Chronic kidney disease (CKD) is associated with the development of mineral bone disorder (MBD), osteoporosis, and fragility fractures. Among CKD patients, adynamic bone disease or low bone turnover ...is the most common type of renal osteodystrophy. The consequences of CKD-MBD include increased fracture risk, greater morbidity, and mortality. Thus, the goal is to prevent the occurrences of fractures by means of alleviating CKD-induced MBD and treating subsequent osteoporosis. Changes in mineral and humoral metabolism as well as bone structure develop early in the course of CKD. CKD-MBD includes abnormalities of calcium, phosphorus, PTH, and/or vitamin D; abnormalities in bone turnover, mineralization, volume, linear growth, or strength; and/or vascular or other soft tissue calcification. In patients with CKD-MBD, using either DXA or FRAX to screen fracture risk should be considered. Biomarkers such as bALP and iPTH may assist to assess bone turnover. Before initiating an antiresorptive or anabolic agent to treat osteoporosis in CKD patients, lifestyle modifications, such as exercise, calcium, and vitamin D supplementation, smoking cessation, and avoidance of excessive alcohol intake are important. Managing hyperphosphatemia and SHPT are also crucial. Understanding the complex pathogenesis of CKD-MBD is crucial in improving one's short- and long-term outcomes. Treatment strategies for CKD-associated osteoporosis should be patient-centered to determine the type of renal osteodystrophy. This review focuses on the mechanism, evaluation and management of patients with CKD-MBD. However, further studies are needed to explore more details regarding the underlying pathophysiology and to assess the safety and efficacy of agents for treating CKD-MBD.
In response to a national call for re-evaluation of the use of race in clinical algorithms, the National Kidney Foundation (NKF) and the American Society of Nephrology (ASN) established a Task Force ...to reassess inclusion of race in the estimation of glomerular filtration rate (GFR) in the United States and its implications for diagnosis and management of patients with, or at risk for, kidney diseases.
The Task Force organized its activities over 10 months in phases to (1) clarify the problem and evidence regarding GFR estimating equations in the United States (described previously in an interim report), and, in this final report, (2) evaluate approaches to address use of race in GFR estimation, and (3) provide recommendations. We identified 26 approaches for the estimation of GFR that did or did not consider race and narrowed our focus, by consensus, to 5 of those approaches. We holistically evaluated each approach considering 6 attributes: assay availability and standardization; implementation; population diversity in equation development; performance compared with measured GFR; consequences to clinical care, population tracking, and research; and patient centeredness. To arrive at a unifying approach to estimate GFR, we integrated information and evidence from many sources in assessing strengths and weaknesses in attributes for each approach, recognizing the number of Black and non-Black adults affected.
(1) For US adults (>85% of whom have normal kidney function), we recommend immediate implementation of the CKD-EPI creatinine equation refit without the race variable in all laboratories in the United States because it does not include race in the calculation and reporting, included diversity in its development, is immediately available to all laboratories in the United States, and has acceptable performance characteristics and potential consequences that do not disproportionately affect any one group of individuals. (2) We recommend national efforts to facilitate increased, routine, and timely use of cystatin C, especially to confirm estimated GFR in adults who are at risk for or have chronic kidney disease, because combining filtration markers (creatinine and cystatin C) is more accurate and would support better clinical decisions than either marker alone. If ongoing evidence supports acceptable performance, the CKD-EPI eGFR–cystatin C (eGFRcys) and eGFR creatinine–cystatin C (eGFRcr-cys_R) refit without the race variables should be adopted to provide another first-line test, in addition to confirmatory testing. (3) Research on GFR estimation with new endogenous filtration markers and on interventions to eliminate race and ethnic disparities should be encouraged and funded. An investment in science is needed for newer approaches that generate accurate, unbiased, and precise GFR measurement and estimation without the inclusion of race, and that promote health equity and do not generate disparate care.
This unified approach, without specification of race, should be adopted across the United States. High-priority and multistakeholder efforts should implement this solution.
