Robert R. Quinn

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.

The 2009 Canadian Hypertension Education Program recommendations for the management of hypertension: Part 2 – therapy

OBJECTIVE To update the evidence-based recommendations for the prevention and management of hypertension in adults for 2009. OPTIONS AND OUTCOMES For lifestyle and pharmacological interventions, evidence from randomized controlled trials and systematic reviews of trials was preferentially reviewed. Changes in cardiovascular morbidity and mortality were the primary outcomes of interest. However, for lifestyle interventions, blood pressure lowering was accepted as a primary outcome given the lack of long-term morbidity and mortality data in this field. Progression of kidney dysfunction was also accepted as a clinically relevant primary outcome among patients with chronic kidney disease. EVIDENCE A Cochrane collaboration librarian conducted an independent MEDLINE search from 2007 to August 2008 to update the 2008 recommendations. To identify additional published studies, reference lists were reviewed and experts were contacted. All relevant articles were reviewed and appraised independently by both content and methodological experts using prespecified levels of evidence. RECOMMENDATIONS For lifestyle modifications to prevent and treat hypertension, restrict dietary sodium to less than 2300 mg (100 mmol)/day (and 1500 mg to 2300 mg [65 mmol to 100 mmol]/day in hypertensive patients); perform 30 min to 60 min of aerobic exercise four to seven days per week; maintain a healthy body weight (body mass index 18.5 kg/m(2) to 24.9 kg/m(2)) and waist circumference (smaller than 102 cm for men and smaller than 88 cm for women); limit alcohol consumption to no more than 14 units per week in men or nine units per week in women; follow a diet that is reduced in saturated fat and cholesterol, and that emphasizes fruits, vegetables and low-fat dairy products, dietary and soluble fibre, whole grains and protein from plant sources; and consider stress management in selected individuals with hypertension. For the pharmacological management of hypertension, treatment thresholds and targets should be predicated on by the patients global atherosclerotic risk, target organ damage and comorbid conditions. Blood pressure should be decreased to lower than 140/90 mmHg in all patients, and to lower than 130/80 mmHg in those with diabetes mellitus or chronic kidney disease. Most patients will require more than one agent to achieve these target blood pressures. Antihypertensive therapy should be considered in all adult patients regardless of age (caution should be exercised in elderly patients who are frail). For adults without compelling indications for other agents, initial therapy should include thiazide diuretics. Other agents appropriate for first-line therapy for diastolic and/or systolic hypertension include angiotensin- converting enzyme (ACE) inhibitors (in patients who are not black), long-acting calcium channel blockers (CCBs), angiotensin receptor antagonists (ARBs) or beta-blockers (in those younger than 60 years of age). A combination of two first-line agents may also be considered as the initial treatment of hypertension if the systolic blood pressure is 20 mmHg above the target or if the diastolic blood pressure is 10 mmHg above the target. The combination of ACE inhibitors and ARBs should not be used. Other agents appropriate for first-line therapy for isolated systolic hypertension include long- acting dihydropyridine CCBs or ARBs. In patients with angina, recent myocardial infarction or heart failure, beta-blockers and ACE inhibitors are recommended as first-line therapy; in patients with cerebrovascular disease, an ACE inhibitor/diuretic combination is preferred; in patients with proteinuric nondiabetic chronic kidney disease, ACE inhibitors or ARBs (if intolerant to ACE inhibitors) are recommended; and in patients with diabetes mellitus, ACE inhibitors or ARBs (or, in patients without albuminuria, thiazides or dihydropyridine CCBs) are appropriate first-line therapies. All hypertensive patients with dyslipidemia should be treated using the thresholds, targets and agents outlined in the Canadian Cardiovascular Society position statement (recommendations for the diagnosis and treatment of dyslipidemia and prevention of cardiovascular disease). Selected high-risk patients with hypertension who do not achieve thresholds for statin therapy according to the position paper should nonetheless receive statin therapy. Once blood pressure is controlled, acetylsalicylic acid therapy should be considered. VALIDATION All recommendations were graded according to strength of the evidence and voted on by the 57 members of the Canadian Hypertension Education Program Evidence-Based Recommendations Task Force. All recommendations reported here achieved at least 95% consensus. These guidelines will continue to be updated annually.

