James B. Wetmore

Effects of Cinacalcet and Concurrent Low-Dose Vitamin D on FGF23 Levels in ESRD

BACKGROUND AND OBJECTIVES Fibroblast growth factor-23 (FGF23) levels are elevated in ESRD and have been associated with adverse outcomes. The effects of various treatments for secondary hyperparathyroidism on FGF23 levels in ESRD have not been examined in a clinical trial. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS We assessed intact FGF23 levels in 91 subjects over the course of the ACHIEVE trial, which was designed to compare escalating doses of Cinacalcet plus fixed low-dose calcitriol analogs (Cinaclcet-D) with titration of calcitriol analogs alone (Flex-D) to suppress parathyroid hormone. Between-group and within-group changes in log-transformed FGF23 levels were analyzed. Factors associated with change in FGF23 were assessed using a multiple regression model. RESULTS Intact FGF23 levels were markedly elevated in subjects at baseline. A statistically significant difference in percent change in log FGF23 levels was observed between treatment groups (P < 0.002). The Cinacalcet-D group had a significant decrease in percent change in log FGF23 levels (corrected P = 0.021), whereas FGF23 levels trended toward an increase in the Flex-D group. Change in FGF23 level was significantly associated with changes in levels of phosphate (P < 0.0001) and calcium (P = 0.0002) but not parathyroid hormone. CONCLUSIONS Treatment with Cinacalcet plus low-dose calcitriol analogs results in lower FGF23 levels compared with a treatment regimen using calcitriol analogs alone in ESRD. The mechanisms underlying the differential effects of these treatment regimens on FGF23 levels and the clinical impact of these changes on FGF23 remain to be defined.

Serum Trimethylamine-N-Oxide is Elevated in CKD and Correlates with Coronary Atherosclerosis Burden

Trimethlyamine-N-oxide (TMAO) was recently identified as a promoter of atherosclerosis. Patients with CKD exhibit accelerated development of atherosclerosis; however, no studies have explored the relationship between TMAO and atherosclerosis formation in this group. This study measured serum concentrations and urinary excretion of TMAO in a CKD cohort (n=104), identified the effect of renal transplant on serum TMAO concentration in a subset of these patients (n=6), and explored the cross-sectional relationship between serum TMAO and coronary atherosclerosis burden in a separate CKD cohort (n=220) undergoing coronary angiography. Additional exploratory analyses examined the relationship between baseline serum TMAO and long-term survival after coronary angiography. Serum TMAO concentrations demonstrated a strong inverse association with eGFR (r(2)=0.31, P<0.001). TMAO concentrations were markedly higher in patients receiving dialysis (median [interquartile range], 94.4 μM [54.8-133.0 μM] for dialysis-dependent patients versus 3.3 μM [3.1-6.0 μM] for healthy controls; P<0.001); whereas renal transplantation resulted in substantial reductions in TMAO concentrations (median [min-max] 71.2 μM [29.2-189.7 μM] pretransplant versus 11.4 μM [8.9-20.2 μM] post-transplant; P=0.03). TMAO concentration was an independent predictor for coronary atherosclerosis burden (P=0.02) and predicted long-term mortality independent of traditional cardiac risk factors (hazard ratio, 1.26 per 10 μM increment in TMAO concentration; 95% confidence interval, 1.13 to 1.40; P<0.001). In conclusion, serum TMAO concentrations substantially increase with decrements in kidney function, and this effect is reversed by renal transplantation. Increased TMAO concentrations correlate with coronary atherosclerosis burden and may associate with long-term mortality in patients with CKD undergoing coronary angiography.

The prevalence of and factors associated with chronic atrial fibrillation in Medicare/Medicaid-eligible dialysis patients

Atrial fibrillation is an important comorbidity with substantial therapeutic implications in dialysis patients but its prevalence varies in different studies. We used a database that includes patients in the United States on hemodialysis who were eligible for government assistance with prescription drugs. We then used ICD-9 codes from billing claims in this database to identify patients with chronic atrial fibrillation. Multivariable logistic regression was used to determine adjusted prevalence odds ratios for associated factors. Of 63,884 individuals, the prevalence of chronic atrial fibrillation was 7%. The factors of age over 60 years, male, Caucasian, body mass index over 25 kg/m(2), coronary artery disease, and heart failure were all significantly associated with chronic atrial fibrillation. Prevalence rates, particularly in younger patients, were far higher than those reported in an age group-matched nondialysis population. Thus, given its clinical impact, future efforts are needed to examine risk factors for adverse outcomes in chronic atrial fibrillation, and to identify appropriate management strategies for this disorder, as well as opportunities for quality improvement in this vulnerable population.

