CKD as an Underrecognized Threat to Patient Safety
Jeffrey C. Fink, MD; Jeanine Brown, MS; Van Doren Hsu, PharmD; Stephen L. Seliger, MD; Loreen Walker, BS; Min Zhan, PhD
Chronic kidney disease (CKD) is common, but underrecognized, in patients in the health care system, where improving patient safety is a high priority. Poor disease recognition and several other features of CKD make it a high-risk condition for adverse safety events. In this review, we discuss the unique attributes of CKD that make it a high-risk condition for patient safety mishaps. We point out that adverse safety events in this disease have the potential to contribute to disease progression; namely, accelerated loss of kidney function and increased incidence of end-stage renal disease. We also propose a framework in which to consider patient safety in CKD, highlighting the need for disease-specific safety indicators that reflect unsafe practices in the treatment of this disease. Finally, we discuss the hypothesis that increased recognition of CKD will reduce disease-specific safety events and in this way decrease the likelihood of adverse outcomes, including an accelerated rate of kidney function loss and increased incidence of end-stage renal disease.
Uric Acid and Long-term Outcomes in CKD
Magdalena Madero, MD; Mark J. Sarnak, MD; Xuelei Wang, MS; Tom Greene, PhD; Gerald J. Beck, PhD; John W. Kusek, PhD; Allan J. Collins, MD; Andrew S. Levey, MD; Vandana Menon, MD
Background: Hyperuricemia is prevalent in patients with chronic kidney disease (CKD); however, data are limited about the relationship of uric acid levels with long-term outcomes in this patient population.
Study Design: Cohort study.
Setting & Participants: The Modification of Diet in Renal Disease (MDRD) Study was a randomized controlled trial (N = 840) conducted from 1989 to 1993 to examine the effects of strict blood pressure control and dietary protein restriction on progression of stages 3 to 4 CKD. This analysis included 838 patients.
Predictor: Uric acid level.
Outcomes & Measurements: The study evaluated the association of baseline uric acid levels with all-cause mortality, cardiovascular disease (CVD) mortality, and kidney failure.
Results: Mean age was 52 ± 12 (SD) years, glomerular filtration rate was 33 ± 12 mL/min/1.73 m2, and uric acid level was 7.63 ± 1.66 mg/dL. During a median follow-up of 10 years, 208 (25%) participants died of any cause, 127 (15%) died of CVD, and 553 (66%) reached kidney failure. In multivariate models, the highest tertile of uric acid was associated with increased risk of all-cause mortality (hazard ratio [HR], 1.57; 95% confidence interval [CI], 1.07 to 2.32), a trend toward CVD mortality (HR, 1.47; 95% CI, 0.90 to 2.39), and no association with kidney failure (HR, 1.20; 95% CI, 0.95 to 1.51) compared with the lowest tertile. In continuous analyses, a 1-mg/dL greater uric acid level was associated with 17% increased risk of all-cause mortality (HR, 1.17; 95% CI, 1.05 to 1.30) and 16% increased risk of CVD mortality (HR, 1.16; 95% CI, 1.01 to 1.33), but was not associated with kidney failure (HR, 1.02; 95% CI, 0.97 to 1.07).
Limitations: Primary analyses were based on a single measurement of uric acid. Results are generalizable primarily to relatively young white patients with predominantly nondiabetic CKD.
Conclusions: In patients with stages 3 to 4 CKD, hyperuricemia appears to be an independent risk factor for all-cause and CVD mortality, but not kidney failure.
New Formula Promises More Accurate Estimation of Kidney Function
Lynda A. Szczech, MD, MSCE
Ann Intern Med. 2009;150:604-612
Levey AS, Stevens LA, Schmid CH, et al
Creatinine has been, is now, and will be for the foreseeable future our easiest way to monitor kidney function. However, the inadequacies and limitations of creatinine as such a marker are well described. Due to the nonlinear relationship between creatinine and kidney function, as well as the effect of a patient's muscle mass on the association between absolute value of creatinine and kidney function, formulas to approximate kidney function using serum creatinine and proxies for muscle mass are essential.
