Long-term outcomes and management considerations after parathyroidectomy in the dialysis patient.

Parathyroidectomy (PTX) remains an important intervention for dialysis patients with poorly controlled secondary hyperparathyroidism (SHPT), though there are only retrospective and observational data that show a mortality benefit to this procedure. Potential consequences that we seek to avoid after PTX include persistent or recurrent hyperparathyroidism, and parathyroid insufficiency. There is considerable subjectivity in defining and diagnosing these conditions, given that we poorly understand the optimal PTH targets (particularly post PTX) needed to maintain bone and vascular health. While lowering PTH after PTX decreases bone turnover, long-term changes in bone activity have been poorly explored. High turnover bone disease, usually present at the time a PTX is considered, often swings to a state of low turnover in the setting of sufficiently low PTH levels. It remains unclear if all low bone turnover equate with disease. However, such changes in bone turnover appear to predispose to vascular calcification, with positive calcium balance after PTX being a potential contributor. We know little of how the post-PTX state resets calcium balance, how calcium and VDRA requirements change or what kind of adjustments are needed to avoid calcium loading. The current consensus cautions against excessive reduction of PTH although there is insufficient evidence-based guidance regarding the management of chronic kidney disease - mineral bone disease (CKD-MBD) parameters in the post-PTX state. This article aims to compile existing research, provide an overview of current practice with regard to PTX and post-PTX chronic management. It highlights gaps and controversies and aims to re-orient the focus to clinically relevant contemporary priorities in CKD-MBD management after PTX.

PTH assays in dialysis patients: Practical considerations.

Parathyroid hormone (PTH) 1-84 is the main biologically active hormone produced by the parathyroid cells. Circulating PTH molecules include the whole PTH 1-84 along with amino (N) and carboxyl (C) terminal fragments. While PTH is the best available noninvasive biomarker to assess bone turnover in dialysis patients, the biological roles of individual circulating PTH fragments are still not completely known. The understanding that there is an enormous variation in the target specificity of currently available PTH assays for different circulating forms of PTH has led to the evolution of assays from first to second then third generation. With a reduction in kidney function, there is a preferential increase in circulating C fragments and non-PTH 1-84 forms, resulting in a decrease in the ratio of PTH 1-84/non-PTH 1-84. However, there are also substantial differences in between-assay measurements, with several fold variations in results. Targets based on multiples of the upper limit of normal (ULN) should be used rather than PTH ranges using absolute iPTH values. To date, the second-generation PTH remains the most widely used assay. Current guidelines recommend following iPTH trends rather than absolute values. Herein, we highlight problems and challenges in PTH assays/measurements and their interpretations in dialysis patients.

Chronic kidney disease and acquired mitochondrial myopathy.

PURPOSE OF REVIEW: Sarcopenia and muscle weakness contribute to fragility and limit exercise tolerance among patients with CKD. This review focuses on the role of reduction in mitochondrial mass and function in the myopathy associated with CKD, causes for these muscle mitochondrial abnormalities, and potential therapeutic interventions that may improve mitochondrial biogenesis and function as well as skeletal muscle function and performance in patients with CKD. RECENT FINDINGS: Multiple abnormalities of mitochondrial structure, function, and composition have been shown in both experimental models and patients with CKD. A significant reduction in mitochondrial respiratory function and an increase in mitochondrial complex 1 enzyme activity has been demonstrated in the muscle tissue of male Sprague-Dawley rats following 5/6 nephrectomy. These changes were associated with a substantial reduction in skeletal muscle mitochondrial mass. In patients with CKD, in-vivo magnetic resonance and optical spectroscopy show significantly elevated resting skeletal muscle oxygen consumption and lower mean mitochondrial coupling ratio indicating disrupted muscle mitochondrial metabolism and uncoupling of oxidative phosphorylation. Skeletal muscle biopsies from patients with advanced CKD show lower mitochondrial volume density and mitochondrial DNA (mtDNA) copy number than controls. SUMMARY: Advanced CKD is associated with decreased exercise capacity, skeletal muscle weakness, and muscle atrophy. Impaired mitochondrial respiratory function, reduced muscle mitochondrial mass, and decreased energy production in skeletal muscle play a critical role in this 'acquired mitochondrial myopathy' of CKD. It is reasonable, therefore, to develop therapeutic interventions that enhance mitochondrial biogenesis and function as well as skeletal muscle function and performance in patients with CKD.

