Vitamin D treatment in chronic kidney disease

Activated vitamin D continues to be the major treatment for suppressing parathyroid hormone (PTH) levels in dialysis patients who have secondary hyperparathyroidism. Active vitamin D compounds are distinguished by their ability to bind with high affinity to vitamin D receptors (VDRs) not only in the parathyroid glands, but in cells throughout the body. Because of recent data showing that pulsatile, intravenous vitamin D treatment (calcitriol or paricalcitol) confers a survival advantage in the dialysis population, there is new interest in understanding the systemic effects of VDR activation, particularly in the predialysis stages of chronic kidney disease (CKD), where high mortality rates from cardiovascular disease have recently been documented. Previous underutilization of calcitriol treatment to control PTH levels in stages 3 and 4 CKD was often due to concerns about its potential for accelerating the progression of CKD as a consequence of hypercalcemia, hypercalciuria, or hyperphosphatemia. Vitamin D analogs with selective VDR activity (such as paricalcitol) have great potential for preventing parathyroid hyperplasia and bone loss in early CKD without adversely affecting kidney function. Whether they also reduce cardiovascular morbidity and mortality in early CKD, as they appear to do in dialysis patients, remains to be determined.     

Vitamin D supplements in chronic kidney disease

Abstract

Chronic kidney disease (CKD) is a significant public health problem and Vitamin D deficiency is prevalent in CKD and might be associated with calcium and phosphate metabolism, cardiovascular disease, infections as well as the progress of kidney dysfunction. Emerging evidence implies that Vitamin D supplements may be of benefit to CKD. Based on existing laboratory and clinical evidence, this review intends to discuss the effectiveness of Vitamin D supplements and controversy in clinical practice. The effect of Vitamin D in CKD patients is summarized in detail from CKD–mineral bone disease, the progression of renal function, cardiovascular events and immune system. Considerable disputes exist for the Vitamin D supplements in CKD, and a growing amount of experimental evidence and some clinical evidence are now gathering from in vitro, animal and epidemiological studies.     

Vitamin D and outcomes in chronic kidney disease

PURPOSE OF REVIEW: There is a high prevalence of vitamin D deficiency in the chronic kidney disease population. Vitamin D is often administered to patients to mitigate detrimental effects on bone health and mineral metabolism, though this treatment may be limited by elevations in serum calcium and phosphorus. This article reviews the basic physiology of vitamin D, the survival data in patients receiving vitamin D, and the current quandary of whether vitamin D administration is beneficial in chronic kidney disease. RECENT FINDINGS: Despite potential increases in serum calcium and phosphorus due to activation of vitamin D receptors in the gut, vitamin D administration has been associated with a survival benefit in recent studies. While the mechanism for this possible benefit is unknown, vitamin D administration may have effects beyond its traditional role in mineral metabolism, mediated through the activation of vitamin D receptors distributed in a variety of tissues. SUMMARY: Data currently suggests that the administration of vitamin D confers a survival benefit to patients on dialysis. There is no clear mechanism, however, to explain this association. Further research is needed to clarify the expanding role of vitamin D receptor activation, particularly in vascular calcification, and the effects of the different forms of vitamin D.     

