Matthew T. James

Relation Between Kidney Function, Proteinuria, and Adverse Outcomes

CONTEXT The current staging system for chronic kidney disease is based primarily on estimated glomerular filtration rate (eGFR) with lower eGFR associated with higher risk of adverse outcomes. Although proteinuria is also associated with adverse outcomes, it is not used to refine risk estimates of adverse events in this current system. OBJECTIVE To determine the association between reduced GFR, proteinuria, and adverse clinical outcomes. DESIGN, SETTING, AND PARTICIPANTS Community-based cohort study with participants identified from a province-wide laboratory registry that includes eGFR and proteinuria measurements from Alberta, Canada, between 2002 and 2007. There were 920 985 adults who had at least 1 outpatient serum creatinine measurement and who did not require renal replacement treatment at baseline. Proteinuria was assessed by urine dipstick or albumin-creatinine ratio (ACR). MAIN OUTCOME MEASURES All-cause mortality, myocardial infarction, and progression to kidney failure. RESULTS The majority of individuals (89.1%) had an eGFR of 60 mL/min/1.73 m(2) or greater. Over median follow-up of 35 months (range, 0-59 months), 27 959 participants (3.0%) died. The fully adjusted rate of all-cause mortality was higher in study participants with lower eGFRs or heavier proteinuria. Adjusted mortality rates were more than 2-fold higher among individuals with heavy proteinuria measured by urine dipstick and eGFR of 60 mL/min/1.73 m(2) or greater, as compared with those with eGFR of 45 to 59.9 mL/min/1.73 m(2) and normal protein excretion (rate, 7.2 [95% CI, 6.6-7.8] vs 2.9 [95% CI, 2.7-3.0] per 1000 person-years, respectively; rate ratio, 2.5 [95% CI, 2.3-2.7]). Similar results were observed when proteinuria was measured by ACR (15.9 [95% CI, 14.0-18.1] and 7.0 [95% CI, 6.4-7.6] per 1000 person-years for heavy and absent proteinuria, respectively; rate ratio, 2.3 [95% CI, 2.0-2.6]) and for the outcomes of hospitalization with acute myocardial infarction, end-stage renal disease, and doubling of serum creatinine level. CONCLUSION The risks of mortality, myocardial infarction, and progression to kidney failure associated with a given level of eGFR are independently increased in patients with higher levels of proteinuria.

Early recognition and prevention of chronic kidney disease

Chronic kidney disease is a common disorder and its prevalence is increasing worldwide. Early diagnosis on the basis of presence of proteinuria or reduced estimated glomerular filtration rate could permit early intervention to reduce the risks of cardiovascular events, kidney failure, and death that are associated with chronic kidney disease. In developed countries, screening for the disorder is most efficient when targeted at high-risk groups including elderly people and those with concomitant illness (such as diabetes, hypertension, or cardiovascular disease) or a family history of chronic kidney disease, although the role of screening in developing countries is not yet clear. Effective strategies are available to slow the progression of chronic kidney disease and reduce cardiovascular risk. Treatment of high blood pressure is recommended for all individuals with, or at risk of, chronic kidney disease. Use of angiotensin-converting-enzyme inhibitors or angiotensin-receptor blockers is preferred for patients with diabetic chronic kidney disease or those with the proteinuric non-diabetic disorder. Glycaemic control can help prevent the onset of early stages of chronic kidney disease in individuals with diabetes. Use of statins and aspirin is beneficial for most patients with chronic kidney disease who are at high cardiovascular risk, although research is needed to ascertain how to best prevent cardiovascular disease in this cohort. Models of care that facilitate delivery of the many complex aspects of treatment simultaneously could enhance management, although effects on clinical outcomes need further assessment. Novel clinical methods to better identify patients at risk of progression to later stages of chronic kidney disease, including kidney failure, are needed to target management to high-risk subgroups.

