Age, eGFR, and CKD Complications Editorial

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ally, hyperphosphatemia in those over 80 years of age compared with similarly aged people with. eGFR. 60 ml/min per 1.73 m2 (8). Importantly, elderly patients ...
Editorial

Age, eGFR, and CKD Complications Jean L. Holley

Clin J Am Soc Nephrol 6: 2729 –2731, 2011. doi: 10.2215/CJN.10771011

Using formulas to estimate GFR and stratify levels of kidney function established a less confusing nomenclature, led to the development of clinical practice guidelines addressing complications of chronic kidney disease (CKD), and increased referral of patients to nephrologists. Inherent in the development of guidelines advocating screening for specific conditions is the assumption that diagnosing the condition is worthwhile. By identifying affected individuals, can we decide who will benefit from treatments of these conditions and their related complications? Can we alter prognosis and/or the quality of life of those affected by the condition for which we screen? In many instances applying a screening tool, e.g., estimated GFR (eGFR), allows us to better define disease prevalence and characterize it demographically. Subsequently, with improved understanding of the disease, outcomes can be assessed and effective treatments identified. Clinical study of treatment responses further clarifies disease progression, complications, and outcomes. Increased understanding of the disease process then leads to refinement of the screening tools. Thus, the benefits of screening are in part defined by available effective treatments of the disease and its complications and by patient outcomes. As with many screening tools in clinical medicine, stages of CKD were categorized by eGFR before establishment of a clear understanding of the clinical expression of the CKD stages. Until fairly recently, we had little information on the occurrence of CKD complications in relation to CKD stage. This lack of understanding of the phenotypic expression of CKD led to debates about the applicability of eGFR in certain groups of individuals, notably in elderly patients. Some argued that mildly low eGFR in elderly patients simply reflected age-related decline of normal kidney function, making true kidney disease unlikely (1). The seemingly inappropriate labeling of older individuals with the diagnosis of CKD was believed to have inflated the estimates of CKD prevalence and overburdened nephrologists with inappropriate referrals. Refinement of screening tools often depends on understanding of the expression, course, and complications of disease as well as identification of effective therapies. Such is the case with estimates of GFR as criteria for CKD. CKD-associated progression to www.cjasn.org Vol 6 December, 2011

ESRD and CKD-associated mortality were therefore investigated as consequences of CKD. The risk of CKD progression to ESRD increases with increasing CKD stage (2). However, in older adults, the risk for death tends to be greater than the risk of developing ESRD at most levels of eGFR, making progression to ESRD less likely in elderly patients (3). Those with lower eGFR have higher mortality (4), but the association of eGFR with mortality in elderly patients is attenuated (5), again raising the question of the clinical significance of a mildly low eGFR in older adults. Such findings pushed investigators and clinicians to ask if eGFR alone was an appropriate screening tool and if more clinical information on outcomes and what it means to have CKD would be helpful. Thus, methods for estimating GFR were adjusted (6), and recommendations were advanced for including urine albumin as a marker of CKD and subdividing stage 3 CKD (7). In this issue, Bowling et al. extend our understanding of the clinical expression of CKD as defined by eGFR by analyzing NHANES data to examine the prevalence of CKD complications in cohorts of subjects stratified by eGFR (8). Their evaluation of anemia, acidosis, hyperphosphatemia, hypoalbuminemia, and hypertension in more than 30,000 participants in the NHANES data and hyperparathyroidism in more than 8000 participants suggests that reductions in eGFR in elderly patients are not simply age-related declines equating to normal kidney function. Perhaps more importantly, they found that moderate reductions in eGFR (45 to 59 ml/min per 1.73 m2) are associated with anemia, acidosis, hyperparathryoidism, and, more marginally, hyperphosphatemia in those over 80 years of age compared with similarly aged people with eGFR ⬎60 ml/min per 1.73 m2 (8). Importantly, elderly patients with eGFR ⬍45 ml/min per 1.73 m2 had nearly twice the prevalence ratios of these complications. This and other recent studies examining CKD complications by eGFR levels (9) illustrate the relevance of eGFR as it affects the patients and families we see in our clinics. It is one thing to debate the prevalence of CKD in older adults based on an eGFR that varies by 5 ml/min. It is another thing entirely to consider the potential risk of hip fracture, cognitive impairment, frailty, and impaired quality of life in an elderly patient with stage 3b CKD and to wonder if therapeutic interventions

