Josef Coresh Joseph A. Eustace
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Definition and Staging of Chronic Kidney Disease, 616 |
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Incidence and Prevalence of Chronic Kidney Disease and End-Stage Renal Disease, 617 |
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Incidence of Chronic Kidney Disease, 617 |
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Prevalence of Stages 1 to 4 Chronic Kidney Disease, 617 |
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Incidence of End-Stage Renal Disease in the United States, 619 |
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Prevalence of End-Stage Renal Disease in the United States, 622 |
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Incidence and Prevalence of End-Stage Renal Disease: Global Comparisons, 623 |
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Dialysis Modality, 623 |
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Dialysis Survival, 624 |
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Transplantation, 626 |
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Transplant Outcomes, 628 |
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Conclusion, 629 |
Insight into the occurrence and consequences of kidney disease has rapidly progressed over the last decade. Pivotal to this improved understanding has been recently developed and widely disseminated guidelines providing a standardized definition and staging scheme for chronic kidney disease (CKD), a term used to encompass the entire spectrum of renal dysfunction. The prevalence of CKD has historically been underappreciated on both the population and the clinical levels. When used in isolation, serum creatinine is an inadequate screening tool, especially in the elderly and other groups with reduced muscle mass. The development and ongoing refinement of equations to estimate glomerular filtration rates (GFRs) and the growing appreciation of the need to uniformly calibrate serum creatinine assays is improving the diagnosis and staging of CKD. Moreover, it presents us with multiple, and as yet unmet, challenges as to how we develop the resources and care structures necessary to manage this now-visible substantial population with CKD in the face of clear evidence of complications but limited clinical trial data on efficacious interventions. A major concern in this regard is the inequalities that abound in CKD. Both within the United States and abroad, kidney disease afflicts the socially and economically disadvantaged, affecting those persons who have less access to preventive services and who are less equipped to achieve the many lifestyle modifications that are essential to the successful prevention and management of CKD.
The most evident, and for a long time, sole manifestation of the epidemic of kidney disease was those subjects treated with renal replacement therapy, the prevalence of which is predicted to continue to increase. In a global context, several countries have incidence and prevalence rates that are equal to that of the United States, whereas many more have rates that are rapidly increasing. The previous exponential increase in incidence of treated end-stage renal disease (ESRD) in the United States has decreased to the point at which age- and race-adjusted rates have been constant since 2000. Ominously, the ongoing increase of type 2 diabetes and obesity within the general population, if left uncontrolled, may serve to reignite this epidemic, as will the aging of the population and growth of high-risk minority groups. Renal transplantation continues to be the optimal management strategy for kidney failure; however, its broader application is hindered by the limited number of available grafts. Innovative strategies to overcome this shortage have been developed but suffer from a lack of uniform implementation. Survival rates for patients treated with either dialysis or transplantation have steadily improved over time but, despite much progress, still remain markedly reduced compared with rates in the general population. Renal replacement therapy prolongs life but does not restore a normal life expectancy.
The consequences of CKD are many and complex and include hypertension, anemia, acidosis, the interrelated phenomena of renal malnutrition and inflammation, and varied consequences of aberrant bone mineral metabolism. Increased awareness of CKD has led to greater recognition of the burden of illness that accompanies its progression, that contributes to its outcome, and that develops long before the point of actual kidney failure. Hypertension, despite its impact on both renal and patient survival, remains underdiagnosed and, even when noted in conjunction with kidney disease, is still often undertreated. A better understanding of the epidemiology of these complications, in addition to the traditional study of their pathophysiology, is essential if we are to develop successful, rational, and cost-effective strategies to improve the outcome of CKD.
Numerous studies over the last several years have unequivocally proved that kidney disease is a major risk factor for cardiovascular events. Thus, the most common conclusion for a patient with advanced CKD is progression not to dialysis but to death from cardiovascular disease. Much of the attention has focused on ischemic heart disease and, to a lesser extent, on heart failure. The relationship of CKD with stroke, peripheral vascular disease, and sudden cardiac death remains less fully understood. Similarly, whereas much attention has focused on novel cardiovascular risk factors in CKD, we still know far too little about the role and optimal management of traditional well-established risk factors, although they are likely to explain much of the increased association between diseases of the heart and those of the kidney.
DEFINITION AND STAGING OF CHRONIC KIDNEY DISEASE
In 2002, The National Kidney Foundation's (NKF) “Kidney Disease Outcomes Quality Initiative (KDOQI)” proposed a definition and classification scheme of CKD[1] that has since been widely adopted both within and outside of the United States. [2] [3] [4] [5] [6] This has provided standardization to a terminology that previously was both ambiguous and confusing.[7] The NKF guidelines define CKD on the basis of kidney damage and/or reduced kidney function. Kidney damage may be confirmed through a variety of methods including histologic evidence of kidney disease, abnormalities in the composition of blood or urine, or abnormal findings on renal imaging. Proteinuria is the most frequent early indicator of kidney damage. Given the complex relationship between hypertension and kidney disease, and the uncertainty as to which of the two conditions developed first, from the definition viewpoint, hyper-tension alone is not taken as a sufficient indicator of kidney damage.
A major obstacle to the wider recognition of CKD has been the clinical reliance on isolated unstandardized serum creatinine levels as a marker of kidney function and the frequent tendency to dismiss mild elevation in serum creatinine as clinically insignificant and so to systematically underestimate the severity of CKD even when the condition is recognized. The use of isolated serum creatinine levels as a measure of renal function is fraught with limitations.[8] The degree of elevation in serum creatinine is dependent not only on the decrement in GFR but also on creatinine generation rates, which vary substantially with age, race, gender, and diet.[1] As a result, a considerable proportion of patients, espe-cially elderly women and individuals with low muscle mass, have a clinically significant reduction in renal function but have serum creatinine values that fall within the population reference range.[9]
Not surprisingly, the use of unadjusted serum creatinine measurements as a screening tool for early CKD is insensitive and results in the widespread misclassification. [10] [11] [12] To avoid this, renal function should instead be quantified by the actual measurement or estimation of the GFR. [1] [13] Given that the absolute GFR is expected to vary with body size, the GFR is usually indexed to some measure of body size, traditionally to 1.73 m2 of body surface area, which in an earlier time was the average adult body surface area. In clinical practice, the assessment of GFR is most readily and reliably achieved using estimation equations, such as the Cockcroft-Gault equation or the Modification of Diet in Renal Disease (MDRD) Study equation. The Cockcroft-Gault equation calculates unadjusted creatinine clearance, using serum creatinine, age, gender, and body weight.[14] The formula was developed in 1976 from a sample of 249 men, and uses an empirical adjustment factor for women, based on a theoretical 15% lower muscle mass in women relative to men; the equation tends to overestimate renal function in subjects who are edematous or obese and underestimates renal function in the elderly. [15] [16] [17] [18] The modified MDRD equation was developed from 1628 subjects enrolled in the baseline period of the MDRD study.[1] It estimates GFR adjusted to body surface area and is calculated from the subject's serum creatinine, age, race, and gender. Although mathematically somewhat complicated, it can be readily calculated with the aid of a simple computer or at several web sites [www.nephron.com
; www.renal.org/eGFRcalc/GFR.pl; and www.kidney.org/professionals/KDOQI]. Ideally, estimated GFR (eGFR) should be reported automatically as part of the standardized biochemistry report, in conjunction with appropriate caveats as to its interpretation. [19] [20] [21] [22] A new version of the formula has been developed suitable for use with creatinine assay methods standardized to reference methods. [23] [24] This demonstrates nearly unbiased estimates across all age groups, although, as with the original abbreviated MDRD equation, its accuracy remains limited in subjects with near-normal renal function. [15] [25] [26]
The MDRD equation has been independently validated in several different populations, including transplant recipients. [15] [16] [18] [25] [27] [28] [29] The equation underestimates GFR when it is normal or mildly reduced. [18] [25] [26] [30] In addition, the source population will have an impact on the relationship between measured and eGFR. [24] [26] Whether it is better to develop separate equations for different populations while correcting for limited GFR spread in healthy populations or to use a single equation and interpret the resulting estimated GFR with the source population and individual patient characteristics in mind is uncertain. A National Institutes of Health (NIH)–sponsored initiative, “The Chronic Kidney Disease Epidemiology Collaboration,” is attempting to further refine the accuracy and precision of GFR estimation equations.[18] Regardless of the equation used, an additional major limitation to current clinical practice is the lack of standardization in serum creatinine assays, [13] [31] [32] [33] levels of which can vary in clinically meaningful amounts between different laboratories and over time. Attempts to produce a uniform standard for serum creatinine is a major ongoing challenge in the early and reliable recognition of CKD. [33] [34] An additional approach especially for the identification of early stages of kidney damage and in the elderly has been the measurement of cystatin C, which is superior to serum creatinine in being less dependent on muscle mass, age, sex, and race. This is a major advantage in predicting risk of events among elderly individuals with higher GFR.[35]For estimating GFR, cystatin C is superior to unadjusted serum creatinine measurements. Its advantage relative to creatinine-based estimation equations is less dramatic, and its utility in routine clinical practice requires further evaluation.[36] Cystatin C-based estimates of GFR will require knowledge of the source population in their interpretation, and there is evidence that organ receipients have higher cystatin C levels at the same GFR.[37]
For operational purposes, CKD is defined as the presence, for at least 3 months, of evidence of kidney damage with an abnormal GFR or, alternatively, by a GFR below 60 mL/min/1.73 m2 body surface area.[1] A cutoff of 60 mL/min/1.73 m2 is selected because it represents a decrement to approximately half of normal renal function and because its use avoids the classification of many older individuals who may have mild reductions in their GFR.[38]Whether such reductions truly represent a physiologic alteration or are the consequence of occult pathology is unknown. The accurate assessment of CKD is similarly difficult during and immediately after pregnancy, as GFR increases substantially during the first and second trimesters of pregnancy and may not return to its previous or new baseline level until several weeks postpartum. [39] [40] [41] [42]
The NKF guidelines use a five-stage schema based on the reduction in GFR to help classify the severity of CKD. An international position statement added modifiers for noting whether a patient is treated with dialysis or transplantation ( Table 17-1 ). The presence of hypertension should be noted independently of the CKD stage ( Table 17-2 ). This staging system represents a measure of the “azotemic burden” resulting from the degree of kidney dysfunction, which is largely independent of the underlying etiology or renal pathology. Its use is validated by the established relationships between the number and the severity of complications that develop in parallel with increasing stage of CKD.[1] In essence, this staging system recognizes that the progressive decrement in renal function gives rise to common complications (e.g., hypertension, anemia, hyperparathyroidism) and management issues (e.g., hepatitis B vaccination, dietary modification, patient education) that are independent of the underlying condition that caused the kidney damage. This staging system complements and in no way replaces traditional classification schema, such as those based on clinical features (e.g., the presence and severity of proteinuria) or on pathophysiologic mechanisms (e.g., immune complex deposition on renal biopsy). These earlier classification systems provide important information regarding the rate of progression, long-term prognosis, and management of a given condition, whereas the CKD stage is informative regarding the likely complications and non-disease-specific management steps that relate to the current level of renal function.