Serum Phosphorus and Risk of Cardiovascular Disease, All-Cause Mortality, or Graft Failure in Kidney Transplant Recipients: An Ancillary Study of the FAVORIT Trial Cohort.

BACKGROUND: Mild hyperphosphatemia is a putative risk factor for cardiovascular disease [CVD], loss of kidney function, and mortality. Very limited data are available from sizable multicenter kidney transplant recipient (KTR) cohorts assessing the potential relationships between serum phosphorus levels and the development of CVD outcomes, transplant failure, or all-cause mortality. STUDY DESIGN: Cohort study. SETTING & PARTICIPANTS: The Folic Acid for Vascular Outcome Reduction in Transplantation (FAVORIT) Trial, a large, multicenter, multiethnic, controlled clinical trial that provided definitive evidence that high-dose vitamin B-based lowering of plasma homocysteine levels did not reduce CVD events, transplant failure, or total mortality in stable KTRs. PREDICTOR: Serum phosphorus levels were determined in 3,138 FAVORIT trial participants at randomization. RESULTS: During a median follow-up of 4.0 years, the cohort had 436 CVD events, 238 transplant failures, and 348 deaths. Proportional hazards modeling revealed that each 1-mg/dL higher serum phosphorus level was not associated with a significant increase in CVD risk (HR, 1.06; 95% CI, 0.92-1.22), but increased transplant failure (HR, 1.36; 95% CI, 1.15-1.62) and total mortality risk associations (HR, 1.21; 95% CI, 1.04-1.40) when adjusted for treatment allocation, traditional CVD risk factors, kidney measures, type of kidney transplant, transplant vintage, and use of calcineurin inhibitors, steroids, or lipid-lowering drugs. These associations were strengthened in models without kidney measures: CVD (HR, 1.14; 95% CI, 1.00-1.31), transplant failure (HR, 1.72; 95% CI, 1.46-2.01), and mortality (HR, 1.34; 95% CI, 1.15-1.54). LIMITATIONS: We lacked data for concentrations of parathyroid hormone, fibroblast growth factor 23, or vitamin D metabolites. CONCLUSIONS: Serum phosphorus level is marginally associated with CVD and more strongly associated with transplant failure and total mortality in long-term KTRs. A randomized controlled clinical trial in KTRs that assesses the potential impact of phosphorus-lowering therapy on these hard outcomes may be warranted.

2017 American College of Rheumatology Guideline for the Prevention and Treatment of Glucocorticoid-Induced Osteoporosis.

OBJECTIVE: To develop recommendations for prevention and treatment of glucocorticoid-induced osteoporosis (GIOP). METHODS: We conducted a systematic review to synthesize the evidence for the benefits and harms of GIOP prevention and treatment options. The Grading of Recommendations Assessment, Development and Evaluation methodology was used to rate the quality of evidence. We used a group consensus process to determine the final recommendations and grade their strength. The guideline addresses initial assessment and reassessment in patients beginning or continuing long-term (≥3 months) glucocorticoid (GC) treatment, as well as the relative benefits and harms of lifestyle modification and of calcium, vitamin D, bisphosphonate, raloxifene, teriparatide, and denosumab treatment in the general adult population receiving long-term GC treatment, as well as in special populations of long-term GC users. RESULTS: Because of limited evidence regarding the benefits and harms of interventions in GC users, most recommendations in this guideline are conditional (uncertain balance between benefits and harms). Recommendations include treating only with calcium and vitamin D in adults at low fracture risk, treating with calcium and vitamin D plus an additional osteoporosis medication (oral bisphosphonate preferred) in adults at moderate-to-high fracture risk, continuing calcium plus vitamin D but switching from an oral bisphosphonate to another antifracture medication in adults in whom oral bisphosphonate treatment is not appropriate, and continuing oral bisphosphonate treatment or switching to another antifracture medication in adults who complete a planned oral bisphosphonate regimen but continue to receive GC treatment. Recommendations for special populations, including children, people with organ transplants, women of childbearing potential, and people receiving very high-dose GC treatment, are also made. CONCLUSION: This guideline provides direction for clinicians and patients making treatment decisions. Clinicians and patients should use a shared decision-making process that accounts for patients' values, preferences, and comorbidities. These recommendations should not be used to limit or deny access to therapies.