The Cockcroft-Gault equation was the first widely used formula. Although creatinine clearance using this equation is relatively simple to calculate, it was recognized to overestimate kidney function, and many have raised concerns on the basis of its limited generalizability. Investigators from the Modification of Diet in Renal Disease (MDRD) study subsequently derived a number of formulas to approximate kidney function using that study that performed better than the Cockcroft-Gault formula.[2,3] The formula has been widely applied in both clinical care and research since its publication, but clinicians continue to discuss whether it can be used for patients with clearance of less than 60 mL/min and without diabetes mellitus.
Given these continued generalizability limitations, Levey and colleagues collaborated with multiple investigators to obtain data from studies in which the glomerular filtration rate (GFR) was measured using exogenous filtration markers and serum creatinine. Ten studies were available and were randomly divided into 2 groups for development of the new estimation equation and the internal validation of the new equation. At the Cleveland Clinical Laboratory, serum creatinine values were recalibrated to standardized creatinine measurements using the Roche enzymatic method. The equation was developed with potential clinical predictor variables of serum creatinine, age, race (black vs white and other), and sex. Additional variables available in some models include diabetes mellitus, previous organ transplantation, and weight.
The dataset used for development of the equation contained 5504 subjects. The mean serum creatinine was 1.65 mg/dL with a mean GFR measured at 68 mL/min, providing a robust representation of patients with milder kidney disease than was possible with the MDRD study. Approximately 29% of participants had diabetes mellitus and 32% were African American. The mean age was 47 years with limited representation of the elderly (9% between 66 and 70 years, and 3% > 71 years).
The Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formula developed is represented as the equation below, in which the values of the constants of a, b, and c vary on the basis of race, sex, and serum creatinine.
GFR = a × (serum creatinine/b) c × (0.993)age
The variable a takes on the following values on the basis of race and sex:
- Women = 166
- Men = 163
- Women = 144
- Men = 141
The variable b takes on the following values on the basis of sex:
- Women = 0.7
- Men = 0.9
The variable c takes on the following values on the basis of sex and creatinine measurement:
- Serum creatinine ≤ 0.7 mg/dL = -0.329
- Serum creatinine > 0.7 mg/dL = -1.209
- Serum creatinine ≤ 0.7 mg/dL = -0.411
- Serum creatinine > 0.7 mg/dL = -1.209
The investigators compared the abilities to identify patients with various degrees of kidney disease of the new CKD-EPI formula with the MDRD formula. Although both formulas performed similarly well, in which subjects were misclassified in terms of category of kidney disease, the CKD-EPI formula was more often correct (P < .001). In the separate subset of patients designated to validate the new formula, the CKD-EPI formula demonstrated less bias and improved precision and greater accuracy than the MDRD formula (P < .001), particularly for those patients with an estimated GFR > 60 mL/min. The median difference between measured and estimated GFR was 2.5 mL/min for the CKD-EPI formula and 5.5 mL/min for the MDRD formula (P < .001).
Because of the reduced error of overestimation of kidney function, the CKD-EPI equation yielded a lower estimated prevalence of kidney disease in the National Health and Nutrition Examination Survey (NHANES) dataset. Where the MDRD equation estimated the prevalence of kidney disease at 13.1%, the CKD-EPI formula estimated it slightly lower at a prevalence of 11.5%. This limited extent to which the equation overestimates GFR reflects the major advantage of this newer formula.
The use of serum creatinine is a cheap and easy way to estimate kidney function. Although the manner in which to transform serum creatinine into an accurate measure of absolute kidney function remains a problem, this analysis takes use 1 step closer. Researchers anticipate that it will be quickly adopted in the clinical community to allow an even more accurate equation of kidney function.
Early Detection Aims to Reverse Rising Rate of Kidney Disease
(New York, NY) — The old adage "an ounce of prevention is worth a pound of cure" will take on new meaning this March as kidney experts make plans to help ensure that people at risk don't end up with kidney failure or dying an early death due to complications of the disease. Those with kidney failure require dialysis treatment or a kidney transplant in order to stay alive.
Led by kidney specialists Dr. Andrew S. Levey at Tufts Medical Center in Boston, MA, and Dr. William McClellan at Emory University in Atlanta, GA, the panel of experts designed a comprehensive public health strategy to prevent the development and complications of chronic kidney disease in the U.S.
