Timothy Ellam

Estimated Albumin Excretion Rate Versus Urine Albumin-Creatinine Ratio for the Estimation of Measured Albumin Excretion Rate: Derivation and Validation of an Estimated Albumin Excretion Rate Equation

BACKGROUND Glomerular filtration rate estimation equations use demographic variables to account for predicted differences in creatinine generation rate. In contrast, assessment of albuminuria from urine albumin-creatinine ratio (ACR) does not account for these demographic variables, potentially distorting albuminuria prevalence estimates and clinical decision making. STUDY DESIGN Polynomial regression was used to derive an age-, sex-, and race-based equation for estimation of urine creatinine excretion rate, suitable for use in automated estimated albumin excretion rate (eAER) reporting. SETTING & PARTICIPANTS The MDRD (Modification of Diet in Renal Disease) Study cohort (N=1,693) was used for equation derivation. Validation populations were the CRIC (Chronic Renal Insufficiency Cohort; N=3,645) and the DCCT (Diabetes Control and Complications Trial; N=1,179). INDEX TEST eAER, calculated by multiplying ACR by estimated creatinine excretion rate, and ACR. REFERENCE TEST Measured albumin excretion rate (mAER) from timed 24-hour urine collection. RESULTS eAER estimated mAER more accurately than ACR; the percentages of CRIC participants with eAER within 15% and 30% of mAER were 33% and 60%, respectively, versus 24% and 39% for ACR. Equivalent proportions in DCCT were 52% and 86% versus 15% and 38%. The median bias of ACR was -20.1% and -37.5% in CRIC and DCCT, respectively, whereas that of eAER was +3.8% and -9.7%. Performance of eAER also was more consistent across age and sex categories than ACR. LIMITATIONS Single timed urine specimens used for mAER, ACR, and eAER. CONCLUSIONS Automated eAER reporting potentially is a useful approach to improve the accuracy and consistency of clinical albuminuria assessment.

Dietary Phosphate Modulates Atherogenesis and Insulin Resistance in Apolipoprotein E Knockout Mice—Brief Report

Objective— Epidemiological studies link higher serum phosphate and the phosphatonin fibroblast growth factor 23 with cardiovascular events and atheroma, and they link lower serum phosphate with insulin resistance and the metabolic syndrome. We investigated whether manipulating dietary phosphate influences atherogenesis or insulin sensitivity in mice. Methods and Results— Apolipoprotein E knockout mice were fed an atherogenic diet with low (0.2%), standard (0.6%), or high (1.6%) phosphate content. Serum phosphate and fibroblast growth factor 23 significantly increased with increasing dietary phosphate intake, but lipid profile and blood pressure were unaffected. After 20 weeks, mice on the higher phosphate diet had significantly more atheroma at the aortic sinus (42±1.9% versus 30±1.5% for high versus low phosphate, P<0.01). Compared with standard and high-phosphate diet groups, mice on a low-phosphate diet had more adipose tissue and a 4-fold increase in insulin resistance measured by homeostatic model assessment (43.7±9.3 versus 8.9±0.7 for low versus high phosphate, P<0.005). Conclusion— A high-phosphate diet accelerates atherogenesis in apolipoprotein E−/− mice, whereas low phosphate intake induces insulin resistance. These data indicate for the first time that controlling dietary phosphate intake may influence development of both atherosclerosis and the metabolic syndrome.

Vitamin D Deficiency and Exogenous Vitamin D Excess Similarly Increase Diffuse Atherosclerotic Calcification in Apolipoprotein E Knockout Mice

Background Observational data associate lower levels of serum vitamin D with coronary artery calcification, cardiovascular events and mortality. However, there is little interventional evidence demonstrating that moderate vitamin D deficiency plays a causative role in cardiovascular disease. This study examined the cardiovascular effects of dietary vitamin D deficiency and of vitamin D receptor agonist (paricalcitol) administration in apolipoprotein E knockout mice. Methods Mice were fed atherogenic diets with normal vitamin D content (1.5IU/kg) or without vitamin D. Paricalcitol, or matched vehicle, was administered 3× weekly by intraperitoneal injection. Following 20 weeks of these interventions cardiovascular phenotype was characterized by histological assessment of aortic sinus atheroma, soluble markers, blood pressure and echocardiography. To place the cardiovascular assessments in the context of intervention effects on bone, structural changes at the tibia were assessed by microtomography. Results Vitamin D deficient diet induced significant reductions in plasma vitamin D (p<0.001), trabecular bone volume (p<0.01) and bone mineral density (p<0.005). These changes were accompanied by an increase in calcification density (number of calcifications per mm2) of von Kossa-stained aortic sinus atheroma (461 versus 200, p<0.01). Paricalcitol administration suppressed parathyroid hormone (p<0.001), elevated plasma calcium phosphate product (p<0.005) and induced an increase in calcification density (472 versus 200, p<0.005) similar to that seen with vitamin D deficiency. Atheroma burden, blood pressure, metabolic profile and measures of left ventricular hypertrophy were unaffected by the interventions. Conclusion Vitamin D deficiency, as well as excess, increases atherosclerotic calcification. This phenotype is induced before other measures of cardiovascular pathology associated clinically with vitamin D deficiency. Thus, maintenance of an optimal range of vitamin D signalling may be important for prevention of atherosclerotic calcification.

