamin D has an important regulatory effect on the renin-angiotensin-aldosterone system, playing a central role in the regulation of proteinuria. We therefore studied the antiproteinuric effect of paricalcitol.. 36 patients with an estimated GFR of 30-90 mL/min/1.73 m² and proteinuria >400 mg/d with a stable dose of ACE inhibitor or ARB for at least 3 months were recruited. Patients received oral paricalcitol 1 µg/day for 12 months. Primary endpoint was decrease in proteinuria from baseline. Secondary endpoints were changes in creatinine, eGFR, serum levels of calcium, phosphorus, iPTH, 25(OH)vitD, C-Reactive Protein and blood presure.. Mean proteinuria was 2806 mg/d and fell to 2199 mg/d at month 6 (p<.0001) and 1931.5 mg/d at month 12 (P<.0001). Patients with >3000 mg/d baseline proteinuria (n=12) saw smaller relative reductions in proteinuria (5956.9±2492.6 mg/d to 4220.4±2613 mg/d at 12 months) than patients with <3000 mg/d baseline proteinuria (1371±627.5 mg/d to 821.3±491.5mg/d at 12 months). There were no changes in BP, eGFR and CRP. We observed significant changes in serum levels of calcium, phosphorus, iPTH, 25(OH) vitamin D.. Our study shows an important reduction in proteinuria with a low dose of oral paricalcitol in CKD, that is particularly robust with baseline proteinuria between 1-3 g/d.

Topics: Aged; Aged, 80 and over; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Blood Pressure; C-Reactive Protein; Calcium; Chronic Disease; Creatinine; Ergocalciferols; Female; Follow-Up Studies; Glomerular Filtration Rate; Humans; Kidney Diseases; Male; Middle Aged; Parathyroid Hormone; Phosphorus; Proteinuria; Treatment Outcome; Vitamin D

Paricalcitol is a synthetic vitamin D analogue acting on vitamin D receptor (VDR). The result is inhibition of PTH synthesis and secretion. Paricalcitol appears also to block the renin-angiotensin-aldosterone system. We evaluated the role of paricalcitol in the management of proteinuria of various aetiology. A total of 19 patients participated. Most had diabetic nephropathy; however patients with other types of glomerulopathy leading to proteinuria were also included. Paricalcitol 1-2 μg daily, according to response, was administered for three months. Serum Ca, PO4, Ca × PO4, PTH, creatinine clearance and albumin, as well as 24 hour urine protein were measured before and after treatment. Five out of 19 patients did not respond to the treatment. The remaining 14 patients had an average 32.9% reduction of proteinuria. The drug was well tolerated. Paricalcitol appears to have a role in the treatment of proteinuria. However, our study raises a question regarding why some patients do not respond to paricalcitol. Patients with proteinuria due to diabetic nephropathy seem to respond better than patients with glomerulopathy.

Topics: Aged; Aged, 80 and over; Diabetic Nephropathies; Ergocalciferols; Female; Glomerulonephritis; Humans; Male; Middle Aged; Proteinuria; Vitamins

Vitamin D has key roles in regulating systems that could be important in the pathobiological state of proteinuria. Because of this, it could be helpful in treating patients with proteinuric renal diseases. The objective is to determine the effect of oral paricalcitol on protein excretion in patients with proteinuric chronic kidney disease.. Double-blind randomized study.. 61 patients with estimated glomerular filtration rate of 15 to 90 mL/min/1.73 m(2) and protein excretion greater than 400 mg/24 h.. Randomization to 6 months of treatment with paricalcitol, 1 mug/d, or placebo.. The predefined primary end point was to compare change in mean spot urinary protein-creatinine ratio between the baseline measurement and the last study evaluation (6 months in study completers) between the 2 groups. Every 4 weeks, there was measurement of serum intact parathyroid hormone, serum calcium, serum phosphorus, serum creatinine, and urine spot protein and creatinine.. At baseline, mean urinary protein-creatinine ratios were 2.6 and 2.8 g/g in the placebo and paricalcitol groups, respectively. At final evaluation, mean ratios were 2.7 and 2.3, respectively. Changes in protein excretion from baseline to last evaluation were +2.9% for controls and -17.6% for the paricalcitol group (P = 0.04). A 10% decrease in proteinuria occurred in controls (7 of 27; 25.9%) and the paricalcitol group (16 of 28; 57.1%; P = 0.03).. The relatively small sample size limits the extent to which results should be generalized.. Paricalcitol resulted in a significant reduction in protein excretion in patients with proteinuric renal disease.

Topics: Administration, Oral; Adult; Aged; Biomarkers; Bone Density Conservation Agents; Calcium; Creatinine; Double-Blind Method; Ergocalciferols; Female; Glomerular Filtration Rate; Humans; Male; Middle Aged; Parathyroid Hormone; Phosphorus; Proteinuria; Renal Insufficiency, Chronic; Sample Size; Treatment Outcome; Vitamin D Deficiency

Proteinuria is a marker of cardiovascular and renal disease in patients with chronic kidney disease (CKD), and reduction in proteinuria has been associated with improved cardiovascular and renal outcomes. While active vitamin D and its analogs have been shown to have renal protective effects in animals, these hormones have not been shown to reduce proteinuria in CKD patients.. In three double-blind, randomized, placebo-controlled studies to evaluate the safety and efficacy of oral paricalcitol, 220 CKD stage 3 and 4 patients with secondary hyperparathyroidism (SHPT) were randomized to oral paricalcitol (N= 107, mean dose 9.5 microg/week) or placebo (N= 113) and followed for up to 24 weeks. In conjunction with other safety measures, proteinuria was measured by dipstick and read by an automated reader at the beginning and end of trial. We subsequently analyzed the dipstick data to evaluate the effect of paricalcitol on proteinuria.. At baseline, proteinuria was present in 57 patients randomized to oral paricalcitol and 61 patients randomized to placebo (NS). At the final visit, 29/57 (51%) of the paricalcitol patients compared to 15/61 (25%) placebo patients had reduction in proteinuria, P= 0.004 (odds for reduction in proteinuria 3.2 times greater for paricalcitol patients, 95% CI 1.5-6.9). For the patients who had both proteinuria at baseline and parathyroid hormone (PTH) suppression (end point defined as 2 consecutive > or =30% decreases in iPTH from baseline), 27/51 (53%) patients had a reduction in the proteinuria in the paricalcitol group and 0/7 (0%) had a reduction in proteinuria in the placebo group. Reduction of proteinuria favored patients on paricalcitol, regardless of age, sex, race, diabetes mellitus, hypertension, or use of therapies to block the renin-angiotensin-aldosterone system (RAAS).. Our results demonstrate that the reduction in proteinuria was associated with paricalcitol treatment, and the reduction in proteinuria was independent of concomitant use of agents that block the RAAS. Paricalcitol as a potential pharmacologic means of reducing proteinuria in CKD patients warrants further investigation.

