Rachel J. Middleton

Serum phosphate and mortality in patients with chronic kidney disease

BACKGROUND AND OBJECTIVES Higher phosphate is associated with mortality in dialysis patients but few prospective studies assess this in nondialysis patients managed in an outpatient nephrology clinic. This prospective longitudinal study examined whether phosphate level was associated with death in a referred population. DESIGN, SETTING, PARTICIPANTS & MEASUREMENTS Patients (1203) of nondialysis chronic kidney disease (CKD) in the Chronic Renal Insufficiency Standards Implementation Study were assessed. Survival analyses were performed for quartiles of baseline phosphate relative to GFR, 12-month time-averaged phosphate, and baseline phosphate according to published phosphate targets. RESULTS Mean (SD) eGFR was 32 (15) ml/min per 1.73 m(2), age 64 (14) years, and phosphate 1.2 (0.30) mmol/L. Cox multivariate adjusted regression in CKD stages 3 to 4 patients showed an increased risk of all-cause and cardiovascular mortality in the highest quartile compared with that in the lowest quartile of phosphate. No association was found in CKD stage 5 patients. Patients who had values above recommended targets for phosphate control had increased risk of all-cause and cardiovascular death compared with patients below target. The highest quartile compared with the lowest quartile of 12-month time-averaged phosphate was associated with an increased risk of mortality. CONCLUSIONS In CKD stages 3 to 4 patients, higher phosphate was associated with a stepwise increase in mortality. As phosphate levels below published targets (as opposed to within them) are associated with better survival, guidelines for phosphate in nondialysis CKD patients should be re-examined. Intervention trials are required to determine whether lowering phosphate will improve survival.

The Effects of Statins on the Progression of Atherosclerotic Renovascular Disease

Background/Aims: The aim was to examine the influence of statin therapy on the natural history of atherosclerotic renal artery stenosis (RAS). Methods: Our hospital atherosclerotic renovascular disease (ARVD) database was analysed for patients who underwent repeat renal angiography during clinical follow-up. Patients with ≧1 RAS lesion and ≧4 months between baseline and repeat renal angiography were analysed. 79 patients were included. Baseline renal arterial anatomy was classified as normal, ≤50% RAS, >50% RAS or renal artery occlusion. Results: Mean follow-up time between angiograms was 27.8 ± 22.3 (4.0–101.9) months. Progression of RAS occurred in 28 (23%) vessels, regression in 14 (12%) and no significant change in 79 (65%). Multivariate regression analysis showed that baseline proteinuria >0.6 g/day increased the risk of progressive disease (relative risk, RR, 3.8; 95% confidence interval, CI, 1.2–12.1), treatment with statin reduced the risk of progression (RR 0.28; 95% CI 0.10–0.77). 14 renal arteries from 12 patients showed RAS regression with a greater proportion on statin [statin treatment 10 (83%) versus no statin treatment 2 (17%), p = 0.001]. Change in estimated glomerular filtration rate (eGFR) per year was not different between statin- and no-statin-treated groups. Conclusions: Progression or development of RAS was significantly less likely to occur with statin therapy. ΔeGFR did not correlate with progression of RAS, reflecting the importance of intrarenal injury in the aetiology of renal dysfunction. Our results suggest statin therapy can alter the natural history of ARVD.

Factors Associated With Kidney Disease Progression and Mortality in a Referred CKD Population

BACKGROUND Knowing how kidney disease progresses is important for decision making in patients with chronic kidney disease (CKD) and for designing clinical services. STUDY DESIGN Prospective cohort study. SETTING & PARTICIPANTS We examined renal function trajectories in CRISIS (Chronic Renal Insufficiency Standards Implementation Study), in which 1,325 patients with CKD stages 3-5 and mean age of 65.1 years were followed up prospectively for a median of 26 months after referral to a regional nephrology center in the United Kingdom. By protocol, estimated glomerular filtration rate was determined every 12 months. PREDICTORS CKD stage defined as estimated glomerular filtration rate ≥ 45 (stage 3a), 30-44 (3b), 15-29 (4), and < 15 (5) mL/min/1.73 m². OUTCOMES Onset of renal replacement therapy (RRT), death, the composite end point of RRT or death, or decreasing CKD stage. RESULTS During a median follow-up of 26 months, 13% reached the end point of RRT (5.1 events/100 patient-years), 20% died (9.6 deaths/100 patient-years), and 33% reached the combined end point of RRT or death (14.7 events/100 patient-years). For stage 3a, baseline prevalence and annual probabilities of decreasing CKD stage, RRT, and death were 18.0%, 0.41, 0.01, and 0.02, respectively. Corresponding values for stage 3b were 32.5%, 0.22, < 0.01, and 0.06; for stage 4, 36.5%, 0.17, 0.03, and 0.10; and for stage 5, 13.2%, zero (by definition), 0.31, and 0.08, respectively. Markov model projections suggested a steady decrease for proportions with stages 3a, 3b, and 4; a steady increase for death and RRT; and a biphasic pattern for (non-RRT) stage 5, with a plateau in the first 2 years followed by a steady decrease. LIMITATIONS Single-center observational study. CONCLUSION This study suggests that death and RRT are the dominant outcomes in patients referred for management of CKD and that most patients spend comparatively little time in late stages without RRT.