The body composition and excretory burden of lean, obese, and severely obese individuals has implications for the assessment of chronic kidney disease

Obesity could affect associations between creatinine generation, estimated body surface area, and excretory burden, with effects on chronic kidney disease assessment. We therefore examined the impact of obesity on the performances of estimated glomerular filtration rate (eGFR), the urine albumin:creatinine ratio (ACR), and excretory burden in 3611 participants of the Chronic Renal Insufficiency Cohort. Urine creatinine excretion significantly increased with body mass index (BMI) (34 and 31% greater at 40 kg/m(2) or more versus the normal of 18.5-25 kg/m(2)) in men and women, respectively, such that patients with a normal BMI and an ACR of 30 mg/g had the same 24-h albuminuria as severely obese patients with ACR 23 mg/g. The bias of eGFR (referenced to body surface area-indexed iothalamate (i-)GFR) had a U-shaped relationship to obesity in men but progressively increased in women. Nevertheless, obesity-associated body surface area increases were accompanied by a greater absolute (non-indexed) iGFR for a given eGFR, particularly in men. Two men with eGFRs of 45 ml/min per 1.73 m(2), height 1.76 m, and BMI 22 or 45 kg/m(2) had absolute iGFRs of 46 and 62 ml/min, respectively. The excretory burden, assessed as urine urea nitrogen and estimated dietary phosphorus, sodium, and potassium intakes, also increased in obesity. However, obese men had lower odds of anemia, hyperkalemia, and hyperphosphatemia. Thus, for a given ACR and eGFR, obese individuals have greater albuminuria, absolute GFR, and excretory burden. This has implications for chronic kidney disease management, screening, and research.

Albumin:Creatinine Ratio – A Flawed Measure? The Merits of Estimated Albuminuria Reporting

Current guidelines illogically recommend that a different approach is taken to the correction for creatinine generation rate when estimating glomerular filtration rate (GFR) and when interpreting urine albumin:creatinine ratio (ACR). Age, gender and race are routinely used to adjust for predicted muscle mass in GFR estimation, even though estimated GFR is expressed per unit body surface area. Conversely, ACR is at most adjusted with the use of gender-specific classification thresholds. This difference is surprising since the proportional effect of muscle mass on serum and urine creatinine is identical. Failure to adjust for creatinine generation rate compromises ACR, potentially adversely affecting management decisions and mislabelling individuals as having/not having CKD. A greater ACR is also a marker of low muscle mass, which has confounding prognostic effects. Determination of the optimal method to adjust ACR for estimated muscle mass should improve its performance. Routine reporting of the resulting ‘estimated albumin excretion rate’, as for routine eGFR reporting, would remove the need for gender-specific thresholds.

Modification of the Relationship Between Blood Pressure and Renal Albumin Permeability by Impaired Excretory Function and DiabetesNovelty and Significance

In animal models, reduced nephron mass impairs renal arteriolar autoregulation, increasing vulnerability of the remaining nephrons to elevated systemic blood pressure (BP). A feature of the resulting glomerular capillary hypertension is an increase in glomerular permeability. We sought evidence of a similar remnant nephron effect in human chronic kidney disease. In participants from the United States National Health and Nutrition Examination Surveys 1999 to 2010 (N=23 710), we examined the effect of reduced estimated glomerular filtration rate (eGFR) on the relationship between brachial artery BP and albumin permeability. Renal albumin permeability increased exponentially with systolic BP >110 mm Hg, and this association was modified by independent interactions with both excretory impairment and diabetes mellitus. Each 10 mm Hg increase in systolic BP was accompanied by an increase in fractional albumin excretion of 1.10-, 1.11-, 1.17-, 1.22-, and 1.38-fold for participants with eGFR≥90, 90>eGFR≥60, 60>eGFR≥45, 45>eGFR≥30, and eGFR<30 mL/min/1.73 m2, respectively, adjusted for age, sex, race, antihypertensive use, eGFR category, diabetes mellitus, smoking, history of cardiovascular disease, body mass index, and C-reactive protein. A 10 mm Hg systolic BP increment was associated with increases in fractional albumin excretion of 1.10- and 1.21-fold in nondiabetic and diabetic participants, respectively. Using urine albumin creatinine ratio as an alternative measure of albumin leak in eGFR-adjusted analyses gave the same conclusions. Our findings are consistent with the presence of a remnant nephron effect in human kidney disease. Future trials should consider the nephroprotective benefits of systolic BP lowering in kidney disease populations stratified by eGFR.

