Shona Methven

Assessing proteinuria in chronic kidney disease: protein–creatinine ratio versus albumin–creatinine ratio

BACKGROUND Quantification of proteinuria is important in the assessment of chronic kidney disease (CKD). The aim of this study was to investigate the optimal test to identify significant proteinuria. METHODS We retrospectively assessed the relationship between total protein:creatinine ratio (TPCR), albumin:creatinine ratio (ACR) and 24-h urine total protein in 6842 patients with CKD focusing on performance at thresholds of 0.5 and 1 g/day of proteinuria. RESULTS The relationship between ACR and TPCR is non-linear. TPCR is highly correlated with 24-h urine protein (Spearmans rho = 0.91), though ACR also performs well (rho = 0.84). Using receiver-operator characteristic curve analysis, TPCR outperforms ACR at predicting 0.5 g/day [area under the curve (AUC) 0.967 vs 0.951, P < 0.001] and 1 g/day of proteinuria (AUC 0.968 vs 0.947, P = 0.004). A TPCR threshold of 100 mg/mmol had a higher sensitivity (94% vs 79%) but lower specificity (88% vs 95%) than an ACR of 70 mg/mmol to predict 1 g/day of total proteinuria. To achieve comparable sensitivity, the ACR threshold falls to 17.5 mg/mmol, with lower specificity than TPCR (69.8%). Sensitivity of TPCR rose with increasing age, and in females: to achieve 95% sensitivity in a man <49 years, requires a TPCR of 65 mg/mmol, compared to 179 mg/mmol in a woman >79 years. Non-albumin proteinuria was a lower proportion of total proteinuria in patients receiving angiotensin-converting enzyme inhibitors or angiotensin receptor blockade than in those who were not (P < 0.001). CONCLUSIONS TPCR is a more sensitive screening test than ACR to predict clinically relevant proteinuria. The diagnostic performance of both tests varies substantially with age and gender, and should be taken into consideration when interpreting results. Total proteinuria cannot be adequately predicted from ACR, and our results suggest that caution is appropriate before utilizing ACR in patients with non-diabetic CKD.

Comparison of Urinary Albumin and Urinary Total Protein as Predictors of Patient Outcomes in CKD

BACKGROUND Proteinuria is common and is associated with adverse patient outcomes. The optimal test of proteinuria to identify those at risk is uncertain. This study assessed albuminuria and total proteinuria as predictors of 3 patient outcomes: all-cause mortality, start of renal replacement therapy (RRT), and doubling of serum creatinine level. STUDY DESIGN Retrospective longitudinal cohort study. SETTING & PARTICIPANTS Nephrology clinic of a city hospital in Scotland; 5,586 patients with chronic kidney disease (CKD) and proteinuria measured in random urine samples (n = 3,378) or timed urine collections (n = 1,808). PREDICTORS Baseline measurements of albumin-creatinine ratio (ACR), total protein-creatinine ratio (PCR), 24-hour albuminuria, and total proteinuria. OUTCOMES All-cause mortality, start of RRT, and doubling of serum creatinine level were assessed using receiver operating characteristic curves and Cox proportional hazards models. MEASUREMENTS Blood pressure, serum creatinine level, ACR, PCR, date of death, date of starting RRT. RESULTS Patients were followed up for a median of 3.5 (25th-75th percentile, 2.1-6.0) years. For all outcomes, adjusted HRs were similar for PCR and ACR (derived from random urine samples and timed collections): death, 1.41 (95% CI, 1.31-1.53) vs 1.38 (95% CI, 1.28-1.50); RRT, 1.96 (95% CI, 1.76-2.18) vs 2.33 (95% CI, 2.06-3.01); and doubling of serum creatinine level, 2.03 (95% CI, 1.87-2.19) vs 1.92 (95% CI, 1.78-2.08). Receiver operating characteristic curves showed almost identical performance for ACR and PCR for the 3 outcome measures. Adjusted HRs for ACR and PCR were similar when derived from random urine samples or timed collections and compared with 24-hour total protein and albumin excretion for each outcome measure. LIMITATIONS This is a retrospective study. CONCLUSIONS Total proteinuria and albuminuria perform equally as predictors of renal outcomes and mortality in patients with CKD. ACR and PCR were as effective as 24-hour urine samples at predicting outcomes and are more convenient for patients, clinicians, and laboratories. Both ACR and PCR stratify risk in patients with CKD.

