UP FRONT MATTERSSpecial Articles

Prediction, Progression, and Outcomes of Chronic Kidney Disease in Older Adults

Sharon Anderson, Jeffrey B. Halter, William R. Hazzard, Jonathan Himmelfarb, Frances McFarland Horne, George A. Kaysen, John W. Kusek, Susan G. Nayfield, Kenneth Schmader, Ying Tian, John R. Ashworth, Charles P. Clayton, Ryan P. Parker, Erika D. Tarver, Nancy F. Woolard, Kevin P. High and ; for the workshop participants
JASN June 2009, 20 (6) 1199-1209; DOI: https://doi.org/10.1681/ASN.2008080860

Abstract

Chronic kidney disease is a large and growing problem among aging populations. Although progression of chronic kidney disease to end-stage renal disease (ESRD) is a costly and important clinical event with substantial morbidity, it appears less frequently in aging people compared with cardiovascular mortality. The measurement of kidney function and management of kidney disease in older individuals remain challenging, partly because the pathophysiologic mechanisms underlying age-related decline in kidney function, the interactions between age and other risk factors in renal progression, and the associations of chronic kidney disease with other comorbidities in older people are understudied and poorly understood. The Association of Specialty Professors, the American Society of Nephrology, the American Geriatrics Society, the National Institute on Aging, and the National Institute of Diabetes and Digestive and Kidney Diseases held a workshop, summarized in this article, to review what is known about chronic kidney disease, identify research gaps and resources available to address them, and identify priority areas for future research. Answers to emerging research questions will support the integration of geriatrics and nephrology and thus improve care for older patients at risk for chronic kidney disease.

Chronic kidney disease (CKD), defined by reduced glomerular filtration rate (GFR), proteinuria, or structural kidney disease, is a growing problem among the aging population (Figure 1).1 Although ESRD, defined as kidney failure treated with dialysis or transplantation, is less prevalent than earlier CKD stages, the number of patients who have ESRD and are older than 65 yr almost doubled during 25 yr, and the fastest growing segment of that population during the past decade is older than 75 yr.

Figure 1.
Figure 1.

Prevalence of CKD by age group in National Health and Nutrition Examination Survey (NHANES) data 1988 through 1994 and 1999 through 2004. Adapted from Coresh et al.65

Proteinuria, hypertension, diabetes, race, and ethnicity are strong risk factors for progression from CKD to ESRD,2–9 and the higher ESRD incidence among men than among women is most pronounced in older patients. Declines in renal function, measured by creatinine clearance, occur in approximately two thirds of “healthy” older adults over time10 but progresses to ESRD in only 1 to 2% of these patients,1 yet mortality rates are high among older patients with CKD.11 Few studies of older patients with CKD have addressed the mechanisms leading to ESRD or mortality.

MECHANISMS UNDERLYING CKD IN AGED PEOPLE

The cause of age-related increases in renal fibrosis, which leads to glomerulosclerosis, interstitial fibrosis, tubular atrophy, vascular sclerosis, and loss of renal function, is poorly understood; however, in animal models, collagen seems to accumulate with age in the glomerulus, peritubular capillary, and tubulointerstitium because of increased transcription of the gene encoding type III collagen.12 Preliminary studies in aged rats showed a loss of polycomb-mediated (epigenetic) collagen gene silencing despite a significant decrease in histone modifications associated with repressed genes, suggesting that other polycomb-related abnormalities contribute to age-associated loss of gene regulation.13,14 Calorie restriction, a robust antiaging intervention in animal models, resulted in increases in histone modifications, similar to those seen in aged rats on a regular diet, but restored gene expression and prevention of kidney sclerosis in the calorie-restricted animals suggest the restoration of effective polycomb-mediated silencing. How increases in epigenetic silencing mechanisms are circumvented in these models is not known.

Telomere shortening and increased p16INK4A expression, which are implicated in somatic cellular senescence pathways (Figure 2), are observed in aging human kidneys.15,16 Increased p16INK4A expression is also observed in aging rodents,17 but telomere shortening is not.16 Cellular senescence is associated with several features of the aging kidney15 and accelerates in patients with progressive kidney disease18,19 and transplant nephropathy,18 in biopsies from patients with hypertensive nephropathy,20 and in animal models of experimental hypertension20 and ischemia/reperfusion-induced injury.21,22

Figure 2.
Figure 2.

Senescence-associated changes in gene expression.145 Cellular senescence is marked by increased expression of cell-cycle inhibitors and extracellular matrix proteins and by decreased expression of proteins involved in cell-cycle progression. Redrawn from ref. 145 (Melk A: Senescence of renal cells: Molecular basis and clinical implications. Nephrol Dial Transplant 18(12): 2474–2478, 2003), by permission of Oxford University Press.

GENES AND CKD

Efforts are under way to identify genes associated with CKD and diabetic nephropathy and to establish biomarkers of risk for CKD and likelihood of benefit from intensive treatment; however, replication of potential CKD candidate genes is inconsistent because of phenotype specificity, varying genotyping technologies, and challenges with study design. How genetic variation will predict CKD risk, how patients will respond to their individual risk assessment, and how genetic risk contribution differs across ancestral groups are not clear. Gene–gene and gene–environment interactions are also poorly understood. Several candidate age-associated genes have been identified, including genes involved in regulating metabolism and enhancing tissue integrity. Global age-associated changes in gene expression also have been observed for the kidney.23 Selection pressure,24 epigenetic mechanisms, and changes in telomere biology and the proliferative capacity of renal stem or progenitor cells25–27 also might modulate dysfunction in the aging kidney.28

ACUTE KIDNEY INJURY AND CKD PROGRESSION

The incidence of acute kidney injury (AKI) is increasing,29 particularly among older patients.30 Patients with CKD are more likely to experience AKI,31 and AKI is a risk factor for progression to ESRD. In the rat ischemia/reperfusion model, AKI is characterized by a temporary but substantial decrease in GFR, compromised urine-concentrating ability, proteinuria and interstitial fibrosis, and impaired sodium processing.32 Injured kidneys in this model also show a dramatic increase in hypoxia and renal fibrosis.33,34 Glomerular capillary density and interstitial peritubular vascular density decrease with age in the absence of other insults and are exacerbated by acute injury,35,36 and the ability to repair and regenerate tissue after injury declines with age.37 Thus, progression of CKD might not be a smooth, continuous course so much as a stepwise function marked by repeated episodes of AKI.

MEASURING AND CLASSIFYING CKD

Although measured GFR is considered the best overall measurement of kidney function, it is often not practical in clinical or epidemiologic settings. Thus, there are few studies of measured GFR in older adults, and they have small sample sizes.38 GFR declines with age in the general population,38 but the rate of decline varies widely among individuals, and it is not clear whether declining GFR is part of “normal aging.” The annual rate of GFR decline was only 0.8 to 1.4 ml/min per 1.73 m2 in one community-based cohort of adults who were older than 65 yr and did not have diabetes,39 and one third of “healthy” older patients in another study showed no appreciable declines in kidney function during 10 yr.10

GFR is usually estimated (eGFR) from serum levels of endogenous filtration markers, most commonly creatinine and recently cystatin C40,41; however, factors other than filtration, including generation, tubular secretion or reabsorption, and extrarenal elimination, affect these markers.42 Estimating equations, which incorporate some of these non-GFR determinants, yield more accurate estimates of kidney function than do serum marker levels alone; however, current creatinine-based estimating equations have been reported to be less accurate in patients without kidney disease, and muscle wasting and inflammation might interfere with the accuracy of creatinine or cystatin C–based estimating equations in older people with frailty or comorbid illnesses. Improved measures of kidney function in older patients are needed to estimate better the prevalence of CKD and AKI, to manage and diagnose comorbidities appropriately, and to dose medications properly.

A new creatinine-based estimating equation,41 developed in a pooled sample in which the mean age was 52 yr, reduces bias by 50% and offers small but consistent improvement in precision and accuracy, compared with the most commonly used equation. In addition, accuracy of creatinine-based equations does not differ significantly from that of cystatin C–based equations in populations studied thus far, but equations based on the combination of the two markers might provide the best accuracy.41 Non-GFR determinants affecting each marker, such as low muscle mass and possibly obesity, might lead to systematic over or underestimation of GFR in specific individuals.