TABLE 17-1 -- Stages of Chronic Kidney Disease
|
Stage |
Description |
GFR (mL/min/1.73 m2) |
|
1 |
Kidney damage with normal or ↑ GFR |
≥90 |
|
2 |
Kidney damage with mild ↓ GFR |
60–89 |
|
3 |
Moderate ↓ GFR |
30–59 |
|
4 |
Severe ↓ GFR |
15–29 |
|
5 |
Kidney failure |
<15 (or dialysis) |
From National Kidney Foundation: K/DOQI clinical practice guidelines for chronic kidney disease: Evaluation, classification and stratification. Am J Kidney Dis 39(suppl 1):S1–S266, 2002.
|
Chronic kidney disease is defined as either kidney damage or GFR <60 mL/min/1.73 m2 for ≥3 months. Kidney damage is defined as pathologic abnormalities or markers of damage, including abnormalities in blood or urine tests or imaging studies. |
TABLE 17-2 -- Definition and Stages of Chronic Kidney Disease
|
GFR (mL/min/1.73 m2) |
With Kidney Damage[*] |
Without Kidney Damage[*] |
||
|
|
With HBP[†] |
Without HBP[†] |
With HBP[†] |
Without HBP[†] |
|
≥90 |
1 |
1 |
“High blood pressure” |
“Normal” |
|
60–89 |
2 |
2 |
“High blood pressure with ↓ GFR” |
“↓ GFR”[‡] |
|
30–59 |
3 |
3 |
3 |
3 |
|
15–29 |
4 |
4 |
4 |
4 |
|
<15 (or dialysis) |
5 |
5 |
5 |
5 |
From National Kidney Foundation: K/DOQI clinical practice guidelines for chronic kidney disease: Evaluation, classification and stratification. Am J Kidney Dis 39(suppl 1):S1–S266, 2002.
|
Shaded area represents chronic kidney disease; numbers designate state of chronic kidney disease. |
|
* |
Kidney damage is defined as pathologic abnormalities or markers of damage, including abnormalities in blood or urine tests or imaging studies. |
|
† |
High blood pressure (HBP) is defined as ≥140/90 in adults and >90th percentile for height and gender in children. |
|
‡ |
May be normal in infants and in the elderly. |
Stage 5 CKD representing kidney failure is defined either by GFR below 15 mL/min/1.73 m2 or by the need for dialysis. Following renal transplantation, patients are defined by the stage according to the posttransplant GFR.[43] It is unclear, however, whether the relationship between complications and CKD stage posttransplantation is identical to that reported with decrements in native kidney function. In a study of 459 renal transplant recipients, the definition of CKD was met in 90% of patients, with 60% of subjects having stage 3 CKD.[44] A higher stage was associated with significantly higher rates of hypertension, number of antihypertensive medications, and presence of anemia.
INCIDENCE AND PREVALENCE OF CHRONIC KIDNEY DISEASE AND END-STAGE RENAL DISEASE
Incidence of Chronic Kidney Disease
Estimating the incidence of CKD requires a large cohort followed for many years with several estimates of kidney function. Among 2585 Framingham participants with baseline eGFR greater than 60, and a mean age of 43 years, 9.4% developed CKD, defined by eGFR less than 60, over a mean follow-up period of 18 years.[45] Risk was related to baseline GFR, diabetes, hypertension, low high-density lipoprotein (HDL) and smoking. Among 10,661 white and 3859 African American participants in the Atherosclerosis Risk in Communities (ARIC) study, age 45 to 64 years, the incidence of a 0.4 mg/dL rise in creatinine or hospitalization or death with CKD was 4.4/1000 person-years in whites and 8.8/1000 person-years in African Americans.[46] Risk was related to age, male gender, African American race, diabetes, hypertension, coronary heart disease at baseline, dyslipidemia, low GFR, elevated body mass index, and apo E genotype. Studies of CKD incidence are limited and complicated because creatinine assay calibration often changes over time by amounts of comparable magnitude to creatinine changes associated with the progression of CKD. Conversely, prevalence data are becoming more widely available.
Prevalence of Stages 1 to 4 Chronic Kidney Disease
The occurrence of kidney damage and CKD in the general population is important because only a minority of pati-ents progress to kidney failure and are thereby identified on national ESRD registries. Instead, the majority of patients with CKD die from competing mortality [47] [48] or else maintain relatively stable, although reduced, renal function [47] [49] and suffer the consequences of CKD without ever progressing to the need for dialysis. Thus, ESRD registries provide only limited insight into the true burden of morbidity and mortality associated with CKD. Several challenges limit the better description of CKD in the absence of renal replacement therapy. The early stages of kidney dysfunction are often clinically silent, especially when the condition is only slowly progressive and complications have a gradual onset. The symptoms that do ultimately arise are usually nonspecific, are often recognized late, and even then, are typically nonspecific and commonly attributed to comorbidities or age-related frailty.[50] As a consequence, hospital-based case series tend to be unrepresentative of the broader spectrum of CKD.
Table 17-3 summarizes the literature on the prevalence of decreased kidney function in large studies conducted recently. [4] [11] [51] [52] [53] [54] [55] [56] [57] [58] [59] [60] [61] [62] [63] [64] Interpretation of the studies should take into account the source population, sampling methods, thresholds for defining different aspects of CKD, creatinine calibration, and the strong age dependence of measures of CKD. The latter is particularly strong because prevalence of disease can vary by an order of magnitude from young adults to older subgroups of the population. Large cross-sectional health surveys using probability sampling allow for estimates that represent the entire population (National Health and Nutrition Examination Survey [NHANES],[51] The Inter Asia study,[59] and AusDiab[4]). These estimates are least likely to be biased for common conditions but require a dedicated research setting. Alternatively, large amounts of data have been collected in screening programs of unselected groups (e.g., The Okinawa Screening Project[62]), high-risk subgroups (e.g., Kidney Early Evaluation Program [KEEP][54]), and the databases of large clinical practices or laboratories. [50] [53] [65] [66] A major advantage of surveys of a random sample of the population is that, with the use of appropriately adjusted weights to control for nonresponse bias and missing data, they allow inferences to be drawn regarding the national prevalence of CKD. In addition, they provide relatively unbiased estimates of the concurrent complication rates. Such surveys have the limitation that, as they are cross-sectional, they measure prevalence, which represents both the rate of occurrence of new cases and the duration of established disease. Milder cases of longer duration due to either better survival or slow progression will influence prevalence more than incidence. To the extent that sicker individuals in stages 4 and 5 CKD are less likely to participate in surveys, prevalence estimates will be too low. The results of health screenings, especially if focused to a particular disease, may be strongly influenced by differential participation rates, with health-conscious subjects being more likely and those with less insight or interest in their long-term health being less likely to participate. Estimates based on clinical or laboratory databases are less informative because they require that the subject first come to medical attention, a major limitation in an often asymptomatic condition such as CKD.