The use of eGFR and ACR to predict decline in renal function in people with diabetes

BACKGROUND There have been few attempts to estimate progression of kidney disease in people with diabetes in a single large population with predictive modelling. The aim of this study was to investigate the rate of progression of chronic kidney disease in people with diabetes according to their estimated glomerular filtration rate (eGFR) and presence of albuminuria. METHODS Data were collected on all people with diabetes in Salford, UK, where an eGFR could be calculated using the four-variable MDRD formula and urinary albumin-creatinine ratio (uACR) was available. All data between 2001 and 2007 were used in the model. Classification of albuminuria status was based on the average of their first two uACR measurements. A longitudinal mixed effect dynamic regression model was fitted to the data. Parameters were estimated by maximum likelihood. RESULTS For the analysis of the population, average progression of eGFR, uACR and drug prescribing were available in 3431 people. The regression model showed that in people with diabetes and macroalbuminuria, eGFR declined at 5.7% per annum, while the eGFR of those with microalbuminuria or without albuminuria declined at 1.5% and 0.3% per annum, respectively, independently of age (P < 0.0001). CONCLUSIONS The longitudinal effect of time on eGFR showed that people with diabetes and macroalbuminuria have an estimated 19 times more rapid decline in renal function compared with those without albuminuria. This study demonstrates that the progression of kidney disease in diabetic people without albuminuria is relatively benign compared with those with albuminuria.

Circulating methylarginine levels and the decline in renal function in patients with chronic kidney disease are modulated by DDAH1 polymorphisms

In patients with chronic kidney disease, high plasma levels of the endogenous nitric oxide synthase inhibitor, asymmetric dimethylarginine, are thought to contribute to decline in renal function. Here we took a candidate gene approach to determine any causal role of asymmetric dimethylarginine in the progression of chronic kidney disease. The impact of single-nucleotide polymorphisms in the genes encoding the two isoforms of the asymmetric dimethylarginine-degrading enzyme, dimethylarginine dimethylaminohydrolase (DDAH1 and DDAH2), on enzyme expression, plasma asymmetric dimethylarginine levels, and longitudinal changes in estimated glomerular filtration rate were determined in various patient groups. There was evidence suggesting that the rs17384213 DDAH1 GG genotype was associated with increased expression of its mRNA in kidney allografts. Healthy subjects carrying the rs17384213 G allele had lower plasma asymmetric dimethylarginine, and a similar borderline association was found in patients with chronic kidney disease. This allele, however, was independently associated with a steeper decline in renal function in two separate cohorts of patients with chronic kidney disease. We conclude that polymorphisms in DDAH1 alter the rate of decline of glomerular filtration rate in subjects with chronic kidney disease. Our findings show that DDAH1 modulates plasma asymmetric dimethylarginine and contributes to the decline in renal function. However, it appears that increases in circulating methylarginine did not mediate progressive kidney injury.

Body mass index has no effect on rate of progression of chronic kidney disease in non-diabetic subjects

BACKGROUND Chronic kidney disease (CKD) is increasingly prevalent worldwide. Furthermore, obesity is now a global problem with major health implications. There is a clear association between obesity and the development of CKD but it is not known whether obesity is a risk factor for the progression of pre-existing kidney disease. We examined the relationship between the body mass index (BMI) and the rate of progression of CKD in non-diabetic adults. METHODS The Chronic Renal Insufficiency Standards Implementation Study (CRISIS) is a prospective observational study in a predominantly white population in Greater Manchester. From the CRISIS database, we assessed rate of progression of CKD in 499 adults attending the hospital. Baseline measurements including BMI were obtained and estimated glomerular filtration rate (eGFR) was monitored. The rate of deterioration of eGFR was derived over time, defined as ΔeGFR (mL/min/1.73 m2/year) and assessed using univariate analysis of variance. RESULTS In the groups as a whole, no relationship between BMI and ΔeGFR was shown. Dividing the subjects into obese (BMI≥30) and non-obese (BMI<30) groups and further breakdown into CKD stages 3, 4 and 5, also showed no relationship between BMI and ΔeGFR. Univariate analysis of variance was used. CONCLUSIONS Neither BMI as a continuous variable nor obesity (BMI≥30) as a categorical variable was associated with an increased rate of progression of existing CKD in this predominantly white population.

