Predictors of renal and patient outcomes in chronic kidney disease

Chronic kidney disease (CKD) is associated with an increased risk of cardiovascular disease and end stage renal failure. Accurate identification of those with a reduced glomerular filtration rate and significant proteinuria facilitates early diagnosis and risk stratification. This thesis explores the optimal measure of proteinuria, to accurately quantify proteinuria and as a predictor of renal and patient outcomes. We examine the prevalence of CKD in a general population cohort and assess the impact of different estimated glomerular filtration rate (eGFR) formulae. We explore the prognostic role of reduced eGFR and proteinuria in patients with hypertension and present the baseline characteristics of a community cohort study of patients with predominantly early CKD. They will be followed for ten years to identify predictors of cardiovascular and renal outcome. Urine total protein:creatinine ratio (TPCR) and albumin:creatinine ratio (ACR) have largely replaced 24-hour urine collections for proteinuria quantification. The performance of these spot measures to identify significant proteinuria is compared in a cohort of 6842 patients attending a general nephrology clinic. Both tests perform well overall but TPCR is statistically significantly superior as a predictor of 24-hour total proteinuria than ACR (as measured by the area under the receiver operator characteristic (ROC) curve to predict 1g/day total proteinuria). On sub-group analysis the performance of the spot samples is poorer in women and the elderly, likely as a result of low muscle mass and low urine creatinine (the denominator in TPCR/ACR). The performance of TPCR and ACR were then compared as predictors of outcome in a similar cohort of 5586 CKD patients using a hierarchical Cox survival model. TPCR and ACR both performed well as independent predictors of death, commencement of renal replacement therapy (RRT) and doubling of serum creatinine. Notably TPCR performed well at low levels where albuminuria has been considered superior. These findings are novel. The spot samples performed as well as 24-hour collections in the sub-group with timed urine collections. The National Institute for Health and Clinical Excellence in England recommend ACR to monitor all patients with CKD; the Scottish Intercollegiate Guidelines Network recommend TPCR for non-diabetic renal disease. Therefore, we investigated the implications of these recommendations using survival modelling. The same cohort was divided into 5 groups: no proteinuria, low proteinuria (using TPCR and ACR), high proteinuria (TPCR and ACR) and two groups where TPCR and ACR were discordant (i.e. TPCR above the diagnostic threshold but ACR below it and vice versa) using the recommended thresholds (ACR 30mg/mmol/TPCR 50mg/mmol to predict 0.5g/day total proteinuria and ACR 70mg/mmol/TPCR 100mg/mmol to predict 1g/day total proteinuria). Using univariate survival analysis the discordant group had significantly poorer outcomes (using the same outcomes as previously) than those with significant proteinuria as measured by both tests. The discordant group was older with poorer renal function and some of the excess risk was abolished on multivariate analysis, however the risk did not return to the level of those without detectable proteinuria. TPCR, but not ACR, measures non-albumin proteins and these may have pathophysiological roles in progression. This requires further study. However this analysis confirmed that TPCR identifies patients at high risk of adverse outcomes. TPCR and ACR may vary as a result of muscle mass. We adjusted TPCR and ACR for estimated creatinine excretion (ECE) (calculated using the Cockcroft and Gault formula) and performed cross-sectional and longitudinal analyses. Adjusting TPCR and ACR for ECE improves prediction of significant proteinuria in sub-groups with poor baseline test performance (such as women and the elderly) using ROC curve analysis. However when adjusted and unadjusted values were compared as predictors of outcome (using a net reclassification index analysis) adjusted values were significantly inferior. Urine creatinine is an independent predictor of mortality and hence may be directly contributing to the predictive value of TPCR and ACR rather than simply correcting for urine flow rate. As such, adjusting for ECE may act to remove the effect of a second independent predictor, leading to inferior test performance. Therefore the decision to adjust TPCR and ACR for ECE depends on the test application: to predict significant proteinuria adjustment of TPCR and ACR is of benefit, but adjustment leads to inferior performance as a prognostic test. The prevalence of CKD stages 3-5 was assessed using a general population laboratory database. Overall population prevalence was 5.63% using the modification of diet in renal disease (MDRD) formula and fell to 4.94% when the CKD-Epidemiology group (CKD-EPI) formulae were applied. Those reclassified to an earlier stage of CKD were predominantly middle aged women. Prevalence over a five year period was found to be stable using the CKD-EPI formulae but rose slightly according to MDRD. Proteinuria and eGFR were assessed as predictors of outcome in a large specialist hypertension clinic cohort. On multivariate survival analysis both baseline dipstick proteinuria and an eGFR<60ml/min/1.73m2 remained strong independent predictors of cardiovascular and all-cause mortality, despite intensive specialist intervention to control blood pressure. These simple tests should be advocated for risk stratification in these patients. Lastly the baseline characteristics of a community CKD cohort are presented. We recruited 411 participants from seven general practices around Ayrshire and a detailed baseline clinical and biochemical assessment was performed. Patients were invited to participate if they were included in the primary care register of CKD stages 3-5. Over a quarter had an eGFR>60ml/min/1.73m2 on the meat-fasted study sample. Proteinuria was of notably low prevalence and the cohort had a large burden of cardiovascular disease. Complications of renal disease were uncommon. The characteristics of the cohort differ from those under hospital follow-up. Their long term outcomes should contribute to refining risk stratification in this population. Proteinuria and eGFR are key aspects of diagnosis and monitoring in CKD. Identification of the optimal measures of both is essential and findings presented here contribute to that. There is a need to refine risk stratification in CKD, to identify those who require intensive intervention, and to reassure the rest. The findings of this thesis also contribute to that. Further study is required to refine the core aspects of diagnosis and investigation of CKD