Risk of coronary events in people with chronic kidney disease compared with those with diabetes: a population-level cohort study

BACKGROUND Diabetes is regarded as a coronary heart disease risk equivalent-ie, people with the disorder have a risk of coronary events similar to those with previous myocardial infarction. We assessed whether chronic kidney disease should be regarded as a coronary heart disease risk equivalent. METHODS We studied a population-based cohort with measures of estimated glomerular filtration rate (eGFR) and proteinuria from Alberta, Canada. We used validated algorithms based on hospital admission and medical-claim data to classify participants with baseline history of myocardial infarction or diabetes and to ascertain which patients were admitted to hospital for myocardial infarction during follow-up (the primary outcome). For our primary analysis, we defined baseline chronic kidney disease as eGFR 15-59·9 mL/min per 1·73 m(2) (stage 3 or 4 disease). We used Poisson regression to calculate unadjusted rates and relative rates of myocardial infarction during follow-up for five risk groups: people with previous myocardial infarction (with or without diabetes or chronic kidney disease), and (of those without previous myocardial infarction), four mutually exclusive groups defined by the presence or absence of diabetes and chronic kidney disease. FINDINGS During a median follow-up of 48 months (IQR 25-65), 11,340 of 1,268,029 participants (1%) were admitted to hospital with myocardial infarction. The unadjusted rate of myocardial infarction was highest in people with previous myocardial infarction (18·5 per 1000 person-years, 95% CI 17·4-19·8). In people without previous myocardial infarction, the rate of myocardial infarction was lower in those with diabetes (without chronic kidney disease) than in those with chronic kidney disease (without diabetes; 5·4 per 1000 person-years, 5·2-5·7, vs 6·9 per 1000 person-years, 6·6-7·2; p<0·0001). The rate of incident myocardial infarction in people with diabetes was substantially lower than for those with chronic kidney disease when defined by eGFR of less than 45 mL/min per 1·73 m(2) and severely increased proteinuria (6·6 per 1000 person-years, 6·4-6·9 vs 12·4 per 1000 person-years, 9·7-15·9). INTERPRETATION Our findings suggest that chronic kidney disease could be added to the list of criteria defining people at highest risk of future coronary events. FUNDING Alberta Heritage Foundation for Medical Research.

Associations Between Acute Kidney Injury and Cardiovascular and Renal Outcomes After Coronary Angiography

Background— Acute kidney injury (AKI) is associated with early mortality after percutaneous coronary revascularization procedures, but its prognostic relevance to long-term clinical outcomes remains controversial. Methods and Results— We conducted a retrospective study of 14 782 adults who received coronary angiography in the province of Alberta, Canada, between 2004 and 2006. AKI was identified on the basis of changes in serum creatinine concentration within 7 days of the procedure according to AKI Network criteria. The associations between AKI and long-term outcomes, including mortality, end-stage renal disease, and cardiovascular and renal hospitalizations, were studied with the use of Cox regression of multiple failure times. The adjusted risk of death increased with increasing severity of AKI; compared with no AKI, the adjusted hazard ratio for death was 2.00 (95% confidence interval, 1.69 to 2.36) with stage 1 AKI and 3.72 (95% confidence interval, 2.92 to 4.76) with stage 2 or 3 AKI. The adjusted risk of end-stage renal disease requiring renal replacement therapy also increased according to the severity of AKI (hazard ratio, 4.15 [95% confidence interval, 2.32 to 7.42] and 11.74 [95% confidence interval, 6.38 to 21.59], respectively), as did the risks of subsequent hospitalizations for heart failure and acute renal failure. Conclusions— These findings inform the controversy surrounding AKI after angiography, demonstrating that it is a significant risk factor for long-term mortality, end-stage renal disease, and hospitalization for cardiovascular and renal events after coronary angiography.