Stratifying risk in chronic kidney disease: an observational study of UK guidelines for measuring total proteinuria and albuminuria*

BACKGROUND Proteinuria predicts poor renal and cardiovascular outcomes. Some guidelines recommend measuring proteinuria using albumin:creatinine ratio (ACR), while others recommend total protein:creatinine ratio (TPCR). AIM To compare renal outcomes and mortality in the populations identified by these different recommendations. DESIGN Retrospective longitudinal cohort study. METHODS Baseline ACR and TPCR measurements were obtained from 5586 patients with chronic kidney disease (CKD) attending a Scottish hospital nephrology clinic. The cohort was divided into three groups with concordant results by ACR and TPCR (no proteinuria; low proteinuria; significant proteinuria) and one group with discordant results (significant proteinuria with TPCR, but not ACR). Outcomes were assessed using Kaplan-Meier plots and Cox proportional hazards models. RESULTS Median follow-up was 3.5 years [interquartile range (IQR) 2.1-6.0]; 844 (15%) died at 3.0 years (IQR 1.8-4.7) and 468 (8%) started renal replacement therapy (RRT) at 1.7 years (IQR 0.6-3.4). Proteinuria was associated with a substantially increased risk of RRT and death. Patients with significant proteinuria by TPCR, but not ACR (n = 231) had high renal risk, and the highest all-cause mortality (log-rank P < 0.001). With multivariate analysis the risk fell below those with significant proteinuria with concordant results by ACR and TPCR but remained considerably higher than those without significant proteinuria. CONCLUSION Proteinuria screening with TPCR identifies an additional 16% of patients with significant proteinuria, not identified using ACR. This subgroup has high renal risk, and high risk of all-cause mortality and therefore warrant identification. Guideline recommendations on proteinuria screening in CKD should be reconsidered.

Chronic kidney disease prevalence and secular trends in a UK population: the impact of MDRD and CKD-EPI formulae

INTRODUCTION Most UK laboratories use the MDRD4 formula to estimate glomerular filtration rate (eGFR), but this may exaggerate chronic kidney disease (CKD) prevalence. In a large adult population, we examined the impact of the more accurate CKD-EPI formulae on prevalence estimates, and on secular trends in prevalence. METHODS We extracted all serum creatinine (SCr) results for adults, processed in our laboratory during two 1-year periods (2004, 2009-10). To minimize the effect of acute illness, a patients lowest SCr was used for each period. eGFR (traceable to isotope dilution mass spectrometry value) was calculated using the MDRD4 and CKD-EPI formulae. Prevalence estimates were compared, with sub-group analysis by age and sex. RESULTS In 2004, 102 322 patients had SCr tested (35.4% of the adult population), rising to 123 121 (42.3%) in 2009-10. The proportion tested rose with age to 86% of 85- to 89-year olds. The prevalence of CKD stages 3-5 was lower with the CKD-EPI formulae than the MDRD4 formula. The CKD-EPI formulae reclassified 17 014 patients (5.8%) to milder stages of CKD, most commonly from eGFR 60-89 ml/min/1.73m(2) and CKD stage 3A, in women, and in those <70 years old. 5172 patients (1.8%), mostly elderly women, were reclassified to more severe stages of CKD. Between the two time periods, the prevalence of CKD stages 3-5 rose from 5.44% to 5.63% of the population using MDRD4, but was static at 4.94% with CKD-EPI. CONCLUSION The CKD-EPI formulae, which are more accurate than the MDRD4 formula at higher GFR, reduced the estimated prevalence of CKD stages 3-5 by 0.5% in 2004 and 0.7% in 2009-10. The greatest reclassification was seen in CKD 3A, particularly amongst middle-aged females. The minor rise in CKD prevalence between 2004 and 2009-10 seen with the MDRD4 formula was not confirmed with the CKD-EPI formulae. The CKD-EPI formulae may reduce overdiagnosis of CKD, but further assessment in the elderly is required before widespread implementation.