Topics: Administration, Oral; Aged; Ergocalciferols; Female; Humans; Hyperparathyroidism, Secondary; Male; Middle Aged; Parathyroid Hormone; Proteinuria; Renal Insufficiency, Chronic; Treatment Outcome

Topics: Ergocalciferols; Humans; Kidney Transplantation; Prospective Studies; Proteinuria

Body stores of vitamin D are measured as "total" serum 25-hydroxy vitamin D (25(OH)D). Its largest component is protein bound and lost in urine in nephrotic syndrome (NS). Our study investigates whether "free" 25(OH)D levels are a better guide to bone health and need for vitamin D supplementation in patients with steroid-sensitive NS (SSNS).. A cross-sectional study was performed in children with SSNS and healthy controls. Blood was tested for albumin, creatinine, calcium, phosphate, ALP, total and free (by direct ELISA) 25(OH)D, iPTH, and urine for protein-creatinine ratio.. These results confirm that total 25(OH)D levels are low in NS and related to degree of proteinuria. However levels of free 25(OH)D, ALP, and iPTH did not change in relapse or remission in comparison with healthy controls. Our results suggest that in proteinuric renal diseases, free 25(OH)D rather than total 25(OH)D levels should be used to diagnose vitamin D deficiency and guide therapy.

Topics: Case-Control Studies; Child; Child, Preschool; Cholecalciferol; Cross-Sectional Studies; Dietary Supplements; Ergocalciferols; Female; Glucocorticoids; Humans; Male; Nephrotic Syndrome; Proteinuria; Risk Factors; Serum Albumin, Human; Severity of Illness Index; Vitamin D Deficiency

Diabetic nephropathy (DN) is one of the most common microvascular complications of diabetes and is the leading cause of end-stage renal disease (ESRD) and replacement therapy worldwide. Vitamin D levels in DN patients are very low due to the decrease in the synthesis and activity of 1-. Diabetes mellitus (DM) was induced in 94 8-week-old DBA/2J mice by intraperitoneal injection of streptozotocin (STZ). DM mice were randomly divided into receiving vehicle or treatment with paricalcitol, the active vitamin D analog, 1 week after DM induction or paricalcitol treatment 3 weeks after DM induction. An additional control group of healthy wild-type mice was not treated. Urine albumin, blood urea nitrogen, and creatinine levels were measured before and at the end of the paricalcitol treatment. Periodic acid-Schiff, immunohistochemistry staining, and western blot of the renal tissues of vitamin D receptor, villin, nephrin, and podocin expressions, were analyzed.. Paricalcitol treatment restored villin, nephrin, and podocin protein levels that were downregulated upon DM induction, and reduced fibronectin protein level. Vitamin D receptor activation by paricalcitol may reduce proteinuria of DN in mice and alleviate high-glucose-induced injury of kidney podocytes by regulating the key molecules such nephrin-podocin.. Paricalcitol treatment was associated with improved structural changes in type 1 diabetic mice including upregulation of vitamin D receptor expression, and decreased fibrosis markers such as fibronectin. These effects may contribute to the consistent benefit of vitamin D analog to slow the deterioration in glomerular function and reduce the risk of ESRD in patients with type 1 and 2 diabetes mellitus. Our results suggest that additional use of paricalcitol may be beneficial in treating patients with diabetes under standard therapeutic strategies.

Topics: Animals; Diabetes Mellitus, Experimental; Diabetic Nephropathies; Disease Progression; Ergocalciferols; Fibronectins; Fibrosis; Kidney; Mice, Inbred DBA; Proteinuria; Receptors, Calcitriol; Streptozocin

BACKGROUND Fabry disease is a rare and progressive X-linked inherited disorder of glycosphingolipid metabolism that is due to deficient or absent lysosomal a-galactosidase A activity. Among its other associated signs and symptoms, patients present with renal failure and proteinuria, which are markers of disease progression. Renin-angiotensin-aldosterone system (RAAS) blockers can slow the progression of chronic renal failure and proteinuria. In fact, some studies have shown the beneficial effects of paricalcitol on proteinuria. CASE REPORT We present a case of a female patient with the classic variant of Fabry disease. She was treated with a high dose of paricalcitol as an antiproteinuric agent due to unsatisfactory double-RAAS blockage, which resulted in transient worsening of cardiac and renal function. CONCLUSIONS Despite the positive effects of paricalcitol as an antiproteinuric agent, as previously shown by some authors, our case highlights the possible serious adverse effects associated with the use of high doses of this drug.