血浆维生素D与慢性肾脏病患者心血管疾病的相关性研究

目的了解慢性肾脏病(chronic kidney disease,CKD)患者维生素D状态及缺乏原因,并探讨血浆维生素D缺乏是否独立影响CKD患者心血管疾病(cardiovasculardisease,CVD)的发生。方法选取北京医院肾脏内科住院的CKD 1~5期非透析患者80例为研究对象,门诊健康查体人群10例为对照组,测定其血浆25-OH-D_3、1,25(OH)_2D_3水平并进行相关实验室检查。根据血浆25-OH-D_3水平将患者分为维生素D缺乏组和非维生素D缺乏组,比较组间临床和实验室检查资料以及心脏超声检查相关参数差异;根据超声心动图结果,将患者分为左室肥厚(1eft ventricular hypertrophy,LVH)组和非LVH组,比较组间患者相关临床资料差异,并采用多因素分析CKD患者LVH的独立危险因素。结果 CKD组及对照组25-OH-D3分别为(15.09±2.44)μg/L和(18.60±1.88)μg/L;2组维生素D水平均较低,但CKD组较对照组更低,组间有统计学差异(P0.05)。CKD患者维生素D水平普遍偏低,血浆25-OH-D_3波动于10.29~20.51μg/L,1,25(OH)2 D3波动于16.23~54.32 ng/L,两者之间存在线性相关,两者与CKD患者肾功能分期均无线性相关。CKD患者维生素D缺乏组(≤15μg/L)和非维生素D缺乏组(15μg/L)组间比较,发现2组血磷、左心室质量指数存在统计学差异(P0.05)。维生素D水平与左心室质量指数无线性相关;比较LVH组及非LVH组相关临床资料,单因素分析发现血肌酐、尿素氮、估算肾小球滤过率、脑钠肽、肌钙蛋白、血红蛋白、红细胞比容、24h尿蛋白定量、高密度脂蛋白均存在统计学差异(P0.05);多元逐步Logistic回归发现BNP升高(≥1 000 ng/L),24h尿蛋白定量(≥3.5 g),LDL升高(≥2.59 mmol/L)可进入方程(P0.05)。结论 CKD患者25-OH-D_3水平低于普通人群,但与CKD患者肾功能水平无线性相关;BNP升高、24h尿蛋白定量、高低密度脂蛋白血症是CKD患者左室肥厚的独立危险因素,目前尚不认为25-OH-D_3水平下降影响CKD患者左室肥厚的发生。     

Vitamin D for health and in chronic kidney disease

Vitamin D is taken for granted and is not appreciated for its importance in overall health and well-being. Vitamin D, known as the sunshine vitamin, is appreciated as being important for the prevention of rickets in children. It is now recognized that vitamin D is important for not only the growing skeleton, but for the maintenance of a healthy musculoskeletal system throughout life. Vitamin D deficiency in adults precipitates and exacerbates osteoporosis and causes the painful bone disease osteomalacia. The revelation that vitamin D is biologically inactive and requires sequential hydroxylations in the liver and kidney to form 1,25-dihydroxyvitamin D helps explain why patients with renal failure are often resistant to vitamin D and suffer from secondary hyperparathyroidism and renal osteodystrophy. In addition to its role in maintaining calcium and phosphorus homeostasis, vitamin D is now being recognized as important for maintaining maximum muscle strength and for the prevention of many chronic diseases, including type I diabetes, multiple sclerosis, rheumatoid arthritis, hypertension, cardiovascular heart disease, and many common cancers. Vitamin D status is best determined by the measurement of circulating levels of 25-hydroxyvitamin D. Vigilance for maintaining a 25-hydroxyvitamin D level of at least 20 ng/ml and preferably 30-50 ng/ml has important benefits for both healthy children and adults, as well as children and adults suffering from chronic kidney disease.     

Vitamin D and vascular calcification in chronic kidney disease

Vascular calcification is common in patients with chronic kidney disease (CKD) and contributes to the increased rate of cardiovascular morbidity and mortality. The mechanisms regulating vascular calcification are under investigation; it is accepted that vascular calcification is an active and complex process involving many factors that promote or inhibit calcification. Vascular smooth muscle cells undergo transformation into osteogenic cells. This transformation is being stimulated by high phosphate, and more recently the role of the calcium phosphate nanocrystals has gained attention. Experimental models of uremia and in vitro studies have shown that an excess of calcitriol accelerates vascular calcification. However, observational studies suggest that vitamin D provides a survival advantage for patients with CKD. Experimental work shows that for similar serum concentrations of calcium and phosphate paricalcitol produces less vascular calcification than calcitriol suggesting a differential effect at the cellular level. Important issues regarding the role of vitamin D compounds on vascular calcification will be commented in this review.     

Vitamin D status in children with chronic kidney disease

Background

The role of vitamin D status in patients with renal insufficiency and its relation to dietary intake and parathyroid hormone (PTH) secretion is of utmost interest given the morbidity and mortality associated with the disordered mineral metabolism seen in chronic kidney disease (CKD).

Methods

We conducted a cross-sectional study of 100 pediatric patients with a diagnosis of CKD stage 1–5 at Children's Hospital Boston, measuring blood levels of 25-hydroxyvitamin D [25(OH)D], 1,25-dihydroxyvitamin D [1,25(OH)₂D], and parathyroid hormone and obtaining data on nutrient intake and other variables related to vitamin D status.