Commissioned by the U.S. Centers for Disease Control and Prevention (CDC), their report is published in the March issue of the American Journal of Kidney Diseases, the official journal of the National Kidney Foundation, scheduled to coincide with National Kidney Month (March) and World Kidney Day on March 12.
The treachery of chronic kidney disease, which currently affects 26 million Americans, is its silent progression in the early stages when it is most treatable. If left unchecked, the most deadly form of the disease - kidney failure - occurs when the kidneys can no longer function to filter out the body's waste products. Kidney failure is expected to affect a growing number of patients over the next decade, devouring an increasing fraction of available health care dollars.
But according to the authors, the ravages of kidney failure, also known as end stage kidney disease, can be held at bay by preventing the disease to begin with, detecting it in its earliest stages and providing treatment.
Their plan begins by targeting people who may not yet have kidney disease but are at risk, either because of their advancing age, a family history of the condition, or the presence of conditions that damage the kidneys, such as high blood pressure, diabetes, or cardiovascular disease.
The authors propose concrete measures to reduce this public health threat, such as:
- Raising awareness of the danger among those at risk
- Routine testing to detect the condition in its earliest stages, with a urine test to detect albumin and a blood test for creatinine to estimate the glomerular filtration rate (a measure of how well the kidneys are functioning)
- Reducing risk by improving blood pressure control among those with hypertension
- Reducing risk by improving blood sugar control among those with diabetes
"Equally as important is preventing progression in patients who already have chronic kidney disease," said Dr. Levey, who is a member of the National Kidney Foundation's Scientific Advisory Board. "One important measure is treating hypertension with drugs called ACE inhibitors and angiotensin-receptor blockers (ARBs) that protect the kidneys while keeping blood pressure in check."
For patients with more advanced stages of chronic kidney disease, and those with kidney failure, the panel urges continuing education for health care providers as to best treatment practices. Proper interventions for complications of reduced kidney function, such as anemia, malnutrition, and bone and mineral disorders, are necessary to prolong survival, enhance quality of life, and reduce the cost of care.
"While all the proposed measures are important, as a physician, I stress routine testing of patients at increased risk for chronic kidney disease," Dr. Levey said. "Given the high prevalence of hypertension and diabetes in the elderly, this would include testing most older individuals with a chronic medical condition."
"Routine reporting of glomerular filtration rate estimates by clinical laboratories whenever serum creatinine is measured has been a big help, and should receive continued emphasis," adds Dr. Kerry Willis, Senior VP for Scientific Activities, National Kidney Foundation.
Of paramount importance to the success of this initiative, the specialists say, is their final recommendation to increase public awareness of chronic kidney disease in order to improve health-related decisionecommendation to increase public awareness of chronic kidney disease in order to improve health-related decision-making.
In order to enact these recommendations, "Cooperation among federal, state and local governmental and private organizations will be necessary," noted Dr. Levey.
As a first step towards increasing public awareness of and making early detection as easy as possible, the National Kidney Foundation is offering 50 free screenings in locations around the U.S. on World Kidney Day, March 12 through the Kidney Early Evaluation Program (KEEP). KEEP is offered to those at risk -anyone with diabetes, high blood pressure or a family history- with the goal of preventing kidney disease from becoming kidney failure. For locations and schedules, visit www.keeponline.org.
The National Kidney Foundation is dedicated to preventing and treating kidney and urinary tract diseases, improving the health and well being of individuals and families affected by these diseases, and increasing availability of all organs for transplantation.
To learn more about CKD risk factors, prevention and treatment, contact the National Kidney Foundation at www.kidney.org or (800)622-9010.
Treatment of Chronic Kidney Disease After Solid Organ Transplantation
Robert J. Stratta, MD
Kidney Transplantation in Previous Heart or Lung Recipients
Lonze BE, Warren DS, Stewart ZA, et al
Am J Transplant. 2009;9:578-585
Should Heart, Lung, and Liver Transplant Recipients Receive Immunosuppression Induction for Kidney Transplantation?