TABLE 17-3 -- Prevalence Studies of Chronic Kidney Disease
|
Study |
Source Population |
Country or Region (age, yr) |
N |
Proteinuria/Albuminuria (Cutoff) (%) |
Hematuria (%) |
GFR ≤ 60 mL/min/1.73 m2 |
|
|
Overall (%) |
Age Dependence (%) |
||||||
|
NHANES III[51] |
GP (PS) |
US 1988–1994 (20+) |
15,488 |
4.4 (>30 mg/g) |
NA |
4.4c |
0.2–25.8 |
|
NHANES 99–00[51] |
GP (PS) |
US 1999–2000 (20+) |
4,101 |
5.6 (>30 mg/g) |
NA |
3.8c |
0.5–23.1 |
|
REGARDS[52] |
GP (PS) |
Southeastern US (45+) |
20,667 |
NA |
NA |
43.3c |
19.3–71.0 |
|
Kaiser[53] |
Clinical |
US Northern California (20+) |
1,120,295 |
NA |
NA |
17.5c |
Strong |
|
KEEP[54] |
High risk |
US |
11,246 |
32.5 |
3 |
14.9 |
Strong |
|
NEOERICA[55] |
Clinical |
UK region (0–90+) |
28,862 |
NA |
NA |
4.9 |
0.2–33.4 |
|
Salford[11] |
Diabetes |
UK Salford region (adult) |
7,596 |
9 |
NA |
27.5 |
Strong |
|
SAPALDIA[56] |
GP (PS) |
Swiss 1991 (adult) |
6,317 |
NA |
NA |
NA |
0–35 |
|
HUNT II[57] |
GP (Cohort) |
Norway, Nord-Trondelag 1995–97 (20+) |
65,181 |
5.9 (>30 mg/g) |
NA |
4.4c |
0.2–18.6 |
|
Ausdiab[4] |
GP (PS) |
Australia (25+) |
11,247 |
2.4 (>200 mg/g) |
4.6 |
11.2 |
0–54.8 |
|
Aboriginies[58] |
High risk (V) |
Australia, Tiwi (18+) |
237 |
44 |
— |
12 |
Strong |
|
InterAsia[59] |
GP (PS) |
China (35–74) |
15,540 |
NA |
NA |
2.5c |
0.7–8.1 |
|
Beijing[60] |
GP (V) |
China, Beijing (40+) |
2,310 |
8.4 (S) |
0.7 |
4.9c |
0.3–11.5 |
|
Okinawa[61] |
GP (V) |
Japan, Okinawa (30–79) |
6,980 |
NA |
NA |
NA |
NA |
|
Okinawa Screening[62] |
GP (V) |
Japan, Okinawa GHMA (20+) |
95,255 |
47.4 (≥1+) |
NA |
42.6 |
Strong |
|
Karachi[63] |
GP (V) |
Pakistan, Karachi (40+) |
1,166 |
NA |
NA |
10 |
6–21.2 |
|
Thailand EGA[64] |
Workplace |
Thailand, Nonthaburi 1985 (35–55) |
3,499 |
2.64 (1+) |
NA |
1.7 |
Strong |
|
Source population: GP, general population; PS, probability sampling survey design; V, volunteer sample; Cohort, an existing cohort; Clinical and Workplace populations without specific criteria are noted. S, Albuminuria sex-specific definition: >17 mg/g in men and >25 mg/g in women. C, some calibration of the serum creatinine assay to the MDRD equation laboratory. Age dependence shows the prevalence from youngest to the oldest age group studied. |
All prevalence estimates show a strong age dependence consistent with the most common forms of CKD being progressive and increasing with age. Several of the initial studies examining the prevalence of CKD were based on elevated serum creatinine levels. [65] [67] [68] [69] With the increased recognition of the many limitations of this approach, more recent surveys have instead used estimation equations with attention to creatinine assay calibration. The diagnosis of stages 1 and 2 CKD requires the presence of kidney damage in addition to a reduced GFR. From an epidemiologic perspective, the most commonly used surrogate for kidney damage in this setting has been albuminuria. Other potential markers of kidney damage include renal imaging[70] or hematuria, although the latter is less specific for CKD because the bleeding may often originate from the lower genitourinary tract rather than the kidney.
Over the last several years, the NHANES have provided a wealth of information regarding the prevalence of CKD and its complications within the United States. The third NHANES was conducted between 1998 and 1994 and included over 15,488 subjects who were older than 20 years and who had available laboratory data. The serum creatinine value that was used to estimate GFR was recalibrated to the original assay used to develop the MDRD equation. Kidney damage was identified using spot urine protein-to-creatinine ratios and adjusted for the estimated degree of persistence over time, based on results from a subsample of 1241 subjects who underwent repeat proteinuria testing approximately 2 weeks after the original test. Recent NHANES are carried out in 2-year intervals starting in 1999 to 2000 using similar methods as NHANES III. The smaller sample size (n = 4101) in 1999 to 2000 resulted in less precision in prevalence estimates. Updated results for NHANES 1999-2004 with calibration to standard creatinine should be available by 2008 and preliminary analysis suggest the prevalence of CKD has risen.
In NHANES III, the mean (standard error [se]) prevalence estimate for KDOQI-defined mild, moderate, and severe levels of decreased kidney function was 31.2% (0.78), 4.2% (0.25), and 0.19% (0.03). [51] [71] In NHANES 1999 to 2000, the mean (se) prevalence of mildly reduced GFR had significantly increased to 36.3% (1.26), but estimates were otherwise similar for moderate and severe reductions in GFR at 3.7% (0.37) and 0.13% (0.06), respectively.[51]Both surveys showed similar declines in eGFR with age. In NHANES III, the median (95% confidence interval [CI]) eGFR for subjects aged 20 to 29 years was 113 mL/min/1.73 m2 (112–114) and for those aged 70 years and above it was 75 ml/min/1.73 m2 (73–77). Approximately one quarter of all subjects aged over 70 had an eGFR of below 60 mL/min/1.73 m2. Decreased kidney function was more common in women than in men, but this difference disappeared with adjustment for age differences. Early stages of kidney damage were more common among non-Hispanic whites than among non-Hispanic blacks. Odds ratio of CKD in blacks as compared with whites, adjusted for age, gender, history of hypertension, use of hypertensive medications, and history of diabetes in normal, mild, moderate, and severe reductions in GFR were 1.0 (reference), 0.37 (0.32–0.43), 0.56 (0.44–0.71) and 1.1 (0.51–2.37), respectively.[71] Prevalence was lowest for Mexican Americans. The extent to which these differences from the pattern of ESRD incidence reflect limitations of equations to estimate GFR or a shorter duration due to more rapid progression or poorer survival in different subgroups is uncertain.
In NHANES III, approximately 11.7% of subjects had abnormal urine albumin-to-creatinine ratios and the prevalence was higher at lower levels of kidney function. In the subsample of NHANES III that underwent repeat urine testing, macroalbuminuria always persisted on repeat testing, whereas microalbuminuria persisted in only 54% of patients with an eGFR of greater than 90 mL/min/1.73 m2 and 73% of those with a GFR of 60 to 89. These findings may reflect an initial false-positive result, a subsequent false-negative result, or the presence of intermittent proteinuria—the significance of which is unknown. It is notable that, given the differences in muscle mass between the sexes, the urine protein-to-creatinine threshold level used to define microalbuminuria should ideally be gender specific, at approximately 17 to 250 mg/g creatinine in men and 25 to 355 mg/g creatinine in women.[72] Such gender specific cutoffs have not entered standard clinical practice. The most widely used non-gender-specific cutoff is an albumin-to-creatinine ratio greater than or equal to 30 mg/g for microalbuminuria. Using this cutoff, the overall prevalence of albuminuria rose significantly from 8.2% in 1988 to 1994 to 10.1% in 1999 to 2000, P = .01, and the estimated proportion of the U.S. population with CKD stages 1 to 4 was 8.8% in 1988 to 1994 and 9.4% in 1999 to 2000 ( Table 17-4 ).