Glomerular filtration rate, proteinuria, and the incidence and consequences of acute kidney injury: a cohort study

BACKGROUND Low values of estimated glomerular filtration rate (eGFR) predispose to acute kidney injury, and proteinuria is a marker of kidney disease. We aimed to investigate how eGFR and proteinuria jointly modified the risks of acute kidney injury and subsequent adverse clinical outcomes. METHODS We did a cohort study of 920,985 adults residing in Alberta, Canada, between 2002 and 2007. Participants not needing chronic dialysis at baseline and with at least one outpatient measurement of both serum creatinine concentration and proteinuria (urine dipstick or albumin-creatinine ratio) were included. We assessed hospital admission with acute kidney injury with validated administrative codes; other outcomes were all-cause mortality and a composite renal outcome of end-stage renal disease or doubling of serum creatinine concentration. FINDINGS During median follow-up of 35 months (range 0-59 months), 6520 (0·7%) participants were admitted with acute kidney injury. In those with eGFR 60 mL/min per 1·73 m(2) or greater, the adjusted risk of admission with this disorder was about 4 times higher in those with heavy proteinuria measured by dipstick (rate ratio 4·4 vs no proteinuria, 95% CI 3·7-5·2). The adjusted rates of admission with acute kidney injury and kidney injury needing dialysis remained high in participants with heavy dipstick proteinuria for all values of eGFR. The adjusted rates of death and the composite renal outcome were also high in participants admitted with acute kidney injury, although the rise associated with this injury was attenuated in those with low baseline eGFR and heavy proteinuria. INTERPRETATION These findings suggest that information on proteinuria and eGFR should be used together when identifying people at risk of acute kidney injury, and that an episode of acute kidney injury provides further long-term prognostic information in addition to eGFR and proteinuria. FUNDING The study was funded by an interdisciplinary team grant from Alberta Heritage Foundation for Medical Research.

Use of high potency statins and rates of admission for acute kidney injury: multicenter, retrospective observational analysis of administrative databases

Objective To quantify an association between acute kidney injury and use of high potency statins versus low potency statins. Design Retrospective observational analysis of administrative databases, using nine population based cohort studies and meta-analysis. We performed as treated analyses in each database with a nested case-control design. Rate ratios for different durations of current and past statin exposure to high potency or low potency statins were estimated using conditional logistic regression. Ratios were adjusted for confounding by high dimensional propensity scores. Meta-analytic methods estimated overall effects across participating sites. Setting Seven Canadian provinces and two databases in the United Kingdom and the United States. Participants 2 067 639 patients aged 40 years or older and newly treated with statins between 1 January 1997 and 30 April 2008. Each person hospitalized for acute kidney injury was matched with ten controls. Intervention A dispensing event was new if no cholesterol lowering drug or niacin prescription was dispensed in the previous year. High potency statin treatment was defined as ≥10 mg rosuvastatin, ≥20 mg atorvastatin, and ≥40 mg simvastatin; all other statin treatments were defined as low potency. Statin potency groups were further divided into cohorts with or without chronic kidney disease. Main outcome measure Relative hospitalization rates for acute kidney injury. Results Of more than two million statin users (2 008 003 with non-chronic kidney disease; 59 636 with chronic kidney disease), patients with similar propensity scores were comparable on measured characteristics. Within 120 days of current treatment, there were 4691 hospitalizations for acute kidney injury in patients with non-chronic kidney injury, and 1896 hospitalizations in those with chronic kidney injury. In patients with non-chronic kidney disease, current users of high potency statins were 34% more likely to be hospitalized with acute kidney injury within 120 days after starting treatment (fixed effect rate ratio 1.34, 95% confidence interval 1.25 to 1.43). Users of high potency statins with chronic kidney disease did not have as large an increase in admission rate (1.10, 0.99 to 1.23). χ2 tests for heterogeneity confirmed that the observed association was robust across participating sites. Conclusions Use of high potency statins is associated with an increased rate of diagnosis for acute kidney injury in hospital admissions compared with low potency statins. The effect seems to be strongest in the first 120 days after initiation of statin treatment.

