History of Sleep Disorders in Chronic Kidney Disease: First Approach.

OBJECTIVES: In this study, we examined the history of sleep disorders in chronic kidney disease, 60 years after the advent of hemodialysis and renal transplant of genetically nonrelated organs, which have spurred a critical mass of data. MATERIALS AND METHODS: We analyzed selected literature on sleep disorders in chronic kidney disease from 1959 onward. RESULTS: Sleep disturbances are present in the general population. They cause loss of renal function and progressive nephron loss. Insomnia, sleep apnea, restless leg syndrome, and periodic limb movements represent sleep disturbances in chronic kidney disease. These symptoms manifest early in chronic kidney disease and are a rule in patients on dialysis and kidney transplant recipients. Sleep disturbances cause fatigue, excessive daily sleepiness, impaired daytime function, impaired health-related quality of life, increased morbidity, and increased mortality. CONCLUSIONS: Sleep disorders affect most patients with chronic kidney disease. No ascertained pharmacological therapy exists, and even a successful transplant does not totally restore a refreshing sleep. Longer nocturnal hemodialysis is of benefit. Sleep apnea may be cured with continuous positive airway pressure.

Short-Chain Fatty Acids in Chronic Kidney Disease: Focus on Inflammation and Oxidative Stress Regulation.

Chronic Kidney Disease (CKD) is a debilitating disease associated with several secondary complications that increase comorbidity and mortality. In patients with CKD, there is a significant qualitative and quantitative alteration in the gut microbiota, which, consequently, also leads to reduced production of beneficial bacterial metabolites, such as short-chain fatty acids. Evidence supports the beneficial effects of short-chain fatty acids in modulating inflammation and oxidative stress, which are implicated in CKD pathogenesis and progression. Therefore, this review will provide an overview of the current knowledge, based on pre-clinical and clinical evidence, on the effect of SCFAs on CKD-associated inflammation and oxidative stress.

Calcifediol supplementation in adults on hemodialysis: a randomized controlled trial.

BACKGROUND: Vitamin D deficiency is associated with increased risks of mortality in people with chronic kidney disease. The benefits and harm of vitamin D supplementation on cardiovascular outcomes and mortality are unknown. We aimed to assess the effectiveness of calcifediol in reducing mortality in patients with vitamin D insufficiency on hemodialysis compared to no additional therapy. METHODS: A phase III, multicenter, randomized, open-label trial was conducted including 284 adults with vitamin D insufficiency undergoing hemodialysis who were randomly assigned to receive oral calcifediol or standard care for 24 months. RESULTS: Two hundred eighty-four participants were enrolled (143 assigned to the calcifediol group and 141 to the no additional therapy group). The primary outcome (mortality) occurred in 34 and 31 participants in the calcifediol and control group, respectively [hazard ratio (HR) 1.03; 95% confidence interval (CI) 0.63-1.67]. Calcifediol had no detectable effects on cardiovascular death (HR 1.06; 95% CI 0.41-2.74), non-cardiovascular death (HR 1.13; 95% CI 0.62-2.04), nonfatal myocardial infarction (HR 0.20; 95% CI 0.02-1.67) or nonfatal stroke (HR could not be estimated). The incidence of hypercalcemia and hyperphosphatemia was similar between groups. None of the participants underwent parathyroidectomy. CONCLUSIONS: In adults treated with hemodialysis and who had vitamin D insufficiency, calcifediol supplementation for 24 months had inconclusive effects on mortality and cardiovascular outcomes. TRIAL REGISTRATION NUMBER: NCT01457001.

No additional benefit of prescribing a very low-protein diet in patients with advanced chronic kidney disease under regular nephrology care: a pragmatic, randomized, controlled trial.