TABLE 17-4 -- Trends in the Prevalence of Chronic Kidney Disease in the U.S.
|
CKD |
Prevalence (%) |
Prevalence Ratio (95% CI)[†] |
No. in U.S. in 2000,[‡] Thousands (95% CI) |
||
|
Stage |
Description |
1988–1994[*] |
1999–2000[*] |
||
|
1 |
GFR ≥90 and persistent albuminuria[†] |
2.2 |
2.8 |
1.26 (1.00–1.59) |
5,600 (4,000–7,200) |
|
2 |
GFR 60–89 and persistent albuminuria[†] |
2.2 |
2.8 |
1.27 (1.00–1.61) |
5,700 (4,200–7,200) |
|
3 |
GFR 30–59 |
4.2 |
3.7 |
0.88 (0.67–1.10) |
7,400 (6,000–8,900) |
|
4 |
GFR 15–29 |
0.19 |
0.13[§] |
0.68 (0.07–1.44) |
300 (24–500) |
|
Total |
Stages 1–4 |
8.8 |
9.4 |
1.07 (0.93–1.22) |
19,000 (16,300–21,600) |
|
ACR, albumin-to-creatinine ratio; CKD, chronic kidney disease; CI, confidence interval; GFR in ml/min per 1.73 m2; MEC, mobile examination center; NHANES, National Health and Nutrition Examination Survey. |
|
* |
MEC examined respondents with nonmissing serum creatinine measures and estimated GFR >15 and for albuminuria nonmissing ACR data, nonpregnant and not in menses. |
|
† |
Bootstrap CI estimates include variability in the persistence estimates of albuminuria but assume persistence to be the same in the two surveys. |
|
‡ |
Based on NHANES 1999–2000 prevalence and 200,948,641 adults age 20 yr and older in 2000 census. |
|
§ |
From Coresh J, Byrd-Holt D, Astor BC, et al: Chronic kidney disease awareness, prevalence, and trends among U.S. adults, 1999 to 2000. J Am Soc Nephrol 16(1):180–188, 2005. |
Internationally, it is clear that both proteinuria and decreased eGFR are quite common in many settings (see Table 17-3 ). However, it is hard to relate the prevalence of these markers of CKD to rates of ESRD due to methodologic differences between studies and different reports. A focused comparison of Norway to the United States revealed very similar prevalence rates of albuminuria and CKD stage 3, despite markedly higher treated ESRD incidence in the United States than in Norway. This suggests that factors determining progression from CKD to ESRD, not the least of which are treatment availability and patient management, will be important to understand.[57] It is also clear that CKD prevalence rates are substantial in countries with low income in which ESRD treatment is very limited or not available, such as Pakistan.[63]
Incidence of End-Stage Renal Disease in the United States
Much more precise data are available on the occurrence of treated ESRD compared with earlier stages of CKD. In the United States, ESRD is tracked by the U.S. Renal Disease Registry (USRDS) and detailed reports are published annually. The 2005 report includes data up until 2003 and is the year referred to in the following text, unless otherwise stated. In that year, 102,567 new patients commenced treatment with renal replacement therapy in the United States, equivalent to an age-, gender-, and race-adjusted rate of 338 per million population (pmp). Throughout most of the 1980s and early 1990s, the incidence of ESRD increased by 5% to 10% over consecutive years, resulting in an adjusted incidence rate for 1981, 1991, and 2001 of 91, 223, and 334 pmp, respectively ( Fig. 17-1 ). However, in the last several years, this rate of increase has leveled off, and in 2003, for the first time, the adjusted incidence rate actually decreased, albeit marginally, by 2 pmp. The rate for 2004 has decreased by 0.9%. Despite this recent stabilization in the ESRD incidence rate, the absolute number of patients commencing renal replacement therapy continues to rise, increasing by 2% in 2003, in keeping with the overall population aging and growth, particularly among minorities within the United States. Furthermore, even with the stabilization of the incidence rate, on the basis of the anticipated demographic changes in general population and of the sustained increase in diabetes, it is estimated that, by 2015, the incidence (95% CI) rate for ESRD will have increased to 136,166 (110,989–164,550) cases per year.[73]
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FIGURE 17-1 Adjusted U.S. incidence rates of ESRD and annual percent change. (From U.S. Renal Data System: USRDS 2005 Annual Data Report: Atlas of End-Stage Renal Disease in the United States. Bethesda, MD, National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases, 2005, p 68.) |
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Trends and Determinants of End-Stage Renal Disease Incidence Rates
The reasons underlying the epidemic growth in incident ESRD and the more recent stabilization of this trend are not completely understood. The incidence of renal replacement therapy will vary with the prevalence of CKD in the general population, the rate of progression of CKD to ESRD, the rate of acceptance of patients onto renal replacement programs, and effects of competing causes of mortality, which result in the death of patients prior to the initiation of dialysis. Furthermore, the relative impact of these different factors with regard to increasing incidence may differ substantially by race.[74]
Prevalence of Chronic Kidney Disease.
As described earlier, the prevalence of CKD in the general U.S. population as estimated from the NHANES has not demonstrated the dramatic increase seen in ESRD prevalence. Whereas recent analysis of 12,866 enrollees of the Multiple Risk Factor Intervention Trial (MRFIT) study confirmed that the presence of proteinuria and a low GFR (<60) were strongly and independently associated with the 25-year risk of developing ESRD,[75] it is clear that only a minority of such patients progress to ESRD, with the remainder presumably demonstrating relatively stable or only slowly deteriorating renal function [47] [49] or else succumbing to competing mortality. [47] [48] The last 2 decades have witnessed an epidemic growth in the number of subjects with type 2 diabetes, typically in association with obesity and increasingly sedentary lifestyles within the population.[76] Given the relatively slow natural history of diabetic glomerulosclerosis, it is possible that we are only beginning to see the impact of this increase in diabetes on the occurrence of kidney failure and that this may in part be responsible for the increased prevalence of proteinuria and early stages of CKD seen in NHANES 1999 to 2000 relative to the 1988 to 1994 survey.[51] Thus, although changes in the prevalence of CKD do not appear to explain the dramatic growth in ESRD seen over the last 2 decades, there is the ominous possibility that an increased prevalence of diabetes will considerably escalate future rates. Ethnic differences in CKD prevalence rates reflect differences in CKD and ESRD incidence rates, as discussed previously. [51] [71] [77] U.S. NHANES data through 2004 should be published in 2008.
Rate of Progression of Chronic Kidney Disease.
The rate of progression of CKD is influenced by a wide range of potentially modifiable risk factors, including blood pressure control [78] [79] [80] [81]; proteinuria [80] [82]; hyperglycemia [83] [84] [85]; dietary intake [82] [86] [87]; obesity[88]; the activity of the renin-angiotensin-aldosterone system [89] [90] [91]; smoking [15] [92] [93] [94] [95]; illicit drug use[96]; socioeconomic factors, including issues such as access to care [97] [98] [99] [100] [101]; and possibly hyperlipidemia [102] [103] and anemia[104]; as well as exposure to potential environmental or industrial toxins. [105] [106] Multiple opportunities thereby exist to intervene and change the natural history of the renal decline, especially through the focus of tight blood pressure control and inhibition of the renin-angiotensin-aldosterone system. It is suggested that the recent improvement in the incidence rate of ESRD seen in the USRDS reflects better secondary prevention of kidney damage, such as through the increased use of angiotensin-converting enzyme (ACE) inhibition, as well as better glycemic and overall blood pressure management.[66] In keeping with this, the incidence rates of ESRD for type 1 diabetes have steadily declined over the last decades in U.S. whites, though not in blacks.[66] In a Finnish cohort of all patients with type 1 diabetes, diagnosed between 1965 and 1999 (n = 20,005), and followed for a total of 346,851 patient-years, the incidence of ESRD decreased steadily over time; the relative risk for ESRD in 1965 to 1969, 1970 to 1974, 1975 to 1979, and 1980 to 1999 was 1.0 (reference), 0.78, 0.72, and 0.47, respectively, (P trend <.001).[107] The control of type 2 diabetes, which is by far the more common form of diabetes, is much more problematic, in part due to the fact that it represents a combined glycemic, ischemic, and hypertensive renal injury as well as presenting a far greater challenge in early recognition and appropriate management.