Interventions for age-related diseases: Shifting the paradigm

Over 60% of people aged over 65 are affected by multiple morbidities, which are more difficult to treat, generate increased healthcare costs and lead to poor quality of life compared to individual diseases. With the number of older people steadily increasing this presents a societal challenge. Age is the major risk factor for age-related diseases and recent research developments have led to the proposal that pharmacological interventions targeting common mechanisms of ageing may be able to delay the onset of multimorbidity. Here we review the state of the knowledge of multimorbidity, appraise the available evidence supporting the role of mechanisms of ageing in the development of the most common age-related diseases and assess potential molecules that may successfully target those key mechanisms.

Proteinuria Thresholds Are Irrational: A Call for Proteinuria Indexing

Current guidelines for chronic kidney disease (CKD) diagnosis, referral and management are based on absolute thresholds of proteinuria/albuminuria with no reference to the residual nephron mass or function. This is illogical since the severity of proteinuria is a direct reflection of the number of filtering nephrons as well as their pathology and the capacity of the tubules to reabsorb filtered protein/albumin. The current simplistic approach to proteinuria may also compromise its usefulness as a robust guide to appropriate treatment, e.g. preferential use of inhibitors of the renin-angiotensin-aldosterone system. The routine measurement of the urinary protein/albumin:creatinine ratio (PCR/ACR) and estimated glomerular filtration rate (eGFR) gives rise to the opportunity to index proteinuria for renal function (i.e. a PCR:eGFR or ACR:eGFR ratio). Since both PCR/ACR and eGFR are reflections of quantities assessed per unit body surface area, this is a logical approach to the assessment of proteinuria/albuminuria. We advocate a consideration of the benefits of indexing PCR/ACR for eGFR to optimise treatment decisions based on proteinuria/albuminuria.

Chronic kidney disease in elderly people: disease or disease label?

Timothy Ellam and colleagues argue for a focus on what diagnosis means for individual patients rather than population risks

Bone Mineral Metabolism Parameters and Urinary Albumin Excretion in a Representative US Population Sample

Background and Hypothesis Even within accepted normal ranges, higher serum phosphorus, dietary phosphorus density, parathyroid hormone (PTH) and alkaline phosphatase (ALP) are independent predictors of cardiovascular mortality. Lower serum 25-hydroxy vitamin D (25(OH)D) also predicts adverse cardiovascular outcomes. We hypothesized that vascular dysfunction accompanying subtle disturbances of these bone metabolism parameters would result in associations with increased low grade albuminuria. Study Population and Measures We examined participants in the National Health and Nutrition Examination Surveys 1999–2010 (N = 19,383) with estimated glomerular filtration rate (eGFR) ≥60 ml/min/1.73 m2 and without severe albuminuria (urine albumin:creatinine ratio (ACR) <300 mg/g). Albuminuria was quantified as ACR and fractional albumin excretion (FEalb). Results Increasing quintiles of dietary phosphorus density, serum phosphorus and ALP were not associated with higher ACR or FEalb. The lowest versus highest quintile of 25(OH)D was associated with greater albuminuria, but not after adjustment for other covariates including cardiovascular risk factors. An association between the highest versus lowest quintile of bone-specific ALP and greater ACR persisted after covariate adjustment, but was not accompanied by an independent association with FEalb. Increasing quintiles of PTH demonstrated associations with both higher ACR and FEalb that were not abolished by adjusting for covariates including age, gender, race, body mass index, diabetes, blood pressure, history of cardiovascular disease, smoking, eGFR, 25(OH)D, season of measurement, lipids, hemoglobin and C-reactive protein. Adjusted increases in ACR and FEalb associated with the highest versus lowest quintile of PTH were 19% (95% confidence interval 7–28% p<0.001) and 17% (8–31% p = 0.001) respectively. Conclusion In this population, of the bone mineral parameters associated with cardiovascular outcomes, only PTH is independently associated with ACR and FEalb.