Association Between Glycemic Control and Adverse Outcomes in People With Diabetes Mellitus and Chronic Kidney Disease: A Population-Based Cohort Study

BACKGROUND Better glycemic control as reflected by lower hemoglobin A(1c) (HbA(1c)) level may prevent or slow progression of nephropathy in people with diabetes mellitus (DM). Whether a lower HbA(1c) level improves outcomes in people with DM and chronic kidney disease (CKD) is unknown. METHODS From all people with serum creatinine measured as part of routine care in a single Canadian province from 2005 through 2006, we identified those with CKD based on laboratory data (estimated glomerular filtration rate [eGFR], <60.0 mL/min/1.73 m(2)]) and DM using a validated algorithm applied to hospitalization and claims data. Patients were classified based on their first HbA(1c) measurement; Cox regression models were used to assess independent associations between HbA(1c) level and 5 study outcomes (death, progression of kidney disease based on a doubling of serum creatinine level, or new end-stage renal disease [ESRD], cardiovascular events, all-cause hospitalization). RESULTS We identified 23,296 people with DM and an eGFR lower than 60.0 mL/min/1.73 m(2). The median HbA(1c) level was 6.9% (range, 2.8%-20.0%), and 11% had an HbA(1c) value higher than 9%. Over the median follow-up period of 46 months, 3665 people died, and 401 developed ESRD. Regardless of baseline eGFR, a higher HbA(1c) level was strongly and independently associated with excess risk of all 5 outcomes studied (P < .001 for all comparisons). However, the association with mortality was U-shaped, with increases in the risk of mortality apparent at HbA(1c) levels lower than 6.5% and higher than 8.0%. The increased risk of ESRD associated with a higher HbA(1c) level was attenuated at a lower baseline eGFR (P value for interaction, <.001). Specifically, among those with an eGFR of 30.0 to 59.9 mL/min/1.73 m(2), the risk of ESRD was increased by 22% and 152% in patients with HbA(1c) levels of 7% to 9% and higher than 9%, respectively, compared with patients with an HbA(1c) level lower than 7% (P < .001), whereas corresponding increases were 3% and 13%, respectively, in those with an eGFR of 15.0 to 29.9 mL/min/1.73 m(2). CONCLUSIONS A hemoglobin A(1c) level higher than 9% is common in people with non-hemodialysis-dependent CKD and is associated with markedly worse clinical outcomes; lower levels of HbA(1c) (<6.5%) also seemed to be associated with excess mortality. The excess risk of kidney failure associated with a higher HbA(1c) level was most pronounced among people with better kidney function. These findings suggest that appropriate and timely control of HbA(1c) level in people with DM and CKD may be more important than previously realized, but suggest also that intensive glycemic control (HbA(1c) level <6.5%) may be associated with increased mortality.

Using Proteinuria and Estimated Glomerular Filtration Rate to Classify Risk in Patients With Chronic Kidney Disease: A Cohort Study

BACKGROUND The staging system for chronic kidney disease relies almost exclusively on estimated glomerular filtration rate (eGFR), although proteinuria is also associated with adverse outcomes. OBJECTIVE To validate a 5-category system for risk stratification based on the combination of eGFR and proteinuria. DESIGN Retrospective cohort study. SETTING A provincial laboratory registry in Alberta, Canada, and a representative sample of noninstitutionalized U.S. adults. PATIENTS A derivation data set of 474 521 adult outpatients, 2 independent internal validation cohorts with 51 356 and 460 623 patients, and an external validation cohort of 14 358 patients. MEASUREMENTS Glomerular filtration rate, estimated by using the Modification of Diet in Renal Disease Study equation, and proteinuria, measured by using urine albumin-to-creatinine ratio or dipstick urinalysis. Outcomes included all-cause mortality and a composite renal outcome of kidney failure or doubling of serum creatinine level. RESULTS Over a median follow-up of 38 months in the internal validation cohorts, higher risk categories (indicating lower eGFR or more proteinuria) were associated with a graded increase in the risk for the composite renal outcome. The projected number of U.S. adults assigned to risk categories 3 and 4 in the alternate system was 3.9 million, compared with 16.3 million assigned to stage 3 and 4 in the current staging system. The alternate system was more likely to correctly reclassify persons who did not develop the renal outcome than those who did, although some persons developed the renal outcome despite reclassification to a lower category. However, all analyses of patients reclassified to a lower category showed that substantially fewer such patients developed the renal outcome than did not. Correct reclassification by the alternate system was more likely when proteinuria was measured by using albumin-to-creatinine ratio than with dipstick testing, and also more likely for the composite renal outcome than for mortality. LIMITATION The study had a short follow-up time. CONCLUSION Using proteinuria in combination with eGFR may reduce unnecessary referrals for care at the cost of not referring or delaying referral for some patients who go on to develop kidney failure. PRIMARY FUNDING SOURCE Alberta Heritage Foundation for Medical Research interdisciplinary research team grant.

