Jocelyn S. Garland

Performance of creatinine-based estimates of GFR in kidney transplant recipients: a systematic review

BACKGROUND Glomerular filtration rate (GFR) commonly is estimated in kidney transplantation by using creatinine-based estimation equations. The performance of these equations in kidney transplant recipients is unclear, with conflicting results between studies. STUDY DESIGN Systematic review. SETTING & POPULATION Stable adult kidney transplant recipients more than 6 months posttransplantation. SELECTION CRITERIA Reporting of or ability to calculate from available data the GFR estimation equation bias (mean difference between measured GFR and estimated GFR) and percent accuracy (percentage of GFR estimates within 10%, 20%, or 30% of measured GFR). INDEX TESTS Creatinine-based GFR estimation equations (Cockcroft-Gault, 6-variable Modification of Diet in Renal Disease [MDRD] Study, 4-variable MDRD Study, and Nankivell). REFERENCE TESTS GFR determination using plasma or renal clearance of inulin, radioisotopes, or nonradiographic contrast. RESULTS The search yielded 23 studies. For the 4-variable MDRD Study equation, bias ranged from -11.4 to +9.2 mL/min/1.73 m(2) (0.15 mL/s/1.73 m(2)). Only 76% of estimates were within 30% of measured GFR. For the Cockcroft-Gault equation, bias ranged from -4.0 to +16 mL/min/1.73 m(2) and 73% of estimates were within 30% of measured GFR. For the Nankivell equation, bias ranged from -1.4 mL/min to 36.3 mL/min with a 30% accuracy of only 68%. LIMITATIONS This review is limited by the inability to pool bias data, lack of calibration of serum creatinine in the majority of studies, and inclusion of nonindependent observations in many studies. CONCLUSIONS Differences in patient populations, baseline GFRs of the study group, reference standard GFR used, and creatinine assay calibration likely account for the heterogeneity in results. These factors need to be considered by investigators and clinicians when interpreting estimates of GFR in kidney transplant recipients.

Prevalence and Associations of Coronary Artery Calcification in Patients With Stages 3 to 5 CKD Without Cardiovascular Disease

BACKGROUND Patients with chronic kidney disease (CKD) have a high prevalence of coronary artery calcification, suggesting that CKD itself is a risk factor for its occurrence. Existing studies are confounded by the inclusion of patients who may not have CKD by means of diagnostic criteria and by failing to account for existing cardiovascular disease. STUDY DESIGN Cross-sectional study. PARTICIPANTS & SETTING 119 patients with CKD stages 3 to 5 (excluding dialysis) without known cardiovascular disease receiving care at a single center in Kingston, Ontario, Canada. PREDICTORS Glomerular filtration rate was estimated (eGFR) by using the 4-variable Modification of Diet in Renal Disease Study equation. Traditional and nontraditional coronary artery calcification risk factors were defined a priori. OUTCOMES Coronary artery calcification was measured by means of multislice computed tomographic scan. RESULTS Mean and median coronary artery calcification scores were 566.5 +/- 1,108 and 111 (interquartile range, 2 to 631.5), respectively. A total of 32.8% of patients showed little calcification (score, 0 to 10). Calcification correlated with age (r = 0.44; P < 0.001), body mass index (r = 0.28; P = 0.002), high-density lipoprotein cholesterol level (r = -0.23; P = 0.01), diabetes mellitus (r = 0.23; P = 0.01), and cardiovascular risk score (r = 0.35; P < 0.001). By means of multivariable linear regression controlling for eGFR and diabetes mellitus, age (beta = 0.05; 95% confidence interval, 0.03 to 0.06; P < 0.001), body mass index (beta = 0.04; 95% confidence interval, 0.02 to 0.07; P = 0.001), and serum calcium level (beta = 0.9; 95% confidence interval, 0.15 to 1.6; P = 0.02), were risk factors for coronary artery calcification. LIMITATIONS Inadequate sample size and uncontrolled confounding are possible limitations, but are unlikely to have changed the main study findings. CONCLUSIONS In this study, traditional cardiovascular disease risk factors and serum calcium level were associated with coronary artery calcification. No association was shown with eGFR. Studies exploring protective mechanisms against coronary artery calcification are needed.