The race- and age-adjusted incidence of ESRD is higher in men (413 pmp) than in women (280 pmp), a differential that has increased over time ( Fig. 17-2 ). Whereas several studies have suggested that women progress less quickly to ESRD than do men, [108] [109] an observation that is supported by several animal models,[110] this has not been a uniform finding in all human studies.[111] Indeed, in a patient level meta-analysis of trials of nondiabetic subjects examining the effect of ACE inhibition on progression of CKD, the mean systolic blood pressure and proteinuria were greater in women than in men. There was no significant difference in the rate of progression by gender in an unadjusted analysis, the relative risk being 0.98. However, after adjustment for baseline variables, changes in ACE inhibitor use, and changes in blood pressure over follow up, the relative risk (95% CI) for progression in females compared with males was 1.36 (1.06–1.75).[112] As the mean (standard deviation [sd]) age of women in this study was 53 (13), the majority of the women were likely to have been postmenopausal, and these observations may not extend to younger women. In light of these results, whether the lower incidence of ESRD in women relative to men represents a true biologic effect of gender or is the result of underdiagnosis or undertreatment of ESRD in women requires further evaluation.
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FIGURE 17-2 Adjusted U.S. incidence rates of ESRD by gender. (From U.S. Renal Data System: USRDS 2005 Annual Data Report: Atlas of End-Stage Renal Disease in the United States. Bethesda, MD, National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases, 2005, p 68.) |
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Acceptance for Dialysis.
The occurrence of renal failure increases dramatically with increasing age. The race- and gender-adjusted treated ESRD incidence rate is currently almost 30-fold higher for those in their 8th decade of life (1703 pmp) compared with those in their 20s (58 pmp) ( Fig. 17-3 ). Traditionally, older subjects, especially those with significant comorbidities, may not have been offered or may not have been willing to accept dialysis. More recently, whether because of better management of comorbidities, higher patient expectations, or greater availability of renal replacement therapy, this has substantially changed. Whereas the adjusted, age-specific incidence rate for those younger than 65 has decreased since 2000 (currently 606 pmp), the rate for those aged 65 to 74 and those older than 74 years has continued to steadily increase and is currently 1435 pmp and 1687 pmp, respectively. The hypothesis that part of this sustained increase has been due to the acceptance of older and sicker patients onto renal replacement programs is supported by the increased burden of comorbidities, indicated by administrative billing codes in a random 5% of Medicare enrollees.[66] Increased acceptance of patients onto dialysis is less likely to contribute to the increase seen in younger subjects, the majority of whom have traditionally been offered dialysis, if deemed medically appropriate.
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FIGURE 17-3 Adjusted U.S. ESRD incidence rates by age and race/ethnicity. (From U.S. Renal Data System: USRDS 2005 Annual Data Report: Atlas of End-Stage Renal Disease in the United States. Bethesda, MD, National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases, 2005, p 36.) |
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Competing Mortality.
The mortality rates for patients with advanced CKD prior to initiation of renal replacement therapy are very high. [47] [48] This has a dramatic potential influence on the numbers of patients with progressive kidney disease who survive long enough to require dialysis. Analysis linking NHANES and USRDS data estimated that improved survival from myocardial infarction and stroke explained only 4.8% of the increase in incident ESRD from 1978 to 1991 compared with 28% due to the higher prevalence of diabetes and 8% from U.S. population growth.[113] However, the time period examined may have predated the period of increased recognition and better management of patients with CKD, and similarly, this analysis does not quantify the effects of the primary prevention of cardiovascular disease or competing mortality from other causes such as infection or cancer.
Variation in End-Stage Renal Disease Incidence Rates
Adjusted ESRD incidence rate differs substantially by race, with African Americans having a 3.5-fold higher age- and gender-adjusted incidence rate (996 pmp) than do whites (259 pmp); rates for Native Americans (504 pmp) are midway between those of whites and blacks; and the rate in Asians (346 pmp) is closer to that of whites (see Fig. 17-3 ). One examination of the excess risk of ESRD in blacks compared with whites suggests differences in socioeconomic factors explained 12%, lifestyle differences 24%, and clinical differences 32%, whereas all three groups of factors combined explained 44% of this excess risk. Thus, some but not all of the excess risk in blacks compared with whites is understood.[101] Some of this unexplained excess may relate to residual confounding, owing to imprecision in the measurement of known risk factors; however, it is possible that some of the unexplained excess relates to genetic factors and/or to genetic-environmental interactions. The observation of higher rates of kidney failure, in many cases from different etiologies, in some families; especially within African Americans, further supports a genetic component to this increased risk. [114] [115] The age- and gender-adjusted incidence rate is similarly higher in Hispanics (496 pmp) than in those of non-Hispanic ethnicity (323 pmp).
Substantial geographical variability exists in the adjusted ESRD incidence rate, with over 2.5-fold difference in incidence rates despite adjusting for demographic differences; the rate is highest in South Dakota (411 pmp) and lowest in Wyoming (166 pmp). Incidence rates are also significantly higher in urban than in rural settings. This may be due to a movement of patients on treatment from rural to urban environments or to limited access to care in rural settings, with reduced opportunities for disease recognition and management. Similar findings were observed in a nested case-control study of patients developing ESRD based on an NHANES II study in which living in a more heavily populated than a less heavily populated area was associated with a relative risk of kidney failure (95% CI) of 4.33 (2.09–8.97).[116]
Prevalence of End-Stage Renal Disease in the United States
In 2003, a total of 324,826 patients were treated with renal replacement therapy in the United States, equivalent to a rate per million population of 1496. The prevalence of ESRD has grown consistently over the last several decades, as a result of both the increased incidence rate and better survival rates. The current prevalence is five times higher than in 1980. However, more recently, as seen with the incidence rate, the rate of increase has stabilized, with recent annual increases of less than 4% per year ( Fig. 17-4 ). Prevalence rates are higher in urban than in rural areas and vary substantially across states, with the highest rates seen in the Southwest and Midwest.[66]
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FIGURE 17-4 Adjusted U.S. prevalence rates of ESRD and annual percent change. (From U.S. Renal Data System: USRDS 2005 Annual Data Report: Atlas of End-Stage Renal Disease in the United States. Bethesda, MD, National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases, 2005, p 72.) |
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The median age of the prevalent ESRD population is 58.2 years, and it has remained relatively constant over the last decade; it is 6.6 years younger than the average age of persons starting dialysis, owing to the higher mortality in older patients. Whereas the prevalence rate for those younger than 65 has remained stable over the last decade, the rate for those aged 65 to 74 (5300 pmp) has increased by two thirds, and for those aged 75 years and older (4609 pmp) has nearly doubled ( Fig. 17-5 ). However, owing to the age structure of the underlying general U.S. population, in terms of actual number of patients, the highest count is for those aged 45 to 64, whose prevalence rate has been consistently between 37 and 42 pmp over the last 2 decades.
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FIGURE 17-5 Prevalent U.S. ESRD counts and adjusted rates by age. (From U.S. Renal Data System: USRDS 2005 Annual Data Report: Atlas of End-Stage Renal Disease in the United States. Bethesda, MD, National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases, 2005, p 72.) |
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There is a slightly larger differential between blacks and whites with regard to the age and gender-adjusted prevalence—4700 pmp versus 1096 pmp, a 4-fold difference—as compared with the incidence rate, for which there is a 3.5-fold differential. The difference is due to better survival rates among blacks on dialysis. The adjusted prevalence rate for Hispanics is 46% higher than for non-Hispanics and mirrors the difference in their respective incidence rate, whereas the prevalence in men (1806 pmp) is 1.5-fold higher than in women (1242 pmp).