Overview of the Alberta Kidney Disease Network

BackgroundThe Alberta Kidney Disease Network is a collaborative nephrology research organization based on a central repository of laboratory and administrative data from the Canadian province of Alberta.DescriptionThe laboratory data within the Alberta Kidney Disease Network can be used to define patient populations, such as individuals with chronic kidney disease (using serum creatinine measurements to estimate kidney function) or anemia (using hemoglobin measurements). The administrative data within the Alberta Kidney Disease Network can also be used to define cohorts with common medical conditions such as hypertension and diabetes. Linkage of data sources permits assessment of socio-demographic information, clinical variables including comorbidity, as well as ascertainment of relevant outcomes such as health service encounters and events, the occurrence of new specified clinical outcomes and mortality.ConclusionThe unique ability to combine laboratory and administrative data for a large geographically defined population provides a rich data source not only for research purposes but for policy development and to guide the delivery of health care. This research model based on computerized laboratory data could serve as a prototype for the study of other chronic conditions.

Nephrology Visits and Health Care Resource Use Before and After Reporting Estimated Glomerular Filtration Rate

CONTEXT Laboratory reporting of estimated glomerular filtration rate (GFR) has been widely implemented, with limited evaluation. OBJECTIVE To examine trends in nephrologist visits and health care resource use before and after estimated GFR reporting. DESIGN, SETTING, AND PATIENTS Community-based cohort study (N = 1,135,968) with time-series analysis. Participants were identified from a laboratory registry in Alberta, Canada, and followed up from May 15, 2003, to March 14, 2007 (with estimated GFR reporting implemented October 15, 2004). MAIN OUTCOME MEASURE Nephrologist visits and patient management. RESULTS Following estimated GFR reporting, the rate of first outpatient visits to a nephrologist for patients with chronic kidney disease (CKD; estimated GFR <60 mL/min/1.73 m(2)) increased by 17.5 (95% confidence interval [CI], 16.5-18.6) visits per 10,000 CKD patients per month, corresponding to a relative increase from baseline of 68.4% (95% CI, 65.7%-71.2%). There was no association between estimated GFR reporting and rate of first nephrologist visit among patients without CKD. Among patients with an estimated GFR of less than 30 mL/min/1.73 m(2), the rate of first nephrologist visits increased by 134.4 (95% CI, 60.0-208.7) visits per 10,000 patients per month. This increase was predominantly seen in women, patients aged 46 to 65 years as well as those aged 86 years or older, and those with hypertension, diabetes, and comorbidity. Reporting of estimated GFR was not associated with increased rates of internal medicine or general practitioner visits or increased use of angiotensin-converting enzyme inhibitors/angiotensin II receptor blockers among patients with CKD and proteinuria or the subgroup limited to patients with diabetes. CONCLUSIONS Reporting of estimated GFR was associated with an increase in first nephrologist visits, particularly among patients with more severe kidney dysfunction, women, middle-aged and very elderly patients, and those with comorbidities. Any effect on outcomes remains to be shown.