Cardioprotective medication use in hemodialysis patients

BACKGROUND Cardiovascular disease is the leading cause of mortality in patients with renal failure, accounting for more than 50% of deaths in end-stage renal disease. Risk factor modification with the use of cardioprotective medications such as angiotensin-converting enzyme inhibitors (ACEIs), beta-adrenergic antagonists (beta-blockers), acetylsalicylic acid (ASA) and 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) has been shown to reduce mortality in the general population. OBJECTIVE To determine the extent of use of these medications in a hemodialysis population. METHODS This was a cross-sectional study of a cohort of 185 prevalent hemodialysis patients. The inclusion criterion was dialysis dependence and there were no exclusion criteria. Data collection was by chart review. Contraindications to individual medication classes were not obtained. RESULTS There were 185 patients enrolled, the mean age was 63.42+/-15.1 years and 126 (68.1%) were male. Sixty-six (35.7%) patients had diabetes and 89 (48.1%) patients had established coronary artery disease (CAD). Forty-six (24.9%) patients were on ACEIs or angiotensin II receptor blockers, 59 (31.9%) were on beta-blockers, 70 (37.8%) were on ASA and 84 (45.4%) were on statins. Although these medications were used in fewer than 60% of patients, those with CAD were more likely to be prescribed an ACEI or an angiotensin II receptor blocker (P=0.026), a beta-blocker (P<0.001), ASA (P<0.001) or a statin (P=0.001) than those without CAD. There were no differences in the use of these medications between diabetic and nondiabetic patients. CONCLUSIONS Many hemodialysis patients are not prescribed cardioprotective medications. Given the high cardiovascular mortality in this high-risk population, more attention to reducing cardiovascular risk is warranted.

Associations of epicardial fat with coronary calcification, insulin resistance, inflammation, and fibroblast growth factor-23 in stage 3-5 chronic kidney disease.

BackgroundEpicardial fat, quantified in a single multi-slice computed tomography (MSCT) slice, is a reliable estimate of total epicardial fat volume (EFV). We sought to determine risk factors for EFV detected in a single-slice MSCT measurement (ssEFV) in pre-dialysis chronic kidney disease (CKD) patients. Our primary objective was to determine the association between ssEFV and coronary artery calcification (CAC).Methods94 pre-dialysis stage 3–5 CKD patients underwent MSCT to measure ssEFV and CAC. ssEFV was quantified at the level of the left main coronary artery. Measures of inflammation, traditional and kidney-related cardiovascular disease risk factors were collected.ResultsMean age: 63.7 ± 14 years, 56% male, 39% had diabetes, and mean eGFR: 25.1 ± 11.9 mL/min/1.73 m2. Mean ssEFV was 5.03 ± 2.4 cm3. By univariate analysis, body mass index (BMI) (r = 0.53; P = <0.0001), abdominal obesity (r = 0.51; P < 0.0001), high density lipoprotein (HDL) cholesterol (r = − 0.39; P = <0.0001), insulin resistance (log homeostasis model assessment of insulin resistance (log HOMA-IR)) (r = 0.38, P = 0.001), log interleukin-6 (IL-6) (r = 0.34; P = 0.001), and log urinary albumin to creatinine ratio (UACR) (r = 0.30, P = 0.004) demonstrated the strongest associations with ssEFV. Log coronary artery calcification (log CAC score) (r = 0.28, P = 0.006), and log fibroblast growth factor-23 (log FGF-23) (r = 0.23, P = 0.03) were also correlated with ssEFV. By linear regression, log CAC score (beta =0.40; 95% confidence interval (CI), 0.01-0.80; P = 0.045), increasing levels of IL-6 (beta = 0.99; 95% CI, 0.38 – 1.61; P = 0.002), abdominal obesity (beta = 1.86; 95% CI, 0.94 - 2.8; P < 0.0001), lower HDL cholesterol (beta = −2.30; 95% CI, – 3.68 to −0.83; P = 0.002) and albuminuria (log UACR, beta = 0.81; 95% CI, 0.2 to 1.4; P = 0.01) were risk factors for increased ssEFV.ConclusionsIn stage 3–5 CKD, coronary calcification and IL-6 and were predictors of ssEFV. Further studies are needed to clarify the mechanism by which epicardial fat may contribute to the pathogenesis of coronary disease, particularly in the CKD population.