BACKGROUND: Whether a very low-protein diet supplemented with ketoanalogues (sVLPD), compared with a standard low-protein diet (LPD), improves outcomes in patients with chronic kidney disease (CKD) under stable nephrology care is undefined. OBJECTIVES: To compare the effectiveness of sVLPD compared with LPD in patients regularly seen in tertiary nephrology care. METHODS: Participants were patients with CKD stages 4-5, followed for at least 6 mo, randomly allocated to receive sVLPD or LPD [0.35 or 0.60 g/kg ideal body weight (IBW)/d, respectively], stratified by center and CKD stage. The primary outcome was time to renal death, defined as the first event between end-stage renal disease (ESRD) and all-cause mortality; secondary outcomes were the single components of the primary outcome, cardiovascular outcome, and nutritional status. RESULTS: We analyzed 223 patients (sVLPD, n = 107; LPD, n = 116). Mean age was 64 y, 61% were male, and 35% had diabetes. Median protein intake (PI), which was 0.8 g/kg IBW/d at baseline in both groups, was 0.83 and 0.60 g/kg IBW/d in LPD and sVLPD, respectively, during the trial with a large decrease only in sVLPD (P = 0.011). During a median of 74.2 mo, we recorded 180 renal deaths (141 dialysis and 39 deaths before dialysis). Risk of renal death did not differ in sVLPD compared with LPD (HR: 1.17; 95% CI: 0.88, 1.57; P = 0.28). No difference was observed for ESRD (HR: 1.12; 95% CI: 0.81, 1.56; P = 0.51), mortality (HR: 0.95; 95% CI: 0.62, 1.45; P = 0.82), or time to fatal/nonfatal cardiovascular events (P = 0.2, log-rank test). After 36 mo, still active patients were 45 in sVLPD and 56 in LPD. No change of nutritional status emerged during the study in any arm. CONCLUSIONS: This long-term pragmatic trial found that in patients with CKD under stable nephrology care, adherence to protein restriction is low. Prescribing sVLPD compared with standard LPD is safe but does not provide additional advantage to the kidney or patient survival.

New evidence of direct oral anticoagulation therapy on cardiac valve calcifications, renal preservation and inflammatory modulation.

BACKGROUND: Rivaroxaban is a direct inhibitor of activated Factor X (FXa), an anti-inflammatory protein exerting a protective effect on the cardiac valve and vascular endothelium. We compare the effect of Warfarin and Rivaroxaban on inflammation biomarkers and their contribution to heart valve calcification progression and renal preservation in a population of atrial fibrillation (AF) patients with chronic kidney disease (CKD) stage 3b - 4. METHODS: This was an observational, multicenter, prospective study enrolling 347 consecutive CKD stage 3b - 4 patients newly diagnosed with AF: 247 were treated with Rivaroxaban and 100 with Warfarin. Every 12 months, we measured creatinine levels and cardiac valve calcification via standard trans-thoracic echocardiogram, while plasma levels of inflammatory mediators were quantified by ELISA at baseline and after 24 months. RESULTS: Over a follow-up of 24 months, long-term treatment with Rivaroxaban was associated with a significative reduction of cytokines. Patients treated with Rivaroxaban experienced a more frequent stabilization/regression of valve calcifications comparing with patients treated with Warfarin. Rivaroxaban use was related with an improvement in kidney function in 87.4% of patients, while in those treated with Warfarin was reported a worsening of renal clearance in 98% of cases. Patients taking Rivaroxaban experienced lower adverse events (3.2% vs 49%, p-value <0.001). CONCLUSIONS: Our findings suggest that Rivaroxaban compared to Warfarin is associated with lower levels of serum markers of inflammation. The inhibition of FXa may exert an anti-inflammatory effect contributing to reduce the risk of cardiac valve calcification progression and worsening of renal function.

Vascular Calcification Progression Modulates the Risk Associated with Vascular Calcification Burden in Incident to Dialysis Patients.

Background: It is estimated that chronic kidney disease (CKD) accounts globally for 5 to 10 million deaths annually, mainly due to cardiovascular (CV) diseases. Traditional as well as non-traditional CV risk factors such as vascular calcification are believed to drive this disproportionate risk burden. We aimed to investigate the association of coronary artery calcification (CAC) progression with all-cause mortality in patients new to hemodialysis (HD). Methods: Post hoc analysis of the Independent study (NCT00710788). At study inception and after 12 months of follow-up, 414 patients underwent computed tomography imaging for quantification of CAC via the Agatston methods. The square root method was used to assess CAC progression (CACP), and survival analyses were used to test its association with mortality. Results: Over a median follow-up of 36 months, 106 patients died from all causes. Expired patients were older, more likely to be diabetic or to have experienced an atherosclerotic CV event, and exhibited a significantly greater CAC burden (p = 0.002). Survival analyses confirmed an independent association of CAC burden (hazard ratio: 1.29; 95% confidence interval: 1.17-1.44) and CACP (HR: 5.16; 2.61-10.21) with all-cause mortality. CACP mitigated the risk associated with CAC burden (p = 0.002), and adjustment for calcium-free phosphate binder attenuated the strength of the link between CACP and mortality. Conclusions: CAC burden and CACP predict mortality in incident to dialysis patients. However, CACP reduced the risk associated with baseline CAC, and calcium-free phosphate binders attenuated the association of CACP and outcomes, suggesting that CACP modulation may improve survival in this population. Future endeavors are needed to confirm whether drugs or kidney transplantation may attenuate CACP and improve survival in HD patients.