The term “preclinical kidney disease”43 has been proposed to describe patients with a creatinine-based eGFR >60 ml/min per 1.73 m2 and a cystatin C level >1.0 mg/L (equivalent to an eGFR of approximately 75 ml/min per 1.73 m2). On the basis of these criteria, 39% of the Cardiovascular Health Study sample, in which the mean age is 75 yr and patients do not meet the GFR-based criteria for CKD, have preclinical kidney disease. The incidences of death and CKD, defined on the basis of creatinine-based eGFR, is higher among these patients than it is among patients with eGFR >60 ml/min per 1.73 m2 and low cystatin C (Figure 3).

Figure 3.
Figure 3.

Effects of preclinical kidney disease.43 Incidence for progression to CKD and for all-cause mortality is higher among patients with preclinical kidney disease, defined as GFR >60 ml/min per 1.73 m2 and cystatin C >1.0 mg/L, than it is among patients with normal kidney function. Redrawn from ref. 43.

CKD, CARDIOVASCULAR DISEASE, AND ALL-CAUSE MORTALITY

Age-associated macrovascular changes include increased arterial diameter, wall thickness, and stiffness; changes in gene expression related to vascular elasticity and hypertension; increased migration of smooth muscle cells from the media to the epithelial space; and increased endothelial dysfunction.44–47 Similar changes have been observed in kidney disease45,48 and attributed to increased production of reactive oxygen species, decreased production of telomerase reverse transcriptase, and, ultimately, increased levels of C-reactive protein and oxidized LDL cholesterol.49 Impaired vasodilation has also been associated with proteinuria.50

Both aging and ESRD are independently associated with exponential increases in mortality from cardiovascular disease (CVD),51 but they exert an additive effect on mortality risk. The high rate of CVD is also a large factor in the high mortality rates seen among older patients with CKD.11 Among patients undergoing cardiac surgery, mortality risk increases even with a 0.2-mg/dl increase in serum creatinine,52 and patients with serum creatinine levels between 1.2 and 2.1 mg/dl before cardiovascular surgery are at increased risk for AKI requiring dialysis.53

The GFR threshold predictive of cardiovascular events and all-cause mortality has not been established. Several studies have shown increased risk with moderate chronic renal insufficiency or preclinical kidney disease in both older and younger patients.43,54–58 Other studies have observed that increasing age attenuates the association of eGFR with mortality.59–61 Consequently, the threshold eGFR at which mortality or cardiovascular risk increases might differ across the age spectrum, although risk for mortality is consistently increased at eGFR <45 ml/min per 1.73 m2 in all age groups. Furthermore, the association between creatinine-based GFR62 and mortality differs slightly from that seen with cystatin C–based GFR (Figure 3).

Standard risk factors for CVD do not fully explain the increased risk for CVD seen in patients with CKD.63 Urinary albumin concentration, which is a strong risk factor for progression to ESRD64 and increases in prevalence with age,65 is an independent risk factor for CVD.66,67 GFR and albuminuria are poorly correlated, but they exert an additive effect on CVD outcomes,67–70 even in patients aged ≥70 yr.68 Microalbuminuria, defined as 30 to 300 mg/g albumin in the urine, has been associated with left ventricular abnormalities,71 increased inflammatory markers,72 insulin resistance,73 endothelial dysfunction,50,74 and abnormalities in fibrinolytic and coagulation pathways. Antihypertensive drugs used to reduce microalbuminuria might be associated with a lower risk for incident cardiovascular events.75,76

Vascular calcification and hyperphosphatemia are also independent risk factors for CVD in patients with CKD,77–80 as demonstrated by mechanistic data in animal81 and cell culture models.82 CKD bone mineral disorder is characterized by phosphorus, calcium, vitamin D, and pH values associated with abnormal bone turnover and vascular calcification. Higher phosphorus levels, even within the “normal reference range,” also might be associated with all-cause mortality in the general population.83,84 The osteoblastic transcription factor osterix might participate in the causative pathway involving phosphorus, vascular calcification, and CVD.82

Oxidized LDL correlates with increased mortality risk in dialysis patients85 and might play a role in endothelial injury.86 Vascular dropout occurs in patients with hypertension and even more so in patients with CKD,87 and endothelin production increases in animal models of CKD.88 Treatment with an endothelin inhibitor prevents podocyte injury, proteinuria, and glomerulosclerosis in animal models.88,89

Initiation of maintenance dialysis for ESRD is associated with significant improvement in BP and left ventricular mass,90 but common approaches toward management of CVD, including statins91 or reductions in calcification and phosphorus metabolism,92 may not be as successful in patients with CKD or ESRD. Although anemia is a risk factor for CVD in patients with CKD,93,94 data from recent randomized trials of erythropoietin treatment suggested that targeting specific hemoglobin levels might not be appropriate for treatment or prevention.95

CKD, COMORBID CONDITIONS, AND AGING

Frailty is more prevalent among older patients with CKD than it is among those with normal kidney function.96 Although a large proportion of dialysis patients are frail even at younger ages, frailty is common among older dialysis patients.97 The natural history of frailty in patients with CKD and the factors that increase risk are not known, which has stymied the identification and evaluation of interventions to address frailty in patients with CKD.

Physical activity decreases with age, particularly among patients on dialysis,98 and mortality risk during 1 yr is higher among sedentary than among nonsedentary dialysis patients.99 In older patients, physical performance–based measures predict falls, hospitalizations, length of hospital stay, discharge to a nursing home, or mortality.100 The significance of these measures for CKD or ESRD is not known. Low physical functioning, measured by objective laboratory tests or self-reported measures, predicts survival in ESRD.101–103 Sarcopenia is a significant problem in CKD and may contribute to low functioning and frailty. Although muscle size is comparable between healthy control subjects and dialysis patients, the proportion of contractile tissue in dialysis patients is only two thirds that in control subjects.104

Exercise training improves exercise capacity and physical performance–based measures,105 as well as CVD-related factors,106–110 protein uptake into skeletal muscles,111 dialysis efficiency,112 and quality of life.113 Cardiovascular training improves peak oxygen uptake and muscle strength in patients with CKD,114 and resistance training increases muscle fiber size, improves muscle strength, and reduces inflammation.115 Thus, nephrology practice should include assessments of physical function and interventions to address low function in patients with CKD.

Although age-related criteria for defining anemia in older people are debated, anemia is highly prevalent among older people and associated with depression and impaired physical and cognitive function.116 The prevalence of anemia is much higher117,118 among patients with a GFR <30. The aging process may have an inflammatory component, and some clinical markers of inflammation-associated anemia overlap with those of iron deficiency. The role of inflammation in CKD-associated anemia in older people is poorly understood.

CKD is associated with an increased risk for cognitive decline and dementia.119–121 Accumulating data120,122 suggest that the prevalence of cognitive impairment begins to increase early in CKD, as GFR drops <60 ml/min per 1.73 m2. Other CKD markers, including increased cystatin C and microalbuminuria, have also been linked with an increased risk for cognitive impairment.123,124 Thirty percent of dialysis patients overall and up to 70% of dialysis patients aged ≥55 yr have moderate to severe impairment.125,126 Cerebrovascular disease, both clinical (e.g., stroke) and subclinical, might play a large role in the development of cognitive impairment among patients with CKD and ESRD.119,127 Other factors that might contribute to cognitive impairment include anemia128; accumulation of uremic toxins; and, in patients with ESRD, a dialysis delirium–like syndrome that, over time, might have deleterious effects on cognition.129

GOALS FOR CLINICAL MANAGEMENT IN OLDER PATIENTS WITH CKD

Among older patients with CKD, mortality and cardiovascular events are more common than progression to ESRD.56,130–132 Studies suggest that hypertension therapy that preserves cardiac muscle might not prevent ESRD or a 50% decline in GFR.56,130,131,133 Thus, care for patients with CKD should focus more on reducing CVD risk than on progression to ESRD. Furthermore, functional outcomes, such as cognition and physical functioning, might be more meaningful outcomes in older patients with CKD. More study is needed to determine how CKD affects independent function, and interventions should be developed and assessed in terms of maintaining active life expectancy. Such approaches might facilitate intervention in older patients before disability develops.

