Adam Shardlow

Chronic Kidney Disease in Primary Care: Outcomes after Five Years in a Prospective Cohort Study.

Background Chronic kidney disease (CKD) is commonly managed in primary care, but most guidelines have a secondary care perspective emphasizing the risk of end-stage kidney disease (ESKD) and need for renal replacement therapy. In this prospective cohort study, we sought to study in detail the natural history of CKD in primary care to better inform the appropriate emphasis for future guidance. Methods and Findings In this study, 1,741 people with CKD stage 3 were individually recruited from 32 primary care practices in Derbyshire, United Kingdom. Study visits were undertaken at baseline, year 1, and year 5. Binomial logistic regression and Cox proportional hazards models were used to model progression, CKD remission, and all-cause mortality. We used Kidney Disease: Improving Global Outcomes (KDIGO) criteria to define CKD progression and defined CKD remission as the absence of diagnostic criteria (estimated glomerular filtration rate [eGFR] >60 ml/min/1.73 m2 and urine albumin-to-creatinine ratio [uACR] <3 mg/mmol) at any study visit. Participants were predominantly elderly (mean ± standard deviation (SD) age 72.9 ± 9.0 y), with relatively mild reduction in GFR (mean ± SD eGFR 53.5 ± 11.8 mL/min/1,73 m2) and a low prevalence of albuminuria (16.9%). After 5 y, 247 participants (14.2%) had died, most of cardiovascular causes. Only 4 (0.2%) developed ESKD, but 308 (17.7%) evidenced CKD progression by KDIGO criteria. Stable CKD was observed in 593 participants (34.1%), and 336 (19.3%) met the criteria for remission. Remission at baseline and year 1 was associated with a high likelihood of remission at year 5 (odds ratio [OR] = 23.6, 95% CI 16.5–33.9 relative to participants with no remission at baseline and year 1 study visits). Multivariable analyses confirmed eGFR and albuminuria as key risk factors for predicting adverse as well as positive outcomes. Limitations of this study include reliance on GFR estimated using the Modification of Diet in Renal Disease study (MDRD) equation for recruitment (but not subsequent analysis) and a study population that was predominantly elderly and white, implying that the results may not be directly applicable to younger populations of more diverse ethnicity. Conclusions Management of CKD in primary care should focus principally on identifying the minority of people at high risk of adverse outcomes, to allow intervention to slow CKD progression and reduce cardiovascular events. Efforts should also be made to identify and reassure the majority who are at low risk of progression to ESKD. Consideration should be given to adopting an age-calibrated definition of CKD to avoid labelling a large group of people with age-related decline in GFR and low associated risk as having CKD.

Associations of fibroblast growth factor 23, vitamin D and parathyroid hormone with 5-year outcomes in a prospective primary care cohort of people with chronic kidney disease stage 3.

Objectives Vitamin D deficiency, elevated fibroblast growth factor 23 (FGF23) and elevated parathyroid hormone (PTH) have each been associated with increased mortality in people with chronic kidney disease (CKD). Previous studies have focused on the effects of FGF23 in relatively advanced CKD. This study aims to assess whether FGF23 is similarly a risk factor in people with early CKD, and how this risk compares to that associated with vitamin D deficiency or elevated PTH. Design Prospective cohort study. Setting Thirty-two primary care practices. Participants One thousand six hundred and sixty-four people who met Kidney Disease: Improving Global Outcomes (KDIGO) definitions for CKD stage 3 (two measurements of estimated glomerular filtration rate (eGFR) between 30 and 60 mL/min/1.73 m2 at least 90 days apart) prior to study recruitment. Outcome measures All-cause mortality over the period of study follow-up and progression of CKD defined as a 25% fall in eGFR and a drop in GFR category, or an increase in albuminuria category. Results Two hundred and eighty-nine participants died during the follow-up period. Vitamin D deficiency (HR 1.62, 95% CI 1.01 to 2.58) and elevated PTH (HR 1.42, 95% CI 1.09 to 1.84) were independently associated with all-cause mortality. FGF23 was associated with all-cause mortality in univariable but not multivariable analysis. Fully adjusted multivariable models of CKD progression showed no association with FGF23, vitamin D status or PTH. Conclusions In this cohort of predominantly older people with CKD stage 3 and low risk of progression, vitamin D deficiency and elevated PTH were independent risk factors for all-cause mortality but elevated FGF23 was not. While FGF23 may have a role as a risk marker in high-risk populations managed in secondary care, our data suggest that it may not be as important in CKD stage 3, managed in primary care. Trial registration number National Institute for Health Research Clinical Research Portfolio Study Number 6632.