Current Management of Hyperkalemia in Non-Dialysis CKD: Longitudinal Study of Patients Receiving Stable Nephrology Care.

BACKGROUND: No study has explored the limitations of current long-term management of hyperkalemia (HK) in outpatient CKD clinics. METHODS: We evaluated the association between current therapeutic options and control of serum K (sK) during 12-month follow up in ND-CKD patients stratified in four groups by HK (sK ≥ 5.0 mEq/L) at baseline and month 12: Absent (no-no), Resolving (yes-no), New Onset (no-yes), Persistent (yes-yes). RESULTS: We studied 562 patients (age 66.2 ± 14.5 y; 61% males; eGFR 39.8 ± 21.8 mL/min/1.73 m2, RAASI 76.2%). HK was "absent" in 50.7%, "resolving" in 15.6%, "new onset" in 16.6%, and "persistent" in 17.1%. Twenty-four hour urinary measurements testified adherence to nutritional recommendations in the four groups at either visit. We detected increased prescription from baseline to month 12 of bicarbonate supplements (from 5.0 to 14.1%, p < 0.0001), K-binders (from 2.0 to 7.7%, p < 0.0001), and non-K sparing diuretics (from 34.3 to 41.5%, p < 0.001); these changes were consistent across groups. Similar results were obtained when using higher sK level (≥5.5 mEq/L) to stratify patients. Mixed-effects regression analysis showed that higher sK over time was associated with eGFR < 60, diabetes, lower serum bicarbonate, lower use of non-K sparing diuretics, bicarbonate supplementation, and K-binder use. Treatment-by-time interaction showed that sK decreased in HK patients given bicarbonate (p = 0.003) and K-binders (p = 0.005). CONCLUSIONS: This observational study discloses that one-third of ND-CKD patients under nephrology care remain with or develop HK during a 12-month period despite low K intake and increased use of sK-lowering drugs.

Ketoanalogs' Effects on Intestinal Microbiota Modulation and Uremic Toxins Serum Levels in Chronic Kidney Disease (Medika2 Study).

Nutritional therapy (NT) is a therapeutic option in the conservative treatment of chronic kidney disease (CKD) patients to delay the start of dialysis. The aim of this study was to evaluate the specific effect of ketoanalogs (KA)-supplemented diets for gut microbiota modulation. In a previous study we observed that the Mediterranean diet (MD) and a KA-supplemented very-low-protein diet (VLPD) modulated beneficially gut microbiota, reducing indoxyl- and p-cresyl-sulfate (IS, PCS) serum levels, and ameliorating the intestinal permeability in CKD patients. In the current study, we added a third diet regimen consisting of KA-supplemented MD. Forty-three patients with CKD grades 3B-4 continuing the crossover clinical trial were assigned to six months of KA-supplemented MD (MD + KA). Compared to MD, KA-supplementation in MD + KA determined (i) a decrease of Clostridiaceae, Methanobacteriaceae, Prevotellaceae, and Lactobacillaceae while Bacteroidaceae and Lachnospiraceae increased; (ii) a reduction of total and free IS and PCS compared to a free diet (FD)-more than the MD, but not as effectively as the VLPD. These results further clarify the driving role of urea levels in regulating gut integrity status and demonstrating that the reduction of azotemia produced by KA-supplemented VLPD was more effective than KA-supplemented MD in gut microbiota modulation mainly due to the effect of the drastic reduction of protein intake rather than the effect of KA.

Predictive Value of Measures of Vascular Calcification Burden and Progression for Risk of Death in Incident to Dialysis Patients.