The appropriate treatment of older patients with CKD is not clear. Among patients who had CKD and were not referred to a nephrologist, increasing age attenuated the association of serum creatinine with mortality risk, but in a multivariable analysis, reduced eGFR independently predicted death, whereas age did not.134 Other work demonstrated that early referral to nephrology care reduced adverse CKD outcomes.135–138 The effects of multidisciplinary care are also debated. Two studies correlated multidisciplinary care with modest improvements in survival,39,139 but another study showed no differences in kidney function or mortality between patients who received multidisciplinary, intensive care and those who did not.140

The benefits of long-term dialysis in older patients are controversial. Although one study suggested that dialysis improves survival in patients aged ≥65 yr,141 mortality rates are exceedingly high among very old patients who initiate dialysis.141 In one small observational study of patients who were aged ≥75 yr and had stage 5 CKD, those who initiated dialysis survived longer than those who did not; however, among the subgroup with a high number of comorbidities, survival was similar among those treated conservatively and those who initiated dialysis.142

AREAS OF FUTURE RESEARCH

Potential research questions in the areas of CKD biology, measurement and prognosis, CVD, other comorbidities, and management are listed in Table 1.

View this table:
Table 1.

Questions for future research

View this table:
Table 2.

Relationship between change in creatinine clearance during 3 yr and total PUFAs at baseline144a

The manifestations and prognosis of CKD differ between older and younger adults. Additional studies are needed to delineate age-related differences in the mechanisms and pathways that contribute to progression of CKD and adverse cardiovascular and metabolic events. Randomized clinical trials are also needed to explore novel therapeutic approaches to reduce CVD and mortality in older patients with CKD. More study is needed to determine not only whether aging and CKD mechanisms differ but also how they interact.

Measurement of GFR in representative populations without significant illnesses is needed to determine “normal” GFR and allow development of more accurate estimating equations for older people. Improved methods to estimate GFR in the frail and in sick older patients will likely require new filtration markers or combinations of markers, particularly those not affected by muscle or disease. In addition, more study is needed to determine the length of time needed to see decreases in the numbers of glomerular and functional tubular cells.

Additional information on CKD complications would facilitate greater understanding of the overall impact of CKD on the patient. Markers other than GFR, such as AKI markers, are needed to assess patients’ risk and to measure kidney damage more directly. Although proteinuria already has been identified as an important risk factor, other risk factors might include microalbuminuria, erythropoietin/anemia ratios, advanced glycation end products and their receptors, vitamin D metabolism, and serum phosphate. The identification of new measures that are clearly in the causal pathway for CKD and ESRD would be useful, as would studies including the long-term follow-up needed to distinguish true kidney disease from normal GFR declines in older people.

How age influences vascular biology and cardiovascular risk factors and how these changes contribute to CKD-associated increases in risk for CVD are not clear. The connection between CKD and other comorbidities, such as frailty and cognitive impairment, and how age influences these connections should be explored further. Further study is also needed to determine how age affects interventions to prevent or reduce these comorbidities in patients with CKD.

Geriatricians, internists, general family practitioners, and nephrologists should work together to optimize care for older patients with CKD and ESRD. Recent epidemiologic evidence correlated serum polyunsaturated fatty acid levels, which have a strong anti-inflammatory effect,143 with slower rates of decline in creatinine clearance in an aging population (Figure 4).144 How target BP and other surrogate markers can be used to preserve patients’ ability and independence, as opposed to preventing progression to ESRD, should be studied further. More study is also needed to determine how to identify patients most likely to benefit from dialysis, reduce the number of inappropriate dialysis starts, and aid patients and family members in decision-making regarding dialysis. More clinical trials are needed, particularly those that include physical and cognitive function as outcomes.

Figure 4.
Figure 4.

Polyunsaturated fatty acids (PUFAs) and creatinine clearance. Higher PUFA serum levels have been associated with shallower declines in creatinine clearance in an aging population.144 n-3 PUFAs seem to have the greatest effect (Table 2). Redrawn from ref. 144.

DISCLOSURES

None.

Acknowledgments

This workshop was supported by a generous grant from the John A. Hartford Foundation to the Association of Specialty Professors. For a list of the planning committee and attendees of the conference, please visit http://www.im.org/CareerDevelopment/GrantsandScholarships/IGP/ExpandingResearchEfforts/Pages/Workshoponprediction,Progression,andOutcomesofChronicKidneyDiseaseinOlderAdults.aspx.

Footnotes

  • Published online ahead of print. Publication date available at www.jasn.org.