University of Illinois, Urbana-Champaign and Carle Physician Group, Urbana, Illinois Correspondence: Dr. Jean L. Holley Carle Physician Group, Nephrology, S2S2, 602 West University Avenue, Urbana, IL 61801. Phone: 217383-3605; Fax: 217383-3812; E-mail: [email protected]

Copyright © 2011 by the American Society of Nephrology

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to avoid these potential CKD complications (10 –12) are warranted. Bowling et al. have shown that an eGFR of 45 to 59 ml/min per 1.73 m2 in an 80-year-old white person significantly increases the likelihood that that person will have anemia, acidosis (defined as hypobicarbonatemia), hyperphosphatemia, and hyperparathyroidism. Even higher prevalence ratios for these CKD complications were seen in those with eGFR ⬍45 ml/min per 1.73 m2. We await studies definitively linking these abnormal laboratory results characteristic of CKD with patient outcomes and with evidence that treating these abnormal laboratory values in patients alters those patients’ lives. Analysis by Bowling et al. suggests that elderly patients with only mildly abnormal eGFR do have CKD and are therefore at risk of CKD complications. Their data also support stratifying stage 3 CKD into two distinct categories based on eGFR (8). Bowling et al. based their analysis on the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formula for estimating GFR (8). The CKD-EPI equation (6) was developed to improve accuracy of GFR determination in patients with higher Modification of Diet in Renal Disease (MDRD) eGFR. The slope of the CKD-EPI equation differs for creatinine values below 0.9 mg/dl in men and 0.7 mg/dl in women. Like the MDRD equation, adjustments are made for patient age, gender, and race. However, the data from studies used to develop the CKD-EPI included few patients older than 70 years of age. Moreover, when eGFR results using the CKD-EPI, MDRD, and the Cockcroft-Gault equations were compared with measured GFR using iothalamate and hippurate, similar GFR accuracy was seen in all equations when applied to elderly patients (13). Thus, the CKD-EPI is not more accurate than the MDRD in elderly patients. In addition, as pointed out by Bowling et al., their study lacked demographic diversity, suggesting that more investigation of ethnically diverse elderly patients with CKD is needed (8). When Congress passed the 1972 legislation making dialysis treatment available to all with ESRD, no one anticipated today’s dialysis population; elderly patients are the fastest growing group of dialysis patients despite a 1-year mortality of nearly 50% (14). Moreover, functional status in elderly dialysis patients is poor, and symptom burden is high (15,16). It is incumbent upon nephrologists to consider supportive care as an ethically viable alternative to renal replacement therapy in elderly CKD stage 5 patients, especially those with significant comorbidity and poor functional status (17). With treatment of CKD-associated complications, it may be possible to improve the quality of life of elderly CKD patients in addition to avoiding progression to ESRD. Clarification of the effects of CKD complications on the survival and life quality of older adults with low eGFR is needed. Moreover, an understanding of the effects of treating CKD complications on patient survival, functional status, and morbidity would be welcomed by nephrologists entrusted with the care of these patients and their families. Such information would assist in discussions of prognosis and determining goals of care. We can applaud Bowling et al. for showing that CKD complications as defined by abnormalities of biochemistry and hematology are more common in older adults with im-

paired eGFR. We now need to know if the acidosis, hyperphosphatemia, and hyperparathyroidism actually affect patient survival and well being and, additionally, if treatment of those complications directly benefits the patient. Our experience with erythropoietin-stimulating agents and anemia in CKD has taught us that the world of CKD is more complicated than we had first envisioned (18). The phenotypic expression of CKD and its complications holds the key to improvements in the care of our older CKD patients and their families. Disclosures None.

