Chronic kidney disease (CKD) is associated with elevations in serum phosphate, calcium–phosphorus product and bone-specific alkaline phosphatase (BAP), with attendant risks of cardiovascular and bone disorders. Active vitamin D can suppress parathyroid hormone (PTH), but may raise serum calcium and phosphate concentrations. Paricalcitol, a selective vitamin D activator, suppressed PTH in CKD patients (stages 3 and 4) with secondary hyperparathyroidism (SHPT) with minimal changes in calcium and phosphate metabolism.
The VITAL study enrolled patients with CKD stages 2–4. We examined the effect and relationship of paricalcitol to calcium and phosphate metabolism and bone markers in a post hoc analysis of VITAL. The study comprised patients with diabetic nephropathy enrolled in a double-blind, placebo-controlled, randomized trial of paricalcitol (1 or 2 μg/day). Urinary and serum calcium and phosphate, serum BAP, and intact PTH (iPTH) concentrations were measured throughout the study.
Baseline demographics and calcium, phosphate, PTH (49% with iPTH <70 pg/mL), and BAP concentrations were similar between groups. A transient, modest yet significant increase in phosphate was observed for paricalcitol 2 μg/day (+0.29 mg/dL; P < 0.001). Dose-dependent increases in serum and urinary calcium were observed; however, there were few cases of hypercalcemia: one in the 1-μg/day group (1.1%) and three in the 2-μg/day group (3.2%). Significant reductions in BAP were observed that persisted for 60 days after paricalcitol discontinuation (P < 0.001 for combined paricalcitol groups versus placebo). Paricalcitol dose-dependent reductions in iPTH were observed. Paricalcitol in CKD patients (±SHPT) was associated with modest increases in calcium and phosphate.
Paricalcitol reduces BAP levels, which may be beneficial for reducing vascular calcification.
Trial is registered with ClinicalTrials.gov, number NCT00421733.
bone-specific alkaline phosphatase; calcitriol; hypercalcemia; hyperphosphatemia; paricalcitol; vitamin D receptor activation
Introduction. 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. Methods. A meta-analysis was conducted using the Cochrane Collaboration's RevMan 4.2 software. Results. 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. Conclusion. 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.
Secondary hyperparathyroidism (SHPT) is commonly seen in patients with chronic kidney disease (CKD). Even in early CKD, parathyroid hormone (PTH) levels are elevated, maintaining mineral homeostasis at the cost of long-term bone health. One potent stimulus for PTH secretion is a deficiency of active vitamin D. Replacement with calcitriol, the active form of vitamin D, lowers PTH but often raises calcium and phosphorus levels, predisposing patients to an increased risk of ectopic calcifications. Paricalcitol is a vitamin D analog designed to treat SHPT without raising serum calcium and phosphorus levels. The intravenous preparation of paricalcitol is used routinely in the hemodialysis population and has demonstrated a survival benefit over calcitriol in hemodialysis patients. A new oral preparation has now been developed for use in the pre-dialysis CKD population. Thus far, oral paricalcitol has been shown to reduce PTH by an average of 42% in CKD patients, while having minimal effects on serum calcium and phosphorus. While long term effects of the oral preparation have yet to be studied, emerging evidence suggests that paricalcitol mediates a variety of beneficial effects through the activation of vitamin D receptors which may result in improved survival.
paricalcitol; secondary hyperparathyroidism; chronic kidney disease
Vitamin D receptor activators reduce albuminuria, and may improve survival in chronic kidney disease (CKD). Animal studies suggest that these pleiotropic effects of vitamin D may be mediated by suppression of renin. However, randomized trials in humans have yet to establish this relationship.
In a randomized, placebo-controlled, double-blinded crossover study, the effect of oral paricalcitol (2 μg/day) was investigated in 26 patients with non-diabetic, albuminuric stage III-IV CKD. After treatment, plasma concentrations of renin (PRC), angiotensin II (AngII) and aldosterone (Aldo) were measured. GFR was determined by 51Cr-EDTA clearance. Assessment of renal NO dependency was performed by infusion of NG-monomethyl-L-arginine (L-NMMA). Albumin excretion rate (AER) was analyzed in 24-h urine and during 51Cr-EDTA clearance.
Paricalcitol did not alter plasma levels of renin, AngII, Aldo, or urinary excretion of sodium and potassium. A modest reduction of borderline significance was observed in AER, and paricalcitol abrogated the albuminuric response to L-NMMA.
In this randomized, placebo-controlled trial paricalcitol only marginally decreased AER and did not alter circulating levels of renin, AngII or Aldo. The abrogation of the rise in albumin excretion by paricalcitol during NOS blockade may indicate that favourable modulation of renal NO dependency could be involved in mediating reno-protection and survival benefits in CKD.