REFERENCES

  1. ↵
    US Renal Data System: USRDS 2007 Annual Data Report: Atlas of Chronic Kidney Disease and End-Stage Renal Disease in the United States, Bethesda, National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases, 2007
  2. ↵
    Xue JL, Eggers PW, Agodoa LY, Foley RN, Collins AJ: Longitudinal study of racial and ethnic differences in developing end-stage renal disease among aged Medicare beneficiaries. J Am Soc Nephrol 18 : 1299– 1306, 2007
    OpenUrlAbstract/FREE Full Text
  3. Gooch K, Culleton BF, Manns BJ, Zhang J, Alfonso H, Tonelli M, Frank C, Klarenbach S, Hemmelgarn BR: NSAID use and progression of chronic kidney disease. Am J Med 120 : 280– 287, 2007
    OpenUrl
  4. Kiberd B: The chronic kidney disease epidemic: Stepping back and looking forward. J Am Soc Nephrol 17 : 2967– 2973, 2006
    OpenUrlAbstract/FREE Full Text
  5. Merkin SS, Coresh J, Roux AV, Taylor HA, Powe NR: Area socioeconomic status and progressive CKD: The Atherosclerosis Risk in Communities (ARIC) Study. Am J Kidney Dis 46 : 203– 213, 2005
    OpenUrlCrossRefPubMed
  6. Keith DS, Nichols GA, Gullion CM, Brown JB, Smith DH: Longitudinal follow-up and outcomes among a population with chronic kidney disease in a large managed care organization. Arch Intern Med 164 : 659– 663, 2004
    OpenUrlCrossRefPubMed
  7. Neugarten J, Acharya A, Silbiger SR: Effect of gender on the progression of nondiabetic renal disease: A meta-analysis. J Am Soc Nephrol 11 : 319– 329, 2000
    OpenUrlAbstract/FREE Full Text
  8. Krop JS, Coresh J, Chambless LE, Shahar E, Watson RL, Szklo M, Brancati FL: A community-based study of explanatory factors for the excess risk for early renal function decline in blacks vs whites with diabetes: The Atherosclerosis Risk in Communities study. Arch Intern Med 159 : 1777– 1783, 1999
    OpenUrlCrossRefPubMed
  9. ↵
    Klag MJ, Whelton PK, Randall BL, Neaton JD, Brancati FL, Ford CE, Shulman NB, Stamler J: Blood pressure and end-stage renal disease in men. N Engl J Med 334 : 13– 18, 1996
    OpenUrlCrossRefPubMed
  10. ↵
    Lindeman RD, Tobin J, Shock NW: Longitudinal studies on the rate of decline in renal function with age. J Am Geriatr Soc 33 : 278– 285, 1985
    OpenUrlCrossRefPubMed
  11. ↵
    O'Hare AM, Choi AI, Bertenthal D, Bacchetti P, Garg AX, Kaufman JS, Walter LC, Mehta KM, Steinman MA, Allon M, McClellan WM, Landefeld CS: Age affects outcomes in chronic kidney disease. J Am Soc Nephrol 18 : 2758– 2765, 2007
    OpenUrlAbstract/FREE Full Text
  12. ↵
    Abrass CK, Adcox MJ, Raugi GJ: Aging-associated changes in renal extracellular matrix. Am J Pathol 146 : 742– 752, 1995
    OpenUrlPubMed
  13. ↵
    Bracken AP, Kleine-Kohlbrecher D, Dietrich N, Pasini D, Gargiulo G, Beekman C, Theilgaard-Mönch K, Minucci S, Porse BT, Marine JC, Hansen KH, Helin K: The Polycomb group proteins bind throughout the INK4A-ARF locus and are disassociated in senescent cells. Genes Dev 21 : 525– 530, 2007
    OpenUrlAbstract/FREE Full Text
  14. ↵
    Breiling A, Sessa L, Orlando V: Biology of polycomb and trithorax group proteins. In: International Review of Cytology: A Survey of Cell Biology, edited by Kwang W, San Diego, Academic Press, 2007 , pp 83– 136
  15. ↵
    Melk A, Schmidt BM, Takeuchi O, Sawitzki B, Rayner DC, Halloran PF: Expression of p16INK4a and other cell cycle regulator and senescence associated genes in aging human kidney. Kidney Int 65 : 510– 520, 2004
    OpenUrlCrossRefPubMed
  16. ↵
    Melk A, Ramassar V, Helms LM, Moore R, Rayner D, Solez K, Halloran PF: Telomere shortening in kidneys with age. J Am Soc Nephrol 11 : 444– 453, 2000
    OpenUrlAbstract/FREE Full Text
  17. ↵
    Melk A, Kittikowit W, Sandhu I, Halloran KM, Grimm P, Schmidt BM, Halloran PF: Cell senescence in rat kidneys in vivo increases with growth and age despite lack of telomere shortening. Kidney Int 63 : 2134– 2143, 2003
    OpenUrlCrossRefPubMed
  18. ↵
    Melk A, Schmidt BM, Vongwiwatana A, Rayner DC, Halloran PF: Increased expression of senescence-associated cell cycle inhibitor p16INK4a in deteriorating renal transplants and diseased native kidney. Am J Transplant 5 : 1375– 1382, 2005
    OpenUrlCrossRefPubMed
  19. ↵
    Sis B, Tasanarong A, Khoshjou F, Dadras F, Solez K, Halloran PF: Accelerated expression of senescence associated cell cycle inhibitor p16INK4A in kidneys with glomerular disease. Kidney Int 71 : 218– 226, 2007
    OpenUrlCrossRefPubMed
  20. ↵
    Westhoff JH, Hilgers KF, Steinbach MP, Hartner A, Klanke B, Amann K, Melk A: Hypertension induces somatic cellular senescence in rats and humans by induction of cell cycle inhibitor p16INK4a. Hypertension 52 : 123– 129, 2008
    OpenUrlAbstract/FREE Full Text
  21. ↵
    Chkhotua A, Abendroth D, Schelzig H: Renal ischemia/reperfusion and its influence on telomere length and expression of cell cycle regulatory genes. Georgian Med News 22– 26, 2006
  22. ↵
    Chkhotua A, Shapira Z, Tovar A, Shabtai E, Yussim A: Cellular senescence: A new marker of kidney function recovery after ischemic injury in rats. Transplant Proc 33 : 2910– 2915, 2001
    OpenUrlCrossRefPubMed
  23. ↵
    Wiggins JE, Goyal M, Sanden SK, Wharram BL, Shedden KA, Misek DE, Kuick RD, Wiggins RC: Podocyte hypertrophy, “adaptation,” and “decompensation” associated with glomerular enlargement and glomerulosclerosis in the aging rat: Prevention by calorie restriction. J Am Soc Nephrol 16 : 2953– 2966, 2005
    OpenUrlAbstract/FREE Full Text
  24. ↵
    Ji W, Foo JN, O'Roak BJ, Zhao H, Larson MG, Simon DB, Newton-Cheh C, State MW, Levy D, Lifton RP: Rare independent mutations in renal salt handling genes contribute to blood pressure variation. Nat Genet 40 : 592– 599, 2008
    OpenUrlCrossRefPubMed
  25. ↵
    Humphreys BD, Valerius MT, Kobayashi A, Mugford JW, Soeung S, Duffield JS, McMahon AP, Bonventre JV: Intrinsic epithelial cells repair the kidney after injury. Cell Stem Cell 2 : 284– 291, 2008
    OpenUrlCrossRefPubMed
  26. Oliver JA, Maarouf O, Cheema FH, Martens TP, Al-Awqati Q: The renal papilla is a niche for adult kidney stem cells. J Clin Invest 114 : 795– 804, 2004
    OpenUrlCrossRefPubMed
  27. ↵
    Singh SR, Liu W, Hou SX: The adult Drosophila malpighian tubules are maintained by multipotent stem cells. Cell Stem Cell 1 : 191– 203, 2007
    OpenUrlCrossRefPubMed
  28. ↵
    Sustained effect of intensive treatment of type 1 diabetes mellitus on development and progression of diabetic nephropathy: The Epidemiology of Diabetes Interventions and Complications (EDIC) study. JAMA 290 : 2159– 2167, 2003
    OpenUrlCrossRefPubMed
  29. ↵
    Hsu CY, McCulloch CE, Fan D, Ordonez JD, Chertow GM, Go AS: Community-based incidence of acute renal failure. Kidney Int 72 : 208– 212, 2007
    OpenUrlCrossRefPubMed
  30. ↵
    Xue JL, Daniels F, Star RA, Kimmel PL, Eggers PW, Molitoris BA, Himmelfarb J, Collins AJ: Incidence and mortality of acute renal failure in Medicare beneficiaries, 1992 to 2001. J Am Soc Nephrol 17 : 1135– 1142, 2006
    OpenUrlAbstract/FREE Full Text
  31. ↵
    Hsu CY, Ordonez JD, Chertow GM, Fan D, McCulloch CE, Go AS: The risk of acute renal failure in patients with chronic kidney disease. Kidney Int 74 : 101– 107, 2008
    OpenUrlCrossRefPubMed
  32. ↵
    Spurgeon-Pechman KR, Donohoe DL, Mattson DL, Lund H, James L, Basile DP: Recovery from acute renal failure predisposes hypertension and secondary renal disease in response to elevated sodium. Am J Physiol Renal Physiol 293 : F269– F278, 2007