a global network of chronic kidney disease cohorts

Background Chronic kidney disease (CKD) is a global health burden, yet it is still underrepresented within public health agendas in many countries. Studies focusing on the natural history of CKD are challenging to design and conduct, because of the long time-course of disease progression, a wide variation in etiologies, and a large amount of clinical variability among individuals with CKD. With the difference in health-related behaviors, healthcare delivery, genetics, and environmental exposures, this variability is greater across countries than within one locale and may not be captured effectively in a single study. Methods Studies were invited to join the network. Prerequisites for membership included: 1) observational designs with a priori hypotheses and defined study objectives, patient-level information, prospective data acquisition and collection of bio-samples, all focused on predialysis CKD patients; 2) target sample sizes of 1,000 patients for adult cohorts and 300 for pediatric cohorts; and 3) minimum follow-up of three years. Participating studies were surveyed regarding design, data, and biosample resources. Results Twelve prospective cohort studies and two registries covering 21 countries were included. Participants age ranges from >2 to >70 years at inclusion, CKD severity ranges from stage 2 to stage 5. Patient data and biosamples (not available in the registry studies) are measured yearly or biennially. Many studies included multiple ethnicities; cohort size ranges from 400 to more than 13,000 participants. Studies’ areas of emphasis all include but are not limited to renal outcomes, such as progression to ESRD and death. Conclusions iNET-CKD (International Network of CKD cohort studies) was established, to promote collaborative research, foster exchange of expertise, and create opportunities for research training. Participating studies have many commonalities that will facilitate comparative research; however, we also observed substantial differences. The diversity we observed across studies within this network will be able to be leveraged to identify genetic, behavioral, and health services factors associated with the course of CKD. With an emerging infrastructure to facilitate interactions among the investigators of iNET-CKD and a broadly defined research agenda, we are confident that there will be great opportunity for productive collaborative investigations involving cohorts of individuals with CKD

COVID-19 in patients undergoing chronic kidney replacement therapy and kidney transplant recipients in Scotland: findings and experience from the Scottish Renal Registry

BackgroundInfection with the severe acute respiratory coronavirus 2 (SARS-CoV-2) has led to a worldwide pandemic with coronavirus disease 2019 (COVID-19), the disease caused by SARS-CoV-2, overwhelming healthcare systems globally. Preliminary reports suggest a high incidence of infection and mortality with SARS-CoV-2 in patients receiving kidney replacement therapy (KRT). The aims of this study are to report characteristics, rates and outcomes of all patients affected by infection with SARS-CoV-2 undergoing KRT in Scotland.MethodsStudy design was an observational cohort study. Data were linked between the Scottish Renal Registry, Health Protection Scotland and the Scottish Intensive Care Society Audit Group national data sets using a unique patient identifier (Community Health Index (CHI)) for each individual by the Public Health and Intelligence unit of Public Health, Scotland. Descriptive statistics and survival analyses were performed.Results During the period 1st March 2020 to 31st May 2020, 110 patients receiving KRT tested positive for SARS-CoV-2 amounting to 2% of the prevalent KRT population. Of those affected, 86 were receiving haemodialysis or peritoneal dialysis and 24 had a renal transplant. Patients who tested positive were older and more likely to reside in more deprived postcodes. Mortality was high at 26.7% in the dialysis patients and 29.2% in the transplant patients. ConclusionThe rate of detected SARS-CoV-2 in people receiving KRT in Scotland was relatively low but with a high mortality for those demonstrating infection. Although impossible to confirm, it appears that the measures taken within dialysis units coupled with the national shielding policy, have been effective in protecting this population from infection. <br/

