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Epidemiology of Kidney Disease
Chapter 9
Epidemiology of Kidney Disease A standardized definition and staging scheme for chronic kidney disease (CKD), a term used to encompass the entire spectrum of renal dysfunction, has dramatically improved our understanding of the occurrence and consequences of renal disease. CKD is defined as the presence, for at least 3 months, of evidence of kidney damage with an abnormal glomerular filtration rate (GFR) or, alternatively, by a GFR below 60 mL/ min/1.73 m2 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. The formula 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. The modified MDRD equation was developed from subjects enrolled in the baseline period of the MDRD Study. 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 and www.kidney.org/professionals/KDOQI; see also Chapter 2, Laboratory Assessment of Renal Disease). The National Kidney Foundation (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 9-1). This staging system represents a measure of the “azotemic burden” resulting from the degree of kidney dysfunction. 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,
189
190
Epidemiology of Renal Disease
III
Table 9-1
Stages of Chronic Kidney Disease GFR (mL/min/ 1.73 m2)
Stage
Description
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)
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. GFR, glomerular filtration rate. Data 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.
but 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. Stage 5 CKD representing kidney failure is defined either by GFR less than 15 mL/min/1.73 m2 or by the need for dialysis. Following renal transplantation, patients are defined by the stage according to the post-transplant GFR. It is unclear, however, whether the relationship between complications and CKD stage post-transplantation is identical to that reported with decrements in native kidney function.
INCIDENCE AND PREVALENCE OF CHRONIC KIDNEY DISEASE AND END-STAGE RENAL DISEASE Chronic Kidney Disease Incidence 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
Prevalence of Stages 1 to 4 The occurrence of kidney damage and CKD in the general population is important because only a minority of patients progress to kidney failure and are thereby identified on national ESRD registries. Instead, the majority of patients with CKD die from concurrent disease or else maintain relatively stable, although reduced, renal function 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 death associated with CKD. 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. 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 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 National Health and Nutrition Examination Survey (NHANES) has provided a wealth of information regarding the prevalence of CKD and its complications within the United States. In NHANES III, the mean prevalence estimate for a GFR less than 60 mL/min/1.73 m2 was 4.4%. Internationally, it is clear that both proteinuria and decreased eGFR are quite common in many settings. 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. 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.
Epidemiology of Kidney Disease
estimated GFR (eGFR) greater than 60 mL/min/1.73 m2, and a 191 mean age of 43 years, 9.4% developed CKD, defined by eGFR less than 60 mL/min/1.73 m2, over a mean follow-up period of 18 years. Risk was related to baseline GFR, diabetes, hypertension, low high-density lipoprotein (HDL) levels, and smoking. CH 9 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.
192 End-Stage Renal Disease
Incidence in the United States
Epidemiology of Renal Disease
Much more precise data are available on the occurrence of treated III ESRD compared with earlier stages of CKD. In the United States, ESRD is tracked by the U.S. Renal Disease Survey (USRDS) and detailed reports are published annually. In the year 2003, 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. However, in the last several years, this rate of increase has leveled off. 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 the general population and of the sustained increase in diabetes, it is estimated that, by 2015, the incidence for ESRD will have increased to more than 130,000 cases per year.
Trends and Determinants of 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 the effects of competing causes of death, 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. The mortality rates for patients with advanced CKD prior to initiation of renal replacement therapy are very high. This has a dramatic potential influence on the numbers of patients with progressive kidney disease who survive long enough to require dialysis. Improved survival from myocardial infarction and stroke explains less than 5% of the increase in incidence of ESRD from 1978 to 1991, compared with 28% due to the higher prevalence of diabetes and 8% from U.S. population growth.
Variation in 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
Epidemiology of Kidney Disease
(259 pmp); rates for Native Americans (504 pmp) are midway 193 between those of whites and blacks; and the rate in Asians (346 pmp) is closer to that of whites. One examination of the excess risk of ESRD in blacks compared with whites suggests differences in socioeconomic factors explained 12%, lifestyle CH 9 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. Substantial geographic variability exists in the adjusted ESRD incidence rate in the United States, 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.