Topics: Adult; Bone Density Conservation Agents; Clinical Deterioration; Dose-Response Relationship, Drug; Ergocalciferols; Fabry Disease; Female; Heart Failure; Humans; Kidney Failure, Chronic; Proteinuria

Diabetic nephropathy (DN) is a major cause of end-stage renal disease and proteinuria is one of the most prominent clinical manifestations. The expression of Vitamin D receptor (VDR) in patients with chronic kidney diseases was decreased, while VDR agonists could partially alleviate the proteinuria of DN in animal models. The present study was designed to determine the expression of VDR in renal tissues and its relationship with proteinuria the diabetic model db/db mice.. The regulation effects of VDR on the Wnt signaling pathway were analyzed using RNA interference and VDR agonist paricalcitol.. With the increase in age of the db/db mice, the VDR protein and mRNA levels in renal tissues were decreased, proteinuria increased, and the protein and mRNA levels of GSK-3β of and β-catenin increased. Paricalcitol treatment resulted in the up-regulation of VDR and down-regulation of GSK-3β and β-catenin, indicating that VDR had a regulatory effect on the Wnt signaling pathway.. VDR activation could reduce proteinuria of DN mice and alleviate high-glucose-induced injury of kidneys and podocytes by regulating the key molecules of Wnt signaling pathway.

Topics: Aging; Animals; beta Catenin; Cells, Cultured; Diabetic Nephropathies; Down-Regulation; Ergocalciferols; Glucose; Glycogen Synthase Kinase 3 beta; Kidney; Male; Mice; Mice, Inbred C57BL; Podocytes; Proteinuria; Receptors, Calcitriol; RNA Interference; Up-Regulation; Wnt Signaling Pathway

Renin-angiotensin-aldosterone system (RAAS) blockade provides renoprotective effects in chronic kidney disease (CKD); yet progressive renal function loss remains common. Dietary sodium restriction potentiates the renoprotective effects of RAAS blockade. Vitamin D receptor activator (VDRA) treatment reduces proteinuria, inflammation and fibrosis, but whether these effects depend on sodium intake has not been studied. We hypothesized that the renoprotective effects of VDRA treatment, with or without RAAS blockade, are modulated by sodium intake.. Six weeks after the induction of adriamycin nephrosis in Wistar rats, i.e. with established proteinuria, animals were treated with the VDRA paricalcitol, lisinopril, the combination, or vehicle; each treatment was given during either a high- (2% NaCl) or a low-sodium (0.05% NaCl) diet for 6 weeks. We assessed proteinuria, blood pressure, renal macrophage accumulation and renal expression of the pre-fibrotic marker alpha-smooth muscle actin (α-SMA) at the end of the treatment.. Both paricalcitol and lisinopril individually, as well as in combination, reduced proteinuria and glomerular and interstitial inflammation during a low-sodium diet, but not during a high-sodium diet. All interventions also reduced focal glomerulosclerosis and interstitial expression of α-SMA during the low-sodium diet, while similar trends were observed during the high-sodium diet. The renoprotective effects of paricalcitol were not accompanied by blood pressure reduction. As proteinuria was already abolished by lisinopril during the low-sodium diet, the addition of paricalcitol had no further effect on proteinuria or downstream inflammatory or pre-fibrotic changes.. The renoprotective effects of the VDRA paricalcitol are blood pressure independent but do depend on dietary sodium status. The combination of RAAS blockade, dietary sodium restriction and VDRA may be a promising intervention to further retard renal function loss in CKD.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Blood Pressure; Bone Density Conservation Agents; Diet, Sodium-Restricted; Ergocalciferols; Glomerulonephritis, Membranous; Glomerulosclerosis, Focal Segmental; Kidney; Lisinopril; Male; Peptidyl-Dipeptidase A; Proteinuria; Rats; Rats, Wistar; Receptors, Calcitriol; Renin-Angiotensin System; Sodium Chloride, Dietary; Sodium, Dietary

Excessive lymphangiogenesis is associated with cancer progression and renal disease. Attenuation of lymphangiogenesis might represent a novel strategy to target disease progression although clinically approved anti-lymphangiogenic drugs are not available yet. VitaminD(VitD)-deficiency is associated with increased cancer risk and chronic kidney disease. Presently, effects of VitD on lymphangiogenesis are unknown. Given the apparently protective effects of VitD and the deleterious associations of lymphangiogenesis with renal disease, we here tested the hypothesis that VitD has direct anti-lymphangiogenic effects in vitro and is able to attenuate lymphangiogenesis in vivo. In vitro cultured mouse lymphatic endothelial cells (LECs) expressed VitD Receptor (VDR), both on mRNA and protein levels. Active VitD (calcitriol) blocked LEC tube formation, reduced LEC proliferation, and induced LEC apoptosis. siRNA-mediated VDR knock-down reversed the inhibitory effect of calcitriol on LEC tube formation, demonstrating how such inhibition is VDR-dependent. In vivo, proteinuric rats were treated with vehicle or paricalcitol for 6 consecutive weeks. Compared with vehicle-treated proteinuric rats, paricalcitol showed markedly reduced renal lymphangiogenesis. In conclusion, our data show that VitD is anti-lymphangiogenic through VDR-dependent anti-proliferative and pro-apoptotic mechanisms. Our findings highlight an important novel function of VitD demonstrating how it may have therapeutic value in diseases accompanied by pathological lymphangiogenesis.

Topics: Animals; Apoptosis; Cell Movement; Cell Proliferation; Doxorubicin; Endothelial Cells; Ergocalciferols; Gene Expression; Humans; Kidney; Lymphangiogenesis; Lymphatic Vessels; Mice; Proteinuria; Rats; Rats, Wistar; Receptors, Calcitriol; RNA, Small Interfering; Vitamin D

Data on paricalcitol lowering albuminuria and proteinuria already exist; however, it is unclear how paricalcitol withdrawal affects both. Forty-two nondialysis chronic kidney disease (CKD) patients (29 men) aged 62.3 ± 12 years completed the study. CKD patients with proteinuria and intact parathyroid hormone ≥65 pg/mL received paricalcitol (1 μg/day po) for 6 months. After paricalcitol withdrawal we followed them for 6 more months. Paricalcitol treatment significantly reduced urinary albumin/creatinine ratio (UACR), 24-hour albuminuria (24hA), and 24-hour proteinuria (24hP). Six months after drug withdrawal UACR increased significantly, 24hA and 24hP did not change significantly. Serum creatinine and cystatin C significantly increased during treatment, and estimated glomerular filtration rate (eGFR) decreased. After drug withdrawal serum creatinine, cystatin C, and eGFR did not change significantly. In conclusion, 6-month paricalcitol treatment (1 μg/day) in nondialysis CKD patients significantly reduced albuminuria and proteinuria. Six months after paricalcitol withdrawal 24hA and 24hP did not change significantly. Kidney function decreased during paricalcitol treatment; after paricalcitol withdrawal it remained stable. The unaltered values of 24hA, 24hP, and kidney function after paricalcitol withdrawal could be a delayed effect of paricalcitol treatment.