Results

Subjects ranged in age from 6 months to 18?years, and 60 were male, 40 female. Of the 100 patients, 16 % were deficient in 25(OH)D (≤20?ng/mL) and another 24 % were insufficient (≤30?ng/mL), with 40 % in the suboptimal range. Serum 25(OH)D and dietary vitamin D intake were not correlated.

Conclusions

We found a high prevalence of hyperparathyroidism in early-stage CKD and a significant relationship between 25(OH)D and PTH regardless of calcitriol level. Our study results support the suggestion that optimization of vitamin D levels may provide additional benefit in preventing or improving hyperparathyroidism in patients with early CKD and likely remains important as an adjunctive therapy in children with advanced CKD.     

Vitamin D receptor ligand therapy in chronic kidney disease

Chronic kidney disease is a growing public health concern, and secondary hyperparathyroidism is one of the most serious associated comorbidities. In healthy individuals, precisely controlled feedback loops dynamically modulate parathyroid hormone (PTH) levels. As kidney function declines, phosphate retention, decreased 1a,25-dihydroxyvitamin D3, and a tendency to hypocalcemia leads to overstimulation of PTH production and parathyroid hyperplasia. Vitamin D receptor (VDR) ligands are essential tools for controlling parathyroid activity. This review highlights the current clinical and biochemical VDR ligand studies, focusing on the differences between selective and nonselective VDR ligands. It is apparent that VDR ligands have important roles in the management of secondary hyperparathyroidism. Selective VDR ligands, in particular, may offer additional benefits in the treatment of bone disease, and may potentially reduce adverse effects related to cardiovascular disease.     

Vitamin D levels and patient outcome in chronic kidney disease

Vitamin D deficiency has been linked to cardiovascular disease and early mortality in patients on hemodialysis; however, it is not known if the same association exists at earlier stages of chronic kidney disease. To determine this we enrolled 168 consecutive new referrals to a chronic kidney disease clinic over a 2 year period and followed them for up to 6 years. All patients were clinically stable and had an estimated glomerular filtration rate (eGFR) at stage 2 or less and were without an imminent need for dialysis. Baseline 25-hydroxyvitamin D levels directly and significantly correlated with eGFR. After an average follow-up of 48 months, 48 patients started dialysis and 78 had died. In crude analyses, 25-hydroxyvitamin D predicted both time to death and end-stage renal disease. A dual-event Cox's model confirmed 25-hydroxyvitamin D as an independent predictor of study outcomes when adjusted for age, heart failure, smoking, C-reactive protein, albumin, phosphate, use of converting enzyme inhibitors or angiotensin receptor blockers, and eGFR. Our study shows that plasma 25-hydroxyvitamin D is an independent inverse predictor of disease progression and death in patients with stage 2-5 chronic kidney disease.     

慢性肾脏病患者维生素D不足与缺乏

目的 了解慢性肾脏病(CKD)患者维生素D不足与缺乏的患病率,为合理的维生素D治疗提供依据。 方法 对358例住院CKD患者的临床资料进行回顾性分析。用酶标法测定血清25（OH）D3水平,并常规检测血红蛋白（Hb）、Scr、BUN、CO2CP、白蛋白(Alb)、血清钙、磷、全段甲状旁腺激素（iPTH）等。分析25（OH）D3水平与临床指标的关系。 结果 358例患者的25（OH）D3平均水平为（18.58±11.7） µg/L,显著低于正常值（P < 0.01）;CKD1~5期患者25（OH）D3水平分别为（25.84±9.71）、（20.76±6.99）、（20.40±17.02）、（19.49±11.29）和（14.16±7.98） µg/L。维生素D缺乏患病率为39.66%;在CKD1~5期中分别为5.00%、17.50%、37.21%、42.37%和57.14%,患病率随CKD分期逐级增加。维生素D不足患病率为44.97%,在CKD1~5期中分别为72.50%、47.50%、45.35%、33.90%和40.60%。维生素D缺乏及不足患病率为84.63%,在CKD1~5期中分别为77.50%、65.00%、82.56%、76.27%和97.74%,CKD各期间差异无统计学意义。单因素相关分析显示,25（OH）D3与Hb（r = 0.163）、Alb（r = 0.291）、Scr（r = -0.236）、eGFR（r = 0.156）和iPTH（r = -0.178）相关（P < 0.01）。多元线性回归分析显示,25（OH）D3与Alb呈正相关,而和iPTH、Scr呈负相关。CRP、钙磷乘积等与25（OH）D3无相关。按K/DOQI指南,根据25（OH）D3和iPTH水平,CKD3~5期患者符合维生素D治疗指征的比例分别为87.20%、83.05%和26.31%;而仅根据iPTH水平,符合治疗指征的比例仅为16.28%、35.59%和26.31%。 结论 CKD患者维生素D缺乏和不足患病率高。Alb、Scr和iPTH是CKD患者维生素D水平的重要影响因子。应在CKD人群中开展维生素D水平检测,并早期、合理治疗维生素D缺乏和不足。     