Prevalence 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 of 1496 pmp. 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 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 rate 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) the rate has nearly doubled.
Global Comparisons The occurrence of ESRD varies widely between different countries and, on many occasions, within different regions of the same country. 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
194 these limitations, the increase in ESRD in Europe has mirrored
Epidemiology of Renal Disease
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 III last several years. 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 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. The unadjusted incidence rate in Australia and New Zealand is considerably lower than the aforementioned rates at 92 and 107 pmp, respectively. In Australia, the annual incidence rates increased by twofold. This is largely reflected in the increase in those aged over 65, with rates in those younger than 65 being relatively stable. As in the United States, racial minorities in people of native descent, such as the Australian Aborigines or the New Zealand Maori, bear a disproportionate degree of the overall burden of ESRD.
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 cyclerbased therapy, 3.2% with manual, noncycler therapy), and 28.5% with transplantation.
Dialysis Survival Rates Improved survival rates have contributed to the increased number of prevalent patients on dialysis. 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, with the resulting potential for “lead time bias” in the comparisons of survival rates from earlier time periods. The overwhelming primary cause of death in patients treated with dialysis is due to premature and often accelerated cardiovascular disease. In recognition of this, a recent position statement from the American Heart Association recommended
Epidemiology of Kidney Disease
that patients with ESRD be considered to be at “highest risk” 195 with regard to future cardiovascular events. Moreover, overwhelming evidence now indicates that the entire spectrum of CKD is associated with increased rates of cardiovascular disease (see Chapter 27). The mortality rate seen with CKD CH 9 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. 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 239.3/1000 patient-years, respectively, with adjusted rates of 210.9 and 211.1/1000 patient-years; 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 significant persistent confounding factors, owing to the substantial differences in clinical characteristics between the two modalities at initiation of dialysis, both in terms of comorbidity and in the level of residual renal function. More recent USRDS data suggest that the age-, race-, and gender-adjusted 5-year mortality rate difference between hemodialysis and peritoneal dialysis has decreased over time. This improvement has been more marked in peritoneal dialysis, in which the crude mortality rate has reduced by 12% since 1985, compared with an 8% reduction over the same time period for hemodialysis.
TRANSPLANTATION While the number of renal transplants has slowly increased over time, this increase has been overshadowed by the far greater increase in the number of patients starting dialysis. Thus, in 2003, the number of patients transplanted was one seventh the number of patients who commenced renal replacement therapy and two thirds the number of patients who were added to the transplant waiting list. Median wait-list time has progressively
196 increased over the last decade, with little variation by gender
Epidemiology of Renal Disease
but substantially shorter wait-list times in whites than in other racial groups. Much of the increase in the absolute number of transplants performed in the United States over the last decade III is a result of an increase in living donation rates, now representing over 50% of transplant donations. Transplant rates are highest in patients younger than 18 years and decrease with advancing age. Rates have remained relatively constant in subjects younger 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 many times more likely to receive a transplant than African Americans. 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. Cadaveric donation rates increased by less than 10% from 1994 to 2003 and have more recently decreased. 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 years), 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, where they have been judged to be individually inadequate, into a single recipient and by 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.
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
Epidemiology of Kidney Disease
survival rates for a deceased donor transplant are 88% and 197 95%, respectively; the comparable figures for a living donor are 94% and 98%. The cumulative rejection rates in the first 6 months are now less than 20%. Unfortunately, the long-term graft outcome has failed to improve to a comparable degree. CH 9 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 patientyears, 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 a functioning graft. 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. The risk of death due to cardiovascular disease 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. Infection accounts for 26.3% of deaths in the remaining patients and malignancy for 10.7%. Unfortunately, in approximately 30% of transplant patients, the cause of death is unknown.