    OpenUrlCrossRefPubMed
  33. ↵
    Basile DP, Donohoe D, Roethe K, Osborn JL: Renal ischemic injury results in permanent damage to peritubular capillaries and influences long-term function. Am J Physiol Renal Physiol 281 : F887– F899, 2001
    OpenUrlCrossRefPubMed
  34. ↵
    Basile DP, Donohoe DL, Roethe K, Mattson DL: Chronic renal hypoxia after acute ischemic injury: Effects of L-arginine on hypoxia and secondary damage. Am J Physiol Renal Physiol 284 : F338– F348, 2003
    OpenUrlCrossRefPubMed
  35. ↵
    Kang DH, Kanellis J, Hugo C, Truong L, Anderson S, Kerjaschki D, Schreiner GF, Johnson RJ: Role of the microvascular endothelium in progressive renal disease. J Am Soc Nephrol 13 : 806– 816, 2002
    OpenUrlAbstract/FREE Full Text
  36. ↵
    Kang DH, Anderson S, Kim YG, Mazzalli M, Suga S, Jefferson JA, Gordon KL, Oyama TT, Hughes J, Hugo C, Kerjaschki D, Schreiner GF, Johnson RJ: Impaired angiogenesis in the aging kidney: Vascular endothelial growth factor and thrombospondin-1 in renal disease. Am J Kidney Dis 37 : 601– 611, 2001
    OpenUrlCrossRefPubMed
  37. ↵
    Schmitt R, Coca S, Kanbay M, Tinetti ME, Cantley LG, Parikh CR: Recovery of kidney function after acute kidney injury in the elderly: A systematic review and meta-analysis. Am J Kidney Dis 52 : 262– 271, 2008
    OpenUrlCrossRefPubMed
  38. ↵
    Wesson L Jr: Renal hemodynamics in physiological states. In: Physiology of the Human Kidney, edited by Wesson L Jr, New York, Grune and Stratton, 1969 , pp 96– 108
  39. ↵
    Hemmelgarn BR, Zhang J, Manns BJ, Tonelli M, Larsen E, Ghali WA, Southern DA, McLaughlin K, Mortis G, Culleton BF: Progression of kidney dysfunction in the community-dwelling elderly. Kidney Int 69 : 2155– 2161, 2006
    OpenUrlCrossRefPubMed
  40. ↵
    Levey AS, Coresh J, Greene T, Stevens LA, Zhang YL, Hendriksen S, Kusek JW, Van Lente F, Chronic Kidney Disease Epidemiology Collaboration: Using standardized serum creatinine values in the modification of diet in renal disease study equation for estimating glomerular filtration rate [published erratum appears in Ann Intern Med 149: 519, 2008]. Ann Intern Med 145 : 247– 254, 2006
    OpenUrlCrossRefPubMed
  41. ↵
    Stevens LA, Coresh J, Schmid CH, Feldman HI, Froissart M, Kusek J, Rossert J, Van Lente F, Bruce RD 3rd, Zhang YL, Greene T, Levey AS: Estimating GFR using serum cystatin C alone and in combination with serum creatinine: A pooled analysis of 3,418 individuals with CKD. Am J Kidney Dis 51 : 395– 406, 2008
    OpenUrlCrossRefPubMed
  42. ↵
    Stevens LA, Coresh J, Greene T, Levey AS: Assessing kidney function: Measured and estimated glomerular filtration rate. N Engl J Med 354 : 2473– 2483, 2006
    OpenUrlCrossRefPubMed
  43. ↵
    Shlipak MG, Katz R, Sarnak MJ, Fried LF, Newman AB, Stehman-Breen C, Seliger SL, Kestenbaum B, Psaty B, Tracy RP, Siscovick DS: Cystatin C and prognosis for cardiovascular and kidney outcomes in elderly persons without chronic kidney disease. Ann Intern Med 145 : 237– 246, 2006
    OpenUrlCrossRefPubMed
  44. ↵
    Xiong Y, Yuan LW, Deng HW, Li YJ, Chen BM: Elevated serum endogenous inhibitor of nitric oxide synthase and endothelial dysfunction in aged rats. Clin Exp Pharmacol Physiol 28 : 842– 847, 2001
    OpenUrlCrossRefPubMed
  45. ↵
    Morris ST, McMurray JJ, Spiers A, Jardine AG: Impaired endothelial function in isolated human uremic resistance arteries. Kidney Int 60 : 1077– 1082, 2001
    OpenUrlCrossRefPubMed
  46. Najjar SS, Scuteri A, Lakatta EG: Arterial aging: Is it an immutable cardiovascular risk factor? Hypertension 46 : 454– 462, 2005
    OpenUrlAbstract/FREE Full Text
  47. ↵
    Wang M, Takagi G, Asai K, Resuello RG, Natividad FF, Vatner DE, Vatner SF, Lakatta EG: Aging increases aortic MMP-2 activity and angiotensin II in nonhuman primates. Hypertension 41 : 1308– 1316, 2003
    OpenUrlAbstract/FREE Full Text
  48. ↵
    Bahlmann FH, De GK, Spandau JM, Landry AL, Hertel B, Duckert T, Boehm SM, Menne J, Haller H, Fliser D: Erythropoietin regulates endothelial progenitor cells. Blood 103 : 921– 926, 2004
    OpenUrlAbstract/FREE Full Text
  49. ↵
    Tsirpanlis G, Chatzipanagiotou S, Boufidou F, Kordinas V, Zoga M, Alevyzaki F, Stamatelou K, Frangou E, Savva L, Nicolaou C: Serum oxidized low-density lipoprotein is inversely correlated to telomerase activity in peripheral blood mononuclear cells of haemodialysis patients. Nephrology (Carlton) 11 : 506– 509, 2006
    OpenUrlCrossRefPubMed
  50. ↵
    Paisley KE, Beaman M, Tooke JE, Mohamed-Ali V, Lowe GD, Shore AC: Endothelial dysfunction and inflammation in asymptomatic proteinuria. Kidney Int 63 : 624– 633, 2003
    OpenUrlCrossRefPubMed
  51. ↵
    Parfrey PS, Foley RN: The clinical epidemiology of cardiac disease in chronic renal failure. J Am Soc Nephrol 10 : 1606– 1615, 1999
    OpenUrlFREE Full Text
  52. ↵
    Lassnigg A, Schmidlin D, Mouhieddine M, Bachmann LM, Druml W, Bauer P, Hiesmayr M: Minimal changes of serum creatinine predict prognosis in patients after cardiothoracic surgery: A prospective cohort study. J Am Soc Nephrol 15 : 1597– 1605, 2004
    OpenUrlAbstract/FREE Full Text
  53. ↵
    Thakar CV, Arrigain S, Worley S, Yared JP, Paganini EP: A clinical score to predict acute renal failure after cardiac surgery. J Am Soc Nephrol 16 : 162– 168, 2005
    OpenUrlAbstract/FREE Full Text
  54. ↵
    Manjunath G, Tighiouart H, Coresh J, Macleod B, Salem DN, Griffith JL, Levey AS, Sarnak MJ: Level of kidney function as a risk factor for cardiovascular outcomes in the elderly. Kidney Int 63 : 1121– 1129, 2003
    OpenUrlCrossRefPubMed
  55. Manjunath G, Tighiouart H, Ibrahim H, MacLeod B, Salem DN, Griffith JL, Coresh J, Levey AS, Sarnak MJ: Level of kidney function as a risk factor for atherosclerotic cardiovascular outcomes in the community. J Am Coll Cardiol 41 : 47– 55, 2003
    OpenUrlPubMed
  56. ↵
    Rahman M, Pressel S, Davis BR, Nwachuku C, Wright JT Jr, Whelton PK, Barzilay J, Batuman V, Eckfeldt JH, Farber MA, Franklin S, Henriquez M, Kopyt N, Louis GT, Saklayen M, Stanford C, Walworth C, Ward H, Wiegmann T, ALLHAT Collaborative Research Group: Cardiovascular outcomes in high-risk hypertensive patients stratified by baseline glomerular filtration rate. Ann Intern Med 144 : 172– 180, 2006
    OpenUrlCrossRefPubMed
  57. Garg AX, Clark WF, Haynes RB, House AA: Moderate renal insufficiency and the risk of cardiovascular mortality: Results from the NHANES I. Kidney Int 61 : 1486– 1494, 2002
    OpenUrlCrossRefPubMed
  58. ↵
    Go AS, Chertow GM, Fan D, McCulloch CE, Hsu CY: Chronic kidney disease and the risks of death, cardiovascular events, and hospitalization. N Engl J Med 351 : 1296– 1305, 2004
    OpenUrlCrossRefPubMed
  59. ↵
    Raymond NT, Zehnder D, Smith SC, Stinson JA, Lehnert H, Higgins RM: Elevated relative mortality risk with mild-to-moderate chronic kidney disease decreases with age. Nephrol Dial Transplant 22 : 3214– 3220, 2007
    OpenUrlCrossRefPubMed
  60. O'Hare AM, Bertenthal D, Covinsky KE, Landefeld CS, Sen 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
    OpenUrlAbstract/FREE Full Text
  61. ↵
    Drey N, Roderick P, Mullee M, Rogerson M: A population-based study of the incidence and outcomes of diagnosed chronic kidney disease. Am J Kidney Dis 42 : 677– 684, 2003