Topics: Adult; Aged; Aged, 80 and over; Albuminuria; Bone Density Conservation Agents; Ergocalciferols; Female; Follow-Up Studies; Humans; Male; Middle Aged; Proteinuria; Renal Insufficiency, Chronic; Treatment Outcome; Withholding Treatment

Circulating and renal activity of angiotensin-converting enzyme 2 (ACE2) is increased in non-obese diabetic (NOD) mice. Because paricalcitol has been reported to protect against diabetic nephropathy, we investigated the role of paricalcitol in modulating ACE2 in these mice. In addition, renal ADAM17, a metalloprotease implied in ACE2 shedding, was assessed. NOD female and non-diabetic control mice were studied for 21 days after diabetes onset and divided into various treatment groups. Diabetic animals received either vehicle; 0.4 or 0.8 μg/kg paricalcitol, aliskiren, or a combination of paricalcitol and aliskiren. We then studied the effect of paricalcitol on ACE2 expression in proximal tubular epithelial cells. Paricalcitol alone or in combination with aliskiren resulted in significantly reduced circulating ACE2 activity in NOD mice but there were no changes in urinary albumin excretion. Serum renin activity was significantly decreased in mice that received aliskiren but no effect was found when paricalcitol was used alone. Renal content of ADAM17 was significantly decreased in animals that received a high dose of paricalcitol. Renal and circulating oxidative stress (quantified by plasma H2O2 levels and immunolocalization of nitrotyrosine) were reduced in high-dose paricalcitol-treated mice compared with non-treated diabetic mice. In culture, paricalcitol incubation resulted in a significant increase in ACE2 expression compared with nontreated cells. In NOD mice with type 1 diabetes, paricalcitol modulates ACE2 activity, ADAM17, and oxidative stress renal content independently from the glycemic profile and urinary albumin excretion. In tubular cells, paricalcitol may modulate ACE2 by blocking its shedding. In the early stage of diabetic nephropathy, paricalcitol treatment counterbalances the effect of diabetes on circulating ACE2 activity. Our results suggest that additional use of paricalcitol may be beneficial in treating patients with diabetes under standard therapeutic strategies.

Topics: ADAM Proteins; ADAM17 Protein; Angiotensin-Converting Enzyme 2; Animals; Blood Pressure; Diabetes Mellitus, Experimental; Diabetic Nephropathies; Drug Evaluation, Preclinical; Ergocalciferols; Female; Kidney; Mice, Inbred NOD; Oxidative Stress; Peptidyl-Dipeptidase A; Proteinuria; Random Allocation; Renin

Proteinuria is the predominant risk factor for renal disease progression in Fabry disease (FD). When urine protein excretion is controlled to <0.50 g/24 h, the rate loss of glomerular filtration rate (GFR) is not significantly different from 0. However, enzyme replacement therapy (ERT) alone does not decrease proteinuria and it has been recommended that patients receiving ERT also receive anti-renin-angiotensin system (RAS) therapy. Emerging evidence show that paricalcitol (PCT) reduces proteinuria in the presence of intensified inhibition of RAS; however, there is no evidence in FD. We evaluated the antiproteinuric effect of PCT in FD patients with proteinuria >0.50 g/24 h persisting despite ERT and anti-RAS therapy titrated to maximum tolerated dosage.. Fifteen FD patients were selected and studied in the first 6 months of add-on oral PCT (1 µg/day) and, in order to verify the dependence of proteinuria reduction on PCT, 3 months after drug withdrawal.. At baseline, proteinuria was 1.3 ± 0.6 g/24 h. Six months of add-on PCT significantly decreased proteinuria to 0.4 ± 0.3 g/24 h, with levels <0.50 g/24 h achieved in four patients at Month 1, six at Month 3, and in 12 by Month 6, in the absence of changes to BP and GFR. Proteinuria recovered to basal value after drug withdrawal.. In conclusion, our study is the first evidence that PCT is effective in reducing proteinuria in FD patients in the presence of ERT and anti-RAS therapy.

Topics: Adolescent; Adult; Bone Density Conservation Agents; Enzyme Replacement Therapy; Ergocalciferols; Fabry Disease; Female; Follow-Up Studies; Glomerular Filtration Rate; Humans; Male; Middle Aged; Prospective Studies; Proteinuria; Renin-Angiotensin System

Topics: Administration, Oral; Adult; Aged; Biomarkers; Ergocalciferols; Glomerular Filtration Rate; Humans; Hyperparathyroidism, Secondary; Kidney; Kidney Transplantation; Logistic Models; Middle Aged; Multivariate Analysis; Odds Ratio; Parathyroid Hormone; Proteinuria; Risk Factors; Time Factors; Treatment Outcome