Clinical Outcomes after Parathyroidectomy in a Nationwide Cohort of Patients on Hemodialysis

BACKGROUND AND OBJECTIVES Patients receiving dialysis undergo parathyroidectomy to improve laboratory parameters in resistant hyperparathyroidism with the assumption that clinical outcomes will also improve. However, no randomized clinical trial data demonstrate the benefits of parathyroidectomy. This study aimed to evaluate clinical outcomes up to 1 year after parathyroidectomy in a nationwide sample of patients receiving hemodialysis. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS Using data from the US Renal Data System, this study identified prevalent hemodialysis patients aged ≥18 years with Medicare as primary payers who underwent parathyroidectomy from 2007 to 2009. Baseline characteristics and comorbid conditions were assessed in the year preceding parathyroidectomy; clinical events were identified in the year preceding and the year after parathyroidectomy. After parathyroidectomy, patients were censored at death, loss of Medicare coverage, kidney transplant, change in dialysis modality, or 365 days. This study estimated cause-specific event rates for both periods and rate ratios comparing event rates in the postparathyroidectomy versus preparathyroidectomy periods. RESULTS Of 4435 patients who underwent parathyroidectomy, 2.0% died during the parathyroidectomy hospitalization and the 30 days after discharge. During the 30 days after discharge, 23.8% of patients were rehospitalized; 29.3% of these patients required intensive care. In the year after parathyroidectomy, hospitalizations were higher by 39%, hospital days by 58%, intensive care unit admissions by 69%, and emergency room/observation visits requiring hypocalcemia treatment by 20-fold compared with the preceding year. Cause-specific hospitalizations were higher for acute myocardial infarction (rate ratio, 1.98; 95% confidence interval, 1.60 to 2.46) and dysrhythmia (rate ratio 1.4; 95% confidence interval1.16 to 1.78); fracture rates did not differ (rate ratio 0.82; 95% confidence interval 0.6 to 1.1). CONCLUSIONS Parathyroidectomy is associated with significant morbidity in the 30 days after hospital discharge and in the year after the procedure. Awareness of clinical events will assist in developing evidence-based risk/benefit determinations for the indication for parathyroidectomy.

The medicinal use of water in renal disease

Although water is essential for life, its use for medicinal purposes is not universally accepted. We performed a comprehensive review of the literature to determine where the evolving state of knowledge lies regarding the benefits of water as a therapy for renal diseases. In the past two decades, water has emerged as a potential therapeutic agent in nephrolithiasis, chronic kidney disease (CKD), and polycystic kidney disease (PKD) in particular. In nephrolithiasis, the benefit of drinking water beyond that demanded by thirst is a cornerstone of therapy for both primary and secondary disease. In CKD, recent observational studies suggest a strong, direct association between preservation of renal function and fluid intake. In PKD, increased water intake slows renal cyst growth in animals via direct vasopressin suppression, and pharmacologic blockade of renal vasopressin-V2 receptors has recently been shown to be efficacious in retarding cyst growth in PKD patients. Although evidence is lacking to support increased water intake in the general population, available evidence indicates that individuals who are at risk for nephrolithiasis as well as those with CKD and PKD may benefit from 3 to 4 l of urine output each day, a level of excretion that is likely to be safe.

The Donor Kidney Biopsy and Its Implications in Predicting Graft Outcomes: A Systematic Review.

Despite a growing organ shortage in the United States, many deceased donor kidneys removed for transplantation are discarded. Kidney biopsy findings often play a role in these discards, although it is not clear whether biopsies reliably inform acceptance decisions. Therefore, we carried out a systematic review of the medical literature on the utility of both procurement and implantation biopsies for predicting posttransplant outcomes. Between January 1, 1994 and July 1, 2014, 47 studies were published in the English language literature that examined the association between pretransplant donor biopsy findings from 50 or more donors (with more than half being from deceased donors) and either posttransplant graft failure, delayed graft function, or graft function. In general, study quality was poor. All were retrospective or did not indicate if they were prospective. Results were heterogeneous, with authors as often as not concluding that biopsy results did not predict posttransplant outcomes. The percent glomerular sclerosis was most often examined, and failed to predict graft failure in 7 of 14 studies. Of 15 semiquantitative scoring systems proposed, none consistently predicted posttransplant outcomes across studies. Routine use of biopsies to help determine whether or not to transplant a kidney should be reexamined.

Effects of short-term alendronate on bone mineral density in haemodialysis patients

Background:  Low bone mineral density (BMD) is common in dialysis patients. Low BMD predicts the fracture risk in the general population. Bisphosphonate therapy improves BMD and lowers the fracture risk in many populations, but has not been tested in dialysis patients because of concerns about toxicity. In this investigation, the effect of a short course of alendronate on BMD in haemodialysis (HD) patients is evaluated.