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In this review of the application of proteomics and metabolomics to kidney disease research, we review key concepts, highlight illustrative examples, and outline future directions. The proteome and ...metabolome reflect the influence of environmental exposures in addition to genetic coding. Circulating levels of proteins and metabolites are dynamic and modifiable, and thus amenable to therapeutic targeting. Design and analytic considerations in proteomics and metabolomics studies should be tailored to the investigator's goals. For the identification of clinical biomarkers, adjustment for all potential confounding variables, particularly GFR, and strict significance thresholds are warranted. However, this approach has the potential to obscure biologic signals and can be overly conservative given the high degree of intercorrelation within the proteome and metabolome. Mass spectrometry, often coupled to up-front chromatographic separation techniques, is a major workhorse in both proteomics and metabolomics. High-throughput antibody- and aptamer-based proteomic platforms have emerged as additional, powerful approaches to assay the proteome. As the breadth of coverage for these methodologies continues to expand, machine learning tools and pathway analyses can help select the molecules of greatest interest and categorize them in distinct biologic themes. Studies to date have already made a substantial effect, for example elucidating target antigens in membranous nephropathy, identifying a signature of urinary peptides that adds prognostic information to urinary albumin in CKD, implicating circulating inflammatory proteins as potential mediators of diabetic nephropathy, demonstrating the key role of the microbiome in the uremic milieu, and highlighting kidney bioenergetics as a modifiable factor in AKI. Additional studies are required to replicate and expand on these findings in independent cohorts. Further, more work is needed to understand the longitudinal trajectory of select protein and metabolite markers, perform transomics analyses within merged datasets, and incorporate more kidney tissue-based investigation.
Background There are established guidelines for recommended dietary intake for hypertension treatment and cardiovascular disease prevention. Evidence is lacking for effective dietary patterns for ...kidney disease prevention. Study Design Prospective cohort study. Setting & Participants Atherosclerosis Risk in Communities (ARIC) Study participants with baseline estimated glomerular filtration rate (eGFR) ≥ 60 mL/min/1.73 m2 (N = 14,882). Predictor The Dietary Approaches to Stop Hypertension (DASH) diet score was calculated based on self-reported dietary intake of red and processed meat, sweetened beverages, sodium, fruits, vegetables, whole grains, nuts and legumes, and low-fat dairy products, averaged over 2 visits. Outcomes Cases were ascertained based on the development of eGFRs < 60 mL/min/1.73 m2 accompanied by ≥25% eGFR decline from baseline, an International Classification of Diseases, Ninth/Tenth Revision code for a kidney disease−related hospitalization or death, or end-stage renal disease from baseline through 2012. Results 3,720 participants developed kidney disease during a median follow-up of 23 years. Participants with a DASH diet score in the lowest tertile were 16% more likely to develop kidney disease than those with the highest score tertile (HR, 1.16; 95% CI, 1.07-1.26; P for trend < 0.001), after adjusting for sociodemographics, smoking status, physical activity, total caloric intake, baseline eGFR, overweight/obese status, diabetes status, hypertension status, systolic blood pressure, and antihypertensive medication use. Of the individual components of the DASH diet score, high red and processed meat intake was adversely associated with kidney disease and high nuts, legumes, and low-fat dairy products intake was associated with reduced risk for kidney disease. Limitations Potential measurement error due to self-reported dietary intake and lack of data for albuminuria. Conclusions Consuming a DASH-style diet was associated with lower risk for kidney disease independent of demographic characteristics, established kidney risk factors, and baseline kidney function. Healthful dietary patterns such as the DASH diet may be beneficial for kidney disease prevention.
Background
Phosphate binders are used to reduce positive phosphate balance and to lower serum phosphate levels for people with chronic kidney disease (CKD) with the aim to prevent progression of ...chronic kidney disease‐mineral and bone disorder (CKD‐MBD). This is an update of a review first published in 2011.
Objectives
The aim of this review was to assess the benefits and harms of phosphate binders for people with CKD with particular reference to relevant biochemical end‐points, musculoskeletal and cardiovascular morbidity, hospitalisation, and death.
Search methods
We searched the Cochrane Kidney and Transplant Register of Studies up to 12 July 2018 through contact with the Information Specialist using search terms relevant to this review. Studies in the Register are identified through searches of CENTRAL, MEDLINE, and EMBASE, conference proceedings, the International Clinical Trials Register (ICTRP) Search Portal and ClinicalTrials.gov.
