Ann M. O'Hare

Age Affects Outcomes in Chronic Kidney Disease

Chronic kidney disease (CKD) is common among the elderly. However, little is known about how the clinical implications of CKD vary with age. We examined the age-specific incidence of death, treated end-stage renal disease (ESRD), and change in estimated glomerular filtration rate (eGFR) among 209,622 US veterans with CKD stages 3 to 5 followed for a mean of 3.2 years. Patients aged 75 years or older at baseline comprised 47% of the overall cohort and accounted for 28% of the 9227 cases of ESRD that occurred during follow-up. Among patients of all ages, rates of both death and ESRD were inversely related to eGFR at baseline. However, among those with comparable levels of eGFR, older patients had higher rates of death and lower rates of ESRD than younger patients. Consequently, the level of eGFR below which the risk of ESRD exceeded the risk of death varied by age, ranging from 45 ml/min per 1.73 m(2) for 18 to 44 year old patients to 15 ml/min per 1.73 m(2) for 65 to 84 year old patients. Among those 85 years or older, the risk of death always exceeded the risk of ESRD in this cohort. Among patients with eGFR levels <45 ml/min per 1.73 m(2) at baseline, older patients were less likely than their younger counterparts to experience an annual decline in eGFR of >3 ml/min per 1.73 m(2). In conclusion, age is a major effect modifier among patients with an eGFR of <60 ml/min per 1.73 m(2), challenging us to move beyond a uniform stage-based approach to managing CKD.

The Society for Vascular Surgery: Clinical practice guidelines for the surgical placement and maintenance of arteriovenous hemodialysis access

Recognizing the impact of the decision making by the dialysis access surgeon on the successful placement of autogenous arteriovenous hemodialysis access, the Society for Vascular Surgery assembled a multispecialty panel to develop practice guidelines in arteriovenous access placement and maintenance with the aim of maximizing the percentage and functionality of autogenous arteriovenous accesses that are placed. The Society commissioned the Knowledge and Encounter Research Unit of the Mayo Clinic College of Medicine, Rochester, Minnesota, to systematically review the available evidence in three main areas provided by the panel: timing of referral to access surgeons, type of access placed, and effectiveness of surveillance. The panel then formulated practice guidelines in seven areas: timing of referral to the access surgeon, operative strategies to maximize the placement of autogenous arteriovenous accesses, first choice for the autogenous access, choice of arteriovenous access when a patient is not a suitable candidate for a forearm autogenous access, the role of monitoring and surveillance in arteriovenous access management, conversion of a prosthetic arteriovenous access to a secondary autogenous arteriovenous access, and management of the nonfunctional or failed arteriovenous access. For each of the guidelines, the panel stated the recommendation or suggestion, discussed the evidence or opinion upon which the recommendation or suggestion was made, detailed the values and preferences that influenced the groups decision in formulating the relevant guideline, and discussed technical remarks related to the particular guideline. In addition, detailed information is provided on various configurations of autogenous and prosthetic accesses and technical tips related to their placement.

Trajectories of Kidney Function Decline in the 2 Years Before Initiation of Long-term Dialysis

BACKGROUND Little is known about patterns of kidney function decline leading up to the initiation of long-term dialysis. STUDY DESIGN Retrospective cohort study. SETTING & PARTICIPANTS 5,606 Veterans Affairs patients who initiated long-term dialysis in 2001-2003. PREDICTOR Trajectory of estimated glomerular filtration rate (eGFR) during the 2-year period before initiation of long-term dialysis. OUTCOMES & MEASUREMENTS Patient characteristics and care practices before and at the time of dialysis initiation and survival after initiation. RESULTS We identified 4 distinct trajectories of eGFR during the 2-year period before dialysis initiation: 62.8% of patients had persistently low level of eGFR < 30 mL/min/1.73 m2 (mean eGFR slope, 7.7 ± 4.7 [SD] mL/min/1.73 m2 per year), 24.6% had progressive loss of eGFR from levels of approximately 30-59 ml/min/1.73 m2 (mean eGFR slope, 16.3 ± 7.6 mL/min/1.73 m2 per year), 9.5% had accelerated loss of eGFR from levels > 60 mL/min/1.73 m2 (mean eGFR slope, 32.3 ± 13.4 mL/min/1.73 m2 per year), and 3.1% experienced catastrophic loss of eGFR from levels > 60 mL/min/1.73 m2 within 6 months or less. Patients with steeper eGFR trajectories were more likely to have been hospitalized and have an inpatient diagnosis of acute kidney injury. They were less likely to have received recommended predialysis care and had a higher risk of death in the first year after dialysis initiation. CONCLUSIONS There is substantial heterogeneity in patterns of kidney function loss leading up to the initiation of long-term dialysis perhaps calling for a more flexible approach toward preparing for end-stage renal disease.