To investigate whether an increase in vitamin D levels in patients with systemic lupus erythematosus (SLE) was associated with improvement in disease activity.. A total of 1,006 SLE patients were monitored over 128 weeks. SLE patients with low levels of 25-hydroxyvitamin D (25[OH]D; <40 ng/ml) were given supplements of 50,000 units of vitamin D2 weekly plus 200 units of calcium/vitamin D3 twice daily. Longitudinal regression models were used to estimate the association between levels of 25(OH)D and various measures of disease activity.. The SLE patients had the following characteristics: 91% were female, their mean age was 49.6 years, and their ethnicity was 54% Caucasian, 37% African American, and 8% other. For those with levels of 25(OH)D <40 ng/ml, a 20-unit increase in the 25(OH)D level was associated with a mean decrease of 0.22 (95% confidence interval [95% CI] -0.41, -0.02) (P = 0.032) in the Safety of Estrogens in Lupus Erythematosus National Assessment (SELENA) version of the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI). This corresponded to a 21% decrease in the odds of having a SELENA-SLEDAI ≥5 (95% CI 1, 37). The mean urine protein-to-creatinine ratio decreased by 2% (95% CI -0.03, -0.01) (P = 0.0001), corresponding to a 15% decrease in the odds of having a ratio >0.5 (95% CI 2, 27).. We found that a 20-ng/ml increase in the 25(OH)D level was associated with a 21% decrease in the odds of having a high disease activity score and a 15% decrease in the odds of having clinically important proteinuria. Although these associations were statistically significant, the clinical importance is relatively modest. There was no evidence of additional benefit of 25(OH)D beyond a level of 40 ng/ml.

Topics: Adult; Calcium; Cholecalciferol; Cohort Studies; Creatinine; Ergocalciferols; Female; Humans; Longitudinal Studies; Lupus Erythematosus, Systemic; Male; Middle Aged; Proteinuria; Severity of Illness Index; Treatment Outcome; Vitamin D; Vitamin D Deficiency

Nutritional vitamin D [25(OH)D] deficiency is common in patients with chronic kidney disease (CKD). No studies have specifically examined the differences between ethnic groups in response to ergocalciferol ("D2") therapy.. A retrospective analysis was performed to evaluate the effectiveness of D2 therapy as recommended by the KDOQI guidelines in 184 Hispanic and Caucasian nondialysis CKD patients.. Low 25(OH)D levels (<75 nmol/L) were found in 89.4 % of Hispanics versus 61.4 % of Caucasians, despite similar degrees of CKD. Treatment per KDOQI guidelines resulted in 85.5 % of treated Hispanics and 66.7 % of treated Caucasians remaining vitamin D-deficient. Although both Hispanics and Caucasians had significant (P < 0.0001) changes in 25(OH)D levels, absolute changes were modest (12.5 ± 2.0 nmol/mL in Hispanics, 20.0 ± 3.5 nmol/L in Caucasians). The increase seen in Caucasians was significantly greater than in Hispanics (P < 0.0001). In multiple logistic regression modeling, Hispanic ethnicity remained independently associated with poorer response to therapy (P = 0.0055), even after adjustment for other factors.. While both Hispanics and Caucasians demonstrated suboptimal response to the KDOQI-guided vitamin D repletion strategy, Hispanic ethnicity was significantly associated with poorer response. Our findings may have implications for other darker-skinned populations, even in solar-rich environments.

Topics: Adult; Aged; Aged, 80 and over; Calcium; Creatinine; Diabetes Mellitus; Dietary Supplements; Ergocalciferols; Female; Hispanic or Latino; Humans; Male; Middle Aged; Parathyroid Hormone; Phosphates; Proteinuria; Renal Insufficiency, Chronic; Retrospective Studies; Texas; Treatment Outcome; Vitamin D; Vitamin D Deficiency; Vitamins; White People; Young Adult

Paricalcitol, a selective activator of Vitamin D receptors, is successfully used as a treatment of hyperparathyroidism secondary to chronic kidney disease (CKD). In addition, it has been proposed for reducing proteinuria in patients with CKD. Nonetheless, little is known about its effect on peritoneal protein loss in patients on peritoneal dialysis (PD).. To analyse the efficiency of oral paricalcitol in secondary hyperparathyroidism control in PD patients and to verify its effect on urinary and peritoneal effluent protein loss.. Prospective study with a 12-month follow-up on a cohort of PD patients. Invention consisted of the introduction of paricalcitol for the treatment of secondary hyperparathyroidism. Paricalcitol was dosed according to parathyroid hormone (PTH): 1mg/day for patients with PTH < 500 pg/ml, and 2mg/day for those with higher PTH levels. Epidemiological, clinical and analytical data were analysed.. 38 patients (56 ± 19 years, 55% women, 16% diabetics, technique time (14 ± 10 months) were included in the study. Thirty-three of them received 1mg/day of paricalcitol; the rest received 2mg/day. The use of paricalcitol was associated with a PTH decrease of 30.7 ± 6.8% (P<.001) after 12 months of treatment with no changes in calcium (8.82 ± 0.96 vs. 9.02 ± 0.91; P = .153) and phosphate levels (4.78 ± 0.63 vs. 4.93 ± 0.77; P = .693). Patients did not modify treatment concurrent with phosphate binders over the study period, nor did they change the cinacalcet dosage. However, fewer patients needed it by the end of the study. The PTH baseline levels were independent indicators of its decrease (b = 0.689, P = .018), and the rest of the analysed parameters were not affected. Over the study period there was a proteinuria decrease (0.79 ± 0.41 vs. 0.64 ± 0.36 g/day, P = .034) with no changes in renal function (7.2 ± 1.1 vs. 6.3 ± 0.9 ml/min, P =.104). Similarly, no differences were found in in the percentages of patients taking renin-angiotensin system inhibitors (71 vs. 68 %, P = .472) or the doses needed. There was no significant change in peritoneal protein loss (5.8 ± 1.9 vs. 6.0 ± 2.2g/24h, P = .731) nor in serum albumin levels (3.7 ± 1.1 vs. 3.7 ± 1.2g/dl, P = .697).. The use of oral paricalcitol reduces PTH levels safely and substantially in patients on PD. Their use is associated with a proteinuria decrease and is not linked to a decrease of glomerular filtration rate or changes in the medication that could modify it. We have found no modification in the amount of peritoneal protein loss.