Selection criteria
We included randomised controlled trials (RCTs) or quasi‐RCTs of adults with CKD of any GFR category comparing a phosphate binder to another phosphate binder, placebo or usual care to lower serum phosphate. Outcomes included all‐cause and cardiovascular death, myocardial infarction, stroke, adverse events, vascular calcification and bone fracture, and surrogates for such outcomes including serum phosphate, parathyroid hormone (PTH), and FGF23.
Data collection and analysis
Two authors independently selected studies for inclusion and extracted study data. We applied the Cochrane 'Risk of Bias' tool and used the GRADE process to assess evidence certainty. We estimated treatment effects using random‐effects meta‐analysis. Results were expressed as risk ratios (RR) for dichotomous outcomes together with 95% confidence intervals (CI) or mean differences (MD) or standardised MD (SMD) for continuous outcomes.
Main results
We included 104 studies involving 13,744 adults. Sixty‐nine new studies were added to this 2018 update.
Most placebo or usual care controlled studies were among participants with CKD G2 to G5 not requiring dialysis (15/25 studies involving 1467 participants) while most head to head studies involved participants with CKD G5D treated with dialysis (74/81 studies involving 10,364 participants). Overall, seven studies compared sevelamer with placebo or usual care (667 participants), seven compared lanthanum to placebo or usual care (515 participants), three compared iron to placebo or usual care (422 participants), and four compared calcium to placebo or usual care (278 participants). Thirty studies compared sevelamer to calcium (5424 participants), and fourteen studies compared lanthanum to calcium (1690 participants). No study compared iron‐based binders to calcium. The remaining studies evaluated comparisons between sevelamer (hydrochloride or carbonate), sevelamer plus calcium, lanthanum, iron (ferric citrate, sucroferric oxyhydroxide, stabilised polynuclear iron(III)‐oxyhydroxide), calcium (acetate, ketoglutarate, carbonate), bixalomer, colestilan, magnesium (carbonate), magnesium plus calcium, aluminium hydroxide, sucralfate, the inhibitor of phosphate absorption nicotinamide, placebo, or usual care without binder. In 82 studies, treatment was evaluated among adults with CKD G5D treated with haemodialysis or peritoneal dialysis, while in 22 studies, treatment was evaluated among participants with CKD G2 to G5. The duration of study follow‐up ranged from 8 weeks to 36 months (median 3.7 months). The sample size ranged from 8 to 2103 participants (median 69). The mean age ranged between 42.6 and 68.9 years.
Random sequence generation and allocation concealment were low risk in 25 and 15 studies, respectively. Twenty‐seven studies reported low risk methods for blinding of participants, investigators, and outcome assessors. Thirty‐one studies were at low risk of attrition bias and 69 studies were at low risk of selective reporting bias.
In CKD G2 to G5, compared with placebo or usual care, sevelamer, lanthanum, iron and calcium‐based phosphate binders had uncertain or inestimable effects on death (all causes), cardiovascular death, myocardial infarction, stroke, fracture, or coronary artery calcification. Sevelamer may lead to constipation (RR 6.92, CI 2.24 to 21.4; low certainty) and lanthanum (RR 2.98, CI 1.21 to 7.30, moderate certainty) and iron‐based binders (RR 2.66, CI 1.15 to 6.12, moderate certainty) probably increased constipation compared with placebo or usual care. Lanthanum may result in vomiting (RR 3.72, CI 1.36 to 10.18, low certainty). Iron‐based binders probably result in diarrhoea (RR 2.81, CI 1.18 to 6.68, high certainty), while the risks of other adverse events for all binders were uncertain.
In CKD G5D sevelamer may lead to lower death (all causes) (RR 0.53, CI 0.30 to 0.91, low certainty) and induce less hypercalcaemia (RR 0.30, CI 0.20 to 0.43, low certainty) when compared with calcium‐based binders, and has uncertain or inestimable effects on cardiovascular death, myocardial infarction, stroke, fracture, or coronary artery calcification. The finding of lower death with sevelamer compared with calcium was present when the analysis was restricted to studies at low risk of bias (RR 0.50, CI 0.32 to 0.77). In absolute terms, sevelamer may lower risk of death (all causes) from 210 per 1000 to 105 per 1000 over a follow‐up of up to 36 months, compared to calcium‐based binders. Compared with calcium‐based binders, lanthanum had uncertain effects with respect to all‐cause or cardiovascular death, myocardial infarction, stroke, fracture, or coronary artery calcification and probably had reduced risks of treatment‐related hypercalcaemia (RR 0.16, CI 0.06 to 0.43, low certainty). There were no head‐to‐head studies of iron‐based binders compared with calcium. The paucity of placebo‐controlled studies in CKD G5D has led to uncertainty about the effects of phosphate binders on patient‐important outcomes compared with placebo.
