Christopher Farmer

Accuracy of the MDRD (Modification of Diet in Renal Disease) Study and CKD-EPI (CKD Epidemiology Collaboration) Equations for Estimation of GFR in the Elderly

BACKGROUND Glomerular filtration rate (GFR) is a measure of kidney function, commonly estimated using equations that adjust serum creatinine concentration for age, race, and sex. The Modification of Diet in Renal Disease (MDRD) Study equation is widely used, but underestimates GFR at higher levels. The serum creatinine-based Chronic Kidney Disease-Epidemiology Collaboration (CKD-EPI(cr)) equation generally provides more accurate estimation at GFR >60 mL/min/1.73 m(2). Newer equations have been reported using cystatin C concentration either alone (CKD-EPI(cys)) or in combination with creatinine concentration (CKD-EPI(cr-cys)). None of these equations has been well validated in older people. We tested the accuracy of these equations in people 74 years or older compared with GFR measured by a reference method. STUDY DESIGN Diagnostic test evaluation in a prospective cohort. SETTING & PARTICIPANTS Participants (n = 394; median age, 80 [range, 74-97] years) recruited from nephrology clinics and the community. INDEX TEST GFR estimated using the MDRD Study, CKD-EPI(cr), CKD-EPI(cys) and CKD-EPI(cr-cys) equations. REFERENCE TEST GFR measured using an iohexol clearance method. RESULTS Median measured GFR was 53.4 (range, 7.2-100.9) mL/min/1.73 m(2). MDRD Study-, CKD-EPI(cr)-, and CKD-EPI(cr-cys)-estimated GFRs overestimated GFR (median differences of 3.5 [P< 0.001], 1.7 [P < 0.001], and 0.8 [P = 0.02] mL/min/1.73 m(2), respectively); the CKD-EPI(cys) equation was unbiased. Accuracy (percentage of estimates within 30% of measured GFR [P(30)]) was 81%, 83%, 86%, and 86% for the MDRD Study, CKD-EPI(cr), CKD-EPI(cys), and CKD-EPI(cr-cys) equations, respectively. Accuracy of the MDRD Study equation was inferior (P = 0.004) to the CKD-EPI(cr) equation at GFR >60 mL/min/1.73 m(2). LIMITATIONS Those of non-European ancestry were not included. For practical reasons, only a 4-hour sampling protocol was used for iohexol clearance. CONCLUSIONS The CKD-EPI(cr) equation appeared less biased and was more accurate than the MDRD Study equation. No equation achieved an ideal P(30) in the overall population. Our data suggest that GFR estimation is as satisfactory in older people of European ancestry as it has been reported to be in younger individuals.

The allogeneic T and B cell response is strongly dependent on complement components C3 and C4.

BACKGROUND The mechanisms controlling the production of antibodies against histocompatibility antigens are of prime importance in organ transplantation. METHODS We investigated the role of complement in the response to allogeneic stimulation, using mice deficient in C3, C4, or C5 to dissect the role of the alternative, classical, and terminal complement pathways. RESULTS After fully major histocompatibility complex disparate skin grafts, the allospecific immunoglobulin (Ig)G response was markedly impaired in C3- and C4-, but not in C5-deficient mice. This defect was most pronounced for second set responses. C3-deficient mice also demonstrated a decreased range of IgG isotypes. In contrast, there was no impairment of the allospecific IgM response. In functional T cell assays, the proliferative response and interferon-gamma secretion of recipient lymphocytes restimulated in vitro with donor antigen was decreased two- to threefold in C3-deficient mice. CONCLUSIONS These data show impairment of allogeneic T cell and B cell function in mice with defective complement activation and suggest a predominant role for the classical pathway in stimulating alloimmunity. The terminal pathway seems unimportant in this regard. This extends the results reported for soluble protein antigens and demonstrates a surprisingly marked effect on the alloresponse despite the presence of a stringent antigenic stimulus. These results have implications for the prevention of sensitization in naïve transplant recipients.