Topics: Bone Density Conservation Agents; Calcium; Ergocalciferols; Female; Humans; Male; Middle Aged; Peritoneal Dialysis; Peritoneum; Phosphorus; Prospective Studies; Proteins; Proteinuria; Renal Insufficiency, Chronic

Angiotensin-converting enzyme (ACE) inhibitors ameliorate the progression of renal disease. In combination with vitamin D receptor activators, they provide additional benefits. In the present study, uremic (U) rats were treated as follows: U+vehicle (UC), U+enalapril (UE; 25 mg/l in drinking water), U+paricalcitol (UP; 0.8 μg/kg ip, 3 × wk), or U+enalapril+paricalcitol (UEP). Despite hypertension in UP rats, proteinuria decreased by 32% vs. UC rats. Enalapril alone, or in combination with paricalcitol, further decreased proteinuria (≈70%). Glomerulosclerosis and interstitial infiltration increased in UC rats. Paricalcitol and enalapril inhibited this. The increase in cardiac atrial natriuretic peptide (ANP) seen in UC rats was significantly decreased by paricalcitol. Enalapril produced a more dramatic reduction in ANP. Renal oxidative stress plays a critical role in inflammation and progression of sclerosis. The marked increase in p22(phox), a subunit of NADPH oxidase, and decrease in endothelial nitric oxide synthase were inhibited in all treated groups. Cotreatment with both compounds inhibited the uremia-induced increase in proinflammatory inducible nitric oxide synthase (iNOS) and glutathione peroxidase activity better than either compound alone. Glutathione reductase was also increased in UE and UP rats vs. UC. Kidney 4-hydroxynonenal was significantly increased in the UC group compared with the normal group. Combined treatment with both compounds significantly blunted this increase, P < 0.05, while either compound alone had no effect. Additionally, the expression of Mn-SOD was increased and CuZn-SOD decreased by uremia. This was ameliorated in all treatment groups. Cotreatment with enalapril and paricalcitol had an additive effect in increasing CuZn-SOD expression. In conclusion, like enalapril, paricalcitol alone can improve proteinuria, glomerulosclerosis, and interstitial infiltration and reduce renal oxidative stress. The effects of paricalcitol may be amplified when an ACE inhibitor is added since cotreatment with both compounds seems to have an additive effect on ameliorating uremia-induced changes in iNOS and CuZn-SOD expression, peroxidase activity, and renal histomorphometry.

Topics: Aldehydes; Angiotensin-Converting Enzyme Inhibitors; Animals; Atrial Natriuretic Factor; Enalapril; Ergocalciferols; Female; Glomerulonephritis; Kidney; NADPH Oxidases; Nitric Oxide Synthase Type II; Oxidative Stress; Proteinuria; Rats; Receptors, Calcitriol; Superoxide Dismutase; Uremia

Patients on peritoneal dialysis (PD) have protein loss through peritoneal membrane (PM) and experience changes in permeability of the membrane. Paricalcitol is a selective vitamin D receptor activator with an effect upon systemic inflammation and an inhibitory effect upon the renin-angiotensin-aldosterone system (RAAS).. This study explores the possible effect of paricalcitol upon the PM in 23 patients on PD with high iPTH levels. Peritoneal kinetic studies were performed before and after paricalcitol, measuring also ultrafiltration/ day, peritoneal protein losses and proteinuria. Results were compared with a control group of 15 patients not receiving any form of vitamin D.. With a mean dose of 1.3 μg/day, peritoneal protein loss decreased from 0.91 ± 0.35 to 0.76 ± 0.26 g/l (15.4%) (p = 0.007) and from 7.55 to 6.46 g/d (p < 0.033), and ultrafiltration increased from 844 to 1,002 ml/d (15.8%) (p = 0.037) and from 284 to 323 ml/4 h. (NS), with minimal change in the creatinine dialysate/plasma ratio 0.67 ± 0.12 vs. 0.65 ± 0.11. Proteinuria decreased from 1.65 to 1.25 g/l (21.9%) (p = 0.01) and iPTH decreased from 668 ± 303 to 291 ± 148 pg/ml (p < 0.001). In the control group, no changes in peritoneal membrane permeability and proteinuria were found.. The results of the study indicate that paricalcitol is effective in treating hyperparathyroidism in patients on PD, and suggest an effect upon proteinuria and PM permeability (not previously reported), with diminished peritoneal protein loss and increased ultrafiltration. The antiinflammatory, antifibrotic and RAAS-modulating actions described for paricalcitol may be responsible for these findings, and could be important for preserving the peritoneum as a dialyzing membrane.

Topics: Ergocalciferols; Female; Humans; Hyperparathyroidism, Secondary; Male; Middle Aged; Peritoneal Dialysis; Peritoneum; Permeability; Prospective Studies; Proteinuria

Whether paricalcitol (PCT) reduces proteinuria in the presence of intensified inhibition of Renin-Angiotensin-System (RAS) is poorly studied. We evaluated the antiproteinuric effect of PCT in non-dialysis chronic kidney disease (CKD) patients with proteinuria greater than 0.5 g/24 h persisting despite anti-RAS therapy titrated to minimize proteinuria in the absence of adverse effects.. Forty-eight CKD patients were studied in the first six months of add-on oral PCT (1 mcg/day) and three months after drug withdrawal.. Males were 87.5%, age 63 ± 14 yrs, systolic/diastolic blood pressure (BP) 143 ± 22/78 ± 11 mmHg, eGFR 29.7 ± 14.5 mL/min/1.73 m(2), diabetes 40%, and cardiovascular disease 38%. At referral in the center (28 months prior to study baseline), proteinuria was 2.44 (95% CI 1.80-3.04) g/24 h with 6 patients not receiving any anti-RAS and 42 treated with a single agent, at low dosage in most cases. At study baseline, twenty patients were under 2-3 anti-RAS drugs while twenty-eight received 1 agent at full dose and proteinuria resulted to be reduced versus referral to 1.23 g/24 h (95%CI 1.00-1.51). Six months of add-on PCT significantly decreased proteinuria to 0.61 g/24 h (95%CI 0.40-0.93), with levels less than 0.5 g/24 h achieved in 37.5% patients, in the absence of changes of BP and GFR. Proteinuria recovered to basal value after drug withdrawal. The extent of antiproteinuric response to PCT was positively associated with diabetes, eGFR and daily Na excretion (R(2) = 0.459, P < 0.0001). PTH decreased from 201 (IQR 92-273) to 83 (IQR 50-189) pg/mL.. In CKD patients, add-on PCT induces a significant reduction of proteinuria that is evident despite intensified anti-RAS therapy and larger in the presence of diabetes, higher GFR and unrestricted salt intake.