ClinicalTrials.gov identifier: NCT01136564
Albuminuria; Chronic kidney disease; Nitric oxide; Vitamin D; Renin-angiotensin system
Secondary hyperparathyroidism is a common feature in patients with chronic kidney disease. Its serious clinical consequences include renal osteodystrophy, calcific uremic arteriolopathy, and vascular calcifications that increase morbidity and mortality.
Reduced synthesis of active vitamin D contributes to secondary hyperparathyroidism. Therefore, this condition is managed with activated vitamin D. However, hypercalcemia and hyperphosphatemia limit the use of activated vitamin D.
In Denmark alfacalcidol is the primary choice of vitamin D analog.
A new vitamin D analog, paricalcitol, may be less prone to induce hypercalcemia and hyperphosphatemia.
However, a randomised controlled clinical study comparing alfacalcidol and paricalcitol has never been performed.
The primary objective of this study is to compare alfacalcidol and paricalcitol. We evaluate the suppression of the secondary hyperparathyroidism and the tendency towards hyperphosphatemia and hypercalcemia.
This is an investigator-initiated cross-over study. Nine Danish haemodialysis units will recruit 117 patients with end stage renal failure on maintenance haemodialysis therapy.
Patients are randomised into two treatment arms. After a wash out period of 6 weeks they receive increasing doses of alfacalcidol or paricalcitol for a period of 16 weeks and after a further wash out period of 6 weeks they receive the contrary treatment (paricalcitol or alfacalcidol) for 16 weeks.
Hyperparathyroidism, hypercalcemia and hyperphosphatemia are associated with increased cardiovascular mortality in patients with chronic kidney disease.
If there is any difference in the ability of these two vitamin D analogs to decrease the secondary hyperparathyroidism without causing hypercalcemia and hyperphosphatemia, there may also be a difference in the risk of cardiovascular mortality depending on which vitamin D analog that are used. This has potential major importance for this group of patients.
Background. Paricalcitol and cinacalcet are common therapies for patients on haemodialysis with secondary hyperparathyroidism (SHPT). We conducted a multi-centre study in 12 countries to compare the safety and efficacy of paricalcitol and cinacalcet for the treatment of SHPT.
Methods. Patients aged ≥18 years with Stage 5 chronic kidney disease receiving maintenance haemodialysis and with intact parathyroid hormone (iPTH) 300–800 pg/mL, calcium 8.4–10.0 mg/dL (2.09–2.49 mmol/L) and phosphorus ≤6.5 mg/dL (2.09 mmol/L) were randomized within two strata defined by the mode of paricalcitol administration to treatment with paricalcitol- (intra-venous, US and Russian sites, IV stratum; oral, non-US and non-Russian sites, oral stratum) or cinacalcet-centred therapy. The primary endpoint is the proportion of patients in each treatment group who achieve a mean iPTH value of 150–300 pg/mL during Weeks 21–28 of treatment. Assuming efficacy response rates of 36 and 66% for cinacalcet and paricalcitol, respectively, and a 20% discontinuation rate, 124 subjects in each stratum were estimated to provide 81% power to detect a 30% absolute difference in the primary endpoint.
Results. Of 746 patients screened, 272 (mean age, 63 years; mean iPTH, 509 pg/mL) were randomized. Mean duration of haemodialysis at baseline was 3.7 years. Comorbidities included hypertension (90.4%), Type 2 diabetes (40.4%), congestive heart failure (17.3%), coronary artery disease (34.6%) and gastrointestinal disorders (75%).
Conclusions. The study participants are representative of a multinational cohort of patients on haemodialysis with elevated iPTH. The study results will provide valuable information on the best available treatment of SHPT in patients on haemodialysis.
cinacalcet hydrochloride; haemodialysis; hyperparathyroidism; kidney disease; paricalcitol
Although cardiovascular disease (CVD) is the leading cause of mortality in patients with chronic kidney disease (CKD), the pathophysiology is not thoroughly understood. Given that elevated albuminuria or circulating angiopoietin-2 associates with CVD and mortality in CKD patients, we were intrigued by the relationship between albuminuria and angiopoietin-2. A total of 416 patients with CKD stages 3 to 5 were stratified by urine albumin-creatinine ratio as normoalbuminuria (<30 mg/g), microalbuminuria (30–300 mg/g), or macroalbuminuria (>300 mg/g). The levels of plasma angiopoietin-2 and vascular endothelial growth factor (VEGF) increased, and soluble Tie-2 decreased in the subgroups of albuminuria; whereas angiopoietin-1 did not change. Linear regression showed a positive correlation between urine albumin-creatinine ratio (ACR) and plasma angiopoietin-2 (correlation coefficient r = 0.301, 95% confidence interval 0.211–0.386, P<0.0001), but not between ACR and VEGF or soluble Tie-2. Multivariate linear regression analysis showed that plasma angiopoietin-2 was independently associated with ACR (P = 0.025). Furthermore, plasma angiopoietin-2 was positively correlated with high sensitive C-reactive protein (r = 0.114, 95% confidence interval 0.018–0.208, P = 0.020). In conclusion, plasma angiopoietin-2 was associated with albuminuria and markers of systemic microinflammation in CKD patients. Although previous evidence has shown that angiopoietin-2 destabilizes vasculature and induces inflammation in different scenarios, further study will be required to delineate the role of angiopoietin-2 in albuminuria and microinflammation in CKD patients.