Assessing the prevalence, monitoring and management of chronic kidney disease in patients with diabetes compared with those without diabetes in general practice.

Aims  To compare rates of chronic kidney disease (CKD) in patients with diabetes and management of risk factors compared with people without diabetes using general practice computer records, and to assess the utility of serum creatinine and albuminuria as markers of impaired renal function.

Change in the estimated glomerular filtration rate over time and risk of all-cause mortality

Using a community-based cohort we studied the association between changes in the estimated glomerular filtration rate (eGFR) over time and the risk of all-cause mortality. We identified 529,312 adults who had at least three outpatient eGFR measurements over a 4-year period from a provincial laboratory repository in Alberta, Canada. Two indices of change in eGFR were evaluated: the absolute annual rate of change (in ml/min per 1.73 m(2) per year) and the annual percentage change (percent/year). The adjusted mortality risk associated with each category of change in eGFR was assessed, using stable eGFR (no change) as the reference. Over a median follow-up of 2.5 years there were 32,372 deaths. Compared to the reference participants, those with the greatest absolute annual decline less than or equal to 5 ml/min per 1.73 m(2) per year had significantly increased mortality (hazard ratio of 1.52) adjusted for covariates and kidney function at baseline (last eGFR measurement). Participants with the greatest increase in eGFR of 5 ml/min per 1.73 m(2) per year or more also had significantly increased mortality (adjusted hazard ratio of 2.20). A similar pattern was found when change in eGFR was quantified as an annual percentage change. Thus, both declining and increasing eGFR were independently associated with mortality and underscore the importance of identifying change in eGFR over time to improve mortality risk prediction.

External validation of the Berlin equations for estimation of GFR in the elderly.

Chronic kidney disease prevalence increases markedly with age1 and accurate estimation of GFR is an important issue in older people. The Chronic Kidney Disease Epidemiology Collaboration creatinine equation (CKD-EPIcr)2 and variations including cystatin C (CKD-EPIcys) or both creatinine and cystatin C (CKD-EPIcr-cys)3 have been recommended for estimating GFR.4 Recently, the Berlin Initiative Study (BIS) reported 2 GFR equations specifically developed in older people: BIS1, which uses creatinine, and BIS2, which uses both creatinine and cystatin C.5 Here, we compare how the BIS and CKD-EPI equations perform in a large cohort of older people.

One-Year Change in Kidney Function Is Associated with an Increased Mortality Risk

Background: Serum creatinine is routinely measured to estimate glomerular filtration rate (GFR). Long-term cohort studies report that death is a likelier outcome than progression to kidney failure. However, it is unclear how short-term changes in estimated GFR (eGFR) over a 1-year period relate to subsequent mortality risk. Methods: Using a provincial laboratory registry from Alberta, Canada, we identified 598,397 adults who had ≥2 outpatient eGFR measurements at least 6 months apart during a 1-year accrual period. Change in kidney function was categorized by both changes in eGFR category and percent change ≥25% into 5 groups: certain drop, uncertain drop, stable (no change in CKD category), uncertain rise, and certain rise. Cox proportional hazards models, adjusting for baseline covariates, kidney function, and proteinuria were used to estimate the risk of all-cause mortality associated with each group change in kidney function in reference to stable kidney function. Results: Among the study participants, 447,570 (74.8%) had stable kidney function, 19,591 (3.3%) had a certain drop, and 22,171 (3.7%) had a certain rise in kidney function. Participants with change in kidney function (both drop and rise) were older, more likely to be female, and had a higher prevalence of comorbidities in comparison to those with stable kidney function. There were 51,473 (8.6%) deaths during a median follow-up of 3.5 years. Compared to participants with stable kidney function, those with a certain drop had an almost twofold increased mortality risk (hazard ratio 1.89, 95% CI 1.83–1.95) adjusted for baseline eGFR, proteinuria, and covariates. Participants with a certain rise (3.7%) in kidney function also experienced an increased mortality risk (hazard ratio 1.51, 95% CI 1.46–1.56) compared to those with stable kidney function. Risk of death was similarly increased with adjustment for eGFR at the last visit. Conclusion: Change in kidney function of ≥25% in any direction over a 1-year period is associated with a substantially increased risk of mortality.