BACKGROUND: Vascular calcification (VC) is a marker of cardiovascular (CV) disease and various methods allow for presence and extension assessment in different arterial districts. Nevertheless, it is currently unclear which one of these methods for VC evaluation best predict outcome and if this piece of information adds to the predictive value of traditional CV risk factors in patients receiving hemodialysis (HD). METHODS: data of 184 of the 466 patients followed in the Independent study (NCT00710788) were post hoc examined to assess the association three concurrent measures of vascular calcification and all-cause survival. Specifically, coronary artery calcification (CAC) was determined by the Agatston and the volume score while abdominal aorta calcification was determined by plain X-ray of the lumbar spine (Kauppila score (KS)). Survival and regression models as well as metrics of risk recalculation were used to test the association of VC and outcome beyond the Framingham risk score. RESULTS: Middle-age (62.6(15.8) years) men (51%) and women (49%) starting HD were analyzed. Over 36 (median 36; interquartile range: 8-36) months of follow-up 69 patients expired. Each measure of VC (CAC or KS) predicted all-cause mortality independently factors commonly associated with all-cause survival (p < 0.001). Far more importantly, each measurement of VC significantly improved risk prediction and patient reclassification (p < 0.001) beyond traditional cardiovascular risk factors. CONCLUSIONS: Overall, presence and extension of VC, irrespective of the arterial site, predict risk of all-cause of death in patients starting hemodialysis. Of note, both CAC and KS increase risk stratification beyond traditional CV risk factors. However, future efforts are needed to assess whether a risk-based approach encompassing VC screening to guide HD patient management improves survival.

Pro-Inflammatory Effects of Indoxyl Sulfate in Mice: Impairment of Intestinal Homeostasis and Immune Response.

The intestines are recognized as the main source of chronic inflammation in chronic kidney disease (CKD) and, among other cells, macrophages are involved in modulating this process as well as in the impaired immune response which also occurs in CKD patients. In this study, we evaluated the effect of Indoxyl Sulfate (IS), a protein bound uremic toxin poorly eliminated by hemodialysis, on inflammatory, oxidative stress and pro-apoptotic parameters, at the intestinal level in mice, on intestinal epithelial cells (IEC-6) and on primary murine peritoneal macrophages. C57BL/6J mice were treated with IS (800 mg/kg i.p.) for 3 or 6 h and histopathological analysis showed that IS induced intestinal inflammation and increased cyclooxygenase-2 (COX-2), nitrotyrosine and Bax expression in intestinal tissue. In IEC-6 cells, IS (125-1000 µM) increased tumor necrosis factor-α levels, COX-2 and inducible nitric oxide synthase expression and nitrotyrosine formation. Moreover, IS increased pro-oxidant, pro-inflammatory and pro-apoptotic parameters in peritoneal macrophages from IS-treated mice. Also, the serum concentration of IS and pro-inflammatory levels of cytokines resulted increased in IS-treated mice. Our results indicate that IS significantly contributes to affect intestinal homeostasis, immune response, and to induce a systemic pro-inflammatory state thus highlighting its potential role as therapeutic target in CKD patients.

Thromboembolic and Bleeding Risk in Atrial Fibrillation Patients with Chronic Kidney Disease: Role of Anticoagulation Therapy.

Atrial fibrillation (AF) and chronic kidney disease (CKD) are strictly related; several independent risk factors of AF are often frequent in CKD patients. AF prevalence is very common among these patients, ranging between 15% and 20% in advanced stages of CKD. Moreover, the results of several studies showed that AF patients with end stage renal disease (ESRD) have a higher mortality rate than patients with preserved renal function due to an increased incidence of stroke and an unpredicted elevated hemorrhagic risk. Direct oral anticoagulants (DOACs) are currently contraindicated in patients with ESRD and vitamin K antagonists (VKAs), remaining the only drugs allowed, although they show numerous critical issues such as a narrow therapeutic window, increased tissue calcification and an unfavorable risk/benefit ratio with low stroke prevention effect and augmented risk of major bleeding. The purpose of this review is to shed light on the applications of DOAC therapy in CKD patients, especially in ESRD patients.

Legislative proposal in Italy to facilitate contacts between deceased organ donor families and transplant recipients.