References 1. Glassock RJ, Winearls C: Screening for CKD with eGFR: Doubts and dangers. Clin J Am Soc Nephrol 3: 1563–1568, 2008 2. Hemmelgarm BR, Manns BJ, Lloyd A, James MT, Klarenbach S, Quinn RR, Wiebe N, Tonelli M: Alberta Kidney Disease Network: Relation between kidney function, proteinuria, and adverse outcomes. JAMA 303: 423– 429, 2010 3. O’Hare AM, Choi A, Bertenthal D, Bacchetti P, Garg AX, Kaufman JS, Walter LC, Mehta KM, Steinman MA, Allon M, McClellan WM, Landefield CS: Age affects outcomes in chronic kidney disease. J Am Soc Nephrol 18: 2758 –2765, 2007 4. O’Hare AM, Bertenthal D, Covinsky KE, Landefiedl CS, Sens S, Mehta K, Steinman MA, Borzecki A, Walter LC: Mortality risk stratification in chronic kidney disease: One size for all ages? J Am Soc Nephrol 17: 846 – 853, 2006 5. Drey N, Roderick P, Mullee M, Rogerson M: A populationbased study of the incidence and outcomes of diagnosed chronic kidney disease. Am J Kidney Dis 42: 677– 684, 2003 6. Levey AS, Stevens LA, Schmid CH, Zhang YL, Castro AF, Feldman H, Kusek JW, Eggers P, Van Lente F, Greene T, Coresh J: A new equation to estimate GFR. Ann Intern Med 150: 604 – 612, 2009 7. Levey AS, deJong PE, Coresh J, Nahas ME, Astor BC, Matsushita K, Gransevoort RT, Kasiske BL, Eckardt KU: The definition, classification and prognosis of chronic kidney disease: A KIDGO Controversies Conference Report. Kidney Int 80: 17– 28, 2011 8. Bowling CB, Inker LA, Gutierrez OM, Allman RM, Warnock DG, McClellan W, Muntner P: Age-specific associations of reduced estimated glomerular filtration rate with concurrent chronic kidney disease complications. Clin J Am Soc Nephrol 6: 000 – 000, 2011 9. Hsu C-Y, Propert K, Xie D, Hamm L, He J, Miller E, Ojo A, Shlipak M, Teal V, Townsend R, Weir M, Wilson J, Feldman H for the CRIC Investigators: Measured GFR does not outperform estimated GFR in predicting CKD-related complications. J Am Soc Nephrol 22: 1931–1937, 2011 10. Kurella MT, Wadley V, Yaffe K, McClure LA, Howard G, Go R, Allman RM, Warnock DG, McClellan W: Kidney function and cognitive impairment in US adults: The Reasons for Geographic and Racial Differences in Stroke (REGARDS) Study. Am J Kidney Dis 52: 227–234, 2008 11. Shilpak MG, Stehman-Breen C, Fried LF, Song X, Siscovick D, Fried LP, Psaty BM, Newman AB: The presence of frailty in elderly persons with chronic renal insufficiency. Am J Kidney Dis 43: 861– 867, 2004 12. Cook WL, Tomlinson G, Donaldson M, Markowitz SN, Naglie G, Sobolev B, Jassal SV: Falls and fall-related injuries in older dialysis patients. Clin J Am Soc Nephrol 1: 1197–1204, 2006 13. Michaels WM, Grootendorst DC, Verduijn M, Elliott EG, Dekker FW, Kreidet RT: Performance of the Cockcroft-Gault, MDRD, and new CKD-EPI formulas in relation to GFR, age, and body size. Clin J Am Soc Nephrol 5: 1003–1009, 2010 14. US Renal Data Data System: USRDS 2009 Annual Data Report: Atlas of Chronic Kidney Disease and End-Stage Renal

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Disease in the United States. Bethesda, MD: National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Disease; 2009 15. Cook WL, Jassal SV: Functional dependencies among the elderly on hemodialysis. Kidney Int 73: 1289 –1295, 2008 16. Kurella Tamura M, Covinsky KE, Chertow GM, Yaffe K, Landefield CS, McCulloch CE: Functional status of elderly adults before and after initiation of dialysis. N Engl J Med 361: 1539 –1547, 2009 17. Shared Decision-Making in the Appropriate Initiation of and Withdrawal from Dialysis, 2nd ed., Rockville, MD, Renal Physicians Association, 2010

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18. Pfeffer MA, Burdmann EA, Chen CY, Cooper ME, de ZD, Echardt KU, Feyzi JM, Ivanovich P, Kewalramani R, Levey AS, Lewis EF, McGill JB, McMurray JJ, Parfrey P, Parving HH, Remuzzi G, Singh AK, Solomon SD, Toto R: A trial of darbopoietin alfa in type 2 diabetes and chronic kidney disease. N Engl J Med 361: 2019 –2032, 2009 Published online ahead of print. Publication date available at www.cjasn.org. See related article, “Age-Specific Associations of Reduced Estimated Glomerular Filtration Rate with Concurrent Chronic Kidney Disease Complications,” on pages 2822–2828.