Incidence and Prevalence of End-Stage Renal Disease: Global Comparisons
The occurrence of ESRD varies widely between different countries and, on many occasions, within different regions of the same country ( Fig. 17-6 ). In addition to variability in the general factors that determine the incidence of ESRD, which are discussed previously, international comparison of incidence and prevalence rates may be complicated by different administrative definitions of ESRD and in the classification of the underlying cause of kidney failure, as well as by variability in the completeness and accuracy of the reported data. As a result, direct comparison of the data from different national registries must be undertaken with caution. However, within these limitations, the increase in ESRD in Europe has mirrored the U.S. experience, although absolute rates are lower. It is as yet unclear whether the rising incidence of ESRD in Europe is starting to slow, as has occurred in the United States in the last several years.[117]
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FIGURE 17-6 International comparison of ESRD incidence rates in 2003. (From U.S. Renal Data System: USRDS 2005 Annual Data Report: Atlas of End-Stage Renal Disease in the United States. Bethesda, MD, National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases, 2005, p 218.) |
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The age- and gender-adjusted incidence rates for Western Europe between 1990 and 1999 increased 47% from 79.4 pmp in 1990 up to 117 pmp in 1998. Thus, the age- and gender-adjusted incidence rates in Europe are about one third those of the United States. The incidence rates in Western Europe increased linearly by approximately 4.8% per year. As occurred in the United States, rates increased faster in men than in women and were more marked in older age groups. Incidence in those aged over 75 increased 3-fold from 141 to 540 pmp; as in the United States, there is widespread variability between countries in Europe, especially for older subjects. During the 1990s, the incidence rate for patients older than 75 increased 2-fold in the Netherlands, 6.5-fold in Scotland, 9-fold in Denmark, and 30-fold in Finland.[117]
The annual incidence rate of ESRD in Japan increased roughly threefold between 1982 (81 pmp) and 2001 (252 pmp). The unadjusted rate in Taiwan is similar to that of the United States (331 pmp) and has continued to increase at almost double the U.S. rate over the last several years.[66] The unadjusted incidence rate in Australia and New Zealand is considerably less than the aforementioned rates at 92 and 107 pmp, respectively.[118] In Australia, the annual incidence rates increased by twofold. This is largely reflected in the increase of those aged over 65, with rates of those younger than 65 being relatively stable. As in the United States, racial minorities in people of native descent such as the Australian Aboriginals or the New Zealand Maori islanders bear a disproportionate degree of the overall burden of ESRD.[119]
DIALYSIS MODALITY
In 2003, 91% of the incident U.S. ESRD population were treated with hemodialysis, 7% by peritoneal dialysis, and 2% by preemptive transplantation. Of the prevalent population, 65.5% are treated by in-center hemodialysis, 0.3% by home hemodialysis, 5.7% by peritoneal dialysis (2.5% with cycler-based therapy, 3.2% with manual, noncycler therapy), and 28.5% with transplantation. There has been a renewed interest in the potential benefits of more frequent dialysis, using short daily dialysis or quotidian nocturnal dialysis, spurred by promising initial results from what have, in general, been small and poorly controlled studies. [120] [121] [122] [123] [124] [125] [126] This has led to the establishment of an NIH trial to quantify the potential benefits of more frequent dialysis.[127]
Substantial racial differences exist in renal replacement therapy; white patients make up 55% of prevalent hemodialysis patients but 75% of the prevalent transplant population; African Americans account for 38% of prevalent hemodialysis population but only 18% of the transplant population. Over the last decade, substantial changes in dialysis provider characteristics have occurred in the United States with a sustained growth in large dialysis corporations. Currently, approximately 63% of prevalent hemodialysis and 60% of prevalent peritoneal dialysis patients are dialysed in a chain-owned facility, percentages that have increased from 52% and 47%, respectively, 5 years ago ( Fig. 17-7 ). These large chains, the majority of which are for-profit corporations, clearly have an enormous influence on practice patterns and outcomes in ESRD patients, for better or for worse. Concerns have been raised that the latter effect is more likely and that a for-profit chain affiliation may be associated with decreased indicators of quality of care, such as the probability of entering the transplant wait list[128] and higher adjusted mortality rates compared with those of not-for-profit institutions, relative hazard (95% CI): 1.08 (1.04–1.13), P < .001.[129]
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FIGURE 17-7 Incident dialysis patient counts in the United States by first modality and unit type. (From U.S. Renal Data System: USRDS 2005 Annual Data Report: Atlas of End-Stage Renal Disease in the United States. Bethesda, MD, National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases, 2005, p 104.) |
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DIALYSIS SURVIVAL
Improved survival rates have contributed to the increased number of prevalent patients on dialysis. In 2003, the number of new patients exceeded by 17,911 the number of established patients who died. The adjusted mortality rate (adjusted for age, race, ethnicity, gender, primary renal diagnosis, and years on dialysis) decreased from 224.3/1000 patient-years at risk in 1993 to 210.7/1000 patient-years in 2003, a 6.1% reduction. Some of this difference may reflect a recent secular trend toward earlier initiation of dialysis with better preserved GFR ( Fig. 17-8 ) with the resulting potential for “lead time bias” in the comparisons of survival rates from earlier time periods. Against this, early initiation of dialysis has not to date been shown to improve survival[130] and is typically associated with greater degrees of comorbidity, with sicker patients needing to commence dialysis earlier. However, the determination of incident comorbidity is based on the Center for Medicaid and Medicare Services “Medical Evidence Form” (Form 2728), which at least initially was relatively inaccurate and insensitive.[131] More recently, the policy to publish the outcomes of individual dialysis units, which are adjusted for comorbidity using the information provided in Form 2728, has provided a powerful incentive for units to more accurately and fully report comorbidity. Thus, although it is likely that the current incident population has more comorbidities than was historically the case, reliably quantifying this effect is difficult.
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FIGURE 17-8 Estimated GFR (eGFR) at initiation of ESRD treatment in the United States by body mass index (kg/m2). (From U.S. Renal Data System: USRDS 2005 Annual Data Report: Atlas of End-Stage Renal Disease in the United States. Bethesda, MD, National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases, 2005, p 92.) |
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The overwhelming primary cause of death in patients treated with dialysis is due to premature and often accelerated cardiovardiovascular disease. In recognition of this, a recent position statement from the American Heart Association recommended that patients with ESRD be considered to be at “highest risk” with regard to future cardiovascular events.[132] Moreover, overwhelming evidence now indicates that the entire spectrum of CKD is associated with increased rates of cardiovascular disease. [133] [134] [135] Some of the absolute increase in cardiovascular risk seen with reduced renal function is the result of the very high prevalence of traditional Framingham risk factors in patients with CKD. [136] [137] In early CKD, these traditional risk factors appear to have the same relationship with cardiovascular disease as has been described in the general population,[137] but in ESRD, the relationship for some risk factors, most notably hypertension and cholesterol, alters and becomes more U shaped, with lower in addition to higher levels being associated with higher risk. It has been postulated that this increased risk of cardiovascular disease seen with low levels of total cholesterol [138] [139] and low blood pressure levels [140] [141] [142] may be due to reverse causation and the presence of uncontrolled confounding. Although some authors have referred to this observation as “reverse epidemiology,” the term is somewhat misleading because, by definition, observational studies can only demonstrate the presence of an association and thus are unable to directly determine causality, be it in a forward or a reverse direction.
In addition to traditional risk factors, a wide array of novel cardiovascular risk factors cluster in CKD and are implicated in increased cardiovascular risk. A wealth of observational data has associated the presence of anemia with poor cardiovascular outcomes. However, the currently available clinical trial evidence suggests that much of this association is not directly causal in nature. [143] [144] [145] [146] Thus, whereas the correction of anemia remains a cornerstone of the management of CKD with regard to symptom control and quality of life issues, there remains to date no convincing evidence that extending erythropoietin therapy to beyond its current targets exerts a cardioprotective effect. A major potential confounder of the association of anemia with cardiovascular disease is the presence of inflammation and associated malnutrition, both of which are powerful predictors of poor long-term survival on dialysis. [147] [148] [149] With the initiation of dialysis, nutritional status typically improves but then often slowly deteriorates over time with increasing dialysis vintage. [150] [151] Strategies to counteract this progressive nutritional deterioration are currently lacking. It is of note, however, that despite the negative effects of obesity on long-term health in the general population and the transplant population, [152] [153] obese dialysis patients have better outcomes relative to nonoverweight subjects. [154] [155] This may relate to obese subjects effectively having a better nutritional reserve at the start of dialysis or obesity marking patients with fewer comorbidities that result in weight loss. Thus, the mechanisms and ramifications of this paradoxical association require further exploration.
The mortality rate seen with CKD reflects both an increased prevalence of cardiovascular disease and an increased case fatality rate. The latter may result from the severity of the cardiovascular disease, the presence of extensive comorbidities, or a greater degree of therapeutic nihilism in the management of patients with CKD. Several studies have supported this last contention. [156] [157] [158] [159]
Mortality rates in ESRD steadily increase with increasing age, from 102/1000 patient-years in 20- to 44-year-olds to 427/1000 patient-years for those older than 75. The 2003 crude mortality rate for males and females was 229.4 and 239.3, with adjusted rates of 210.9 and 211.1; both the crude and the adjusted rates are higher for whites than for blacks. The adjusted mortality rate is significantly worse for those whose primary renal diagnosis is diabetes (253/1000 patient-years) compared with those whose cause of ESRD is attributed to hypertension (194/1000 patient-years) or glomerulonephritis (157/1000 patient-years).