Racial Differences in End-Stage Renal Disease Rates in HIV Infection versus Diabetes

Few studies have compared the incidence of end-stage renal disease (ESRD) among individuals with the human immunodeficiency virus (HIV) and diabetes. We followed a national sample of 2,015,891 US veterans over a median peroid of 3.7 years for progression to ESRD. The age- and sex-adjusted incidence of ESRD (per 1000 person-years) among HIV-infected black patients was nearly an order of magnitude higher than among HIV-positive white patients, almost twice that of diabetic whites, and similar to that among diabetic blacks. In multivariate Cox proportional hazards analysis, diabetes was associated with an increased risk of ESRD among white patients, but HIV was not. Among black individuals, however, both HIV and diabetes conferred a similar increase in the risk of ESRD (4- to 5-fold increase compared to white individuals without HIV or diabetes). HIV and diabetes carry a similar risk of ESRD among black patients, highlighting the importance of developing strategies to prevent and treat renal disease among HIV-infected black individuals.

Renal Insufficiency and the Risk of Lower Extremity Peripheral Arterial Disease: Results from the Heart and Estrogen/Progestin Replacement Study (HERS)

Renal insufficiency is a risk factor for coronary heart disease and stroke, but whether it predicts lower extremity peripheral arterial disease (PAD) is unknown. The authors evaluated was the association of baseline renal insufficiency with future PAD events in the Heart and Estrogen/Progestin Replacement Study (HERS) and follow-up study (HERS II). A total of 2763 postmenopausal women with known coronary heart disease were enrolled in HERS and randomly assigned to receive hormone therapy with conjugated estrogens and medroxyprogesterone acetate or placebo and followed for up to 8 yr for clinical end points. The outcome was time from randomization to first occurrence of either a lower extremity amputation, revascularization (surgical or percutaneous), or lumbar sympathectomy during follow-up. Incident lower extremity PAD event rates among women with creatinine clearances > or =60, 30 to 59, and < 30 ml/min/1.73 m(2) were, respectively, 0.55%, 0.92%, and 2.73% per year. After multivariable proportional-hazard adjustment for potential confounders and other known risk factors for PAD, women with a creatinine clearance 30 to 59 ml/min/1.73 m(2) (hazard ratio [HR], 1.63; 95% confidence interval [CI], 1.04 to 2.54, P = 0.032) and <30 ml/min/1.73 m(2) (HR, 3.24; 95% CI, 1.20 to 8.78, P = 0.021) had a significantly increased risk of PAD compared with participants with a creatinine clearance > or =60 ml/min/1.73 m(2). Renal insufficiency was independently associated with future PAD events among postmenopausal women with coronary heart disease. Future studies should determine whether this association is present in other populations and investigate its potential mechanisms.

Acute Kidney Injury in Older Adults

Aging kidneys undergo structural and functional changes that decrease autoregulatory capacity and increase susceptibility to acute injury. Acute kidney injury associates with duration and location of hospitalization, mortality risk, progression to chronic kidney disease, and functional status in daily living. Definition and diagnosis of acute kidney injury are based on changes in creatinine, which is an inadequate marker and might identify patients when it is too late. The incidence of acute kidney injury is rising and increases with advancing age, yet clinical studies have been slow to address geriatric issues or the heterogeneity in etiologies, outcomes, or patient preferences among the elderly. Here we examine some of the current literature, identify knowledge gaps, and suggest potential research questions regarding acute kidney injury in older adults. Answering these questions will facilitate the integration of geriatric issues into future mechanistic and clinical studies that affect management and care of acute kidney injury.