It is uncertain whether the effects of binders on clinically‐relevant outcomes were different for patients who were and were not treated with dialysis in subgroup analyses.
Authors' conclusions
In studies of adults with CKD G5D treated with dialysis, sevelamer may lower death (all causes) compared to calcium‐based binders and incur less treatment‐related hypercalcaemia, while we found no clinically important benefits of any phosphate binder on cardiovascular death, myocardial infarction, stroke, fracture or coronary artery calcification. The effects of binders on patient‐important outcomes compared to placebo are uncertain. In patients with CKD G2 to G5, the effects of sevelamer, lanthanum, and iron‐based phosphate binders on cardiovascular, vascular calcification, and bone outcomes compared to placebo or usual care, are also uncertain and they may incur constipation, while iron‐based binders may lead to diarrhoea.
To determine the diagnostic yield and clinical impact of exome sequencing (ES) in patients with suspected monogenic kidney disease.
We performed clinically accredited singleton ES in a prospectively ...ascertained cohort of 204 patients assessed in multidisciplinary renal genetics clinics at four tertiary hospitals in Melbourne, Australia.
ES identified a molecular diagnosis in 80 (39%) patients, encompassing 35 distinct genetic disorders. Younger age at presentation was independently associated with an ES diagnosis (p < 0.001). Of those diagnosed, 31/80 (39%) had a change in their clinical diagnosis. ES diagnosis was considered to have contributed to management in 47/80 (59%), including negating the need for diagnostic renal biopsy in 10/80 (13%), changing surveillance in 35/80 (44%), and changing the treatment plan in 16/80 (20%). In cases with no change to management in the proband, the ES result had implications for the management of family members in 26/33 (79%). Cascade testing was subsequently offered to 40/80 families (50%).
In this pragmatic pediatric and adult cohort with suspected monogenic kidney disease, ES had high diagnostic and clinical utility. Our findings, including predictors of positive diagnosis, can be used to guide clinical practice and health service design.
Although renal osteodystrophy and vitamin D analogs may be related to survival in maintenance hemodialysis (MHD) patients, most studies have examined associations between baseline values and survival ...without accounting for variations in clinical and laboratory measures over time. We examined associations between survival and quarterly laboratory values and administered paricalcitol in a 2-year (July 2001–June 2003) cohort of 58058 MHD patients from all DaVita dialysis clinics in USA using both time-dependent Cox models with repeated measures and fixed-covariate Cox models with only baseline values. Whereas hypercalcemia and hyperphosphatemia were robust predictors of higher death risk in all models, the association between serum calcium and mortality was different in time-varying models. Changes in baseline calcium and phosphorus values beyond the Kidney Disease Outcome Quality Initiative recommended targets were associated with increased mortality. Associations between high serum parathyroid hormone and increased death risk were masked by case-mix characteristics of MHD patients. Time-varying serum alkaline phosphatase had an incremental association with mortality. Administration of any dose of paricalcitol was associated with improved survival in time-varying models. Controlling for nutritional markers may introduce overadjustment bias owing to their strong collinearity with osteodystrophy surrogates. Whereas both time-dependent and fixed-covariate Cox models result in similar associations between osteodystrophy indicators and survival, subtle but potentially clinically relevant differences between the two models exist, probably because fixed models do not account for variations of osteodystrophy indices and changes in medication dose over time.
We tested the hypothesis that single nucleotide polymorphisms (SNPs) in the calcium-sensing receptor (
) alter the response to the calcimimetic cinacalcet.