    OpenUrlCrossRefPubMed
  62. ↵
    Shlipak MG, Sarnak MJ, Katz R, Fried LF, Seliger SL, Newman AB, Siscovick DS, Stehman-Breen C: Cystatin C and the risk of death and cardiovascular events among elderly persons. N Engl J Med 352 : 2049– 2060, 2005
    OpenUrlCrossRefPubMed
  63. ↵
    Berl T: American Society of Nephrology Presidential Address 2005. J Am Soc Nephrol 17 : 926– 931, 2006
    OpenUrlFREE Full Text
  64. ↵
    Ishani A, Grandits GA, Grimm RH, Svendsen KH, Collins AJ, Prineas RJ, Neaton JD: Association of single measurements of dipstick proteinuria, estimated glomerular filtration rate, and hematocrit with 25-year incidence of end-stage renal disease in the multiple risk factor intervention trial. J Am Soc Nephrol 17 : 1444– 1452, 2006
    OpenUrlAbstract/FREE Full Text
  65. ↵
    Coresh J, Selvin E, Stevens LA, Manzi J, Kusek JW, Eggers P, Van Lente F, Levey AS: Prevalence of chronic kidney disease in the United States. JAMA 298 : 2038– 2047, 2007
    OpenUrlCrossRefPubMed
  66. ↵
    Hillege HL, Fidler V, Diercks GF, van Gilst WH, de Zeeuw D, van Veldhuisen DJ, Gans RO, Janssen WM, Grobbee DE, de Jong PE, Prevention of Renal and Vascular End Stage Disease (PREVEND) Study Group: Urinary albumin excretion predicts cardiovascular and noncardiovascular mortality in general population. Circulation 106 : 1777– 1782, 2002
    OpenUrlAbstract/FREE Full Text
  67. ↵
    Cirillo M, Lanti MP, Menotti A, Laurenzi M, Mancini M, Zanchetti A, De Santo NG: Definition of kidney dysfunction as a cardiovascular risk factor: use of urinary albumin excretion and estimated glomerular filtration rate. Arch Intern Med 168 : 617– 624, 2008
    OpenUrlCrossRefPubMed
  68. ↵
    Hallan S, Astor B, Romundstad S, Aasarod K, Kvenild K, Coresh J: Association of kidney function and albuminuria with cardiovascular mortality in older vs younger individuals: The HUNT II Study. Arch Intern Med 167 : 2490– 2496, 2007
    OpenUrlCrossRefPubMed
  69. Foster MC, Hwang SJ, Larson MG, Parikh NI, Meigs JB, Vasan RS, Wang TJ, Levy D, Fox CS: Cross-classification of microalbuminuria and reduced glomerular filtration rate: Associations between cardiovascular disease risk factors and clinical outcomes. Arch Intern Med 167 : 1386– 1392, 2007
    OpenUrlCrossRefPubMed
  70. ↵
    Astor BC, Hallan SI, Miller ER III, Yeung E, Coresh J: Glomerular filtration rate, albuminuria, and risk of cardiovascular and all-cause mortality in the US population. Am J Epidemiol 167 : 1226– 1234, 2008
    OpenUrlCrossRefPubMed
  71. ↵
    Liu JE, Robbins DC, Palmieri V, Bella JN, Roman MJ, Fabsitz R, Howard BV, Welty TK, Lee ET, Devereux RB: Association of albuminuria with systolic and diastolic left ventricular dysfunction in type 2 diabetes: The Strong Heart Study. J Am Coll Cardiol 41 : 2022– 2028, 2003
    OpenUrlCrossRefPubMed
  72. ↵
    Festa A, D'Agostino R, Howard G, Mykkanen L, Tracy RP, Haffner SM: Inflammation and microalbuminuria in nondiabetic and type 2 diabetic subjects: The Insulin Resistance Atherosclerosis Study. Kidney Int 58 : 1703– 1710, 2000
    OpenUrlCrossRefPubMed
  73. ↵
    Parvanova AI, Trevisan R, Iliev IP, Dimitrov BD, Vedovato M, Tiengo A, Remuzzi G, Ruggenenti P: Insulin resistance and microalbuminuria: A cross-sectional, case-control study of 158 patients with type 2 diabetes and different degrees of urinary albumin excretion. Diabetes 55 : 1456– 1462, 2006
    OpenUrlAbstract/FREE Full Text
  74. ↵
    Clausen P, Jensen JS, Jensen G, Borch-Johnsen K, Feldt-Rasmussen B: Elevated urinary albumin excretion is associated with impaired arterial dilatory capacity in clinically healthy subjects. Circulation 103 : 1869– 1874, 2001
    OpenUrlAbstract/FREE Full Text
  75. ↵
    de Zeeuw D, Remuzzi G, Parving HH, Keane WF, Zhang Z, Shahinfar S, Snapinn S, Cooper ME, Mitch WE, Brenner BM: Albuminuria, a therapeutic target for cardiovascular protection in type 2 diabetic patients with nephropathy. Circulation 110 : 921– 927, 2004
    OpenUrlAbstract/FREE Full Text
  76. ↵
    Asselbergs FW, Diercks GF, Hillege HL, van Boven AJ, Janssen WM, Voors AA, de Zeeuw D, de Jong PE, van Veldhuisen DJ, van Gilst WH, Prevention of Renal and Vascular Endstage Disease Intervention Trial (PREVEND IT) Investigators: Effects of fosinopril and pravastatin on cardiovascular events in subjects with microalbuminuria. Circulation 110 : 2809– 2816, 2004
    OpenUrlAbstract/FREE Full Text
  77. ↵
    Block GA, Hulbert-Shearon TE, Levin NW, Port FK: Association of serum phosphorus and calcium x phosphate product with mortality risk in chronic hemodialysis patients: A national study. Am J Kidney Dis 31 : 607– 617, 1998
    OpenUrlCrossRefPubMed
  78. Kestenbaum B, Sampson JN, Rudser KD, Patterson DJ, Seliger SL, Young B, Sherrard DJ, Andress DL: Serum phosphate levels and mortality risk among people with chronic kidney disease. J Am Soc Nephrol 16 : 520– 528, 2005
    OpenUrlAbstract/FREE Full Text
  79. London GM, Guerin AP, Marchais SJ, Metivier F, Pannier B, Adda H: Arterial media calcification in end-stage renal disease: Impact on all-cause and cardiovascular mortality. Nephrol Dial Transplant 18 : 1731– 1740, 2003
    OpenUrlCrossRefPubMed
  80. ↵
    Marchais SJ, Metivier F, Guerin AP, London GM: Association of hyperphosphataemia with haemodynamic disturbances in end-stage renal disease. Nephrol Dial Transplant 14 : 2178– 2183, 1999
    OpenUrlCrossRefPubMed
  81. ↵
    Towler DA, Bidder M, Latifi T, Coleman T, Semenkovich CF: Diet-induced diabetes activates an osteogenic gene regulatory program in the aortas of low density lipoprotein receptor-deficient mice. J Biol Chem 273 : 30427– 30434, 1998
    OpenUrlAbstract/FREE Full Text
  82. ↵
    Mathew S, Tustison KS, Sugatani T, Chaudhary LR, Rifas L, Hruska KA: The mechanism of phosphorus as a cardiovascular risk factor in CKD. J Am Soc Nephrol 19 : 1092– 1105, 2008
    OpenUrlAbstract/FREE Full Text
  83. ↵
    Dhingra R, Sullivan LM, Fox CS, Wang TJ, D'Agostino RB Sr, Gaziano JM, Vasan RS: Relations of serum phosphorus and calcium levels to the incidence of cardiovascular disease in the community. Arch Intern Med 167 : 879– 885, 2007
    OpenUrlCrossRefPubMed
  84. ↵
    Tonelli M, Sacks F, Pfeffer M, Gao Z, Curhan G: Relation between serum phosphate level and cardiovascular event rate in people with coronary disease. Circulation 112 : 2627– 2633, 2005
    OpenUrlAbstract/FREE Full Text
  85. ↵
    Bayes B, Pastor MC, Bonal J, Foraster A, Romero R: Oxidative stress, inflammation and cardiovascular mortality in haemodialysis: Role of seniority and intravenous ferrotherapy—Analysis at 4 years of follow-up. Nephrol Dial Transplant 21 : 984– 990, 2006
    OpenUrlCrossRefPubMed
  86. ↵
    Edwards MS, Wilson DB, Craven TE, Stafford J, Fried LF, Wong TY, Klein R, Burke GL, Hansen KJ: Associations between retinal microvascular abnormalities and declining renal function in the elderly population: The Cardiovascular Health Study. Am J Kidney Dis 46 : 214– 224, 2005
    OpenUrlCrossRefPubMed
  87. ↵
    Amann K, Breitbach M, Ritz E, Mall G: Myocyte/capillary mismatch in the heart of uremic patients. J Am Soc Nephrol 9 : 1018– 1022, 1998
    OpenUrlAbstract
  88. ↵
    Amann K, Munter K, Wessels S, Wagner J, Balajew V, Hergenröder S, Mall G, Ritz E: Endothelin A receptor blockade prevents capillary/myocyte mismatch in the heart of uremic animals. J Am Soc Nephrol 11 : 1702– 1711, 2000