FGF-23 is associated with cardiac troponin T and mortality in hemodialysis patients

Fibroblast growth factor 23 (FGF‐23) is elevated in patients with end‐stage kidney disease and has been linked with mortality, vascular calcification, markers of bone turnover, and left ventricular hypertrophy. In this cohort study, we determined the correlates of FGF‐23 (including cardiac troponin T [cTNT]) and determined its association with mortality over 3.5 years of follow‐up in 103 prevalent hemodialysis patients. Mean age was 61.2 (15.5) and the mean dialysis vintage was 4.19 years (4.6). The median (interquartile range) FGF‐23 was 1259 (491, 2885) RU/mL. Independent predictors (estimate standard error) of log‐transformed FGF‐23 concentrations included phosphorus (0.75 [0.237], P = 0.002) and cardiac troponin T (1.04 [0.41], P = 0.01). There were 57 deaths. In the fully adjusted model, the significant predictors of mortality included age and albumin. The independent association between FGF‐23 and cTNT is a novel finding. Whether this relationship supports the possibility that a downstream effect of dysregulated phosphorous homeostasis may be enhanced cardiac remodeling requires further study.

Elevated body mass index as a risk factor for chronic kidney disease: current perspectives.

Chronic kidney disease (CKD) is defined by the National Kidney Foundation Kidney Disease Outcomes Quality Initiative as the presence of reduced kidney function or kidney damage for a period of 3 months or greater. Obesity is considered a risk factor for CKD development, but its precise role in contributing to CKD and end stage kidney disease is not fully elucidated. In this narrative review, the objectives are to describe the pathogenesis of CKD in obesity, including the impact of altered adipokine secretion in obesity and CKD, and to provide an overview of the clinical studies assessing the risk of obesity and CKD development.

Is the calcium correct? Measuring serum calcium in dialysis patients.

Abnormalities in calcium concentration are frequent in patients receiving dialysis therapy. Most cases of both hypo‐ and hypercalcemia are mild and asymptomatic. There is concern, however, that, on the one hand, hypocalcemia can drive hyperparathyroidism and eventually lead to gland hypertrophy and autonomous function. Hypercalcemia, on the other hand, can be associated with increased extraosseous calcium and phosphate deposition leading to vascular calcification with an attendant mortality and morbidity. Calcium exists in three main forms in the blood: the physiologically active free or ionized fraction (terms often used interchangeably), a protein bound fraction, and a fraction complexed to other anions. Although the ionized calcium can readily be measured using ion‐specific electrodes, it is the total calcium that is most commonly measured because of sample handling and cost concerns. As it is the free or ionized form that is biologically active (and therefore of most relevance), a number of adjustment formulae have been derived to “correct” the total calcium for changes in albumin, protein, and complexing ion concentrations. These formulae show good statistical correlation with measured ionized calcium in populations studied as a whole, but are generally poor predictors of true ionized hypo‐ or hypercalcemia in individual patients. International guideline committees in nephrology recommend frequent assessment of calcium levels in dialysis patients and recommend that these levels be kept within the normal reference range. These guidelines are less clear on which measurement of calcium should be used to guide clinical decision making. This review examines the merits of making any adjustment to the total calcium measurement, and suggests when it is appropriate to measure the ionized or free calcium.

Insulin resistance is associated with Fibroblast Growth Factor-23 in stage 3-5 chronic kidney disease patients☆ , ☆☆