Epidemiology of Kidney Disease A standardized definition and staging scheme for chronic kidney disease (CKD), a term used to encompass the entire spectrum of renal dysfunction, has dramatically improved our understanding of the occurrence and consequences of renal disease. CKD is defined as the presence, for at least 3 months, of evidence of kidney damage with an abnormal glomerular filtration rate (GFR) or, alternatively, by a GFR below 60 mL/ min/1.73 m2 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. The formula 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. The modified MDRD equation was developed from subjects enrolled in the baseline period of the MDRD Study. 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 and www.kidney.org/professionals/KDOQI; see also Chapter 2, Laboratory Assessment of Renal Disease). The National Kidney Foundation (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 9-1). This staging system represents a measure of the “azotemic burden” resulting from the degree of kidney dysfunction. 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,
189
190
Epidemiology of Renal Disease
III
Table 9-1
Stages of Chronic Kidney Disease GFR (mL/min/ 1.73 m2)
Stage
Description
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)
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. GFR, glomerular filtration rate. Data 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.
but 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. Stage 5 CKD representing kidney failure is defined either by GFR less than 15 mL/min/1.73 m2 or by the need for dialysis. Following renal transplantation, patients are defined by the stage according to the post-transplant GFR. It is unclear, however, whether the relationship between complications and CKD stage post-transplantation is identical to that reported with decrements in native kidney function.
INCIDENCE AND PREVALENCE OF CHRONIC KIDNEY DISEASE AND END-STAGE RENAL DISEASE Chronic Kidney Disease Incidence 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
Prevalence of Stages 1 to 4 The occurrence of kidney damage and CKD in the general population is important because only a minority of patients progress to kidney failure and are thereby identified on national ESRD registries. Instead, the majority of patients with CKD die from concurrent disease or else maintain relatively stable, although reduced, renal function 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 death associated with CKD. 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. 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 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 National Health and Nutrition Examination Survey (NHANES) has provided a wealth of information regarding the prevalence of CKD and its complications within the United States. In NHANES III, the mean prevalence estimate for a GFR less than 60 mL/min/1.73 m2 was 4.4%. Internationally, it is clear that both proteinuria and decreased eGFR are quite common in many settings. 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. 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.
Epidemiology of Kidney Disease
estimated GFR (eGFR) greater than 60 mL/min/1.73 m2, and a 191 mean age of 43 years, 9.4% developed CKD, defined by eGFR less than 60 mL/min/1.73 m2, over a mean follow-up period of 18 years. Risk was related to baseline GFR, diabetes, hypertension, low high-density lipoprotein (HDL) levels, and smoking. CH 9 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.
192 End-Stage Renal Disease
Incidence in the United States
Epidemiology of Renal Disease
Much more precise data are available on the occurrence of treated III ESRD compared with earlier stages of CKD. In the United States, ESRD is tracked by the U.S. Renal Disease Survey (USRDS) and detailed reports are published annually. In the year 2003, 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. However, in the last several years, this rate of increase has leveled off. 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 the general population and of the sustained increase in diabetes, it is estimated that, by 2015, the incidence for ESRD will have increased to more than 130,000 cases per year.
Trends and Determinants of 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 the effects of competing causes of death, 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. The mortality rates for patients with advanced CKD prior to initiation of renal replacement therapy are very high. This has a dramatic potential influence on the numbers of patients with progressive kidney disease who survive long enough to require dialysis. Improved survival from myocardial infarction and stroke explains less than 5% of the increase in incidence of ESRD from 1978 to 1991, compared with 28% due to the higher prevalence of diabetes and 8% from U.S. population growth.
Variation in 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
Epidemiology of Kidney Disease
(259 pmp); rates for Native Americans (504 pmp) are midway 193 between those of whites and blacks; and the rate in Asians (346 pmp) is closer to that of whites. One examination of the excess risk of ESRD in blacks compared with whites suggests differences in socioeconomic factors explained 12%, lifestyle CH 9 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. Substantial geographic variability exists in the adjusted ESRD incidence rate in the United States, 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.