    OpenUrlAbstract/FREE Full Text
  89. ↵
    Ortmann J, Amann K, Brandes RP, Kretzler M, Münter K, Parekh N, Traupe T, Lange M, Lattmann T, Barton M: Role of podocytes for reversal of glomerulosclerosis and proteinuria in the aging kidney after endothelin inhibition. Hypertension 44 : 974– 981, 2004
    OpenUrlAbstract/FREE Full Text
  90. ↵
    Culleton BF, Walsh M, Klarenbach SW, Mortis G, Scott-Douglas N, Quinn RR, Tonelli M, Donnelly S, Friedrich MG, Kumar A, Mahallati H, Hemmelgarn BR, Manns BJ: Effect of frequent nocturnal hemodialysis vs conventional hemodialysis on left ventricular mass and quality of life: A randomized controlled trial. JAMA 298 : 1291– 1299, 2007
    OpenUrlCrossRefPubMed
  91. ↵
    Wanner C, Krane V, März W, Olschewski M, Mann JF, Ruf G, Ritz E, German Diabetes and Dialysis Study Investigators: Atorvastatin in patients with type 2 diabetes mellitus undergoing hemodialysis [published erratum appears in N Engl J Med 353: 1640, 2005]. N Engl J Med 353 : 238– 248, 2005
    OpenUrlCrossRefPubMed
  92. ↵
    Suki WN, Zabaneh R, Cangiano JL, Reed J, Fischer D, Garrett L, Ling BN, Chasan-Taber S, Dillon MA, Blair AT, Burke SK: Effects of sevelamer and calcium-based phosphate binders on mortality in hemodialysis patients. Kidney Int 72 : 1130– 1137, 2007
    OpenUrlCrossRefPubMed
  93. ↵
    Drueke TB, Locatelli F, Clyne N, Eckardt KU, Macdougall IC, Tsakiris D, Burger HU, Scherhag A, CREATE Investigators: Normalization of hemoglobin level in patients with chronic kidney disease and anemia. N Engl J Med 355 : 2071– 2084, 2006
    OpenUrlCrossRefPubMed
  94. ↵
    Singh AK, Szczech L, Tang KL, Barnhart H, Sapp S, Wolfson M, Reddan D, CHOIR Investigators: Correction of anemia with epoetin alfa in chronic kidney disease. N Engl J Med 355 : 2085– 2098, 2006
    OpenUrlCrossRefPubMed
  95. ↵
    Phrommintikul A, Haas SJ, Elsik M, Krum H: Mortality and target haemoglobin concentrations in anaemic patients with chronic kidney disease treated with erythropoietin: A meta-analysis. Lancet 369 : 381– 388, 2007
    OpenUrlCrossRefPubMed
  96. ↵
    Shlipak 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
    OpenUrlCrossRefPubMed
  97. ↵
    Johansen KL, Chertow GM, Jin C, Kutner NG: Significance of frailty among dialysis patients. J Am Soc Nephrol 18 : 2960– 2967, 2007
    OpenUrlFREE Full Text
  98. ↵
    Johansen KL, Chertow GM, Ng AV, Mulligan K, Carey S, Schoenfeld PY, Kent-Braun JA: Physical activity levels in patients on hemodialysis and healthy sedentary controls. Kidney Int 57 : 2564– 2570, 2000
    OpenUrlCrossRefPubMed
  99. ↵
    O'Hare AM, Tawney K, Bacchetti P, Johansen KL: Decreased survival among sedentary patients undergoing dialysis: Results from the dialysis morbidity and mortality study wave 2. Am J Kidney Dis 41 : 447– 454, 2003
    OpenUrlCrossRefPubMed
  100. ↵
    Guralnik JM, Ferrucci L, Pieper CF, Leveille SG, Markides KS, Ostir GV, Studenski S, Berkman LF, Wallace RB: Lower extremity function and subsequent disability: Consistency across studies, predictive models, and value of gait speed alone compared with the short physical performance battery. J Gerontol A Biol Sci Med Sci 55 : M221– M231, 2000
    OpenUrlCrossRefPubMed
  101. ↵
    DeOreo PB: Hemodialysis patient-assessed functional health status predicts continued survival, hospitalization, and dialysis-attendance compliance. Am J Kidney Dis 30 : 204– 212, 1997
    OpenUrlCrossRefPubMed
  102. Knight EL, Ofsthun N, Teng M, Lazarus JM, Curhan GC: The association between mental health, physical function, and hemodialysis mortality. Kidney Int 63 : 1843– 1851, 2003
    OpenUrlCrossRefPubMed
  103. ↵
    Sietsema KE, Amato A, Adler SG, Brass EP: Exercise capacity as a predictor of survival among ambulatory patients with end-stage renal disease. Kidney Int 65 : 719– 724, 2004
    OpenUrlCrossRefPubMed
  104. ↵
    Johansen KL, Shubert T, Doyle J, Soher B, Sakkas GK, Kent-Braun JA: Muscle atrophy in patients receiving hemodialysis: Effects on muscle strength, muscle quality, and physical function. Kidney Int 63 : 291– 297, 2003
    OpenUrlCrossRefPubMed
  105. ↵
    Painter P, Carlson L, Carey S, Paul SM, Myll J: Low-functioning hemodialysis patients improve with exercise training. Am J Kidney Dis 36 : 600– 608, 2000
    OpenUrlCrossRefPubMed
  106. ↵
    Hagberg JM, Goldberg AP, Ehsani AA, Heath GW, Delmez JA, Harter HR: Exercise training improves hypertension in hemodialysis patients. Am J Nephrol 3 : 209– 212, 1983
    OpenUrlCrossRefPubMed
  107. Painter PL, Nelson-Worel JN, Hill MM, Thornbery DR, Shelp WR, Harrington AR, Weinstein AB: Effects of exercise training during hemodialysis. Nephron 43 : 87– 92, 1986
    OpenUrlCrossRefPubMed
  108. Miller BW, Cress CL, Johnson ME, Nichols DH, Schnitzler MA: Exercise during hemodialysis decreases the use of antihypertensive medications. Am J Kidney Dis 39 : 828– 833, 2002
    OpenUrlPubMed
  109. Goldberg AP, Geltman EM, Gavin JR III, Carney RM, Hagberg JM, Delmez JA, Naumovich A, Oldfield MH, Harter HR: Exercise training reduces coronary risk and effectively rehabilitates hemodialysis patients. Nephron 42 : 311– 316, 1986
    OpenUrlCrossRefPubMed
  110. ↵
    Mustata S, Chan C, Lai V, Miller JA: Impact of an exercise program on arterial stiffness and insulin resistance in hemodialysis patients. J Am Soc Nephrol 15 : 2713– 2718, 2004
    OpenUrlAbstract/FREE Full Text
  111. ↵
    Pupim LB, Flakoll PJ, Levenhagen DK, Ikizler TA: Exercise augments the acute anabolic effects of intradialytic parenteral nutrition in chronic hemodialysis patients. Am J Physiol Endocrinol Metab 286 : E589– E597, 2004
    OpenUrlCrossRefPubMed
  112. ↵
    Kong CH, Tattersall JE, Greenwood RN, Farrington K: The effect of exercise during haemodialysis on solute removal. Nephrol Dial Transplant 14 : 2927– 2931, 1999
    OpenUrlCrossRefPubMed
  113. ↵
    Vaithilingam I, Polkinghorne KR, Atkins RC, Kerr PG: Time and exercise improve phosphate removal in hemodialysis patients. Am J Kidney Dis 43 : 85– 89, 2004
    OpenUrlCrossRefPubMed
  114. ↵
    Boyce ML, Robergs RA, Avasthi PS, Roldan C, Foster A, Montner P, Stark D, Nelson C: Exercise training by individuals with predialysis renal failure: Cardiorespiratory endurance, hypertension, and renal function. Am J Kidney Dis 30 : 180– 192, 1997
    OpenUrlCrossRefPubMed
  115. ↵
    Castaneda C, Gordon PL, Uhlin KL, Levey AS, Kehayias JJ, Dwyer JT, Fielding RA, Roubenoff R, Singh MF: Resistance training to counteract the catabolism of a low-protein diet in patients with chronic renal insufficiency: A randomized, controlled trial. Ann Intern Med 135 : 965– 976, 2001
    OpenUrlCrossRefPubMed
  116. ↵
    Chaves PH, Xue QL, Guralnik JM, Ferrucci L, Volpato S, Fried LP: What constitutes normal hemoglobin concentration in community-dwelling disabled older women? J Am Geriatr Soc 52 : 1811– 1816, 2004
    OpenUrlCrossRefPubMed
  117. ↵
    Astor BC, Muntner P, Levin A, Eustace JA, Coresh J: Association of kidney function with anemia: The Third National Health and Nutrition Examination Survey (1988–1994). Arch Intern Med 162 : 1401– 1408, 2002
    OpenUrlCrossRefPubMed
  118. ↵
    Ble A, Fink JC, Woodman RC, Klausner MA, Windham BG, Guralnik JM, Ferrucci L: Renal function, erythropoietin, and anemia of older persons: The InCHIANTI study. Arch Intern Med 165 : 2222– 2227, 2005