A Randomized Trial of Cinacalcet versus Vitamin D Analogs as Monotherapy in Secondary Hyperparathyroidism (PARADIGM)

BACKGROUND AND OBJECTIVES Direct comparison of cinacalcet and vitamin D analogs as monotherapies to lower parathyroid hormone (PTH) levels has not been undertaken. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS This was a prospective, multicenter, phase 4, randomized, open-label study that enrolled participants from 2010 to 2012. Adult participants (n=312) on hemodialysis with PTH >450 pg/ml were randomized 1:1 to 12 months of treatment with either cinacalcet (n=155) or vitamin D analogs (n=157) to evaluate the mean percentage change in plasma PTH level (primary end point) and the proportion of participants achieving plasma PTH <300 pg/ml or a ≥30% decrease in PTH (secondary end points). A preplanned analysis to determine whether there were important region-by-treatment interactions was also undertaken. RESULTS Baseline mean PTH was 846 pg/ml (n=155) for cinacalcet and 816 pg/ml (n=157) for vitamin D analog therapy. The mean (95% confidence interval) percentage change from baseline in PTH was -12.1% (-20.0% to -4.1%) in the cinacalcet arm and -7.0% (-14.9% to 0.8%) in the vitamin D analog arm, a difference of -5.0% (-15.4% to 5.4%) (P=0.35). Similarly, there was no difference in achievement of secondary efficacy end points between arms (19.4% and 15.3% of participants with PTH≤300 pg/ml and 42.6% and 33.8% of participants had a PTH reduction >30% in the cinacalcet and vitamin D analog arms, respectively). A prespecified analysis revealed a large treatment-by-region interaction, with nominally greater response to cinacalcet compared with vitamin D analogs in non-United States participants (US versus non-US participants, P<0.001). Hypocalcemia was more common in the cinacalcet arm, whereas hypercalcemia and hyperphosphatemia occurred more often in the vitamin D analog arm. CONCLUSIONS Participants had similar modest reductions in PTH with either cinacalcet or vitamin D analog monotherapy over 52 weeks of treatment, but effects varied by region. Treatments differed with regard to effect on calcium and phosphorus levels.

Polycystic Kidney Disease and Cancer after Renal Transplantation

Autosomal dominant polycystic kidney disease (ADPKD), the most common form of polycystic kidney disease (PKD), is a disorder with characteristics of neoplasia. However, it is not known whether renal transplant recipients with PKD have an increased risk of cancer. Data from the Scientific Registry of Transplant Recipients, which contains information on all solid organ transplant recipients in the United States, were linked to 15 population-based cancer registries in the United States. For PKD recipients, we compared overall cancer risk with that in the general population. We also compared cancer incidence in PKD versus non-PKD renal transplant recipients using Poisson regression, and we determined incidence rate ratios (IRRs) adjusted for age, sex, race/ethnicity, dialysis duration, and time since transplantation. The study included 10,166 kidney recipients with PKD and 107,339 without PKD. Cancer incidence in PKD recipients was 1233.6 per 100,000 person-years, 48% higher than expected in the general population (standardized incidence ratio, 1.48; 95% confidence interval [95% CI], 1.37 to 1.60), whereas cancer incidence in non-PKD recipients was 1119.1 per 100,000 person-years. The unadjusted incidence was higher in PKD than in non-PKD recipients (IRR, 1.10; 95% CI, 1.01 to 1.20). However, PKD recipients were older (median age at transplantation, 51 years versus 45 years for non-PKD recipients), and after multivariable adjustment, cancer incidence was lower in PKD recipients than in others (IRR, 0.84; 95% CI, 0.77 to 0.91). The reason for the lower cancer risk in PKD recipients is not known but may relate to biologic characteristics of ADPKD or to cancer risk behaviors associated with ADPKD.

Geographic Variation in Cardioprotective Antihypertensive Medication Usage in Dialysis Patients

BACKGROUND Despite their high risk of adverse cardiac outcomes, persons on long-term dialysis therapy have had lower use of antihypertensive medications with cardioprotective properties, such as angiotensin-converting enzyme (ACE) inhibitors/angiotensin receptor blockers (ARBs), β-blockers, and calcium channel blockers, than might be expected. We constructed a novel database that permits detailed exploration into the demographic, clinical, and geographic factors associated with the use of these agents in hypertensive long-term dialysis patients. STUDY DESIGN National cross-sectional retrospective analysis linking Medicaid prescription drug claims with US Renal Data System core data. SETTING & PARTICIPANTS 48,882 hypertensive long-term dialysis patients who were dually eligible for Medicaid and Medicare services in 2005. FACTORS Demographics, comorbid conditions, functional status, and state of residence. OUTCOMES Prevalence of cardioprotective antihypertensive agents in Medicaid pharmacy claims and state-specific observed to expected ORs of medication exposure. MEASUREMENTS Factors associated with medication use were modeled using multilevel logistic regression models. RESULTS In multivariable analyses, cardioprotective antihypertensive medication exposure was associated significantly with younger age, female sex, nonwhite race, intact functional status, and use of in-center hemodialysis. Diabetes was associated with a statistically significant 28% higher odds of ACE-inhibitor/ARB use, but congestive heart failure was associated with only a 9% increase in the odds of β-blocker use and no increase in ACE-inhibitor/ARB use. There was substantial state-by-state variation in the use of all classes of agents, with a greater than 2.9-fold difference in adjusted-rate ORs between the highest and lowest prescribing states for ACE inhibitors/ARBs and a 3.6-fold difference for β-blockers. LIMITATIONS Limited generalizability beyond study population. CONCLUSIONS In publicly insured long-term dialysis patients with hypertension, there were marked differences in use rates by state, potentially due in part to differences in Medicaid benefits. However, geographic characteristics also were associated with exposure, suggesting clinical uncertainty about the utility of these medications.