AIM To determine the associations between insulin resistance, fibroblast growth factor 23 (FGF-23), and coronary artery calcification (CAC) in chronic kidney disease (CKD) patients. INTRODUCTION FGF-23 is associated with atherosclerosis and cardiovascular disease, but its association with insulin resistance in CKD has not been explored. SUBJECTS Cross sectional study of 72 stage 3-5 CKD patients receiving care in Ontario, Canada. MATERIALS AND METHODS Insulin resistance was measured by the homeostasis model assessment of insulin resistance (HOMA-IR), FGF-23 was measured by carboxyl terminal enzyme linked immunoassay (ctFGF-23) and CAC was measured by multi-slice computed tomography. RESULTS Median HOMA-IR was 2.19μU/ml (interquartile range 1.19 to 3.94). Patients with HOMA-IR>2.2 had greater ctFGF-23 (179.7 vs 109.6; P=0.03), and 40% higher log CAC scores (2.09±0.87 vs 1.58±1.26; P=0.049). Multivariable linear regression adjusted for 1,25 dihydroxyvitamin D, kidney function, and parathyroid hormone revealed insulin resistance was a risk factor for greater log ctFGF-23 levels (log HOMA IR β=0.37; 95% confidence interval 0.14 to 0.59; P=0.002). CONCLUSIONS Insulin resistant CKD patients demonstrated higher FGF-23 levels, and increased CAC, while PO4 levels remained normal, suggesting a potential link between insulin resistance and PO4 homeostasis in CKD.

Reviews: Is the Calcium Correct? Measuring Serum Calcium in Dialysis Patients

Abnormalities in calcium concentration are frequent in patients receiving dialysis therapy. Most cases of both hypo‐ and hypercalcemia are mild and asymptomatic. There is concern, however, that, on the one hand, hypocalcemia can drive hyperparathyroidism and eventually lead to gland hypertrophy and autonomous function. Hypercalcemia, on the other hand, can be associated with increased extraosseous calcium and phosphate deposition leading to vascular calcification with an attendant mortality and morbidity. Calcium exists in three main forms in the blood: the physiologically active free or ionized fraction (terms often used interchangeably), a protein bound fraction, and a fraction complexed to other anions. Although the ionized calcium can readily be measured using ion‐specific electrodes, it is the total calcium that is most commonly measured because of sample handling and cost concerns. As it is the free or ionized form that is biologically active (and therefore of most relevance), a number of adjustment formulae have been derived to “correct” the total calcium for changes in albumin, protein, and complexing ion concentrations. These formulae show good statistical correlation with measured ionized calcium in populations studied as a whole, but are generally poor predictors of true ionized hypo‐ or hypercalcemia in individual patients. International guideline committees in nephrology recommend frequent assessment of calcium levels in dialysis patients and recommend that these levels be kept within the normal reference range. These guidelines are less clear on which measurement of calcium should be used to guide clinical decision making. This review examines the merits of making any adjustment to the total calcium measurement, and suggests when it is appropriate to measure the ionized or free calcium.

Sequence Variation in Vitamin K Epoxide Reductase Gene Is Associated With Survival and Progressive Coronary Calcification in Chronic Kidney Disease

Objective—Sequence variations in the gene(s) encoding vitamin K epoxide reductase complex subunit 1 (VKORC1), the enzyme target of warfarin, have been associated with increased cardiovascular disease in the general population. Coronary artery calcification (CAC) is a prevalent form of cardiovascular disease in chronic kidney disease. We tested the hypothesis that the VKORC1 rs8050894 CC genotype would be associated with mortality and progression of CAC ⩽4 years. Approach and Results—This study is an observational, prospective study of 167 individuals with stages 3 to 5 chronic kidney disease. Survival ⩽4 years was assessed in all participants, and CAC progression was measured in a subset of 86 patients. Participants with the CG/GG genotype of VKORC1 had higher baseline CAC scores (median score, 112 versus 299; P=0.036). Of those 86 patients who had a 4-year CAC score, those with the CG/GG genotype had an increased risk of progressive CAC (adjusted for age, diabetes mellitus, estimated glomerular filtration rate, and hypertension) compared with those with the CC genotype. Four-year mortality risk was 4 times higher for individuals with the CG/GG genotypes compared with individuals with the CC genotype (odds ratio, 3.8; 95% confidence interval, 1.2–12.5; P=0.02), adjusted for age, sex, diabetes mellitus, estimated glomerular filtration rate, baseline CAC, and hypertension. Conclusions—Patients with the CG/GG genotype of VKORC1 had a higher risk of CAC progression and a poorer survival. These data provide new perspectives on the potential extrahepatic role of VKORC1 in individuals with chronic kidney disease.