2017 American College of Rheumatology Guideline for the Prevention and Treatment of Glucocorticoid-Induced Osteoporosis.

OBJECTIVE: To develop recommendations for prevention and treatment of glucocorticoid-induced osteoporosis (GIOP). METHODS: We conducted a systematic review to synthesize the evidence for the benefits and harms of GIOP prevention and treatment options. The Grading of Recommendations Assessment, Development and Evaluation methodology was used to rate the quality of evidence. We used a group consensus process to determine the final recommendations and grade their strength. The guideline addresses initial assessment and reassessment in patients beginning or continuing long-term (≥3 months) glucocorticoid (GC) treatment, as well as the relative benefits and harms of lifestyle modification and of calcium, vitamin D, bisphosphonate, raloxifene, teriparatide, and denosumab treatment in the general adult population receiving long-term GC treatment, as well as in special populations of long-term GC users. RESULTS: Because of limited evidence regarding the benefits and harms of interventions in GC users, most recommendations in this guideline are conditional (uncertain balance between benefits and harms). Recommendations include treating only with calcium and vitamin D in adults at low fracture risk, treating with calcium and vitamin D plus an additional osteoporosis medication (oral bisphosphonate preferred) in adults at moderate-to-high fracture risk, continuing calcium plus vitamin D but switching from an oral bisphosphonate to another antifracture medication in adults in whom oral bisphosphonate treatment is not appropriate, and continuing oral bisphosphonate treatment or switching to another antifracture medication in adults who complete a planned oral bisphosphonate regimen but continue to receive GC treatment. Recommendations for special populations, including children, people with organ transplants, women of childbearing potential, and people receiving very high-dose GC treatment, are also made. CONCLUSION: This guideline provides direction for clinicians and patients making treatment decisions. Clinicians and patients should use a shared decision-making process that accounts for patients' values, preferences, and comorbidities. These recommendations should not be used to limit or deny access to therapies.

Polygenic overlap between kidney function and large artery atherosclerotic stroke.

BACKGROUND AND PURPOSE: Epidemiological studies show strong associations between kidney dysfunction and risk of ischemic stroke (IS), the mechanisms of which are incompletely understood. We investigated whether these associations may reflect shared heritability because of a common polygenic basis and whether this differed for IS subtypes. METHODS: Polygenic models were derived using genome-wide association studies meta-analysis results for 3 kidney traits: estimated glomerular filtration rate using serum creatinine (eGFRcrea: n=73 998), eGFR using cystatin C (eGFRcys: n=22 937), and urinary albumin to creatinine ratio (n=31 580). For each, single nucleotide polymorphisms passing 10 P value thresholds were used to form profile scores in 4561 IS cases and 7094 controls from the United Kingdom, Germany, and Australia. Scores were tested for association with IS and its 3 aetiological subtypes: large artery atherosclerosis, cardioembolism, and small vessel disease. RESULTS: Polygenic scores correlating with higher eGFRcrea were associated with reduced risk of large artery atherosclerosis, with 5 scores reaching P<0.05 (peak P=0.004) and all showing the epidemiologically expected direction of effect. A similar pattern was observed for polygenic scores reflecting higher urinary albumin to creatinine ratio, of which 3 associated with large artery atherosclerosis (peak P=0.01) and all showed the expected directional association. One urinary albumin to creatinine ratio-based score also associated with small vessel disease (P=0.03). The global pattern of results was unlikely to have occurred by chance (P=0.02). CONCLUSIONS: This study suggests possible polygenic correlation between renal dysfunction and IS. The shared genetic components may be specific to stroke subtypes, particularly large artery atherosclerotic stroke. Further study of the genetic relationships between these disorders seems merited.

Effect of niacin on FGF23 concentration in chronic kidney disease.