Secondary hyperparathyroidism (sHPT) represents an adaptive response to progressively impaired control of calcium, phosphorus and vitamin D in chronic kidney disease (CKD). It is characterized by parathyroid hyperplasia and excessive synthesis and secretion of parathyroid hormone (PTH). Parathyroid hyperplasia in uremic rats can be prevented by calcium-sensing receptor (CaSR) activation with the calcimimetic cinacalcet (Sensipar®/Mimpara®); however, it is unknown, how long the effects of cinacalcet persist after withdrawal of treatment or if cinacalcet is efficacious in uremic rats with established sHPT.
We sought to determine the effect of cinacalcet discontinuation in uremic rats and whether cinacalcet was capable of influencing parathyroid hyperplasia in animals with established sHPT.
Discontinuation of cinacalcet resulted in reversal of the beneficial effects on serum PTH and parathyroid hyperplasia. In rats with established sHPT, cinacalcet decreased serum PTH and mediated regression of parathyroid hyperplasia. The cinacalcet-mediated decrease in parathyroid gland size was accompanied by increased expression of the cyclin-dependent kinase inhibitor p21. Prevention of cellular proliferation with cinacalcet occurred despite increased serum phosphorus and decreased serum calcium.
The animal data provided suggest established parathyroid hyperplasia can be reversed by modulating CaSR activity with cinacalcet and that continued treatment may be necessary to maintain reductions in PTH.
calcimimetics; cinacalcet; parathyroid hormone; parathyroid hyperplasia; secondary hyperparathyroidism
Optimal treatment for secondary hyperparathyroidism (SHPT) has not been defined. The IMPACT SHPT (ClinicalTrials.gov identifier: NCT00977080) study assessed whether dose-titrated paricalcitol plus supplemental cinacalcet only for hypercalcaemia is superior to cinacalcet plus low-dose vitamin D in controlling intact parathyroid hormone (iPTH) levels in patients with SHPT on haemodialysis.
In this 28-week, multicentre, open-label Phase 4 study, participants were randomly selected to receive paricalcitol or cinacalcet plus low-dose vitamin D. Randomization and analyses were stratified by mode of paricalcitol administration [intravenous (IV) or oral]. The primary efficacy end point was the proportion of subjects who achieved a mean iPTH value of 150–300 pg/mL during Weeks 21–28.
Of 272 subjects randomized, 268 received one or more dose of study drug; 101 in the IV and 110 in the oral stratum with two or more values during Weeks 21–28 were included in the primary analysis. In the IV stratum, 57.7% of subjects in the paricalcitol versus 32.7% in the cinacalcet group (P = 0.016) achieved the primary end point. In the oral stratum, the corresponding proportions of subjects were 54.4% for paricalcitol and 43.4% for cinacalcet (P = 0.260). Cochran–Mantel–Haenszel analysis, controlling for stratum, revealed overall superiority of paricalcitol (56.0%) over cinacalcet (38.2%; P = 0.010) in achieving iPTH 150–300 pg/mL during Weeks 21–28. Hypercalcaemia occurred in 4 (7.7%) and 0 (0%) of paricalcitol-treated subjects in the IV and oral strata, respectively. Hypocalcaemia occurred in 46.9% and 54.7% of cinacalcet-treated subjects in the IV and oral strata, respectively.
Paricalcitol versus cinacalcet plus low-dose vitamin D provided superior control of iPTH, with low incidence of hypercalcaemia.
cinacalcet hydrochloride; paricalcitol; secondary hyperparathyroidism; kidney disease; haemodialysis
Chronic kidney disease is common after hematopoietic cell transplant. We prospectively measured urinary albumin to creatinine ratios (ACR) in 142 patients. Total (intact) monomeric albumin was determined by liquid chromatography of untreated urine samples collected weekly to day 100 after transplant. Albuminuria was defined as ACR (mg/g creatinine) >30 and proteinuria as ACR >300. Cox and logistic regressions analyses evaluated ACR as a risk factor for clinical events.