    OpenUrlCrossRefPubMed
  119. ↵
    Seliger SL, Siscovick DS, Stehman-Breen CO, Gillen DL, Fitzpatrick A, Bleyer A, Kuller LH: Moderate renal impairment and risk of dementia among older adults: The Cardiovascular Health Cognition Study. J Am Soc Nephrol 15 : 1904– 1911, 2004
    OpenUrlAbstract/FREE Full Text
  120. ↵
    Kurella M, Chertow GM, Fried LF, Cummings SR, Harris T, Simonsick E, Satterfield S, Ayonayon H, Yaffe K: Chronic kidney disease and cognitive impairment in the elderly: The health, aging, and body composition study. J Am Soc Nephrol 16 : 2127– 2133, 2005
    OpenUrlAbstract/FREE Full Text
  121. ↵
    Hailpern SM, Melamed ML, Cohen HW, Hostetter TH: Moderate chronic kidney disease and cognitive function in adults 20 to 59 years of age: Third National Health and Nutrition Examination Survey (NHANES III). J Am Soc Nephrol 18 : 2205– 2213, 2007
    OpenUrlAbstract/FREE Full Text
  122. ↵
    Kurella-Tamura M, Wadley V, Yaffe K, 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
    OpenUrlCrossRefPubMed
  123. ↵
    Yaffe K, Lindquist K, Shlipak MG, Simonsick E, Fried L, Rosano C, Satterfield S, Atkinson H, Windham BG, Kurella-Tamura M: Cystatin C as a marker of cognitive function in elders: Findings from the health ABC study. Ann Neurol 63 : 798– 802, 2008
    OpenUrlCrossRefPubMed
  124. ↵
    Vupputuri S, Shoham DA, Hogan SL, Kshirsagar AV: Microalbuminuria, peripheral artery disease, and cognitive function. Kidney Int 73 : 341– 346, 2008
    OpenUrlCrossRefPubMed
  125. ↵
    Murray AM, Tupper DE, Knopman DS, Gilbertson DT, Pederson SL, Li S, Smith GE, Hochhalter AK, Collins AJ, Kane RL: Cognitive impairment in hemodialysis patients is common [published erratum appears in Neurology 69: 120, 2007]. Neurology 67 : 216– 223, 2006
    OpenUrlAbstract/FREE Full Text
  126. ↵
    Murray AM: Cognitive impairment in the aging dialysis and chronic kidney disease populations: An occult burden. Adv Chronic Kidney Dis 15 : 123– 132, 2008
    OpenUrlCrossRefPubMed
  127. ↵
    Seliger SL, Longstreth WT Jr, Katz R, Manolio T, Fried LF, Shlipak M, Stehman-Breen CO, Newman A, Sarnak M, Gillen DL, Bleyer A, Siscovick DS: Cystatin C and subclinical brain infarction. J Am Soc Nephrol 16 : 3721– 3727, 2005
    OpenUrlAbstract/FREE Full Text
  128. ↵
    Stivelman JC: Benefits of anaemia treatment on cognitive function. Nephrol Dial Transplant 15[Suppl 3] : 29– 35, 2000
    OpenUrl
  129. ↵
    Murray AM, Pederson SL, Tupper DE, Hochhalter AK, Miller WA, Li Q, Zaun D, Collins AJ, Kane R, Foley RN: Acute variation in cognitive function in hemodialysis patients: A cohort study with repeated measures. Am J Kidney Dis 50 : 270– 278, 2007
    OpenUrlCrossRefPubMed
  130. ↵
    Rahman M, Pressel S, Davis BR, Nwachuku C, Wright JT Jr, Whelton PK, Barzilay J, Batuman V, Eckfeldt JH, Farber M, Henriquez M, Kopyt N, Louis GT, Saklayen M, Stanford C, Walworth C, Ward H, Wiegmann T: Renal outcomes in high-risk hypertensive patients treated with an angiotensin-converting enzyme inhibitor or a calcium channel blocker vs a diuretic: A report from the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). Arch Intern Med 165 : 936– 946, 2005
    OpenUrlCrossRefPubMed
  131. ↵
    Summaries for patients: Do the effects of blood pressure drugs differ by kidney function? Ann Intern Med 144 : I33 , 2006
    OpenUrlPubMed
  132. ↵
    Foley RN, Murray AM, Li S, Herzog CA, McBean AM, Eggers PW, Collins AJ: Chronic kidney disease and the risk for cardiovascular disease, renal replacement, and death in the United States Medicare population, 1998 to 1999. J Am Soc Nephrol 16 : 489– 495, 2005
    OpenUrlAbstract/FREE Full Text
  133. ↵
    Giltay EJ, Zitman FG, Kromhout D: Cardiovascular risk profile and subsequent disability and mental well-being: The Zutphen Elderly Study. Am J Geriatr Psychiatry 16 : 874– 882, 2008
    OpenUrlCrossRefPubMed
  134. ↵
    John R, Webb M, Young A, Stevens PE: Unreferred chronic kidney disease: A longitudinal study. Am J Kidney Dis 43 : 825– 835, 2004
    OpenUrlCrossRefPubMed
  135. ↵
    Martinez-Ramirez HR, Jalomo-Martinez B, Cortes-Sanabria L, Rojas-Campos E, Barragán G, Alfaro G, Cueto-Manzano AM: Renal function preservation in type 2 diabetes mellitus patients with early nephropathy: A comparative prospective cohort study between primary health care doctors and a nephrologist. Am J Kidney Dis 47 : 78– 87, 2006
    OpenUrlCrossRefPubMed
  136. Khan SS, Xue JL, Kazmi WH, Gilbertson DT, Obrador GT, Pereira BJ, Collins AJ: Does predialysis nephrology care influence patient survival after initiation of dialysis? Kidney Int 67 : 1038– 1046, 2005
    OpenUrlCrossRefPubMed
  137. Kazmi WH, Obrador GT, Khan SS, Pereira BJ, Kausz AT: Late nephrology referral and mortality among patients with end-stage renal disease: A propensity score analysis. Nephrol Dial Transplant 19 : 1808– 1814, 2004
    OpenUrlCrossRefPubMed
  138. ↵
    Kinchen KS, Sadler J, Fink N, Brookmeyer R, Klag MJ, Levey AS, Powe NR: The timing of specialist evaluation in chronic kidney disease and mortality. Ann Intern Med 137 : 479– 486, 2002
    OpenUrlCrossRefPubMed
  139. ↵
    Hemmelgarn BR, Manns BJ, Zhang J, Tonelli M, Klarenbach S, Walsh M, Culleton BF: Association between multidisciplinary care and survival for elderly patients with chronic kidney disease. J Am Soc Nephrol 18 : 993– 999, 2007
    OpenUrlAbstract/FREE Full Text
  140. ↵
    Harris LE, Luft FC, Rudy DW, Kesterson JG, Tierney WM: Effects of multidisciplinary case management in patients with chronic renal insufficiency. Am J Med 105 : 464– 471, 1998
    OpenUrlCrossRefPubMed
  141. ↵
    Jassal S, Trpeski L, Zhu N, Fenton S, Hemmelgarn B: Changes in survival among elderly patients initiating dialysis from 1990 to 1999. CMAJ 177 : 1033– 1038, 2007
    OpenUrlAbstract/FREE Full Text
  142. ↵
    Murtagh FE, Marsh JE, Donohoe P, Ekbal NJ, Sheerin NS, Harris FE: Dialysis or not? A comparative survival study of patients over 75 years with chronic kidney disease stage 5. Nephrol Dial Transplant 22 : 1955– 1962, 2007
    OpenUrlCrossRefPubMed
  143. ↵
    Ferrucci L, Cherubini A, Bandinelli S, Bartali B, Corsi A, Lauretani F, Martin A, Andres-Lacueva C, Senin U, Guralnik JM: Relationship of plasma polyunsaturated fatty acids to circulating inflammatory markers. J Clin Endocrinol Metab 91 : 439– 446, 2006
    OpenUrlCrossRefPubMed
  144. ↵
    Lauretani F, Semba RD, Bandinelli S, Miller ER 3rd, Ruggiero C, Cherubini A, Guralnik JM, Ferrucci L: Plasma polyunsaturated fatty acids and the decline of renal function. Clin Chem 54 : 475– 481, 2008
    OpenUrlAbstract/FREE Full Text
  145. ↵
    Melk A: Senescence of renal cells: Molecular basis and clinical implications. Nephrol Dial Transplant 18 : 2474– 2478, 2003
    OpenUrlCrossRefPubMed
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Prediction, Progression, and Outcomes of Chronic Kidney Disease in Older Adults
Sharon Anderson, Jeffrey B. Halter, William R. Hazzard, Jonathan Himmelfarb, Frances McFarland Horne, George A. Kaysen, John W. Kusek, Susan G. Nayfield, Kenneth Schmader, Ying Tian, John R. Ashworth, Charles P. Clayton, Ryan P. Parker, Erika D. Tarver, Nancy F. Woolard, Kevin P. High
JASN Jun 2009, 20 (6) 1199-1209; DOI: 10.1681/ASN.2008080860
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