Reduction in sodium intake is independently associated with improved blood pressure control in people with chronic kidney disease in primary care

Decreasing sodium intake has been associated with improvements in blood pressure (BP) and proteinuria, two important risk factors for CVD and chronic kidney disease (CKD) progression. We aimed to investigate the role of sodium intake by examining the effect of changes in sodium intake over 1 year on BP and proteinuria in people with early stage CKD. From thirty-two general practices, 1607 patients with previous estimated glomerular filtration rate of 59-30 ml/min per 1.73 m² and mean age of 72.9 (sd 9.0) years were recruited. Clinical assessment, urine and serum biochemistry testing were performed at baseline and after 1 year. Sodium intake was estimated from early morning urine specimens using an equation validated for this study population. We found that compared with people who increased their sodium intake from ≤ 100 to >100 mmol/d over 1 year, people who decreased their intake from >100 to ≤ 100 mmol/d evidenced a greater decrease in all BP variables (Δmean arterial pressure (ΔMAP) = -7.44 (SD 10.1) v. -0.23 (SD 10.4) mmHg; P<0.001) as well as in pulse wave velocity (ΔPWV = -0.47 (SD 1.3) v. 0.08 (SD 1.88) m/s; P<0.05). Albuminuria improved only in albuminuric patients who decreased their sodium intake. BP improved in people who maintained low sodium intake at both times and in those with persistent high intake, but the number of anti-hypertensive increased only in the higher sodium intake group, and PWV improved only in participants with lower sodium intake. Decreasing sodium intake was an independent determinant of ΔMAP. Although more evidence is needed, our results support the benefits of reducing and maintaining sodium intake below 100 mmol/d (2.3-2.4 g/d) in people with early stages of CKD.

The clinical utility and cost impact of cystatin C measurement in the diagnosis and management of chronic kidney disease: A primary care cohort study