Socio-economic status influences chronic kidney disease prevalence in primary care: a community-based cross-sectional analysis

BACKGROUND Primary care chronic kidney disease (CKD) registers report widely varying prevalence within the UK. We examined the effects of laboratory ascertainment and adjusting for practice-level variables on the variation in CKD prevalence. We carried out an Ayrshire-wide laboratory database analysis of primary care practices (PCPs). METHODS We analysed 54 PCPs with 313 639 registered patients aged ≥ 18. All patients with a low estimated glomerular filtration rate (<60 mL/min/1.73 m(2)) had their serum creatinine values extracted from 1st January 2009 to 31st March 2012. Individuals with CKD stage 3-5 were identified with an algorithm that confirmed chronicity. These data were linked to PCP attributes from Information Services Division, Scotland. Using laboratory-ascertained CKD prevalence, we examined whether adjusting for practice-level factors [socio-economic status (SES), rurality and patients to general practitioner ratio (PGR)] and patient-level factors (age, gender) explained some of the observed variation among PCPs. Individual and combined hierarchical multilinear regression models were used. RESULTS Eighteen thousand two hundred and eighty-five (5.8%) had CKD stage 3-5 on 31 March 2011. SES, rurality and PGR predicted 39% (F(3,50) = 12.37, P < 0.001) of the variation in prevalence with SES exerting the most influence (25%). With the stepwise addition of explanatory variables, variation between practices fell from 3.9-fold using PCP register prevalence to laboratory ascertained (3.1-fold variation), with age and gender adjustment (further fall to 2.1-fold), and lastly to 1.8-fold variation with adjustment for SES. Funnel plots using these adjustments reduced the number of outliers outside of 3 SD from 15 to 7 to 6, and outliers between 2 and 3 SD by 16 to 13 to 5. CONCLUSIONS Laboratory ascertainment is practicable, reduces variation and facilitates benchmarking. PCP attributes other than age and gender impact on prevalence. Over a third of variation in CKD prevalence among PCPs can be explained by rurality, PGR and especially SES even after age and gender stratification.

Proteinuria and outcome after renal transplantation; ratios or fractions?

Background Proteinuria is associated with poorer outcomes in renal transplant recipients. Fractional excretion of total protein (FEPR) may better reflect kidney damage than urine protein-to-creatinine ratio (PCR). Methods We assessed FEPR (FEPR = [serum creatinine × urine protein] / [serum protein × urine creatinine], %) and PCR ([urinary protein/urinary creatinine] × 1000, mg/mM) 1 year after first renal transplantation as predictors of transplant failure. The primary endpoints were transplant failure and death. The use of the tests was analyzed by constructing receiver operator characteristic curves and comparing the area under the curve. Using receiver operator characteristic analysis, patients were stratified into high- and low-risk groups. Results Two hundred nineteen recipients were followed up for a median of 4.9 years. At a median of 2.7 years, 11.4% (n=25) of the transplants failed. Eight percent (n=17) of the patients died. The area under the curve was higher for FEPR than PCR (0.92 vs. 0.84). Patients with an FEPR of 0.019% or higher had a 3.4-fold (P=0.003) increased risk of transplant failure and a 2.3-fold (P=0.02) increased risk of death compared with those with an FEPR of less than 0.019%. Patients with a PCR of 97 mg/mM or greater had a 2.1-fold (P=0.04) increased risk of transplant failure and a 1.6-fold (P=0.04) increased risk of death compared with those with a PCR of less than 97 mg/mM (P=0.04). In multivariate analysis with time to transplant failure as the dependent variable, FEPR and PCR were independent predictors of transplant failure (hazards ratio, 1.07 [P=0.013] and 1.03 [P=0.03], respectively). Conclusions FEPR and PCR at 1 year are independent predictors of transplant failure, but FEPR may be superior.