The impact of vaccination on incidence and outcomes of SARS-CoV-2 infection in patients with kidney failure in Scotland

Background: Patients with kidney failure requiring kidney replacement therapy (KRT) are at high risk of complications and death following SARS-CoV-2 infection with variable antibody responses to vaccination reported. We investigated the effects of COVID-19 vaccination on incidence of infection, hospitalization and death of COVID-19 infection. Methods: Study design was an observational data linkage cohort study. Multiple healthcare datasets were linked to ascertain all SARS-CoV-2 testing, vaccination, hospitalization, and mortality data for all patients treated with KRT in Scotland, from the start of the pandemic over a period of 20 months. Descriptive statistics, survival analyses, and vaccine effectiveness were calculated. Results: As of 19th September 2021, 93% (n=5281) of the established KRT population in Scotland had received two doses of an approved SARS-CoV-2 vaccine. Over the study period, there were 814 cases of SARS-CoV-2 infection (15.1% of the KRT population). Vaccine effectiveness against infection and hospitalization was 33% (95% CI 0-52) and 38% (95% CI 0-57) respectively. 9.2% of fully vaccinated individuals died within 28 days of a SARS-CoV-2 positive PCR test (7% dialysis patients and 10% kidney transplant recipients). This compares to &lt;0.1% of the vaccinated Scottish population being admitted to hospital or dying death due to COVID19 during that period. Conclusions: These data demonstrate a primary vaccine course of two doses has limited impact on COVID-19 infection and its complications in patients treated with KRT. Adjunctive strategies to reduce risk of both COVID-19 infection and its complications in this population are urgently required

Increasing numbers and improved overall survival of patients on kidney replacement therapy over the last decade in Europe : an ERA Registry study

Background The aim of this study was to describe the trends in the incidence, prevalence and survival of patients on kidney replacement therapy (KRT) for end-stage kidney disease (ESKD) across Europe from 2008 to 2017. Methods Data from renal registries in 9 countries and 16 regions that provided individual patient data to the ERA Registry from 2008 to 2017 were included. These registries cover 34% of the general population in Europe. Crude and standardized incidence and prevalence per million population (pmp) were determined. Trends over time were studied using Joinpoint regression. Survival probabilities were estimated using Kaplan-Meier analysis and hazard ratios (HRs) using Cox regression analysis. Results The standardized incidence of KRT was stable [annual percentage change (APC): -1.48 (-3.15; 0.21)] from 2008 (146.0 pmp) to 2011 (141.6 pmp), followed by a slight increase [APC: 1.01 (0.43; 1.60)] to 148.0 pmp in 2017, although trends in incidence varied across countries. This increase was primarily due to a rise in the incidence of KRT in men older than 65 years. Moreover, as a cause of kidney failure, diabetes mellitus is increasing. The standardized prevalence increased from 2008 (990.0 pmp) to 2017 (1166.8 pmp) [APC: 1.82 (1.75; 1.89)]. Patient survival on KRT improved in the time period 2011-13 compared with 2008-[adjusted HR: 0.94 (0.93; 0.95)]. Conclusion This study showed an overall increase in the incidence and prevalence of KRT for ESKD as well as an increase in the KRT patient survival over the last decade in Europe.Peer reviewe

A programme to spread eGFR graph surveillance for the early identification, support and treatment of people with progressive chronic kidney disease (ASSIST-CKD): protocol for the stepped wedge implementation and evaluation of an intervention to reduce late presentation for renal replacement therapy