Ranney DN, Englesbe MJ, Muhammad W, et al
Clin Transplant. 2009 Feb 17. [Epub ahead of print]
Using national data from the United Network for Organ Sharing (UNOS), Lonze and colleagues evaluated outcomes in 568 kidney after heart (KAH) and 210 kidney after lung (KAL) transplants performed between 1995 and 2008. Median time to kidney transplant was 100.3 months after heart and 90.2 months after lung transplant.
Renal failure was attributed to calcineurin inhibitor toxicity in 69% of KAH and 82% of KAL transplants. In a smaller proportion of cases, renal failure was attributed to hypertensive nephrosclerosis (7% KAH, 5% KAL) or diabetic nephropathy (6% KAH, 1.4% KAL). Outcomes were compared to matched controls to account for numerous pertinent characteristics.
Although 5-year renal graft survival rates were lower than those in primary kidney recipients in matched controls (61% KAH vs 73.8% controls, 63% KAL vs 83% controls, both P < .001), 5-year death-censored-graft survival rates were comparable (85% KAH vs 88% controls, 88% KAL vs 90% controls, both P = NS). Graft survival rates were higher in all populations (KAH, KAH, controls) of live donor compared to deceased donor kidney recipients.
Kidney transplantation reduced the risk for mortality compared with dialysis by 43% for KAH and 54% for KAL recipients. The authors concluded that renal grafts function well and provide survival benefit in KAH and KAL recipients, but are limited in longevity by the general life expectancy of these recipients.
In the second single center study of 42 kidney recipients following heart (n = 11), lung (n = 2), or liver (n = 29) transplantation, 21 patients received antibody induction (14 Thymoglobulin®, 5 ATGAM®, 2 Simulect®) and 21 were managed without antibody induction.
Patients receiving antibody induction had more delayed graft function (48% vs 9.5% without induction, P = .004) and trends toward more infections (47% vs 29% without induction), fewer acute rejection episodes (9.5% vs 14.3% without induction), more readmissions (65% vs 45% without induction), and lower 1-year patient and graft survival rates (both 81% vs 95% without induction, all P = NS).
Based on these results, Ranney and colleagues concluded that there is a trend toward lower patient and graft survival rates and greater morbidity among patients receiving antibody induction vs no induction following KAH, KAL, or kidney after liver transplantation.
Chronic renal failure is an increasingly recognized long-term complication of solid organ transplantation. Chronic kidney disease in the transplant population is associated with a 4- to 5-fold increased risk of death. The 5-year risk of chronic renal failure after transplantation of a nonrenal organ ranges from 7% to 21%, depending on the type of organ transplanted.
Treatment of end-stage renal disease with kidney transplantation in the nonrenal organ transplant population has been associated with a nearly 50% reduction in mortality compared to other renal replacement therapy options. Calcineurin inhibitor therapy, which remains the mainstay of contemporary immunosuppressive regimens, has been implicated as the major cause of posttransplant renal dysfunction due to nephrotoxicity.
Multiple other factors contribute to the development of chronic kidney disease following nonrenal organ transplantation. These include acute tubular necrosis/perioperative renal failure, sepsis, use of diuretics, exposure to radiographic contrast agents, atheroembolism, acute interstitial nephritis, anemia, ventricular dysfunction, increasing recipient age, female recipient gender, diabetes, hypertension, dyslipidemia, hepatitis B or C infection, or administration of other nephrotoxic drugs.
Ironically, the development of chronic kidney disease has become an unexpected measure of success following nonrenal solid organ transplantation because it correlates with longevity and in some respects may be inevitable until safe and efficacious nonnephrotoxic chronic immunosuppression is introduced into clinical transplantation. It is important to note that kidney transplantation in the setting of chronic immunosuppression because of a previous nonrenal organ transplant may pose unique challenges because these patients are considered "high risk" not only from a medical and immunological standpoint, but also "medically urgent" from a transplant perspective.
In the presence of delayed graft function following kidney transplantation, the complexities of patient outcomes underscore the need to carefully weigh the risks for and benefits of antibody induction immunosuppression in these chronically immunosuppressed, chronically ill, and usually elderly patients. Moreover, these patients may not tolerate kidney delayed graft function, which further highlights the role for living donor kidney transplantation in this patient population.