BACKGROUND: Elevated serum phosphorus and FGF23 are independent cardiovascular risk factors in patients with chronic kidney disease. In a randomized controlled trial of patients with dyslipidemia assigned to either extended release niacin (ERN) alone, ERN combined with the selective prostaglandin D2 receptor subtype 1 inhibitor laropiprant (ERN-L) or placebo, niacin lowered serum phosphorus; however, it is not known if it lowers FGF23 concentrations. METHODS: This is an ancillary study to a multicenter, randomized, double-blind, placebo-controlled trial among patients with dyslipidemia and an estimated glomerular filtration rate (eGFR) of 30-74 ml/min/1.73 m(2). Participants were randomized to ERN-L (n = 162), ERN (n = 97), or placebo (n = 68) in a 3:2:1 ratio for 24 weeks. The primary outcome was a change in serum FGF23 concentrations, and secondary outcomes were changes in other mineral metabolism parameters. RESULTS: Both the ERN and ERN-L groups showed significant declines in serum phosphorus, calcium and calcium·phosphorus product at 24 weeks compared to placebo. A significant decline from baseline (10.9%, p < 0.01) in the serum FGF23 concentration was observed in the ERN group compared to placebo, but not in the ERN-L group compared to placebo (p = 0.36 and 0.97 for ERN-L and placebo, respectively), despite equivalent declines in serum phosphorus. Similarly, the most marked declines in PTH occurred in the ERN-only group versus placebo; no change in PTH was observed in the ERN-L group. CONCLUSIONS: In this ancillary study of hyperlipidemic patients with an eGFR of 30-74 ml/min/1.73 m(2), ERN alone but not in combination with laropiprant lowered FGF23 and PTH concentrations. If confirmed, niacin may provide a novel strategy to decrease phosphorus, FGF23, and PTH concentrations in patients with chronic kidney disease.

Mitochondrial cytopathies and cardiovascular disease.

The global epidemic of cardiovascular disease remains the leading cause of death in the USA and across the world. Functional and structural integrity of mitochondria are essential for the physiological function of the cardiovascular system. The metabolic adaptation observed in normal heart is lost in the failing myocardium, which becomes progressively energy depleted leading to impaired myocardial contraction and relaxation. Uncoupling of electron transfer from ATP synthesis leads to excess generation of reactive species, leading to widespread cellular injury and cardiovascular disease. Accumulation of mitochondrial DNA mutation has been linked to ischaemic heart disease, cardiomyopathy and atherosclerotic vascular disease. Mitochondria are known to regulate apoptotic and autophagic pathways that have been shown to play an important role in the development of cardiomyopathy and atherosclerosis. A number of pharmacological and non-pharmacological treatment options have been explored in the management of mitochondrial diseases with variable success.

Common variants in Mendelian kidney disease genes and their association with renal function.

Many common genetic variants identified by genome-wide association studies for complex traits map to genes previously linked to rare inherited Mendelian disorders. A systematic analysis of common single-nucleotide polymorphisms (SNPs) in genes responsible for Mendelian diseases with kidney phenotypes has not been performed. We thus developed a comprehensive database of genes for Mendelian kidney conditions and evaluated the association between common genetic variants within these genes and kidney function in the general population. Using the Online Mendelian Inheritance in Man database, we identified 731 unique disease entries related to specific renal search terms and confirmed a kidney phenotype in 218 of these entries, corresponding to mutations in 258 genes. We interrogated common SNPs (minor allele frequency >5%) within these genes for association with the estimated GFR in 74,354 European-ancestry participants from the CKDGen Consortium. However, the top four candidate SNPs (rs6433115 at LRP2, rs1050700 at TSC1, rs249942 at PALB2, and rs9827843 at ROBO2) did not achieve significance in a stage 2 meta-analysis performed in 56,246 additional independent individuals, indicating that these common SNPs are not associated with estimated GFR. The effect of less common or rare variants in these genes on kidney function in the general population and disease-specific cohorts requires further research.

Two-stage arthroplasty for prosthetic joint infection: a systematic review of acute kidney injury, systemic toxicity and infection control.

Periprosthetic infections of hip and knee joints are now treated by two-stage revision arthroplasty with an infection control rate of 91%. The present systematic review studied the reported incidence of acute kidney injury (AKI) and infection recurrence from January 1989 to June 2012 to assess the risk-benefit ratio of antibiotic spacer use. Ten observational studies (n=544 patients) with clinical outcomes showed an average incidence of AKI of 4.8%. The average reported persistence or recurrence rate of infection was 11% during a follow-up period that ranged from 13 to 108 months. The risk-benefit ratio presently favors treatment although there appears to be higher complication rates and incidence of AKI than previously reported. Marked heterogeneity in practice and lack of detail in reporting precluded more robust quantitative synthesis. Clinicians need to be aware of the potential risk of AKI, particularly in high-risk patients; practice patterns for the use of antibiotic spacers need to be standardized.