Contacts between organ donors and recipients might be possible in the near future in Italy. As suggested by The Italian Committee of Bioethics "anonymity is requested by the Italian National Transplant Centre" before transplantation anonymity shall be strict in order to grant privacy, gratuity, justice, solidarity and benefits and avoids organ trafficking. Following a period that is ethically correct and justifiable, organ donor families and recipients can meet after signing a valid declaration of consent, expressed on a template valid for the whole country. A third party within the body of the National Health Systems shall control the validity of the consent. The opinion stresses that contacts are not a right but a possibility justifiable on ethical grounds if the procedure is followed appropriately. A legislative proposal has been presented before the Chamber of deputies incorporating all suggestions made by the National Committee of Bioethics. The agreement between parties might be signed a year after transplantation. This is a long enough period of time for the recipients to fully appreciate the benefits of the procedure and for the donor families to see the effects of their decision (the opinion and the Law proposal hit the Zeitgeist, and keep Italy in the regulation of European Union).

Correction to: Treatment of metabolic acidosis with sodium bicarbonate delays progression of chronic kidney disease: the UBI Study.

It occurred to us that a simple but significant calculation error was made in Table 2 in the dose of bicarbonate administered. Indeed, contrary to what reported in Table 2, the dose of sodium bicarbonate administered during study was.

Correction: Etelcalcetide in Patients on Hemodialysis with Severe Secondary Hyperparathyroidism. Multicenter Study in "Real Life". J. Clin. Med. 2019, 8, 1066.

The authors wish to make the following corrections to the previous publication [...].

Glifozines and cardiorenal outcomes.

Diabetes mellitus, with its complications, is one of the major health problems in economically developed countries and its prevalence is constantly increasing. Kidneys and heart involvement represent main comorbidities in diabetic patients often leading to organ failure. The treatments available until a few years ago are often associated with hypoglycemia, weight gain, gastro-intestinal disorders and other side effects together with serious adverse effects on renal function. The new frontiers of diabetic cardionephropathy treatment are mainly focused on delay of heart and renal failure both on diabetic and nondiabetic patients ad it was shown by last data reports. In the following review, we will focus on Gliflozins, one of the newest classes of hypoglycemic drugs that have shown to hold peculiar pharmacological properties in managing cardiac and renal complications.

[Native kidney ultrasound in obstructive uropathy].

The term "obstructive uropathy" refers to the complex structural and functional changes following the interruption of normal urinary runoff, which can occur at every level of the urinary tract. Depending on its origin, duration and severity, urinary tract obstructions can be acute or chronic, mono or bilateral, partial or complete. The obstruction can be localized or extended to the entire pielo-caliceal system and/or homolateral urethra. The term "hydronephrosis" indicates the dilation of the pelvis detected through imaging techniques. Among these, ultrasound is considered the gold standard in the diagnosis of obstructive uropathy: it allows to distinguish three degrees of urinary tract dilation, depending on the extent of the dilation itself and the thickness of the parenchyma. Nephrologists are confronted daily with patients who experience kidney failure and must be able to quickly distinguish between chronic and acute and, in the latter case, to discern between issues of nephrological or urological competence. This short review aims at helping them deal with this very common scenario, through the use of ultrasound.

Dietary satisfaction and quality of life in chronic kidney disease patients on low-protein diets: a multicentre study with long-term outcome data (TOrino-Pisa study).

BACKGROUND: Concerns about adherence and quality of life (QoL) limit the diffusion of low-protein diets (LPDs) as a way to slow chronic kidney disease (CKD) progression and postpone dialysis. The aim of this multicentre study is to assess dietary satisfaction in stable CKD patients. METHODS: This was a multicentre cross-sectional study with long-term follow-up data. Prevalent patients on LPD for at least 6 months were selected in four Italian centres. QoL was assessed using the World Health Organization Quality of Life questionnaire, and diet satisfaction with the Modification of Diet in Renal Disease satisfaction questionnaire. Comorbidity was assessed by Charlson Comorbidity Index, estimated glomerular filtration rate (eGFR) was calculated by the CKD Epidemiology Collaboration equation and protein intake by Maroni-Mitch formula. Survival was analysed with Kaplan-Meier curves and Cox Proportional Hazard Model. RESULTS: Four hundred and twenty-two CKD Stages 3-5 patients were enrolled. Over 95% were on moderately restricted diets (0.6 g/kg/day). Compliance was good (protein intake: 0.59 g/kg/day at baseline, 0.72 at the end of follow-up). Median dietary satisfaction was 4 on a 1-5 scale. QoL was not affected by the type of diet, but was influenced by age, comorbidity and setting of care. Two years later, at the end of follow-up, 66.6% of the patients were still on a diet; the main causes of discontinuation were dialysis and death. The dropout rate was low (5.5%); in Cox analysis, patient and renal survival were influenced by age and eGFR, but not by QoL, setting of care or type of diet. CONCLUSIONS: LPDs are compatible with high dietary satisfaction and minimal dropout, at least in patients who are able to follow such a diet for at least 6 months.