Current Guidelines for Using Angiotensin-Converting Enzyme Inhibitors and Angiotensin II–Receptor Antagonists in Chronic Kidney Disease: Is the Evidence Base Relevant to Older Adults?

Key Summary Points Almost one half of adults in the general population who meet criteria for chronic kidney disease are older than 70 years. Persons older than 70 years are underrepresented in most trials underpinning major U.S. practice guidelines for the use of angiotensin-converting enzyme (ACE) inhibitors and angiotensin IIreceptor blockers (ARBs) in chronic kidney disease. More than 85% of persons older than 70 years who meet criteria for chronic kidney disease do not have proteinuria. The relevance of guideline trials to this group may be limited because most favored inclusion of participants with proteinuria. Differences between guidelines in criteria for the use of ACE inhibitors and ARBs in chronic kidney disease lead to considerable variation across guidelines in the proportion of older adults targeted. Practice guidelines specifically recommend the use of ACE inhibitors and ARBs in patients with chronic kidney disease because these agents are renoprotective. However, slowing progression of kidney disease may not be the most patient-centric goal of therapy in many older adults with this condition. Angiotensin-converting enzyme (ACE) inhibitors and angiotensin IIreceptor blockers (ARBs) are widely recommended in clinical practice guidelines for patients with chronic kidney disease. Such recommendations are based on the results of randomized, controlled trials (RCTs) demonstrating that these agents slow progression of kidney disease. The unique renoprotective properties of ACE inhibitors and ARBs are generally attributed to their ability to reduce proteinuria (1, 2). Proteinuria is a major risk factor for end-stage renal disease (3, 4) and may play a direct pathogenic role in progression of chronic kidney disease (2). In RCTs, both ACE inhibitors and ARBs are more likely to slow progression of kidney disease in participants with greater degrees of proteinuria (57). In patients without diabetes excreting less than 500 mg/d of protein, ACE inhibitors may be no more renoprotective than other antihypertensive agents (7). Use of these agents in patients with chronic kidney disease mandates close monitoring for acute renal failure and hyperkalemia, may require dietary modification or long-term administration of an ion-exchange resin, and may limit the use of other medications that also increase serum potassium level (8). More than one third of adults in the general population age 70 years or older have chronic kidney disease (9). Whether evidence supporting current guidelines for the use of ACE inhibitors and ARBs in chronic kidney disease can be extrapolated to this large group is unknown. To address this question, we first examined the representation of older adults in RCTs used to formulate contemporary guidelines from the Kidney Disease Outcomes Quality Initiative (KDOQI); the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7); and the American Diabetes Association (Table 1) (8, 1012). We also examined the representation of older adults in relevant major trials whose results were published after guideline preparation. Second, we compared the characteristics of participants in guideline trials with those of a representative sample of older adults with chronic kidney disease from the general population enrolled in the National Health and Nutrition Examination Survey (NHANES) 19992006. Table 1. Summary of Guidelines Were Older Adults Well Represented in Trials Underpinning Major U.S. Practice Guidelines for the Use of ACE Inhibitors and ARBs in Chronic Kidney Disease? Two coauthors screened all articles referenced in the aforementioned guidelines (Table 1). When the primary article cited in the relevant guideline did not provide all prespecified data elements, we performed directed searches to identify additional publications from that study that might include this information. We restricted these searches to English-language articles published before or during the evidence review period for the most recent guideline in which the primary study was cited (Table 1). We performed these directed searches by using MEDLINE and by hand-searching the reference lists of primary articles. When we could not identify all data elements from published sources, we requested needed information from corresponding authors. For inclusion in our review, the study was required to be an RCT in which at least 1 group was treated with an ACE inhibitor or ARB and was compared with a control group not receiving either agent. Because the rationale for all of the guidelines reviewed here is that ACE inhibitors and ARBs slow progression of kidney disease, we also required that at least 1 of the following renal outcomes was reported in the article cited in the relevant guideline: change in urinary protein or albumin excretion, change in serum creatinine level, creatinine clearance, measured or