The 2013 Canadian Hypertension Education Program recommendations for blood pressure measurement, diagnosis, assessment of risk, prevention, and treatment of hypertension.

We updated the evidence-based recommendations for the diagnosis, assessment, prevention, and treatment of hypertension in adults for 2013. This years update includes 2 new recommendations. First, among nonhypertensive or stage 1 hypertensive individuals, the use of resistance or weight training exercise does not adversely influence blood pressure (BP) (Grade D). Thus, such patients need not avoid this type of exercise for fear of increasing BP. Second, and separately, for very elderly patients with isolated systolic hypertension (age 80 years or older), the target for systolic BP should be < 150 mm Hg (Grade C) rather than < 140 mm Hg as recommended for younger patients. We also discuss 2 additional topics at length (the pharmacological treatment of mild hypertension and the possibility of a diastolic J curve in hypertensive patients with coronary artery disease). In light of several methodological limitations, a recent systematic review of 4 trials in patients with stage 1 uncomplicated hypertension did not lead to changes in management recommendations. In addition, because of a lack of prospective randomized data assessing diastolic BP thresholds in patients with coronary artery disease and hypertension, no recommendation to set a selective diastolic cut point for such patients could be affirmed. However, both of these issues will be examined on an ongoing basis, in particular as new evidence emerges.

Chronic dialysis and death among survivors of acute kidney injury requiring dialysis.

CONTEXT Severe acute kidney injury among hospitalized patients often necessitates initiation of short-term dialysis. Little is known about the long-term outcome of those who survive to hospital discharge. OBJECTIVE To assess the risk of chronic dialysis and all-cause mortality in individuals who experience an episode of acute kidney injury requiring dialysis. DESIGN, SETTING, AND PARTICIPANTS We conducted a population-based cohort study of all adult patients in Ontario, Canada, with acute kidney injury who required in-hospital dialysis and survived free of dialysis for at least 30 days after discharge between July 1, 1996, and December 31, 2006. These individuals were matched with patients without acute kidney injury or dialysis during their index hospitalization. Matching was by age plus or minus 5 years, sex, history of chronic kidney disease, receipt of mechanical ventilation during the index hospitalization, and a propensity score for developing acute kidney injury requiring dialysis. Patients were followed up until March 31, 2007. MAIN OUTCOME MEASURES The primary end point was the need for chronic dialysis and the secondary outcome was all-cause mortality. RESULTS We identified 3769 adults with acute kidney injury requiring in-hospital dialysis and 13 598 matched controls. The mean age was 62 years and median follow-up was 3 years. The incidence rate of chronic dialysis was 2.63 per 100 person-years among individuals with acute kidney injury requiring dialysis, and 0.91 per 100 person-years among control participants (adjusted hazard ratio, 3.23; 95% confidence interval, 2.70-3.86). All-cause mortality rates were 10.10 and 10.85 per 100 person-years, respectively (adjusted hazard ratio, 0.95; 95% confidence interval, 0.89-1.02). CONCLUSIONS Acute kidney injury necessitating in-hospital dialysis was associated with an increased risk of chronic dialysis but not all-cause mortality.

The 2011 Canadian Hypertension Education Program Recommendations for the Management of Hypertension: Blood Pressure Measurement, Diagnosis, Assessment of Risk, and Therapy

We updated the evidence-based recommendations for the diagnosis, assessment, prevention, and treatment of hypertension in adults for 2011. The major guideline changes this year are: (1) a recommendation was made for using comparative risk analogies when communicating a patients cardiovascular risk; (2) diagnostic testing issues for renal artery stenosis were discussed; (3) recommendations were added for the management of hypertension during the acute phase of stroke; (4) people with hypertension and diabetes are now considered high risk for cardiovascular events if they have elevated urinary albumin excretion, overt kidney disease, cardiovascular disease, or the presence of other cardiovascular risk factors; (5) the combination of an angiotensin-converting enzyme (ACE) inhibitor and a dihydropyridine calcium channel blocker (CCB) is preferred over the combination of an ACE inhibitor and a thiazide diuretic in persons with diabetes and hypertension; and (6) a recommendation was made to coordinate with pharmacists to improve antihypertensive medication adherence. We also discussed the recent analyses that examined the association between angiotensin II receptor blockers (ARBs) and cancer.