The impact of pay for performance on the control of blood pressure in people with chronic kidney disease stage 3–5

BACKGROUND The implementation of national estimated glomerular filatration rate reporting and the inclusion of renal-specific indicators in a primary care pay for performance (P4P) system since April 2006 has promoted identification and better management of risk factors related to chronic kidney disease (CKD). In the UK, the P4P framework is known as the Quality and Outcomes Framework (QOF). One of the key targets for intervention in primary care was hypertension. It is clear that hypertension is a major predictor of development and progression of CKD; thus, targeting better blood pressure control is likely to have a positive impact on outcomes in CKD. The aim of this study was to evaluate the effectiveness of renal indicators outlined in P4P on the management of hypertension in primary care. To estimate the cost implications of the resulting changes in prescribing patterns of antihypertensive medication following introduction of such indicators. METHODS We performed a prospective cohort study using a large primary care database. This cohort was taken from a database collated as part of a clinical decision support system used to assist the management of CKD in primary care. We investigated a total population of 90 250 individuals on general practitioner (GP) registers with a valid serum creatinine estimation in the 6-year study period. A total of 10 040 patients had confirmed stage 3-5 CKD in the 2 years pre-QOF and formed the study cohort. Patients were studied over three time periods, pre-QOF (1 April 2004 to 31 March 2006), 2 years post-QOF (1 April 2006 to 31 March 2008) and finally the two subsequent years (1 April 2008 to 31 March 2010). The mean systolic and diastolic blood pressures (BP) together with antihypertensive medication were analysed over the three time periods. Cost calculation was based on 2009 British National Formulary list prices for antihypertensives. RESULTS The mean age of the cohort at the start of the study period was 64.8 years, 55% were female. In those patients with stage 3-5 CKD 83.9% were hypertensive, defined by a pre-P4P BP of >140/85 or currently taking antihypertensive medication. The proportion of patients with CKD 3-5 attaining the BP target of 145/80 increased from 41.5% in the pre-QOF period to 50.0% in the post-QOF period. This increase was even more marked for those with hypertension in the pre-QOF period (28.8-45.1%). In the hypertensive patients, mean BP fell from 146/79 mmHg to 140/76 in the first 2 years post-P4P [P < 0.01, analysis of variance (ANOVA)]. This BP reduction was sustained in the last 2 years of the study, 139/75 (P < 0.01, ANOVA). The proportion of hypertensive patients taking angiotensin-converting enzyme inhibitors or angiotensin blockers increased, this was also sustained in the third time period. An increase in the prescribing of diuretics, calcium channel blockers and β-blockers was also observed. The additional cost of increased prescribing was calculated to be €25.00 per hypertensive patient based on GP prescription data. CONCLUSIONS Population BP control has improved since the introduction of P4P renal indicators, and this improvement has been sustained. This was associated with a significant increase in the use of antihypertensive medication, resulting in increased prescription cost. Longer-term follow-up will establish whether or not this translates to improved outcomes in terms of progression of CKD, cardiovascular disease and patient mortality.

Referral patterns to renal services: what has changed in the past 4 years?