estimated glomerular filtration rate (GFR or eGFR, respectively), requirement for dialysis, or onset of end-stage renal disease. Two coauthors separately abstracted relevant prespecified trial characteristics, participant characteristics, and entry criteria. The guidelines referenced 37 articles describing 32 RCTs (6, 1348). We excluded 2 trials because the referenced article did not include a renal outcome measure (45, 46) and 3 trials because they lacked a comparison with a control group not receiving an ACE inhibitor or ARB (44, 47, 48) (Table 1). We included the remaining 27 trials (total participants, 15794) (Appendix Table 1). Appendix Table 1. Baseline Participant Characteristics and Entry Criteria of Guideline Trials The mean age of trial participants ranged from 29 to 71 years. The maximum age of participants could not be ascertained in 2 trials. Among the remaining trials, 19 (76%) either excluded or did not include participants older than 70 years. No trial provided information on the number and characteristics of participants older than 70 years. Although most trials did not enroll older participants, the 5662 participants in ALLHAT (Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial) (30) with an eGFR less than 60 mL/min per 1.73 m2 had a mean age of 71 years, indicating that this trial enrolled a substantial number of persons older than 70 years. With the notable exception of ALLHAT, older adults were poorly represented in most guideline trials. What Were the Other Characteristics of Participants in Guideline Trials? Most trials (70%) enrolled only participants with diabetes. Six trials were limited to those with type 1 diabetes (n= 775), 12 trials were limited to those with type 2 diabetes (n= 6840), and 1 trial included participants with either type 1 or type 2 diabetes (n= 103). Two trials included participants both with and without diabetes (n= 6245). The remaining 6 trials were conducted among participants without diabetes (n= 1831). Hypertension was an entry requirement for most trials. Female participants ranged from 23% to 70% across trials. Urinary protein excretion of at least 30 mg/d or equivalent was an entry criterion for 79% of trials in persons with diabetes. Only 1 trial that included participants without diabetes explicitly required a minimum level of proteinuria. Nevertheless, mean urinary protein excretion at baseline exceeded 500 mg/d in most trials of nondiabetic chronic kidney disease. The only trial not to ascertain urinary protein level was ALLHAT, which included participants both with and without diabetes. In summary, most guideline trials were conducted among participants with diabetes and most favored inclusion of participants with proteinuria. Are Older Adults Well Represented in Recent Trials Comparing the Effect of ACE Inhibitors or ARBs With That of Other Agents on Progression of Chronic Kidney Disease? We conducted a MEDLINE search from 1 July 2002 through 31 December 2008 to identify the results of major trials published after the most recent review dates for the 2004 KDOQI guideline (for studies of nondiabetic kidney disease) and the 2007 KDOQI guideline (for studies of diabetic kidney disease). We limited our search to English-language publications, human studies, and RCTs. One coauthor reviewed all titles, and abstracts and manuscripts as needed, to identify eligible studies. We included only RCTs that compared the effect of ACE inhibitors or ARBs with a control group not receiving either agent, enrolled more than 200 participants, and included at least 1 renal outcome measure. We excluded trials in specialized populations (for example, patients receiving dialysis, kidney transplant recipients, and patients with heart failure). Two coauthors separately abstracted prespecified baseline participant characteristics and exclusion criteria for eligible trials. We identified 380 MEDLINE citations, obtained 68 articles for further review, and identified 6 eligible trials (Appendix Table 2) (4954). Only 1 trial did not enroll participants older than 70 years. Mean participant age ranged from 45 to 63 years across trials. All but 1 trial included participants without diabetes. Only 2 trials (49, 54) included a substantial number of participants without microalbuminuria or macroalbuminuria. Dagenais and colleagues (49) randomly assigned 5269 adults age 30 years or older with glucose intolerance and without clinical proteinuria to receive ramipril or placebo. The composite renal outcome (increase in proteinuria, decrease in eGFR 30%, or dialysis or transplantation) did not differ between groups over a 3-year follow-up. Vogt and colleagues (54) randomly assigned 614 adults to receive telmisartan, hydrochlorothiazide, or placebo. Most participants did not have diabetes, and only 25% had microalbuminuria or macroalbuminuria. Over a 6-week follow-up, urinary albumin excretion decreased to the greatest extent in the group receiving telmisartan. Change in creatinine clearance did not differ across groups. Our se