Cochlear implantation in adults: a systematic review and meta-analysis.

IMPORTANCE: Sensorineural hearing loss is the third leading cause of years lived with disability worldwide. Cochlear implants may provide a viable alternative to hearing aids for this type of hearing loss. The Coverage and Analysis Group at the Centers for Medicare & Medicaid Services was interested in an evaluation of recently published literature on this topic. In addition, this meta-analysis is to our knowledge the first to evaluate quality-of-life (QOL) outcomes in adults with cochlear implants. OBJECTIVE: To evaluate the communication-related outcomes and health-related QOL outcomes after unilateral or bilateral cochlear implantation in adults with sensorineural hearing loss. DATA SOURCES: MEDLINE, Cochrane Central Register of Controlled Trials, Scopus, and previous reports from January 1, 2004, through May 31, 2012. STUDY SELECTION: Published studies of adult patients undergoing unilateral or bilateral procedures with multichannel cochlear implants and assessments using open-set sentence tests, multisyllable word tests, or QOL measures. DATA EXTRACTION: Five researchers extracted information on population characteristics, outcomes of interest, and study design and assessed the studies for risk of bias. Discrepancies were resolved by consensus. RESULTS: A total of 42 studies met the inclusion criteria. Most unilateral implant studies showed a statistically significant improvement in mean speech scores as measured by open-set sentence or multisyllable word tests; meta-analysis revealed a significant improvement in QOL after unilateral implantation. Results from studies assessing bilateral implantation showed improvement in communication-related outcomes compared with unilateral implantation and additional improvements in sound localization compared with unilateral device use or implantation only. Based on a few studies, the QOL outcomes varied across tests after bilateral implantation. CONCLUSIONS AND RELEVANCE: Unilateral cochlear implants provide improved hearing and significantly improve QOL, and improvements in sound localization are noted for bilateral implantation. Future studies of longer duration, higher-quality reporting, and large databases or registries of patients with long-term follow-up data are needed to yield stronger evidence.

Fibroblast Growth Factor and Mineral Metabolism Parameters among Prevalent Kidney Transplant Patients.

Background. Chronic kidney disease (CKD) related mineral bone disorders persist after kidney transplantation, but little is known about the relationship between fibroblast growth factor-23 (FGF-23) and mineral metabolism in prevalent post-transplant patients. Objectives. To examine mineral metabolism parameters and their relationship to FGF-23 and parathyroid hormone (PTH) in prevalent kidney transplant patients. Methods. Cross-sectional study of 106 kidney transplant patients enrolled November 2005-October 2009 at Tufts Medical Center (TMC), Boston. Results. The prevalence of hypophosphatemia was 34%, hypercalcemia 3%, and elevated PTH levels 66%, at a median (25th-75th percentile) duration of 12.8 (7.5-30.9) months post-transplant. Males had significantly higher levels of PTH (P = 0.04) and lower levels of serum phosphate (P = 0.002). Serum PTH levels did not relate to eGFR, corrected calcium levels or serum phosphate. FGF-23 levels were above the reference limits in 7% of patients; higher levels were associated with higher serum phosphate and PTH levels after adjustment for transplant kidney function. Conclusion. FGF-23 is an important driver of mineral metabolism in prevalent transplant patients. Its modulatory role in mineral metabolism homeostasis may be heightened as feedback suppression of PTH is disturbed. Its role in long term cardiovascular and graft outcomes needs further study.

Meta-analysis of genome-wide linkage scans for renal function traits.