Associations between Hemodialysis Access Type and Clinical Outcomes: A Systematic Review

Clinical practice guidelines recommend an arteriovenous fistula as the preferred vascular access for hemodialysis, but quantitative associations between vascular access type and various clinical outcomes remain controversial. We performed a systematic review of cohort studies to evaluate the associations between type of vascular access (arteriovenous fistula, arteriovenous graft, and central venous catheter) and risk for death, infection, and major cardiovascular events. We searched MEDLINE, EMBASE, and article reference lists and extracted data describing study design, participants, vascular access type, clinical outcomes, and risk for bias. We identified 3965 citations, of which 67 (62 cohort studies comprising 586,337 participants) met our inclusion criteria. In a random effects meta-analysis, compared with persons with fistulas, those individuals using catheters had higher risks for all-cause mortality (risk ratio=1.53, 95% CI=1.41-1.67), fatal infections (2.12, 1.79-2.52), and cardiovascular events (1.38, 1.24-1.54). Similarly, compared with persons with grafts, those individuals using catheters had higher risks for mortality (1.38, 1.25-1.52), fatal infections (1.49, 1.15-1.93), and cardiovascular events (1.26, 1.11-1.43). Compared with persons with fistulas, those individuals with grafts had increased all-cause mortality (1.18, 1.09-1.27) and fatal infection (1.36, 1.17-1.58), but we did not detect a difference in the risk for cardiovascular events (1.07, 0.95-1.21). The risk for bias, especially selection bias, was high. In conclusion, persons using catheters for hemodialysis seem to have the highest risks for death, infections, and cardiovascular events compared with other vascular access types, and patients with usable fistulas have the lowest risk.

Patency rates of the arteriovenous fistula for hemodialysis: a systematic review and meta-analysis.

BACKGROUND Advantages of the arteriovenous fistula (AVF), including long patency and few complications, were ascertained more than 2 decades ago and may not apply to the contemporary dialysis population. STUDY DESIGN Systematic review and meta-analysis. Estimates were pooled using a random-effects model and sources of heterogeneity were explored using metaregression. SETTING & POPULATION Patients treated with long-term hemodialysis using an AVF. SELECTION CRITERIA FOR STUDIES English-language studies indexed in MEDLINE between 2000 and 2012 using prospectively collected data on 100 or more AVFs. PREDICTOR Age, AVF location, and study location. OUTCOMES Outcomes of interest were primary AVF failure and primary and secondary patency at 1 and 2 years. RESULTS 7,011 citations were screened and 46 articles met eligibility criteria (62 unique cohorts; n = 12,383). The rate of primary failure was 23% (95% CI, 18%-28%; 37 cohorts; 7,393 AVFs). When primary failures were included, the primary patency rate was 60% (95% CI, 56%-64%; 13 studies; 21 cohorts; 4,111 AVFs) at 1 year and 51% (95% CI, 44%-58%; 7 studies; 12 cohorts; 2,694 AVFs) at 2 years. The secondary patency rate was 71% (95% CI, 64%-78%; 10 studies; 11 cohorts; 3,558 AVFs) at 1 year and 64% (95% CI, 56%-73%; 6 studies; 11 cohorts; 1,939 AVFs) at 2 years. In metaregression, there was a significant decrease in primary patency rate in studies that started recruitment in more recent years. LIMITATIONS Low quality of studies, variable clinical settings, and variable definitions of primary AVF failure. CONCLUSIONS In recent years, AVFs had a high rate of primary failure and low to moderate primary and secondary patency rates. Consideration of these outcomes is required when choosing a patients preferred access type.

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.