Topics: Aged; Antihypertensive Agents; Drug Therapy, Combination; Ergocalciferols; Female; Humans; Male; Middle Aged; Prospective Studies; Proteinuria; Renal Insufficiency, Chronic; Renin; Renin-Angiotensin System

Recent studies implicate Wnt/β-catenin signaling in podocyte dysfunction. Because vitamin D analogs can inhibit β-catenin in other tissues, we tested whether the vitamin D analog paricalcitol could ameliorate podocyte injury, proteinuria, and renal fibrosis in adriamycin (ADR) nephropathy. Compared with vehicle-treated controls, paricalcitol preserved expression of nephrin, podocin, and WT1; prevented proteinuria; and reduced glomerulosclerotic lesions induced by ADR. Paricalcitol also inhibited expression of proinflammatory cytokines, reduced renal infiltration of monocytes/macrophages, hampered activation of renal myofibroblasts, and suppressed expression of the fibrogenic TGF-β1, CTGF, fibronectin, and types I and III collagen. Selective suppression of renal Wnt4, Wnt7a, Wnt7b, and Wnt10a expression after ADR accompanied these renoprotective effects of paricalcitol. Significant upregulation of β-catenin, predominantly in podocytes and tubular epithelial cells, accompanied renal injury; paricalcitol largely abolished this induction of renal β-catenin and inhibited renal expression of Snail, a downstream effector of Wnt/β-catenin signaling. Administration of paricalcitol also ameliorated established proteinuria. In vitro, paricalcitol induced a physical interaction between the vitamin D receptor and β-catenin in podocytes, which led to suppression of β-catenin-mediated gene transcription. In summary, these findings suggest that paricalcitol prevents podocyte dysfunction, proteinuria, and kidney injury in adriamycin nephropathy by inhibiting Wnt/β-catenin signaling.

Topics: Acute Kidney Injury; Animals; beta Catenin; Disease Models, Animal; Doxorubicin; Ergocalciferols; Glomerular Mesangium; Male; Mice; Mice, Inbred BALB C; Podocytes; Proteinuria; Signal Transduction; Vitamin D; Wnt Proteins

Diet-induced obesity (DIO) and insulin resistance in mice are associated with proteinuria, renal mesangial expansion, accumulation of extracellular matrix proteins, and activation of oxidative stress, proinflammatory cytokines, profibrotic growth factors, and the sterol regulatory element binding proteins, SREBP-1 and SREBP-2, that mediate increases in fatty acid and cholesterol synthesis. The purpose of the present study was to determine whether treatment of DIO mice with the vitamin D receptor (VDR) agonist doxercalciferol (1α-hydroxyvitamin D2) prevents renal disease. Our results indicate that treatment of DIO mice with the VDR agonist decreases proteinuria, podocyte injury, mesangial expansion, and extracellular matrix protein accumulation. The VDR agonist also decreases macrophage infiltration, oxidative stress, proinflammatory cytokines, and profibrotic growth factors. Furthermore, the VDR agonist also prevents the activation of the renin-angiotensin-aldosterone system including the angiotensin II type 1 receptor and the mineralocorticoid receptor. An additional novel finding of our study is that activation of VDR results in decreased accumulation of neutral lipids (triglycerides and cholesterol) and expression of adipophilin in the kidney by decreasing SREBP-1 and SREBP-2 expression and target enzymes that mediate fatty acid and cholesterol synthesis and increasing expression of the farnesoid X receptor. This study therefore demonstrates multiple novel effects of VDR activation in the kidney which prevent renal manifestations of DIO in the kidney.

Topics: Animals; Cytokines; Dietary Fats; Disease Models, Animal; Ergocalciferols; Extracellular Matrix Proteins; Kidney; Kidney Diseases; Lipid Metabolism; Macrophages; Male; Mice; NF-kappa B; Obesity; Podocytes; Proteinuria; Receptors, Calcitriol; Renin-Angiotensin System; Sterol Regulatory Element Binding Proteins

Severe secondary hyperparathyroidism is a complication of chronic kidney disease. Paricalcitol is a vitamin D receptor activator with efficacy in the treatment of hyperparathyroidism that also has the minor side effects of hypercalcemia and hyperphosphatemia. As a pleiotropic effect, paricalcitol reduces proteinuria in patients with chronic kidney disease stages 2-4. Oral paricalcitol offers an alternative way to treat hyperparathyroidism and proteinuria in peritoneal dialysis patients. Our prospective study enrolled 18 patients with hyperparathyroidism (6 with diabetes also) who were given oral paricalcitol at initial dose of 1-2 microg daily, depending on their level of intact parathyroid hormone (iPTH). In the 1st month, iPTH levels declinedsignificantly to 295 +/- 147 pg/mL from 670 +/- 318 pg/mL, and by the 3rd month, they declined to 192 +/- 340 pg/mL (p < 0.001). Without modifications to doses of angiotensin converting-enzyme inhibitor or angiotensin II receptor blocker, proteinuria declined in the 1st month to 1.41 +/- 1.5 g/L from 1.68 +/- 1.7 (p = 0.006) and, in the 3rd month, without statistical significance. In some patients, the dose of paricalcitol was reduced because of iPTH levels that were too low at 1 month. The patients whose doses of paricalcitol were maintained at 3 months showed a reduction in proteinuria to 2.1 +/- 2.1 g/L daily from 3.1 +/- 2. 7 g/L (p = 0.04) and to 2.3 +/- 2.1 g/day from 5.0 +/- 6.1 g/day (p = 0.012). In conclusion, paricalcitol is effective for treating hyperparathyroidism in patients on peritoneal dialysis and seems also to have an antiproteinuric effect in these patients.