The prevalence of albuminuria at baseline, day 100 and 1 year was 37%, 64% and 50%, respectively. Proteinuria occurred in 4% of patients at baseline, 15% at day 100 and 4% at 1 year. Characteristics associated with albuminuria include age, gender, donor type, hypertension and sinusoidal obstruction syndrome. Albuminuria was associated with an increased risk of acute GVHD and bacteremia, but not acute kidney injury. Albuminuria at day 100 was associated with chronic kidney disease at 1 year (OR= 4.0; 95%CI 1.1–14.6). Non-relapse mortality risk was elevated (HR=6.8; 95%CI 1.1–41.5) among patients with overt proteinuria at day 100.
Albuminuria occurs frequently after HCT and correlates with acute GVHD, bacteremia, hypertension and progression of renal disease. Proteinuria at day 100 is associated with an 6-fold increased risk of non-relapse mortality by one year post transplant.
Vascular calcifications produce a high impact on morbidity and mortality rates in patients affected by chronic kidney disease and mineral bone disorder (CKD-MBD). Effects are manifested from the more advanced stages of CKD (stages 3-4), particularly in patients undergoing dialysis (CKD5D). In recent years, a large number of therapeutic options have been successfully used in the treatment of secondary hyperparathyroidism (SHPT), despite eliciting less marked effects on nonbone calcifications associated with CKD-MBD. In addition to the use of Vitamin D and analogues, more recently treatment with calcimimetic drugs has also been undertaken. The present paper aims to analyze comparative and efficacy studies undertaken to assess particularly the impact on morbidity and mortality rates of non-calcium phosphate binders. Moreover, the mechanism of action underlying the depositing of calcium and phosphate along blood vessel walls, irrespective of the specific contribution provided in reducing the typical phosphate levels observed in CKD largely at more advanced stages of the disease, will be investigated. The aim of this paper therefore is to evaluate which phosphate binders are characterised by the above action and the mechanisms through which these are manifested.
Secondary hyperparathyroidism (sHPT) is common in patients with chronic renal failure. Despite the initiation of new therapeutic agents, several patients will require parathyroidectomy (PTX). Total PTX with autotransplantation of parathyroid tissue (TPTX+AT) and subtotal parathyroidectomy (SPTX) are currently considered as standard surgical procedures in the treatment of sHPT. Recurrencerates after TPTX+AT or SPTX are between 10% and 12% (median follow up: 36 months).
Recent retrospective studies demonstrated a lower rate of recurrent sHPT of 0–4% after PTX without autotransplantation and thymectomy (TPTX) with no higher morbidity when compared to the standard procedures. The observed superiority of TPTX is flawed due to different definitions of outcomes, varying follow up periods and different surgical treatment strategies (with and without thymectomy).
Patients with sHPT (intact parathyroid hormone > 10 times above the upper limit of normal) on long term dialysis (>12 months) will be randomized either to TPTX or TPTX+AT and followed for 36 months. Outcome parameters are recurrence rates of sHPT, frequencies of reoperations due to refractory hypoparathyroidism or recurrent/persistent hyperparathyroidism, postoperative morbidity and mortality and quality of life. 50 patients per group will be randomized in order to obtain relevant frequencies of outcome parameters that will form the basis for a large scale confirmatory multicentred randomized controlled trial.
sHPT is a disease with a high incidence in patients with chronic renal failure. Even a small difference in outcomes will be of clinical relevance. To assess sufficient data about the rate of recurrent sHPT after both methods, a multicentred, randomized controlled trial (MRCT) under standardized conditions is mandatory.
Due to the existing uncertainties the calculated number of patients necessary in each treatment arm (n > 4000) makes it impossible to perform this study as a confirmatory trial. Therefore estimates of different outcomes are performed using a pilot MRCT comparing 50 versus 50 randomized patients in order to establish a hypothesis that can be tested thereafter.
If TPTX proves to have a lower rate of recurrent sHPT, no relevant disadvantages and no higher morbidity than TPTX+AT, current surgical practice may be changed.
International Standard Randomized Controlled Trial Number Registration (ISRCTN86202793)
Background and objectives
Secondary hyperparathyroidism (SHPT) in CKD is associated with an increased risk for mortality, but definitive data showing that parathormone control decreases mortality is still lacking. This study aimed to compare the mortality of patients with severe SHPT submitted to parathyroidectomy(PTX) with those who did not have access to surgery.
This is a retrospective study in a cohort of 251 CKD patients with severe SHPT who were referred to a CKD-MBD Center for PTX from 2005 until 2012.
Most of our patients had indication of PTX, but only 49% of them had access to this surgical procedure. After a mean follow-up of 23 months, 72 patients had died. Non-survivors were older; more often had diabetes, lower serum 25 vitamin D and mostly had not been submitted to surgery. The relative risk of death was lower in the PTX patients (0.428; 95% CI, 0.28 to 0.67; p<0.0001). After adjustments, mortality risk was dependent on age (1.04; 95% CI, 1.01 to 1.07; p = 0.002), 25 vitamin D (0.43; 95% CI, 0.24 to 0.81; p = 0.006) and no access to PTX (4.13; 95% CI, 2.16 to 7.88; p<0.0001). Results remained the same in a second model using the PTX date as the study start date for the PTX group.