Vitamin D receptor activation and survival in chronic kidney disease

Replacement of activated vitamin D has been the cornerstone of therapy for secondary hyperparathyroidism (SHPT). Recent findings from several large observational studies have suggested that the benefits of vitamin D receptor activators (VDRA) may extend beyond the traditional parathyroid hormone (PTH)-lowering effect, and could result in direct cardiovascular and metabolic benefits. The advent of several new analogs of the activated vitamin D molecule has widened our therapeutic armamentarium, but has also made therapeutic decisions more complicated. Treatment of SHPT has become even more complex with the arrival of the first calcium-sensing receptor (CSR) agonist (cinacalcet hydrochloride) and with the uncovering of novel mechanisms responsible for SHPT. We provide a brief overview of the physiology and pathophysiology of SHPT, with a focus on vitamin D metabolism, and discuss various practical aspects of VDRA therapy and its reported association with survival in recent observational studies. A detailed discussion of the available agents is aimed at providing the practicing physician with a clear understanding of the advantages or disadvantages of the individual medications. A number of open questions are also analyzed, including the present and future roles of CSR agonists and 25(OH) vitamin D replacement.     

Vitamin D insufficiency and hyperparathyroidism in children with chronic kidney disease

Chronic kidney disease (CKD) is associated with altered calcium-phosphate homeostasis and hyperparathyroidism due to decreased activity of 1alpha-hydroxylase and impaired activation of 25-hydroxyvitamin D3 [25(OH)D3]. In some patients these problems start earlier because of vitamin D deficiency. A retrospective review of patients followed in the chronic renal insufficiency clinic at Children's Hospital of Michigan assessed the prevalence of vitamin D deficiency in CKD stages 2-4 and evaluated the effect of treatment with ergocalciferol on serum parathormone (PTH). Blood levels of 1,25 dihydroxyvitamin D3, 25(OH)D3, and parathormone (PTH) were examined in 57 children (40 boys; mean age 10.6 years). Of 57 subjects, 44 (77.2%) had 25(OH)D3 levels 30 ng/ml was 67.84 +/- 29.09 ng/ml and in the remaining patients was elevated, at 120.36 +/- 86.42 ng/ml (p = 0.05). Following ergocalciferol treatment (22), PTH decreased from 122.13 +/- 82.94 ng/ml to 80.14 +/- 59.24 ng/ml (p < 0.001) over a period of 3 months. We conclude that vitamin D deficiency is common in children with CKD stages 2-4 and is associated with hyperparathyroidism in the presence of normal 1,25 dihydroxyvitamin D3. Its occurrence before significant renal impairment is noteworthy. Early diagnosis and appropriate treatment is emphasized.     

Vitamin D status and mortality risk in patients with chronic kidney disease

Several studies have shown that mineral metabolism disorders play a major role in determining a higher mortality rate for end-stage renal disease patients. Vitamin D deficiency is associated with cardiovascular events in hemodialysis patients. Recently, an association between vitamin D insufficiency and cardiovascular or renal events has been found, in patients with chronic renal failure who have not started renal replacement therapy yet. To further investigate this issue, we evaluated the relationship between blood levels of 25-hydroxyvitamin D (25-OH D; > or ≤30 ng/mL) and mortality or dialysis dependence in 104 incident consecutive patients with chronic kidney disease stages 3-5, over a period of 17 months, with a follow-up of 2 years in a cross-sectional analysis. The correlation between different levels of vitamin D and the risk of events has been estimated by using a probit model. Explanatory variables employed concerned age, sex, blood pressure, BMI, and number of co-morbid factors. The average 25-OH D concentration was of 30.13 ng/mL. During follow-up (>16 months), each patient experienced an average of 1.28 events. Vitamin D has been shown to reduce the probability of cardiovascular or renal events. Vitamin D intake for more than 12 months can reduce the probability of such events by 11.42%. Each co-morbid factor, instead, raises the probability of events by 29%. Lower probabilities of experiencing an adverse cardiovascular event might depend on higher levels of vitamin D. The influence of 25-OH D on survival in chronic kidney disease patients may be related to unrecognized factors that need to be further explored.     