Topics: Administration, Oral; Adult; Aged; Ergocalciferols; Female; Humans; Hyperparathyroidism, Secondary; Kidney Failure, Chronic; Male; Middle Aged; Parathyroid Hormone; Peritoneal Dialysis; Proteinuria

Monotherapy with angiotensin-converting enzyme inhibitors has been shown to be beneficial in suppressing the progression of experimentally induced kidney diseases. Whether such therapy provides additional benefits when combined with vitamin D or an analog of vitamin D has not been established. Rats were made uremic by 5/6 nephrectomy and treated as follows: Uremic + vehicle (UC), uremic + enalapril (30 mg/L in drinking water; E), uremic + paricalcitol (19-nor; 0.8 microg/kg, three times a week), and uremic + enalapril + paricalcitol (E + 19-nor). A group of normal rats served as control (NC). BP was significantly elevated in the UC and 19-nor groups compared with the NC group but was indistinguishable from normal in the E and E + 19-nor groups. The decrease in creatinine clearance and the increase in the excretion of urinary protein that were observed in the UC group were ameliorated by the use of E alone or by E + 19-nor (P < 0.05 versus UC). The glomerulosclerotic index was significantly decreased in both the 19-nor (P < 0.01) and E + 19-nor groups (P < 0.01) compared with the UC group. Tubulointerstitial volume was significantly decreased in both the E (P < 0.05) and E + 19-nor groups (P < 0.01) compared with the UC group. Both macrophage infiltration (ED-1-positive cells) and production of the chemokine monocyte chemoattractant protein-1 were significantly blunted in E + 19-nor compared with E group. TGF-beta1 mRNA and protein expression were increased in the UC group (mRNA: 23.7-fold; protein: 29.1-fold versus NC). These increases were significantly blunted in the 19-nor group (mRNA: 7.1-fold; protein: 8.0-fold versus NC) and virtually normalized in the E + 19-nor group (protein: 0.8-fold versus NC). Phosphorylation of Smad2 was also elevated in the UC group (7.6-fold versus NC) but less so in the 19-nor-treated rats (5.5-fold versus NC). When rats were treated with E + 19-nor, the phosphorylation of Smad2 was normal (1.1-fold versus NC). Thus, 19-nor can suppress the progression of renal insufficiency via mediation of the TGF-beta signaling pathway, and this effect is amplified when BP is controlled via renin-angiotensin system blockade.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Blood Pressure; Disease Models, Animal; Disease Progression; Drug Therapy, Combination; Enalapril; Ergocalciferols; Female; Macrophages; Nephrectomy; Parathyroid Hormone; Proteinuria; Rats; Rats, Sprague-Dawley; Renal Insufficiency; RNA, Messenger; Signal Transduction; Transforming Growth Factor beta1; Uremia; Vitamin D

Topics: Chronic Disease; Ergocalciferols; Humans; Kidney Diseases; Proteinuria; Randomized Controlled Trials as Topic; Retrospective Studies

Patients with the nephrotic syndrome may exhibit low serum 25-OH-D concentrations. We developed a method for isolation of 25-OH-D from urine, with measurement by competitive binding assay. Daily urinary 25-OH-D excretion in healthy subjects averaged 0.17 +/- 0.15 nmol/day. Among nephrotic patients, urinary 25-OH-D excretion ranged from 0.27 to 10 nmol/day, in direct relation to the severity of proteinuria (r=0.76) and averaged 3.7 +/- 3.5 nmol/day. The 25-OH-D in the urine of nephrotic patients was unconjugated, implying that it was excreted with the serum VDBG, which has been shown to have a molecular weight and isoelectric point similar to that of albumin. We conclude that low serum 25-OH-D concentrations among nephrotic patients are principally the result or urinary losses of steroid. (J Lab Clin Med 99:325, 1982.)

Topics: 25-Hydroxyvitamin D 2; Adult; Aged; Creatinine; Ergocalciferols; Female; Humans; Male; Middle Aged; Nephrotic Syndrome; Proteinuria; Serum Albumin

The present study was aimed at answering the following two questions: (1) What is the effect of high dose vitamin D treatment on the serum level of 25-hydroxyvitamin D (25-OH-D) in patients with chronic renal failure (CRF)? (2) Is there any effect of urinary protein loss on the serum 25-OH-D levels during treatment with pharmacological doses of vitamin D? 42 patients with CRF were studied. They were treated conservatively by a low protein diet and received 15 mg of vitamin D2 once a week. Long-term administration of vitamin D caused a significant (5- to 7-fold) increase of plasma 25-OH-D level irrespective of the degree of proteinuria. This increase was noted only during the first 5 months of vitamin D2 treatment. Surprisingly only in some patients moderate hypercalcemia (> 2.75 mmol/l) was found. From the results obtained it is concluded that (1) patients with CRF differ from normal subjects in handling of high doses of vitamin D and (2) high dosage treatment with vitamin D may prevent hypocalcemia in patients with CRF in spite of high proteinuria.

Topics: Adult; Ergocalciferols; Female; Humans; Hydroxycholecalciferols; Hypocalcemia; Kidney Failure, Chronic; Male; Middle Aged; Proteinuria; Time Factors

Topics: Aminohippuric Acids; Animals; Blood Urea Nitrogen; Body Weight; Carbon Isotopes; Creatinine; Diet; Edetic Acid; Ergocalciferols; Female; Kidney; Kidney Tubules; Male; Metals; Pentetic Acid; Proteinuria; Rats