Modality-specific mortality rates for 2001 to 2003 were 194.7/1000 patient-years in peritoneal dialysis compared with 235.4/1000 patient-years for hemodialysis. Considerable caution is needed in interpreting these data. Despite being adjusted for demographic characteristics, the data nevertheless suffer from a major degree of persistent confounding owing to the substantial differences in clinical characteristics between the two modalities at initiation of dialysis, both in terms of comorbidity and in level of residual renal function. [160] [161] In addition, these analyses do not control for switches in dialysis modality over time, with substantially more switching occurring for sick subjects from peritoneal dialysis to hemodialysis than vice versa. A moderately sized prospective observational cohort study compared survival in peritoneal dialysis and hemodialysis among subjects in the mid and late 1990s and reported worse apparent survival for the peritoneal dialysis group when controlling for many of the parameters previously discussed.[162] However, these reports predate the more recent developments in clinical practice and the introduction of newer, more biocompatible dialysate solutions.[163] Observational studies cannot prove causation, particularly in the face of strong confounding. However, a randomized interventional trial to definitively compare modalities is unlikely to be conducted.
More recent USRDS data suggest that the age-, race-, and gender-adjusted 5-year mortality difference between hemodialysis and peritoneal dialysis has decreased over time ( Fig. 17-9 ). This improvement has been more marked in peritoneal dialysis, in which crude mortality has reduced by 12% since 1985 compared with an 8% reduction over the same time period for hemodialysis. The mortality rate for diabetics initiating peritoneal dialysis in 1994 to 1998 (22.8%) was lower than for those initiating hemodialysis (26.7%). For nondiabetics, 5-year survival rates were better in peritoneal dialysis (41.1%) than for hemodialysis (39%). Whether these improvements reflect a secular change in selection criteria, as the numbers of patients treated with peritoneal dialysis has decreased over time, or whether it is indeed a result of improved medical management or technical advance remains speculative.
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FIGURE 17-9 Adjusted 5-year survival of U.S. incident dialysis patients by modality and primary diagnosis. HD, hemodialysis; PD, peritoneal dialysis. (From U.S. Renal Data System: USRDS 2005 Annual Data Report: Atlas of End-Stage Renal Disease in the United States. Bethesda, MD, National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases, 2005, p 131.) |
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The general trend toward overall improvements in survival rates in both dialysis modalities over the last 2 decades obscures significant technique-specific interactions between mortality rates and duration on dialysis (vintage) ( Fig. 17-10 ). In hemodialysis, prior to 1993, mortality rates were substantially higher for those who had been dialyzed for less than 2 years compared with those who had been on therapy for more than 5 years. In 1993, the rates for the two vintages were approximately similar. Since that time, mortality rates for those treated for less than 2 years have progressively declined, and for those of older vintage have steadily risen. In peritoneal dialysys, the 1985 mortality rate was similar for those dialyzed less than 2 years and for those dialyzed for more than 5 years, and since that date, mortality in the less than 2-year vintage patients has decreased while that of those dialyzed for longer than 5 years has increased. The improvement has been attributed to efforts such as improvements in pre-ESRD care and widespread provision of higher dialysis doses, although whether these associations are causal or coincidental is unproved. The trend toward poorer longer-term survival is concerning. It was unclear whether this reflected a carry-over effect from earlier periods of possibly less optimal clinical practice or if it suggests that recent improvements were merely postponing mortality to a slightly later time period. However, the most recent USRDS report found that rates for older vintages have actually stabilized in hemodialysis patients and are decreasing in peritoneal dialysis subjects. Further data are required to see if this trend continues.
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FIGURE 17-10 Adjusted all-cause mortality in U.S. prevalent dialysis patients by number of years on dialysis (vintage) and calendar year. (From U.S. Renal Data System: USRDS 2005 Annual Data Report: Atlas of End-Stage Renal Disease in the United States. Bethesda, MD, National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases, 2005, p 131.) |
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The USRDS tracks survival of incident patients, starting from 90 days following initiation of dialysis. A general trend is evident in the all-cause as well as for both cardiovascular-specific and infectious-specific mortality rates for event rates to peak at approximately 6 months of follow-up by USRDS (i.e., approximately 9 months after the initiation of dialysis). Rates sharply decline over the following 3 to 6 months, with a subsequent more gradual increase in mortality. These trends have persisted over time, although at lower absolute rates. Patients on peritoneal dialysis tend to have lower initial event rates than in those treated with hemodialysis, but have no initial fall, instead demonstrating a monotonic trend toward increasing event rates over time. Understanding the degree to which these differences represent differences in clinical practices as opposed to being the result of different selection biases is important.
The overall impact that having ESRD has on long-term patient outcomes is perhaps most clearly seen in the examination of estimated remaining years of life. When adjusted for gender, the expected remaining life span for a 60- to 64-year-old white dialysis patient is 3.9 years, less than one fifth that of a similarly aged member of the general population (20.5 yr), and the estimated remaining years of life for a similarly aged black subject (4.9 yr) is less than one quarter that of a similarly aged black subject without ESRD (18.5 yr).
TRANSPLANTATION
In 2003, 14,853 renal transplants were performed in the United States. The number of transplants has slowly increased over time. However, this increase has been overshadowed by the far greater increase in the number of patients starting dialysis ( Fig. 17-11 ). Thus, in 2003, the number of patients transplanted (16,043) was one seventh the number of patients who commenced renal replacement therapy and two thirds the number of patients (23,488) who were added to the transplant waiting list. The transplantation rate, expressed as transplants per 100 wait-listed patient-years has decreased to 5.7 in 2003, resulting in longer median wait-list times. Median wait-list time has progressively increased over the last decade, with little variation by gender and substantially shorter wait-list times in whites than in other racial groups ( Fig. 17-12 ).
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FIGURE 17-11 Incident and prevalent U.S. dialysis patient counts and prevalent transplant patient counts. (From U.S. Renal Data System: USRDS 2005 Annual Data Report: Atlas of End-Stage Renal Disease in the United States. Bethesda, MD, National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases, 2005, p 67.) |
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FIGURE 17-12 Transplantation rates in the United States by age, gender, and race. N Am, North American. (From U.S. Renal Data System: USRDS 2005 Annual Data Report: Atlas of End-Stage Renal Disease in the United States. Bethesda, MD, National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases, 2005, p 148.) |
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Transplant rates are highest in patients aged less than 18 years and decrease with advancing age. Rates have remained relatively constant in subjects aged less than 50 years but have doubled over the last decade in those aged 50 to 64 and tripled in those aged 65 and older. Striking gender and racial inequalities remain in current transplant rates, with male patients being wait listed and transplanted relatively more frequently than females and white patients being severalfold more likely to receive a transplant than African Americans. These racial disparities in transplantation rates appear to stem from both clinical characteristics that appropriately influence the subjects candidacy for transplantation and apparent overutilization in whites and underutilization in blacks.[164] These inequalities have narrowed somewhat over time as transplant rates in whites and males have decreased, while those in blacks and in women have remained steady. Similar racial inequalities are evident on a global basis. Indigenous Australians represent less than 2% of the Australian population, account for 8% to 10% of incident dialysis patients, but receive transplants at only one third the rate of nonindigenous patients.[119] There is also widespread geographic variability in rates of transplant wait listing, median wait-list times, and transplantation rates, with an over twofold difference in transplantation rates between states. Transplantation rates are highest in the upper Midwest states such as Iowa and Minnesota. These differentials have led some patients to be listed in multiple organ procurement areas.