Vitamin D deficiency is common in children and adolescents with chronic kidney disease

Here we determined if vitamin D deficiency is more common in children with chronic kidney disease compared to healthy children. In addition, we sought to identify disease-specific risk factors for this deficiency, as well as its metabolic consequences. We found that nearly half of 182 patients (ages 5 to 21) with kidney disease (stages 2 to 5) and a third of age-matched 276 healthy children were 25-hydroxyvitamin D deficient (<20 ng/ml). The risk of deficiency was significantly greater in advanced disease. Focal segmental glomerulosclerosis and low albumin were significantly associated with lower 25-hydroxyvitamin D, which, in turn, was associated with significantly higher intact parathyroid hormone levels. We found that 25-hydroxyvitamin D levels were positively associated with 1,25-dihydroxyvitamin D, the relationship being greatest in advanced disease (significant interaction), and inversely related to those of inflammatory markers C-reactive protein and IL-6. The association with C-reactive protein persisted when adjusted for the severity of kidney disease. Thus, lower 25-hydroxyvitamin D may contribute to hyperparathyroidism, inflammation, and lower 1,25-dihydroxyvitamin D in children and adolescents, especially those with advanced kidney disease.     

Vitamin D insufficiency and effect of cholecalciferol in children with chronic kidney disease

Vitamin D insufficiency is common in patients with chronic kidney disease (CKD) and may contribute to mineral bone disease. In a prospective interventional study, we estimated the prevalence of vitamin D insufficiency (serum 25-hydroxyvitamin D3 [25OHD] < 30 ng/ml), and examined the effect of high-dose (600,000 IU) cholecalciferol supplementation after 6 weeks on serum 25OHD and parathyroid hormone (PTH) levels in children with CKD stages 2–4. Forty-two children (86% boys) with a mean age of 7.7 ± 3.8 (range 2-–5) years were studied. Thirty-seven children (82.1%) had vitamin D insufficiency; 18 (42.8%) had 25OHD < 16 ng/ml. The median 25OHD increased significantly from 16.7 (95% CI 11.3, 19.8) to 46.2 (34.5, 44.6) ng/ml in patients with vitamin D insufficiency (P <0.001). The median PTH decreased significantly from 51.3 (95% CI 46.7, 71.5) to 37.1 (29.0, 54.6) pg/ml (P = 0.003). Nineteen patients (47.5%) had >30% reduction in the PTH after supplementation. Serum calcium, phosphorus, and estimated GFR did not change significantly. We conclude that vitamin D insufficiency is highly prevalent in children with CKD stages 2–4. High-dose cholecalciferol is safe and effective in correcting vitamin D insufficiency and results in a significant reduction in PTH levels in vitamin D-insufficient children.     

Vitamin D supplementation improves endothelial dysfunction in patients with non-dialysis chronic kidney disease

Purpose

Hypovitaminosis D is common in chronic kidney disease (CKD) and is associated with endothelial dysfunction and cardiovascular events. This study aimed to investigate the effects of vitamin D supplementation on endothelial dysfunction in non-dialysis CKD patients.

Materials and methods

Seventy-one non-dialysis CKD patients with low vitamin D (serum 25(OH)D < 30 ng/mL) were recruited. Patients received oral cholecalciferol 50,000 units once a week for 12 weeks. Changes in endothelial function by brachial artery flow-mediated dilation (FMD), soluble vascular cell adhesion molecule-1 (sVCAM-1), and sE-selectin were studied.