Our data confirms the benefit of PTX on mortality in patients with severe SHPT. The high mortality encountered in our population is significant and urges the need to better treat these patients.
Secondary hyperparathyroidism (SHPT) is associated with mortality in patients with chronic kidney disease (CKD), but the economic consequences of SHPT have not been adequately studied in the European population. We assessed the relationship between SHPT parameters (intact parathyroid hormone [iPTH], calcium, and phosphate) and hospitalisations, medication use, and associated costs among CKD patients in Europe.
The analysis of this retrospective cohort study used records of randomly selected patients who underwent haemodialysis between January 1, 2005 and December 31, 2006 at participating European Fresenius Medical Care facilities in 10 countries. Patients had ≥ 1 iPTH value recorded, and ≥ 1 month of follow-up after a 3-month baseline period during which SHPT parameters were assessed. Time at risk was post-baseline until death, successful renal transplantation, loss to follow-up, or the end of follow-up. Outcomes included cost per patient-month, rates of hospitalisations (cardiovascular disease [CVD], fractures, and parathyroidectomy [PTX]), and use of SHPT-, diabetes-, and CVD-related medications. National costs were applied to hospitalisations and medication use. Generalised linear models compared costs across strata of iPTH, total calcium, and phosphate, adjusting for baseline covariates.
There were 6369 patients included in the analysis. Mean ± SD person-time at risk was 13.1 ± 6.4 months. Patients with iPTH > 600 pg/mL had a higher hospitalisation rate than those with lower iPTH. Hospitalisation rates varied little across calcium and phosphate levels. SHPT-related medication use varied with iPTH, calcium, and phosphate. After adjusting for demographic and clinical variables, patients with baseline iPTH > 600 pg/mL had 41% (95% CI: 25%, 59%) higher monthly total healthcare costs compared with those with iPTH in the K/DOQI target range (150–300 pg/mL). Patients with baseline phosphate and total calcium levels above target ranges (1.13–1.78 mmol/L and 2.10–2.37 mmol/L, respectively) had 38% (95% CI: 27%, 50%) and 8% (95% CI: 0%, 17%) higher adjusted monthly costs, respectively. Adjusted costs were 25% (95% CI: 18%, 32%) lower among patients with baseline phosphate levels below the target range. Results were consistent in sensitivity analyses.
These data suggest that elevated SHPT parameters increase the economic burden of CKD in Europe.
Secondary hyperparathyroidism (SHPT) is an early complication and a well-known factor negatively affecting cardiovascular mortality already in the late stages of chronic kidney disease (CKD). Negative effects can also be foreseen in early stages of CKD.
Aim: Set against this background, I performed detailed clinical review of the specific literature from 1975 on the various types of trials used to treat SHPT in order to assess their effect on uremic patients affected by CKD stage 3 stage 4.
Results: Out of the 1,820 papers reviewed, I identified 14 prospective controlled randomized trials involving in total 1,587 patients. Dietary approaches and the use of phosphorus chelating agents, either alone or in association, do not seem to be particularly promising for SHPT in uremic patients with CKD stage 3-4. Pending the publication of statistically wellstructured works on CKD stage 3-4, experience with calciummimetic agents in CKD stage 3-4 seems promising, even if there is a need to decrease the side effects most affecting medication compliance and as well safety calcium-mimetic agents seem to be more useful, especially in association with vitamin D derivatives. Further promising results seem to be provided by the latest generations of vitamin D derivatives such as paracalcitol which produces good SHPT control.
secondary hyperparathyroidism, SHPT, chronic kidney disease stages 3-4, chronic renal failure stages 3-4.
Secondary hyperparathyroidism (SHPT) is an insidious disease that develops early in the course of chronic kidney disease (CKD) and increases in severity as the glomerular filtration rate deteriorates. Recent studies have identified fibroblast growth factor-23 (FGF23) as a new protein with phosphaturic activity. It is mainly secreted by osteoblasts and is now considered the most important factor for regulation of phosphorus homeostasis. It is not yet proven if there is any direct relation between parathyroid hormone (PTH) and FGF23. The present study aims to evaluate the relation between serum FGF23, phosphorus, and PTH in end-stage renal disease in patients with SHPT on regular hemodialysis.
Materials and Methods:
Forty-six consecutive CKD adult patients (case group) and 20 healthy adults (control group) were included in the study. All patients had SHPT and were on regular hemodialysis. Both groups were subjected to full medical history, clinical examination and biochemical studies. Serum phosphorus, calcium, ferritin, hemoglobin level, blood urea, creatinine, PTH, and FGF23 were analyzed.