Background To reduce over-diagnosis of chronic kidney disease (CKD) resulting from the inaccuracy of creatinine-based estimates of glomerular filtration rate (GFR), UK and international guidelines recommend that cystatin-C-based estimates of GFR be used to confirm or exclude the diagnosis in people with GFR 45–59 ml/min/1.73 m2 and no albuminuria (CKD G3aA1). Whilst there is good evidence for cystatin C being a marker of GFR and risk in people with CKD, its use to define CKD in this manner has not been evaluated in primary care, the setting in which most people with GFR in this range are managed. Methods and findings A total of 1,741 people with CKD G3a or G3b defined by 2 estimated GFR (eGFR) values more than 90 days apart were recruited to the Renal Risk in Derby study between June 2008 and March 2010. Using Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equations, we compared GFR estimated from creatinine (eGFRcreat), cystatin C (eGFRcys), and both (eGFRcreat-cys) at baseline and over 5 years of follow-up. We analysed the proportion of participants with CKD G3aA1 reclassified to ‘no CKD’ or more advanced CKD with the latter two equations. We further assessed the impact of using cystatin-C-based eGFR in risk prediction equations for CKD progression and all-cause mortality and investigated non-GFR determinants of eGFRcys. Finally, we estimated the cost implications of implementing National Institute for Health and Care Excellence (NICE) guidance to use eGFRcys to confirm the diagnosis in people classified as CKD G3aA1 by eGFRcreat. Mean eGFRcys was significantly lower than mean eGFRcreat (45.1 ml/min/1.73 m2, 95% CI 44.4 to 45.9, versus 53.6 ml/min/1.73 m2, 95% CI 53.0 to 54.1, P < 0.001). eGFRcys reclassified 7.7% (50 of 653) of those with CKD G3aA1 by eGFRcreat to eGFR ≥ 60 ml/min/1.73 m2. However, a much greater proportion (59.0%, 385 of 653) were classified to an eGFR category indicating more severe CKD. A similar pattern was seen using eGFRcreat-cys, but lower proportions were reclassified. Change in eGFRcreat and eGFRcys over 5 years were weakly correlated (r = 0.33, P < 0.001), but eGFRcys identified more people as having CKD progression (18.2% versus 10.5%). Multivariable analysis using eGFRcreat as an independent variable identified age, smoking status, body mass index, haemoglobin, serum uric acid, serum albumin, albuminuria, and C reactive protein as non-GFR determinants of eGFRcys. Use of eGFRcys or eGFRcreat-cys did not improve discrimination in risk prediction models for CKD progression and all-cause mortality compared to similar models with eGFRcreat. Application of the NICE guidance, which assumed cost savings, to participants with CKD G3aA1 increased the cost of monitoring by £23 per patient, which if extrapolated to be applied throughout England would increase the cost of testing and monitoring CKD by approximately £31 million per year. Limitations of this study include the lack of a measured GFR and the potential lack of ethnic diversity in the study cohort. Conclusions Implementation of current guidelines on eGFRcys testing in our study population of older people in primary care resulted in only a small reduction in diagnosed CKD but classified a greater proportion as having more advanced CKD than eGFRcreat. Use of eGFRcys did not improve risk prediction in this population and was associated with increased cost. Our data therefore do not support implementation of these recommendations in primary care. Further studies are warranted to define the most appropriate clinical application of eGFRcys and eGFRcreat-cys.

Long Term Outcomes after Acute Kidney Injury: Lessons from the ARID Study

The high incidence and poor short-term outcomes of acute kidney injury (AKI) have focused attention on this global healthcare issue. Concurrently, the long-term effects of AKI are increasingly appreciated, namely, increased risk of subsequent chronic kidney disease, end stage kidney disease requiring renal replacement therapies and a higher rate of cardiovascular events. Whilst there is little doubt about the strength of these associations, knowledge gaps remain. To address some of these, the AKI Risk In Derby study commenced in 2013. This is a prospective case-control study investigating the long-term effects of AKI in a general hospitalized population (including those with less severe AKI). This review will summarize the background and rationale of this study, its design and methodology, as well as the 1-year outcome results from a preceding pilot study.

Renal Arcuate Vein Microthrombi-Associated AKI

BACKGROUNDS AND OBJECTIVES This report describes six patients with AKI stages 2-3 (median admission creatinine level, 2.75 mg/dl [range, 1.58-5.44 mg/dl]), hematuria (five with hemoproteinuria), and unremarkable imaging with an unusual and unexplained histologic diagnosis on renal biopsy. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS The patients were young adults who presented to two neighboring United Kingdom nephrology centers over a 40-month period (between July 2010 and November 2013). Four were male, and the median age was 22.5 years (range, 18-27 years). Their principal symptoms were flank pain or lower back pain. All had consumed alcohol in the days leading up to admission. RESULTS Renal biopsy demonstrated microthrombi in the renal arcuate veins with a corresponding stereotypical, localized inflammatory infiltrate at the corticomedullary junction. All patients recovered to baseline renal function with supportive care (median, 17 days; range, 6-60 days), and none required RRT. To date, additional investigations have not revealed an underlying cause for these histopathologic changes. Investigations have included screening for thrombophilic tendencies, renal vein Doppler ultrasonographic studies, and testing for recreational drugs and alcohol (including liquid chromatography-mass spectrometry of urine) to look for so-called designer drugs. Inquiries to the United Kingdom National Poisons Information Centre have identified no other cases with similar presentation or histologic findings. CONCLUSIONS Increased awareness and additional study of future cases may lead to a greater understanding of the underlying pathophysiologic mechanisms that caused AKI in these patients.