Results

There was a significant increase in serum levels of 25(OH)D after cholecalciferol supplementation (33.7 ± 12.1 vs. 13.2 ± 5.4 ng/mL, P < 0.001). Multivariable regression analysis showed that higher proteinuria (β = ? 0.548, P < 0.001) and lower levels of 25(OH)D (β = 0.360, P < 0.001) at baseline were related to lower 25(OH)D level after supplementation. FMD increased significantly from 4.4 ± 1.3 to 5.1 ± 1.5% (P < 0.001), and soluble endothelial biomarkers decreased: sVCAM-1 from 926.9 ± 158.0 to 867.0 ± 129.0 ng/mL (P < 0.001), and sE-selectin 69.7 ± 15.8 to 63.3 ± 14.7 ng/mL (P < 0.001).

Conclusions

Vitamin D supplementation can improve endothelial dysfunction in pre-dialysis CKD patients.

     

Epidemiology of pediatric chronic kidney disease

In contrast to the adult population, in whom a variety of registries have confirmed the incidence, prevalence, and diagnoses associated with chronic kidney disease (CKD), the epidemiological information on pediatric CKD is currently imprecise and flawed by methodological differences between the various data sources. Obstructive uropathy and congenital aplasia/hypoplasia/dysplasia are responsible for almost one half of all cases of CKD in children, underscoring the fact that a substantial percentage of the pediatric CKD population develops renal insufficiency very early in life. However, there are distinct geographic differences in the reported causes of CKD, in part because of environmental, racial, genetic, and cultural (consanguinity) differences. Furthermore, despite apparently comparable incidence rates, high mortality in countries that lack health care resources results in a low prevalence of CKD in those locations. In countries where renal replacement therapy is readily available, the most favored treatment modality is renal transplantation in all pediatric age groups. Additional efforts to define the epidemiology of pediatric CKD worldwide in a more uniform manner are necessary if a better understanding of the full extent of the problem, areas for study, and the potential impact of intervention is desired.     

Vitamin C in chronic kidney disease and hemodialysis patients

Increments of oxidative stress have been addressed as one potential cause for the accelerated atherosclerosis of chronic kidney disease patients. Ascorbate represents one of the most prominent antioxidants both in plasma as well as intracellulary, exerting beneficial effects by an inhibition of lipid peroxidation and by reducing endothelial dysfunction. However, in the presence of transition metals like iron, ascorbate may give rise to an increased generation of oxidants, and ascorbylation may impose additional carbonyl stress to uremic patients. Unsupplemented dialysis patients have reportedly lower plasma levels of ascorbate in comparison to healthy controls, mostly due to a loss into the dialysate or, in case of not dialyzed patients, increased urinary losses. Currently, 60 mg of ascorbate are recommended for chronic kidney disease patients, and 1-1.5 g of oral ascorbate/week in case of suspected subclinical ascorbate deficiency or 300 mg parenteral ascorbate/dialysis session, respectively. Ascorbate's role in modifying arterial blood pressure remains unclear, but anemic patients with functional iron deficiency might benefit from short-term, moderately dosed ascorbate supplements.     

Vitamin D in chronic kidney disease: a systemic role for selective vitamin D receptor activation

Hyperparathyroidism occurs in most patients during the progression of chronic kidney disease (CKD) and one of its initiating events, reduced serum levels of 1,25-dihydroxyvitamin D, results from a decrease in renal 1alpha hydroxylase activity, which converts 25-hydroxyvitamin D to its activated form. The combination of persistently high parathyroid hormone (PTH) and low 1,25-dihydroxyvitamin D is associated with bone loss, cardiovascular disease, immune suppression and increased mortality in patients with end-stage kidney failure. Recent studies in dialysis patients suggest that paricalcitol, a selective activator of the vitamin D receptor (VDR), is associated with a more favorable efficacy to side effect profile than calcitriol, with less morbidity and better survival. One hypothesis derived from such studies suggests that systemic activation of VDRs may have direct effects on the cardiovascular system to decrease mortality in CKD. Although current guidelines for regulating serum calcium, phosphate and PTH recommend specific interventions at the various stages of CKD to prevent or postpone irreversible parathyroid disease and decrease cardiovascular morbidity and mortality, emerging data suggest that vitamin D therapy may prolong survival in this patient population by mechanisms that are independent of calcium, phosphate and PTH. It is suggested that a re-evaluation of current treatment recommendations is needed and that future research should focus on mechanisms that distinguish potential tissue specific benefits of selective VDR activators in patients with CKD.