Much of the increase in the absolute number of transplants performed in the United States over the last decade is a result of an increase in living donation rates, now representing over 50% of transplant donations ( Fig. 17-13 ). Living donation has the advantages of planned elective surgery, reduced cold ischemia time, decreased wait-list time, and closer human leukocyte antigen (HLA) matching.[165] Living kidney donation has excellent outcomes when there is less optimal HLA matching, as may occur with unrelated donors.[166] Live donation is not without risk to the donor.[167] As a result, careful physical and psychological evaluation of potential donors is necessary. Some of this risk may be counterbalanced by emotional benefits experienced by the donor.[168] The risks to the live donor are likely to be greater and less appropriately balanced in paid organ donors. Despite serious ethical objections, paid organ donation is common in several areas. [169] [170] [171]
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FIGURE 17-13 Number of transplants in the United States by donor type. Living unk, living unknown. (From U.S. Renal Data System: USRDS 2005 Annual Data Report: Atlas of End-Stage Renal Disease in the United States. Bethesda, MD, National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases, 2005, p 147.) |
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Cadaveric donation rates increased by less than 10% from 1994 (n = 7700) to 2003 (n = 8389) and have more recently decreased. In contrast, living donor transplantation numbers doubled from 3007 to 6464 over the same decade. Some of this increase may be the result of technical advances in harvesting the donor kidney, especially with the use of laparoscopic organ harvesting that has led to a reduction in patient discomfort and recovery time. [172] [173]Donor characteristics differ in deceased versus living donors. Deceased donation rates are highest in donors aged 45 to 59 years old, and in men compared with women; rates are higher for whites than for blacks, and lowest in Asians. In contrast, living donation rates are highest in older donors (those aged 60-69), higher in women than in men, and similar in whites and blacks, who in turn, have higher rates than Asians or Native Americans. Attempts to increase the number of deceased donor transplants have led to several novel strategies including the use of less optimal allografts. In 2000, the United Network of Organ Sharing (UNOS) established an Extended Criteria Donors (ECD) based on the presence of several characteristics that are associated with an approximately 70% higher failure rate than that found with non-ECD kidneys. Additional strategies have included increased use of marginal kidneys by transplanting both kidneys that are judged to be individually inadequate for use separately and the use of non-heart-beating donors—as distinct from the more usual situation of donation from a patient who is brain dead but whose cardiorespiratory circulation is maintained through artificial life support. Whereas non-heart-beating donation is associated with poorer initial graft function, the long-term outcomes may nonetheless be acceptable.[174] The increased complexity of non-heart-beating donation, especially regarding diagnosis of death, obtaining informed consent, and the timely initiation of organ preservation measures, poses major challenges to its wider utilization.[175] Wider utilization of living donation is limited by unaltered requirements for appropriate tissue cross matching. Based on blood type frequencies in the United States, it is estimated that there is a 35% chance that any two individuals will be ABO incompatible and a 30% chance that persons awaiting transplantation will be highly sensitized owing to allo-HLA antibodies—measured as high levels of panel reactive antibodies (PRA). High PRA levels may result from previous pregnancies, blood transfusions, or prior transplants. Desensitization protocols, based on the use of plasmapheresis and adjunct immunotherapy, have helped overcome these barriers and so facili-tate successful transplantation in subjects with high PRA levels, [176] [177] [178] [179] [180] with ABO-incompatible donors, [181] [182] [183] or both.[184] An alternative approach is that of paired organ exchanges between two or more pairs of donors and recipients, in which a donor is willing to donate a kidney but is an unsuitable match for the desired recipient and therefore provides his or her kidney to an alternative recipient who has a donor who gifts his or her kidney to the original potential recipient. [185] [186] Such paired donation procedures increase the complexity of the transplant procedure, not least because the several surgeries need to be conducted simultaneously.[187] The impact of such paired exchanges on the ever-increasing waiting list for transplantation has to date been limited and is likely to remain so in the absence of national strategies to help optimize their implementation and execution.[186] Ominously, it has been suggested that, even in the event of a substantial increase in the allograft availability, the greater availability of organs, especially in the setting of improved outcomes post-transplantation, is likely to encourage an even higher proportion of dialysis patients to opt for transplantation.[188]
TRANSPLANT OUTCOMES
The reduction in acute rejection rates and improvement in short-term graft survival have been a dramatic success story in the field of transplantation. The 1-year graft and patient survival for a deceased donor transplant is 88% and 95%, the comparable figures for a living donor are 94% and 98%.[66] Transplantation offers a significant survival advantage over continued dialysis ( Fig. 17-14 ). This advantage persists even when accounting for selection biases by use of the transplant wait-listed population as a comparison population. [189] [190] [191] This advantage also extends to elderly patients who are considered medically fit for transplantation.[192] Preemptive kidney transplant—transplantation without preceding dialysis—also enjoys superior outcomes over transplant following initial dialysis.[193] The cumulative rejection rates in the first 6 months are now less than 20%. These steady improvements in patient and graft survival have derived from better tissue cross matching,[176] the improved ability to quickly and accurately diagnose complications such as acute humoral rejection, [194] [195] standardization of diagnostic criteria of complications,[196] better antirejection therapy [165] [197] [198] and improved antimicrobial prophylaxis.[199] Unfortunately, the long-term graft outcome has failed to improve to a comparable degree. [200] [201] One-year conditional graft half-life (the expected length for which half of all grafts that survive 1 year will remain functional) has remained essentially unchanged over the last decade, although this coincides with the increased use of less optimal grafts. The rate of graft failure due to death with a functioning graft has remained constant at 3.4/100 patient-years, whereas the rate of graft failure in surviving patients has steadily declined and is now only slightly greater than the rate of graft failure due to death with function. The rate of death with a functioning graft was similar for men and women, although approximately twofold higher for blacks that for whites or Asians. The proportion of patients who received preemptive retransplant—without any interim return to dialysis—has increased slightly and now represents approximately 10% of all graft failures. Of the patients who return to dialysis, approximately half go on to a subsequent transplant while the remainder stay and ultimately die on dialysis.
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FIGURE 17-14 Adjusted 5-year survival in U.S. incident ESRD by first modality. HD, hemodialysis; PD, peritoneal dialysis; Tx, transplant. (From U.S. Renal Data System: USRDS 2005 Annual Data Report: Atlas of End-Stage Renal Disease in the United States. Bethesda, MD, National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases, 2005, p 27.) |
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The most common cause of death in transplant recipients is cardiovascular disease, which accounts for 43.5% of those with a known cause of death ( Fig. 17-15 ). The risk of cardiovascular mortality in transplant subjects is substantially less than that in dialysis patients but is still higher than race-, age-, and gender-matched rates in the general public. Some improvement in survival of successful transplants is expected on the grounds of the extensive cardiovascular evaluation performed prior to transplant wait listing. However, this survival benefit persists in comparison with transplant wait-listed subjects, who continue on dialysis having undergone a similar initial evaluation as part of their transplant evaluation. Such subjects thereby form a fairer, though still imperfect, control group. The wait-listed population remains a somewhat biased comparator, as it is, by definition, enriched with subjects who have been on the waiting list longer, for example, due to higher PRA status, and who thus may have a higher cardiovascular risk profile. In comparison to the transplant wait-listed population, rates of cardiovascular death, censored for graft loss, among transplant recipients peak during the first 3 months postengraftment and thereafter gradually decline while the rates progressively increase for wait-listed subjects who continue on dialysis.[202]
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FIGURE 17-15 Causes of death among U.S. transplant recipients with a functioning graft. CVD, cardiovascular disease. (From U.S. Renal Data System: USRDS 2005 Annual Data Report: Atlas of End-Stage Renal Disease in the United States. Bethesda, MD, National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases, 2005, p 152.) |
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The etiology of cardiovascular disease in the transplant population is multifactorial. Although much of the increased risk may relate to carryover effects from earlier periods on dialysis or with lesser degrees of CKD, an element of the increased risk remains attributable to the transplantation period. Hypertension often persists following renal transplantation, despite improvements in volume control. It is associated with both donor and recipient characteristics and may be exacerbated by the use of corticosteroids and calcineurin inhibitors. Post-transplant hypertension is associated with both poor cardiovascular outcomes[203] and chronic allograft nephropathy and, despite the close monitoring of transplant patients, is still often poorly controlled. [44] [204] [205]
Infection accounts for 26.3% of the remaining patients and malignancy for 10.7%. Unfortunately, in approximately 30% of transplant patients, the cause of death is unknown. This figure increases with increasing durations of follow up.
The outcome of extended criteria grafts has been examined in a retrospective cohort study based on USRDS data. This examined the 3-year survival among 7790 ECDs versus 41,052 patients receiving standard therapy. It demonstrated initial early excess perioperative mortality, with cumulative survival not equalizing until 3.5 years post-transplantation. Long-term survival was 17% lower for ECD recipients. Subgroups with significant benefit from ECD were those over 40, unsensitized subjects, and those with diabetes. In organ procurement areas with long median wait times (>1350 days), the relative risk reduction (95% CI) in mortality with ECDs was 27% (17%–36%), P < .001. In areas with shorter wait list times, only diabetics demonstrated a benefit with extended criteria donation.[206]
CONCLUSION
The epidemiology of CKD has advanced into recognition of the high prevalence of earlier stages of CKD marked by kidney damage and moderate reductions in GFR. Estimates of the prevalences of CKD are becoming increasingly available internationally but still suffer from limited standardization. The epidemiology of treated kidney failure is more mature, with widely available data internationally showing a progressive increase in all countries. The rate of increase has slowed in the United States with age-specific rates stabilizing, but the total number of cases requiring dialysis is projected to continue increasing substantially. Outcomes on dialysis have improved but are still inferior to outcomes with transplantation. Finally, the complications of CKD include but are clearly not limited to progression to kidney failure requiring renal replacement. These complications, which include hypertension, anemia, acidosis, poor nutrition, mineralization abnormalities, cardiovascular disease, and increased risk of mortality, suggest the need for a wider approach to kidney disease that is not limited to subspecialty care. Strategies for decreasing the progression of kidney disease as well as strategies for controlling metabolic complications at all stages of kidney disease need to be developed, evaluated, and implemented to improve outcomes in CKD.
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