Influence of Race on Kidney Transplant Outcomes within and outside the Department of Veterans Affairs

Inferior outcomes after kidney transplantation among African Americans are poorly understood. It was hypothesized that unequal access to medical care among transplant recipients might contribute to worse posttransplantation outcomes among African Americans and that racial disparities in kidney transplant outcomes would be less pronounced among patients who receive health care within versus outside the Department of Veterans Affairs (VA), because eligible veterans who receive care within the VA are entitled to receive universal access to care, including coverage of prescription drugs. A study cohort of 79,361 patients who were undergoing their first kidney transplant in the United States between October 1, 1991, and October 31, 2000, was assembled, with follow-up data on graft survival obtained through October 31, 2001. After multivariable proportional hazards adjustment for a wide range of recipient and donor characteristics, African-American patients were at increased risk for graft failure compared with non-African-American patients (relative risk [RR] 1.31; 95% confidence interval [CI] 1.26 to 1.36). African-American race was associated with a similarly increased risk for graft failure among patients who were VA users (RR 1.31; 95% CI 1.11 to 1.54) and non-VA users (RR 1.31; 95% CI 1.26 to 1.36). In conclusion, racial disparities in kidney transplant outcomes seem to persist even in a universal access-to-care system such as the VA. Reasons for worse outcomes among African Americans require further investigation.

White/Black Racial Differences in Risk of End-stage Renal Disease and Death

BACKGROUND End-stage renal disease disproportionately affects black persons, but it is unknown when in the course of chronic kidney disease racial differences arise. Understanding the natural history of racial differences in kidney disease may help guide efforts to reduce disparities. METHODS We compared white/black differences in the risk of end-stage renal disease and death by level of estimated glomerular filtration rate (eGFR) at baseline in a national sample of 2,015,891 veterans between 2001 and 2005. RESULTS Rates of end-stage renal disease among black patients exceeded those among white patients at all levels of baseline eGFR. The adjusted hazard ratios for end-stage renal disease associated with black versus white race for patients with an eGFR > or = 90, 60-89, 45-59, 30-44, 15-29, and <15 mL/min/1.73 m2, respectively, were 2.14 (95% confidence interval [CI], 1.72-2.65), 2.30 (95% CI, 2.02-2.61), 3.08 (95% CI, 2.74-3.46), 2.47 (95% CI, 2.26-2.70), 1.86 (95% CI, 1.75-1.98), and 1.23 (95% CI, 1.12-1.34). We observed a similar pattern for mortality, with equal or higher rates of death among black persons at all levels of eGFR. The highest risk of mortality associated with black race also was observed among those with an eGFR 45-59 mL/min/1.73 m2 (hazard ratio 1.32, 95% CI, 1.27-1.36). CONCLUSION Racial differences in the risk of end-stage renal disease appear early in the course of kidney disease and are not explained by a survival advantage among blacks. Efforts to identify and slow progression of chronic kidney disease at earlier stages may be needed to reduce racial disparities.

Optimizing renal replacement therapy in older adults: a framework for making individualized decisions

It is often difficult to synthesize information about the risks and benefits of recommended management strategies in older patients with end-stage renal disease since they may have more comorbidity and lower life expectancy than patients described in clinical trials or practice guidelines. In this review, we outline a framework for individualizing end-stage renal disease management decisions in older patients. The framework considers three factors: life expectancy, the risks and benefits of competing treatment strategies, and patient preferences. We illustrate the use of this framework by applying it to three key end-stage renal disease decisions in older patients with varying life expectancy: choice of dialysis modality, choice of vascular access for hemodialysis, and referral for kidney transplantation. In several instances, this approach might provide support for treatment decisions that directly contradict available practice guidelines, illustrating circumstances when strict application of guidelines may be inappropriate for certain patients. By combining quantitative estimates of benefits and harms with qualitative assessments of patient preferences, clinicians may be better able to tailor treatment recommendations to individual older patients, thereby improving the overall quality of end-stage renal disease care.