BACKGROUND: Several genome scans have explored the linkage of chronic kidney disease phenotypes to chromosomic regions with disparate results. Genome scan meta-analysis (GSMA) is a quantitative method to synthesize linkage results from independent studies and assess their concordance. METHODS: We searched PubMed to identify genome linkage analyses of renal function traits in humans, such as estimated glomerular filtration rate (GFR), albuminuria, serum creatinine concentration and creatinine clearance. We contacted authors for numerical data and extracted information from individual studies. We applied the GSMA nonparametric approach to combine results across 14 linkage studies for GFR, 11 linkage studies for albumin creatinine ratio, 11 linkage studies for serum creatinine and 4 linkage studies for creatinine clearance. RESULTS: No chromosomal region reached genome-wide statistical significance in the main analysis which included all scans under each phenotype; however, regions on Chromosomes 7, 10 and 16 reached suggestive significance for linkage to two or more phenotypes. Subgroup analyses by disease status or ethnicity did not yield additional information. CONCLUSIONS: While heterogeneity across populations, methodologies and study designs likely explain this lack of agreement, it is possible that linkage scan methodologies lack the resolution for investigating complex traits. Combining family-based linkage studies with genome-wide association studies may be a powerful approach to detect private mutations contributing to complex renal phenotypes.

Medication adherence behavior and priorities among older adults with CKD: a semistructured interview study.

BACKGROUND: Older adults with chronic kidney disease (CKD) typically use more than 5 medications and have multiple prescribing physicians. However, little is known about how they prioritize their medical conditions or decide which medications to take. METHODS: Semistructured interviews (average length, 40 minutes) with 20 community-dwelling adults with CKD stages 3-5D receiving nephrology care at a tertiary referral center. Respondents were asked about medications, prescribing physicians, and medication-taking behaviors. We performed thematic analysis to explain patients' decisions regarding medication prioritization, understanding, and adherence decisions. RESULTS: Participants (age range, 55-84 years; mean, 72 years) used 5-14 prescribed medications, had 2-9 physicians, and had 5-11 comorbid conditions. All had assigned implicit priorities to their medications. Although most expressed the intention to be adherent, many regularly skipped medications they considered less important. Most identified the prescribing physician and indication for each medication, but there often was substantial discordance between beliefs about medications and conventional medical opinion. Respondents prioritized medications based on the salience of the particular condition, perceived effects of the treatment, and barriers (physical, logistic, or financial) to using the prescribed drug. Side effects of medications were common and anxiety provoking, but discussions with the prescribing physician often were delayed or unfulfilling for the patient. CONCLUSIONS: Polypharmacy in patients with CKD leads to complex medication choices and adherence behaviors in this population. Most patients we interviewed had beliefs or priorities that were nonconcordant with conventional medical opinion; however, patients rarely discussed these beliefs and priorities or the resultant poor medication adherence with their physicians. Further study is needed to provide quantitative data about the magnitude of adherence barriers. It is likely that more effective communication about medication use could improve patients' health outcomes and reduce potential adverse drug events.

Resistance training increases muscle mitochondrial biogenesis in patients with chronic kidney disease.

BACKGROUND AND OBJECTIVES: Muscle wasting, a common complication in chronic kidney disease (CKD), contributes to poor outcomes. Mitochondrial biogenesis is critical for the maintenance of skeletal muscle function and structural integrity. The present study--a secondary analysis from a published randomized controlled trial--examined the effect of resistance exercise training on skeletal muscle mitochondrial (mt)DNA copy number and determined its association with skeletal muscle phenotype (muscle mass and strength). DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Twenty-three patients with moderate-to-severe CKD were randomized to resistance training (n = 13) or an attention-control (n = 10) group for 12 weeks. After a run-in period of a low-protein diet that continued during the intervention, mtDNA copy number in the vastus lateralis muscle was estimated by quantitative real-time PCR at baseline and 12 weeks. RESULTS: Participants mean age was 64 +/- 10 (SD) years and median (interquartile range, IQR) GFR 27.5 (37.0) ml/min. There were no differences between groups at baseline. Median (IQR) mtDNA copy number was 13,713 (10,618). There was a significant increase in muscle mtDNA with exercise compared with controls (1306 [13306] versus -3747 [15467], P = 0.01). The change in muscle mtDNA copy number was positively correlated with previously reported changes in types I and II muscle fiber cross-sectional area. CONCLUSIONS: In this pilot study, resistance training was highly effective in enhancing mitochondrial content in patients with moderate-to-severe CKD. This finding suggests that the mitochondrial dysfunction observed with chronic disease could potentially be restored with this exercise modality and should be investigated further.