Chronic Kidney Disease: The Silent Epidemy.

Numerous observations suggest that chronic kidney disease (CKD) is an epidemic condition [...].

Treatment of metabolic acidosis with sodium bicarbonate delays progression of chronic kidney disease: the UBI Study.

BACKGROUND: Metabolic acidosis is associated with accelerated progression of chronic kidney disease (CKD). Whether treatment of metabolic acidosis with sodium bicarbonate improves kidney and patient survival in CKD is unclear. METHODS: We conducted a randomized (ratio 1:1). open-label, controlled trial (NCT number: NCT01640119. www.clinicaltrials.gov ) to determine the effect in patients with CKD stage 3-5 of treatment of metabolic acidosis with sodium bicarbonate (SB) on creatinine doubling (primary endpoint), all-cause mortality and time to renal replacement therapy compared to standard care (SC) over 36-months. Parametric, non-parametric tests and survival analyses were used to assess the effect of SB on these outcomes. RESULTS: A total of 376 and 364 individuals with mean (SD) age 67.8 (14.9) years, creatinine clearance 30 (12) ml/min, and serum bicarbonate 21.5 (2.4) mmol/l were enrolled in SB and SC, respectively. Mean (SD) follow-up was 29.6 (9.8) vs 30.3 (10.7) months in SC and SB. respectively. The mean (SD) daily doses of SB was 1.13 (0.10). 1.12 (0.11). and 1.09 (0.12) mmol/kg*bw/day in the first, second and third year of follow-up, respectively. A total of 87 participants reached the primary endpoint [62 (17.0%) in SC vs 25 (6.6%) in SB, p < 0.001). Similarly, 71 participants [45 (12.3%) in SC and 26 (6.9%) in SB, p = 0.016] started dialysis while 37 participants [25 (6.8%) in SC and 12 (3.1%) in SB, p = 0.004] died. There were no significant effect of SB on blood pressure, total body weight or hospitalizations. CONCLUSION: In persons with CKD 3-5 without advanced stages of chronic heart failure, treatment of metabolic acidosis with sodium bicarbonate is safe and improves kidney and patient survival.

Associations of Calcium from Food Sources Versus Phosphate Binders with Serum Calcium and FGF23 in Hemodialysis Patients.

BACKGROUND: Dysregulated serum calcium and FGF23 are associated with increased mortality and morbidity rates in patients receiving hemodialysis. Preliminary data suggest serum calcium regulates FGF23 secretion independently of serum phosphate, parathyroid hormone, and 25-OH vitamin D. It is unclear to what extent dietary and prescription sources of calcium influence calcium and FGF23 levels, and whether they confound this relationship. In this cross-sectional analysis of a multi-ethnic cohort of prevalent hemodialysis patients, association of dietary calcium and prescribed calcium were examined against serum calcium and FGF23. Bi- and multivariable linear regression was used for all analyses. RESULTS: 81 patients (mean age 58 years, dialysis vintage 2 years, 51 men) participated. Dietary calcium was inversely associated with FGF23 (p = 0.04) however association of FGF23 with prescribed calcium did not reach statistical significance (0.08). In multivariable models, dietary calcium and prescribed calcium were associated in opposing directions with serum calcium (prescribed calcium; ß-coefficient = -0.35, p = 0.005 versus dietary calcium; ß-coefficient = 0.35, p = 0.03). FGF23 was independently associated with serum calcium (p = 0.007). CONCLUSIONS: We found differing, sometimes opposing, associations between serum calcium and FGF23 levels when considering prescribed versus dietary sources of calcium. Serum calcium and FGF23 were strongly correlated regardless of possible confounders examined in this hemodialysis cohort. Dietary calcium was associated with higher serum calcium and lower FGF23 concentrations, while prescribed calcium was only inversely associated with serum calcium. Further studies are required to confirm these associations and determine causality.