Extreme Elevations in Blood Pressure and All-Cause Mortality in a Referred CKD Population: Results from the CRISIS Study

Hypertension frequently complicates chronic kidney disease (CKD), with studies showing clinical benefit from blood pressure lowering. Subgroups of patients with severe hypertension exist. We aimed to identify patients with the greatest mortality risk from uncontrolled hypertension to define the prevalence and phenotype of patients who might benefit from adjunctive therapies. 1691 all-cause CKD patients from the CRISIS study were grouped by baseline blood pressure—target (<140/80 mmHg); elevated (140–190/80–100 mmHg); extreme (>190 and/or 100 mmHg). Groups were well matched for age, eGFR, and comorbidities. 77 patients had extreme hypertension at recruitment but no increased mortality risk (HR 0.9, P = 0.9) over a median follow-up period of 4.5 years. The 1.2% of patients with extreme hypertension at recruitment and at 12-months had a significantly increased mortality risk (HR 4.3, P = 0.01). This association was not seen in patients with baseline extreme hypertension and improved 12-month blood pressures (HR 0.86, P = 0.5). Most CKD patients with extreme hypertension respond to pharmacological blood pressure control, reducing their risk for death. Patients with extreme hypertension in whom blood pressure control cannot be achieved have an approximate prevalence of 1%. These patients have an increased mortality risk and may be an appropriate group to consider for further therapies, including renal nerve ablation.

Factors associated with vascular stiffness: Cross-sectional analysis from the chronic renal insufficiency standards implementation study

Background: Vascular stiffness is associated with increased cardiovascular risk. This study aimed to identify factors associated with vascular stiffness in a cohort of chronic kidney disease (CKD) patients. Methods: The Chronic Renal Insufficiency Standards Implementation Study is a prospective epidemiological study of CKD patients not on dialysis, who are managed in a clinic setting. Phenotypic parameters were collected annually, and vascular stiffness was assessed using augmentation index (AI). Cross-sectional analysis was performed across quintiles of AI to evaluate factors associated with vascular stiffness. Results: Mean patient age was 66.1 ± 14.1 years and estimated glomerular filtration rate (eGFR) was 31.2 ± 5.7 ml/min. Corrected calcium was 2.26 ± 0.2 SD mmol/l, phosphate 1.2 ± 0.4 SD mmol/l and intact parathyroid hormone 94 ± 96 SD pg/ml; 18.3% of patients had cardiovascular disease. Increased age and systolic blood pressure were associated with increased AI (all p < 0.001). No statistical association was present between AI and eGFR, intact parathyroid hormone, phosphate or protein excretion. Conclusion: This study identified blood pressure as a potentially modifiable risk factor associated with AI, whereas eGFR was not associated with increased AI in a population of CKD stage 3–5 patients. Further knowledge of factors which influence progression of vascular stiffness will be important in risk quantification and management.

Dapsone‐induced methemoglobinemia in renal transplant recipients: more prevalent than previously thought

After an outbreak of Pneumocystis pneumonia (PCP) in our nephrology unit, dapsone was used as the second‐line chemoprophylactic agent. Dapsone is the most common cause of drug‐induced methemoglobinemia (MHb). Its prevalence is poorly described in the renal transplant population. Because dapsone is excreted by the kidneys, we hypothesized that the rate of MHb in these patients would be higher than previously reported. We aimed to describe the demographics, risk factors, and presenting features of MHb in these renal transplant patients.

Functional status and mortality in chronic kidney disease: results from a prospective observational study

Background/Aims: Measures of functional status are used in the general population to aid prognostication but their use has not been explored in pre-dialysis chronic kidney disease (CKD). This analysis considers the association between the Karnofsky performance score (KPS) and all-cause mortality in a CKD stage 3-5 cohort. Methods: Patients were selected from the Chronic Renal Insufficiency Standards Implementation Study (CRISIS), a prospective observational study of outcome in CKD. Risk for death was assessed using multivariate Cox regression, and differences in progression of biochemical parameters were considered in a mixed-effects model. Results: A total of 1,515 patients with a median follow-up time of 2.9 (1.5-4.8) years were considered. Baseline age was 60 ± 11 years and eGFR was 30 ± 12 ml/min/1.73 m2. Patients with a reduced KPS had an increased risk for death. The hazard ratio (HR) for death was: KPS 90 group, HR 1.2 (95% CI 0.9-1.5), p = 0.1; KPS ≤80 group, HR 1.8 (95% CI 1.4-2.4), p < 0.001. In the mixed-effects model, the average annual loss of eGFR was greater in patients with a KPS ≤80 versus patients with a KPS >80 (5 vs. 3%, p = 0.008). Conclusion: A reduced KPS is independently associated with risk for mortality in patients with CKD stages 3-5. This may relate to a more rapid loss of eGFR.