BACKGROUND Awareness of chronic kidney disease (CKD) has been prompted by the publication of several large epidemiological studies since 2002. This has led to various initiatives for the early identification and management of CKD, including the introduction of automated glomerular filtration rate (GFR) reporting and renal indicators in the primary care quality and outcomes framework (QOF) since April 2006. These initiatives were intended to promote identification of CKD and have had an impact on referral patterns to renal services. The aim of this study was to understand the nature of this impact in a catchment population of 1.2 million people. METHODS Data were collected and recorded from all written referrals from primary care between 1 April 2004 and 31 March 2008. Referral patterns for each postcode sector were mapped using Microsoft MapPoint 2004. The effect of chance on referral patterns was modelled by using small area analysis techniques. The association between the CKD prevalence reported from QOF data and the estimated CKD prevalence was examined at post-code district level. RESULTS There were 1461 referrals in 2 years prior to the introduction of the initiatives and 2890 referrals in the 2 years post-introduction. The main reason for referral in both groups was impaired renal function or previously established renal disease. Reported comorbidity was similar between the groups. Mapping showed that there was wide heterogeneity in referral behaviour in the first 2 years of the study, which was less in the second period. Small area analysis suggested that the variation that led to the extremal quotients observed in both of the study periods was not due to random variation in referral pattern alone. There was no correlation between the reported CKD prevalence and the referral rates. CONCLUSION Referral patterns have changed between 1 April 2004 and 31 March 2008. The main findings were an increase in referral rate and in the age at referral without a significant change in reported comorbidity of the people referred. The main increase in referral rates was seen in more advanced CKD suggesting more targeted referral of patients with CKD to renal services.

Biological Variation of Plasma and Urinary Markers of Acute Kidney Injury in Patients with Chronic Kidney Disease

BACKGROUND Identification of acute kidney injury (AKI) is predominantly based on changes in plasma creatinine concentration, an insensitive marker. Alternative biomarkers have been proposed. The reference change value (RCV), the point at which biomarker change can be inferred to have occurred with statistical certainty, provides an objective assessment of change in serial tests results in an individual. METHODS In 80 patients with chronic kidney disease, weekly measurements of blood and urinary biomarker concentrations were undertaken over 6 weeks. Variability was determined and compared before and after adjustment for urinary creatinine and across subgroups stratified by level of kidney function, proteinuria, and presence or absence of diabetes. RESULTS RCVs were determined for whole blood, plasma, and urinary neutrophil gelatinase-associated lipocalin (111%, 59%, and 693%, respectively), plasma cystatin C (14%), creatinine (17%), and urinary kidney injury molecule 1 (497%), tissue inhibitor of metalloproteinases 2 (454%), N-acetyl-β-d-glucosaminidase (361%), interleukin-18 (819%), albumin (430%), and α1-microglobulin (216%). Blood biomarkers exhibited lower variability than urinary biomarkers. Generally, adjusting urinary biomarker concentrations for creatinine reduced (P < 0.05) within-subject biological variability (CVI). For some markers, variation differed (P < 0.05) between subgroups. CONCLUSIONS These data can form a basis for application of these tests in clinical practice and research studies and are applicable across different levels of kidney function and proteinuria and in the presence or absence of diabetes. Most of the studied biomarkers have relatively high CVI (noise) but also have reported large concentration changes in response to renal insult (signal); thus progressive change should be detectable (high signal-to-noise ratio) when baseline data are available.

IS HIGH BODY MASS INDEX INDEPENDENTLY ASSOCIATED WITH DIMINISHED GLOMERULAR FILTRATION RATE? AN EPIDEMIOLOGICAL STUDY

AIM To examine whether there is an independent association between body mass index (BMI) and estimated glomerular filtration rate (GFR) in a large primary care population. METHODS Anonymous data were sequentially extracted from primary care records between 2006 and 2009 in a primary care population of approximately 220,000 people in Kent, South East UK. Using GFR, BMI, age, gender and comorbidities we examined the association between BMI and GFR. Univariate and multivariate analysis was performed using SPSS(®) (SPSS Inc., Chicago). RESULTS Sixty-one thousand six-hundred thirty seven people fulfilled the inclusion criteria. There was no correlation between BMI and GFR on univariate analysis. When stratified by BMI, ANOVA demonstrated a statistically significant difference in GFR across BMI strata (p < 0.001). However the absolute differences in BMI between groups were very small. There was a small association between BMI and GFR on multivariate analysis, much of which was lost on adjustment for confounding variables. CONCLUSION These findings suggest that elevated BMI is not a biologically significant predictor of diminished GFR and therefore may be an insufficiently accurate measure of risk for the metabolic syndrome and CKD.