Levels of FGF23 were significantly higher in the case group in comparison with those in the control group, viz., 4-fold, and positively correlated with PTH. Phosphorus levels in the case group were significantly high in spite of the increasing levels of FGF23. Both PTH and FGF23 were positively correlated with phosphorus and negatively with hemoglobin levels.
SHPT and FGF23 may have a partial role in the development of anemia in patients with CKD. FGF23 could be a central factor in the pathogenesis of SHPT. Its role in controlling hyperphosphatemia in CKD is vague.
Chronic kidney disease; fibroblast growth factor–23; hyperparathyroidism
Secondary hyperparathyroidism (SHPT) is one of the less recognized reasons of anemia in chronic kidney disease (CKD). In this study, we evaluated the role of SHPT as a cause of anemia and correlation of intact parathyroid hormone (iPTH) and hemoglobin (Hb) level in hemodialysis (HD) patients.
This cross-sectional study was carried out in 63 individuals admitted in HD unit of the institute. Serum samples were collected and urea, creatinine, Hb, ferritin and iPTH levels were measured. Statistical analysis was carried out using the SPSS software (IBM, NY, USA).
Mean ± standard deviation for serum urea, creatinine, Hb, ferritin and intact PTH were 177 ± 15.52, 15.16 ± 2.28 mg/dl, 7.03 ± 2.26 g/dl, 654.7 ± 563.4 ng/ml, 539.18 ± 493.59 pg/ml respectively. A reverse correlation was found between intact PTH and Hb level.
A variety of postulated pathophysiological mechanisms linking SHPT and anemia in CKD are discussed. An efficient control of parathyroid hormone hypersecretion may be required to achieve a better management of anemia in HD patients.
Anemia; chronic kidney disease; ferritin; hemoglobin; intact parathyroid hormone; secondary hyperparathyroidism
Chronic kidney disease (CKD) is a worldwide problem. This study was designed to survey the prevalence and risk factors for CKD in Korea. The 2,356 subjects were selected in proportion to age, gender, and city. Subjects 35 yr of age or older were selected from 7 cities. Estimated glomerular filtration rate (eGFR) was calculated using the Modification of Diet in Renal Disease (MDRD) Study equation, with albuminuria defined as a urine albumin to creatinine ratio of 30 mg/g or more. The overall prevalence of CKD was 13.7%. The prevalences of CKD according to stage were 2.0% stage 1, 6.7% stage 2, 4.8% stage 3, 0.2% stage 4, and 0.0% stage 5. The prevalences of microalbuminuria and macroalbuminuria were 8.6% and 1.6%, respectively. The prevalence of eGFR less than 60 mL/min/1.73 m2 was 5.0%. Age, body mass index (BMI), hypertension, diabetes mellitus, systolic blood pressure (SBP), diastolic blood pressure (DBP), and fasting blood glucose were independent factors related to the presence of CKD. In conclusions, Korea, in which the prevalence of CKD is increasing, should prepare a policy for early detection and appropriate treatment of CKD. The present data will be helpful in taking those actions.
Korea; Kidney Failure, Chronic; Epidemiologic Studies
Low 25-hydroxy vitamin D (25(OH)D) levels have been associated with an increased risk of albuminuria, however an association with glomerular filtration rate (GFR) is not clear. We explored the relationship between 25(OH)D levels and prevalent chronic kidney disease (CKD), albuminuria and impaired GFR, in a national, population-based cohort of Australian adults (AusDiab Study).
10,732 adults ≥25 years of age participating in the baseline survey of the AusDiab study (1999–2000) were included. The GFR was estimated using an enzymatic creatinine assay and the CKD-EPI equation, with CKD defined as eGFR <60 ml/min/1.73 m2. Albuminuria was defined as a spot urine albumin to creatinine ratio (ACR) of ≥2.5 mg/mmol for men and ≥3.5 for women. Serum 25(OH)D levels of <50 nmol/L were considered vitamin D deficient. The associations between 25(OH)D level, albuminuria and impaired eGFR were estimated using multivariate regression models.
30.7% of the study population had a 25(OH)D level <50 nmol/L (95% CI 25.6-35.8). 25(OH)D deficiency was significantly associated with an impaired eGFR in the univariate model (OR 1.52, 95% CI 1.07-2.17), but not in the multivariate model (OR 0.95, 95% CI 0.67-1.35). 25(OH)D deficiency was significantly associated with albuminuria in the univariate (OR 2.05, 95% CI 1.58-2.67) and multivariate models (OR 1.54, 95% CI 1.14-2.07).