Prevalence 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 of 1496 pmp. 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 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 rate 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) the rate has nearly doubled.
Global Comparisons The occurrence of ESRD varies widely between different countries and, on many occasions, within different regions of the same country. 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
194 these limitations, the increase in ESRD in Europe has mirrored
Epidemiology of Renal Disease
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 III last several years. 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 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. The unadjusted incidence rate in Australia and New Zealand is considerably lower than the aforementioned rates at 92 and 107 pmp, respectively. In Australia, the annual incidence rates increased by twofold. This is largely reflected in the increase in those aged over 65, with rates in those younger than 65 being relatively stable. As in the United States, racial minorities in people of native descent, such as the Australian Aborigines or the New Zealand Maori, bear a disproportionate degree of the overall burden of ESRD.
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 cyclerbased therapy, 3.2% with manual, noncycler therapy), and 28.5% with transplantation.
Dialysis Survival Rates Improved survival rates have contributed to the increased number of prevalent patients on dialysis. 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, with the resulting potential for “lead time bias” in the comparisons of survival rates from earlier time periods. The overwhelming primary cause of death in patients treated with dialysis is due to premature and often accelerated cardiovascular disease. In recognition of this, a recent position statement from the American Heart Association recommended
Epidemiology of Kidney Disease
that patients with ESRD be considered to be at “highest risk” 195 with regard to future cardiovascular events. Moreover, overwhelming evidence now indicates that the entire spectrum of CKD is associated with increased rates of cardiovascular disease (see Chapter 27). The mortality rate seen with CKD CH 9 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. 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 239.3/1000 patient-years, respectively, with adjusted rates of 210.9 and 211.1/1000 patient-years; 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 significant persistent confounding factors, owing to the substantial differences in clinical characteristics between the two modalities at initiation of dialysis, both in terms of comorbidity and in the level of residual renal function. More recent USRDS data suggest that the age-, race-, and gender-adjusted 5-year mortality rate difference between hemodialysis and peritoneal dialysis has decreased over time. This improvement has been more marked in peritoneal dialysis, in which the crude mortality rate has reduced by 12% since 1985, compared with an 8% reduction over the same time period for hemodialysis.
TRANSPLANTATION While the number of renal transplants has slowly increased over time, this increase has been overshadowed by the far greater increase in the number of patients starting dialysis. Thus, in 2003, the number of patients transplanted was one seventh the number of patients who commenced renal replacement therapy and two thirds the number of patients who were added to the transplant waiting list. Median wait-list time has progressively
196 increased over the last decade, with little variation by gender
Epidemiology of Renal Disease
but substantially shorter wait-list times in whites than in other racial groups. Much of the increase in the absolute number of transplants performed in the United States over the last decade III is a result of an increase in living donation rates, now representing over 50% of transplant donations. Transplant rates are highest in patients younger than 18 years and decrease with advancing age. Rates have remained relatively constant in subjects younger 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 many times more likely to receive a transplant than African Americans. 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. Cadaveric donation rates increased by less than 10% from 1994 to 2003 and have more recently decreased. 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 years), 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, where they have been judged to be individually inadequate, into a single recipient and by 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.
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
Epidemiology of Kidney Disease
survival rates for a deceased donor transplant are 88% and 197 95%, respectively; the comparable figures for a living donor are 94% and 98%. The cumulative rejection rates in the first 6 months are now less than 20%. Unfortunately, the long-term graft outcome has failed to improve to a comparable degree. CH 9 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 patientyears, 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 a functioning graft. 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. The risk of death due to cardiovascular disease 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. Infection accounts for 26.3% of deaths in the remaining patients and malignancy for 10.7%. Unfortunately, in approximately 30% of transplant patients, the cause of death is unknown.