We analyzed DNA samples in the Evaluation ...of Cinacalcet HCl Therapy to Lower Cardiovascular Events (EVOLVE) trial, a randomized trial comparing cinacalcet to placebo on a background of usual care. Of the 3883 patients randomized, 1919 (49%) consented to DNA collection, and samples from 1852 participants were genotyped for 18
polymorphisms. The European ancestry (EA;
=1067) and African ancestry (AfAn;
=405) groups were assessed separately. SNPs in
were tested for their association with biochemical measures of mineral metabolism at baseline, percent change from baseline to 20 weeks, and risk of clinical fracture as dependent variables.
There were modest associations of
SNPs with increased baseline serum parathyroid hormone and bone alkaline phosphatase primarily with the minor allele in the EA group (all
≤0.03), but not in the AfAn sample. In contrast, there was a modest association of decreased baseline serum calcium and FGF23 with
SNPs (
=0.04) primarily with the minor allele in the AfAn but not in the EA sample. The minor allele of two SNPs was associated with decreased percent reduction in parathyroid hormone from baseline to 20 weeks in the EA population (
<0.04) and this was not altered with cinacalcet. In both EA and AfAn, the same SNP (rs9740) was associated with decreased calcium with cinacalcet treatment (EA and AfAn
≤0.03). Three SNPs in high linkage disequilibrium were associated with a higher risk of clinical fracture that was attenuated by cinacalcet treatment in the EA sample (
<0.04).
These modest associations, if validated, may provide explanations for differences in CKD-mineral bone disorder observed in EA and AfAn populations, and for differential biochemical responses to calcimimetics.
The burden of premature death and health loss from ESRD is well described. Less is known regarding the burden of cardiovascular disease attributable to reduced GFR. We estimated the prevalence of ...reduced GFR categories 3, 4, and 5 (not on RRT) for 188 countries at six time points from 1990 to 2013. Relative risks of cardiovascular outcomes by three categories of reduced GFR were calculated by pooled random effects meta-analysis. Results are presented as deaths for outcomes of cardiovascular disease and ESRD and as disability-adjusted life years for outcomes of cardiovascular disease, GFR categories 3, 4, and 5, and ESRD. In 2013, reduced GFR was associated with 4% of deaths worldwide, or 2.2 million deaths (95% uncertainty interval 95% UI, 2.0 to 2.4 million). More than half of these attributable deaths were cardiovascular deaths (1.2 million; 95% UI, 1.1 to 1.4 million), whereas 0.96 million (95% UI, 0.81 to 1.0 million) were ESRD-related deaths. Compared with metabolic risk factors, reduced GFR ranked below high systolic BP, high body mass index, and high fasting plasma glucose, and similarly with high total cholesterol as a risk factor for disability-adjusted life years in both developed and developing world regions. In conclusion, by 2013, cardiovascular deaths attributed to reduced GFR outnumbered ESRD deaths throughout the world. Studies are needed to evaluate the benefit of early detection of CKD and treatment to decrease these deaths.
Noncommunicable diseases (NCDs) are the most common causes of premature death and morbidity and have a major impact on health-care costs, productivity, and growth. Cardiovascular disease, cancer, ...diabetes, and chronic respiratory disease have been prioritized in the Global NCD Action Plan endorsed by the World Health Assembly, because they share behavioral risk factors amenable to public-health action and represent a major portion of the global NCD burden. Chronic kidney disease (CKD) is a key determinant of the poor health outcomes of major NCDs. CKD is associated with an eight- to tenfold increase in cardiovascular mortality and is a risk multiplier in patients with diabetes and hypertension. Milder CKD (often due to diabetes and hypertension) affects 5–7% of the world population and is more common in developing countries and disadvantaged and minority populations. Early detection and treatment of CKD using readily available, inexpensive therapies can slow or prevent progression to end-stage renal disease (ESRD). Interventions targeting CKD, particularly to reduce urine protein excretion, are efficacious, cost-effective methods of improving cardiovascular and renal outcomes, especially when applied to high-risk groups. Integration of these approaches within NCD programs could minimize the need for renal replacement therapy. Early detection and treatment of CKD can be implemented at minimal cost and will reduce the burden of ESRD, improve outcomes of diabetes and cardiovascular disease (including hypertension), and substantially reduce morbidity and mortality from NCDs. Prevention of CKD should be considered in planning and implementation of national NCD policy in the developed and developing world.
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