Vitamin D deficiency is common in this population, and 25(OH)D levels of <50 nmol/L were independently associated with albuminuria, but not with impaired eGFR. These associations warrant further exploration in prospective and interventional studies.
Albuminuria; Chronic kidney disease; Glomerular filtration rate; and Vitamin D
This study was done to evaluate clinical usefulness of cystatin C levels of serum and urine in predicting renal impairment in normoalbuminuric patients with type 2 diabetes and to evaluate the association between albuminuria and serum/urine cystatin C. Type 2 diabetic patients (n = 332) with normoalbuminuria (n = 210), microalbuminuria (n = 83) and macroalbuminuria (n = 42) were enrolled. Creatinine, urinary albumin levels, serum/urine cystatin C and estimated glomerular filtration rate (eGFR by MDRD [Modification of Diet in Renal Disease] and CKD-EPI [Chronic Kidney Disease Epidemiology Collaboration] equations) were determined. The cystatin C levels of serum and urine increased with increasing degree of albuminuria, reaching higher levels in macroalbuminuric patients (P < 0.001). In multiple regression analysis, serum cystatin C was affected by C-reactive protein (CRP), sex, albumin-creatinine ratio (ACR) and eGFR. Urine cystatin C was affected by triglyceride, age, eGFR and ACR. In multivariate logistic analysis, cystatin C levels of serum and urine were identified as independent factors associated with eGFR < 60 mL/min/1.73 m2 estimated by MDRD equation in patients with normoalbuminuria. On the other hand, eGFR < 60 mL/min/1.73 m2 estimated by CKD-EPI equation was independently associated with low level of high-density lipoprotein in normoalbuminuric patients. The cystatin C levels of serum and urine could be useful markers for renal dysfunction in type 2 diabetic patients with normoalbuminuria.
Cystatin C; Diabetic Nephropathies; Albuminuria
The relationship between glycemic control and lipid abnormalities with urinary albumin-creatinine ratio (ACR) in chronic kidney disease (CKD) patients with diabetes mellitus (DM) is unknown. We sought to investigate the association of dyslipidemia and glycemic control with levels of albuminuria in the National Kidney Foundation (NKF) Kidney Early Evaluation Program (KEEP) participants with DM and CKD stage 3 or higher.
We performed a cross-sectional study of 6639 eligible KEEP patients with DM and CKD Stage 3 to 5 from June 2008 to December 2009. Multivariate logistic regression was used to evaluate the association of lipid parameters (per 10 mg/dl change in serum level) and glycosylated hemoglobin (HbA1c) values with three degrees of albuminuria normo (<30 mg⁄g), micro (30 to 300 mg⁄g) and macro (>300 mg⁄g).
2141 KEEP participants were included. HbA1c levels were strongly associated with micro-albuminuria (compared to normo-albuminuria) and macro-albuminuria (compared to normo-albuminuria and micro-albuminuria). Each 1.0% increase in HbA1c increased the odds of micro-albuminuria by 32% (OR 1.32, 95% CI 1.23-1.42) and the odds of macro-albuminuria (vs. microalbuminuria) by 16% (OR 1.16, 95% CI 1.05-1.28). Only increases in serum HDL were associated with decreased odds of micro-albuminuria; otherwise, the association between other components of the serum lipid profile with urinary ACR did not reach statistical significance.
In this cross-sectional study of 2141 KEEP participants with DM and CKD stages 3–5, overall glycemic control but not lipids were associated with abnormal urinary albumin excretion, a marker of increased risk for progressive disease.
Chronic Kidney Disease; Diabetes Mellitus; Proteinuria; Dyslipidemia; Glycosylated hemoglobin
Objectives. We compared five parathyroid scintigraphy protocols in patients with primary (pHPT) and secondary hyperparathyroidism (sHPT) and studied the interobserver agreement. The dual-tracer method (99mTc-sestamibi/123I) was used with three acquisition techniques (parallel-hole planar, pinhole planar, and SPECT/CT). The single-tracer method (99mTc-sestamibi) was used with two acquisition techniques (double-phase parallel-hole planar, and SPECT/CT). Thus five protocols were used, resulting in five sets of images.
Materials and Methods. Image sets of 51 patients were retrospectively graded by four experienced nuclear medicine physicians. The final study group consisted of 24 patients (21 pHPT, 3 sHPT) who had been operated upon. Surgical and histopathologic findings were used as the standard of comparison. Results. Thirty abnormal parathyroid glands were found in 24 patients. The sensitivities of the dual-tracer method (76.7–80.0%) were similar (P = 1.0). The sensitivities of the single-tracer method (13.3–31.6%) were similar (P = 0.625). All differences in sensitivity between these two methods were statistically significant (P < 0.012). The interobserver agreement was good. Conclusion. This study indicates that any dual-tracer protocol with 99mTc-sestamibi and 123I is superior for enlarged parathyroid gland localization when compared with single-tracer protocols using 99mTc-sestamibi alone. The parathyroid scintigraphy was found to be independent of the reporter.