Chapter 1 UK Renal Replacement Therapy Adult Incidence in 2016: National and Centre-specific Analyses

This article is licensed under the Creative Commons AttributionNonCommercial-NoDerivatives 4.0 International License (CC BYNC-ND) (http://www.karger.com/Services/OpenAccessLicense). Usage and distribution for commercial purposes as well as any distribution of modified material requires written permission. Barnaby Hole UK Renal Registry, Southmead Hospital, Southmead Road, Bristol, BS10 5NB, UK Email: renalregistry@renalregistry.nhs.uk Nephron 2018;139(suppl1):13–46

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.

Empiricism or rationalism: how should we measure proteinuria?

Proteinuria is the cardinal sign of renal disease, therefore accurate identification of clinically significant proteinuria is essential to the diagnosis and management of kidney disease. Spot samples are now widely used, namely protein: creatinine ratio (uPCR) and albumin: creatinine ratio (uACR). In this article we review the evidence comparing uPCR and uACR including clinical, laboratory and financial arguments. uPCR has a superior performance to uACR to predict 24-hour total proteinuria, the measurement on which the evidence for interventions in chronic kidney disease is based. Furthermore a retrospective study comparing uPCR and uACR as predictors of renal outcome found comparable performance to predict all-cause mortality, commencement of renal replacement therapy and doubling of serum creatinine. Only uPCR takes account of non-albumin proteinuria which has been shown to have prognostic significance. uACR was been thought to be superior at low levels (where there is less ‘noise’ from physiological urinary proteins), but uPCR has recently been shown to perform well at levels equivalent to <0.5 g/day (and even within the reference range) as a predictor of outcomes. uACR is measured using an immunoassay that may be technically superior, but is not without shortcomings (such as antigen excess) and is 2–10 times more expensive than uPCR. The theories explaining the superiority of albumin are appealing. However, the available comparative data do not seem to support the theory. We cannot explain the disparity, but in science, if the data do not fit the existing theory, then maybe its time for a new theory.

Routinely measured iohexol glomerular filtration rate versus creatinine-based estimated glomerular filtration rate as predictors of mortality in patients with advanced chronic kidney disease: a Swedish Chronic Kidney Disease Registry cohort study

Background. Estimated glomerular filtration rate (eGFR) becomes less reliable in patients with advanced chronic kidney disease (CKD). Methods. Using the Swedish CKD Registry (2005‐11), linked to the national inpatient, dialysis and death registers, we compared the performance of plasma‐iohexol measured GFR (mGFR) and urinary clearance measures versus eGFR to predict death in adults with CKD stages 4/5. Performance was assessed using survival and prognostic models. Results. Of the 2705 patients, 1517 had mGFR performed, with the remainder providing 24‐h urine clearances. Median eGFR (CKD‐EPIcreatinine) was 20 mL/min/1.73 m2 [interquartile range (IQR) 14‐26], mGFR 18 mL/min/1.73 m2 (IQR 13‐23) and creatinine clearance 23 mL/min (IQR 15‐31). Median follow‐up was 45 months (IQR 26‐59), registering 968 deaths (36%). In fully adjusted Cox models, a rise in mGFR of 1 mL/min/1.73 m2 was associated with a 5.3% fall in all‐cause mortality compared with a 1.7% corresponding fall for eGFR [adjusted hazard ratio (aHR) 0.947 (95% CI, 0.930‐0.964) versus aHR 0.983 (95% CI, 0.970‐0.996)]. mGFR was also statistically superior in prognostic models (discrimination using logistic regression and integrated discrimination improvement). Urinary clearance measures showed a stronger aetiological relationship with death than eGFR, but were not statistically superior in the prognostic models. Conclusions. The performance of mGFR was superior to eGFR, in both aetiological and prognostic models, in predicting mortality in adults with CKD stage 4/5, demonstrating the importance of GFR per se versus non‐GFR determinants of outcome. However, the relatively modest enhancement suggests that eGFR may be sufficient to use in everyday clinical practice while mGFR adds important prognostic information for those where eGFR is believed to be biased.