Background Patients who start renal replacement therapy (RRT) for End-Stage Kidney Disease (ESKD) without having had timely access to specialist renal services have poor outcomes. At one NHS Trust in England, a community-wide CKD management system has led to a decline in the incident rate of RRT and the lowest percentage of patients presenting within 90 days of starting RRT in the UK. We describe the protocol for a quality improvement project to scale up and evaluate this innovation. Methods The intervention is based upon an off-line database that integrates laboratory results from blood samples taken in all settings stored under different identifying labels relating to the same patient. Graphs of estimated glomerular filtration rate (eGFR) over time are generated for patients 65 years with an incoming eGFR <40 ml/min/1.73 m2. Graphs where kidney function is deteriorating are flagged by a laboratory scientist and details sent to the primary care doctor (GP) with a prompt that further action may be needed. We will evaluate the impact of implementing this intervention across a large population served by a number of UK renal centres using a mixed methods approach. We are following a stepped-wedge design. The order of implementation among participating centres will be randomly allocated. Implementation will proceed with unidirectional steps from control group to intervention group until all centres are generating graphs of eGFR over time. The primary outcome for the quantitative evaluation is the proportion of patients referred to specialist renal services within 90 days of commencing RRT, using data collected routinely by the UK Renal Registry. The qualitative evaluation will investigate facilitators and barriers to adoption and spread of the intervention. It will include: semi-structured interviews with laboratory staff, renal centre staff and service commissioners; an online survey of GPs receiving the intervention; and focus groups of primary care staff. Discussion Late presentation to nephrology for patients with ESKD is a source of potentially avoidable harm. This protocol describes a robust quantitative and qualitative evaluation of a quality improvement intervention to reduce late presentation and improve the outcomes for patients with ESKD

Quality of Reporting and Study Design of CKD Cohort Studies Assessing Mortality in the Elderly Before and After STROBE:A Systematic Review

BACKGROUND:The STrengthening the Reporting of OBservational studies in Epidemiology (STROBE) statement was published in October 2007 to improve quality of reporting of observational studies. The aim of this review was to assess the impact of the STROBE statement on observational study reporting and study design quality in the nephrology literature. STUDY DESIGN:Systematic literature review. SETTING & POPULATION:European and North American, Pre-dialysis Chronic Kidney Disease (CKD) cohort studies. SELECTION CRITERIA FOR STUDIES:Studies assessing the association between CKD and mortality in the elderly (>65 years) published from 1st January 2002 to 31st December 2013 were included, following systematic searching of MEDLINE & EMBASE. PREDICTOR:Time period before and after the publication of the STROBE statement. OUTCOME:Quality of study reporting using the STROBE statement and quality of study design using the Newcastle Ottawa Scale (NOS), Scottish Intercollegiate Guidelines Network (SIGN) and Critical Appraisal Skills Programme (CASP) tools. RESULTS:37 papers (11 Pre & 26 Post STROBE) were identified from 3621 potential articles. Only four of the 22 STROBE items and their sub-criteria (objectives reporting, choice of quantitative groups and description of and carrying out sensitivity analysis) showed improvements, with the majority of items showing little change between the period before and after publication of the STROBE statement. Pre- and post-period analysis revealed a Manuscript STROBE score increase (median score 77.8% (Inter-quartile range [IQR], 64.7-82.0) vs 83% (IQR, 78.4-84.9, p = 0.05). There was no change in quality of study design with identical median scores in the two periods for NOS (Manuscript NOS score 88.9), SIGN (Manuscript SIGN score 83.3) and CASP (Manuscript CASP score 91.7) tools. LIMITATIONS:Only 37 Studies from Europe and North America were included from one medical specialty. Assessment of study design largely reliant on good reporting. CONCLUSIONS:This study highlights continuing deficiencies in the reporting of STROBE items and their sub-criteria in cohort studies in nephrology. There was weak evidence of improvement in the overall reporting quality, with no improvement in methodological quality of CKD cohort studies between the period before and after publication of the STROBE statement

Iohexol plasma clearance measurement protocol standardization for adults: a consensus paper of the European Kidney Function Consortium.

peer reviewedInternational consensus supports the development of standardized protocols for measured glomerular filtration rate (mGFR) to facilitate the integration of mGFR testing in both clinical and research settings. To this end, the European Kidney Function Consortium convened an international group of experts with relevant experience in mGFR. The working group performed an extensive literature search to inform the development of recommendations for mGFR determination using 1-compartment plasma clearance models and iohexol as the exogenous filtration marker. Iohexol was selected as it is non-radio labeled, inexpensive, and safe, can be assayed at a central laboratory, and the other commonly used non-radio-labeled tracers have been (inulin) or are soon to be (iothalamate) discontinued. A plasma clearance model was selected over urine clearance as it requires no urine collection. A 1 compartment was preferred to 2 compartments as it requires fewer samples. The recommendations are based on published evidence complemented by expert opinion. The consensus paper covers practical advice for patients and health professionals, preparation, administration, and safety aspects of iohexol, laboratory analysis, blood sample collection and sampling times using both multiple and single-sample protocols, description of the mGFR mathematical calculations, as well as implementation strategies. Supplementary materials include patient and provider information sheets, standard operating procedures, a study protocol template, and support for mGFR calculation