Cardiovascular risk factors are associated with the development of chronic kidney disease (CKD), and CKD and vascular disease are etiologically linked. Evidence suggests deficiencies of vitamins D and K may adversely affect the cardiovascular system, but data from longitudinal studies are lacking. We hypothesized that deficiencies of vitamins D and K may be associated with incident CKD and/or incident albuminuria amongst members of the general population.
We analyzed 1442 Framingham Heart Study participants (mean age 58 years; 50.5% women), free of CKD (eGFR<60 ml/min/1.732), with a mean follow-up of 7.8 years in 2005–2008. Incident albuminuria was defined using sex-specific cutoffs of urine albumin-to-creatinine ratio (≥17 mg/g men and ≥25 mg/g women). Baseline log plasma phylloquinone (vitamin K1) and 25(OH)D levels, analyzed as continuous variables and by quartile, were related to risk of incident CKD (n=108) and incident albuminuria (n=106) using logistic regression models adjusted for standard risk factors.
Participants in the highest phylloquinone quartile (≥1.78 nmol/L) had an increased risk of CKD (multivariable-adjusted OR Q4 vs. Q1 2.39; p=0.006) and albuminuria at follow-up (multivariable-adjusted OR Q4 vs. Q1 1.95; p=0.05), whereas no association was observed with continuous phylloquinone levels for either endpoint. Deficiency of 25(OH)D was not associated with incident CKD or albuminuria in either analysis.
Contrary to our hypothesis, higher plasma phylloquinone levels are associated with an increased risk of incident CKD. Whether plasma phylloquinone is a marker for another unmeasured risk factor requires further study. External validation is necessary given the unexpected nature of these results.
Chronic kidney disease; vitamin K; vitamin D
Vitamin D deficiency appears to be an underestimated risk factor for cardiovascular disease in patients with chronic kidney disease. Evidence from both basic science and clinical studies supports the possible protective role of vitamin D beyond its effect on mineral metabolism. Toxicity of pharmacologic doses of active vitamin D metabolites, in particular calcitriol, is mainly due to the possibility of positive calcium and phosphorus balance. Therefore, vitamin D analogs have been developed, which suppress PTH secretion and synthesis with reduced calcemic and phosphatemic effects. Observational studies suggest that in hemodialysis patients the use of a vitamin D receptor (VDR) activator, such as calcitriol, doxercalciferol, paricalcitol, or alfacalcidol, is associated with a reduced mortality when compared with nonusers of any VDR activator. In this article the existing literature on the topic is reviewed, although a more robust answer to the question of whether or not VDR activators have beneficial effects in hemodialysis patients will hopefully come from a randomized controlled trial.
This study was carried out to evaluate the efficacy and safety of doxercalciferol as therapy for secondary hyperparathyroidism (SHPT) in patients with chronic kidney disease (CKD) stage 4 in a prospective clinical trial. A total of 35 CKD-4 patients who had a baseline parathyroid hormone (iPTH) >150 pg/mL and had not received any vitamin D analog in the preceding 8 weeks were followed up at intervals of 6 weeks for 18 weeks on oral therapy with doxercalciferol. The starting dose was 1.5 μg/day, and the dose was increased in steps of 1 μg/day if iPTH did not decrease by at least 30% on the subsequent visit. Doxercalciferol was stopped temporarily if low iPTH (<70 pg/mL), hypercalcemia (>10.7 mg/dL), or severe hyperphosphatemia (>8.0 mg/dL) occurred, and was restarted at a lower dose on reversal of these abnormalities. Calcium acetate was the only phosphate binder used. Mean iPTH decreased by 35.4 ± 4.4% from 381.7 ± 31.3 pg/mL to 237.9 ± 25.7 pg/mL (P < 0.001). The proportion of patients who achieved 30% and 50% suppression of iPTH levels was 83% and 72%, respectively. Mean serum calcium, phosphorus, and calcium-phosphorus product values did not differ significantly from the baseline values. Four, two, and nine patients developed hypercalcemia, severe hyperphosphatemia, and high CaxP (>55), respectively. Almost all patients recovered to an acceptable level within 2 weeks of stopping doxercalciferol and adjusting the phosphate binder dose. In all, 21 patients required temporary stoppage of therapy. Most of them were restarted on therapy at a reduced dose during the study. It can, therefore, be concluded that doxercalciferol is effective in controlling SHPT in CKD-4 patients with an acceptable risk of hyperphosphatemia and hypercalcemia.
Chronic kidney disease; doxercalciferol; parathyroid hormone; pre-dialysis; secondary hyperparathyroidism; vitamin D