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American Journal of Kidney Diseases

Death, Taxes, and Now CKD

      Related Article, p. 245
      Benjamin Franklin is credited with saying that the only certain things in life were death and taxes. However, if you live long enough, you are almost certain to have chronic kidney disease (CKD) as well. Most nephrologists are familiar with the prevalence of end-stage renal disease (ESRD) being about 1-2 events per 1,000 population. Many nephrologists and even some savvy clinical epidemiologists would be surprised to know that 3%-4% of the general population will reach ESRD before death and that 8% of blacks in the United States will be treated for ESRD before death. Even these cumulative risks are undervalued because they do not fully capture competing risks; some individuals die with acute kidney disease requiring dialysis, opt for conservative management, or die of complications associated with CKD.
      In this month's AJKD, Grams et al
      • Grams M.E.
      • Chow E.K.H.
      • Segev D.L.
      • Coresh J.
      Lifetime incidence of CKD stages 3-5 in the United States.
      provide updated estimates for the cumulative risk of ESRD and also assess the cumulative incidence of a low estimated glomerular filtration rate (eGFR; <60 mL/min/1.73 m2) in the US population. Here the authors estimate the cumulative incidence of the latter (stage 3+ CKD) to be nearly 60%.
      • Grams M.E.
      • Chow E.K.H.
      • Segev D.L.
      • Coresh J.
      Lifetime incidence of CKD stages 3-5 in the United States.
      Even this estimate is low because CKD also can be defined by the presence of proteinuria, which was not examined in the study. In addition, the authors also show in an accompanying article that there are ongoing secular trends for CKD to continue to increase.
      • Grams M.E.
      • Jurasheck S.P.
      • Selvin E.
      • et al.
      Trends in the prevalence of reduced GFR in the United States: a comparison of creatinine- and cystatin C–based estimates.
      The authors used a Markov model and assumed that patients transition to progressively higher (more severe) stages of CKD. They used multiple sources, including mortality data from the National Vital Statistics Report, incident ESRD and ESRD mortality from the US Renal Disease System (USRDS), estimates of the excess mortality associated with low eGFR categories, and age-, sex-, and race-stratified prevalence data for CKD stage from the National Health and Nutrition Examination Survey (NHANES) to calculate transition probabilities and subsequent cumulative incidence. This is no easy feat. Although the big take-home message is overall cumulative risk, the more interesting data are contained in the transition probabilities, and this is worthy of some discussion.
      As noted by the authors, the individualized long-term risk of disease estimates and the mortality associated with diseases are used to inform practice. For instance, similar models have been useful to advise population screening for breast and colorectal cancer.
      • Mandelblatt J.S.
      • Cronin K.A.
      • Bailey S.
      • et al.
      Effects of mammography screening under different screening schedules: model estimates of potential benefits and harms.
      • Zauber A.G.
      • Landsdorp-Vogelaar I.
      • Knudsen A.B.
      • Wilschut J.
      • van Ballegooijen M.
      • Kuntz K.M.
      Age to Begin, Age to End, and Timing of Screening Intervals: Decision Analysis of Colorectal Cancer Screening for the United States Preventive Services Task Force From the Cancer Intervention and Surveillance Modeling Network (CISNET).
      Because these studies showed that the benefit of screening older patients is greatly diminished, recommendations were put in place for an age at which to cease screening. CKD models have been used to examine the cost-effectiveness of screening for proteinuria or low eGFR in various populations.
      • Manns B.
      • Hemmelgarn B.
      • Tonelli M.
      • et al.
      Population based screening for chronic kidney disease: cost effectiveness study.
      • Boulware L.E.
      • Jaar B.G.
      • Tarver-Carr M.E.
      • Brancati F.L.
      • Powe N.R.
      Screening for proteinuria in US adults: a cost-effectiveness analysis.
      Although these types of modeling studies cannot replace randomized trials, randomized trials are not always feasible. Knowledge of transition rates can inform when, in whom, and how frequently to screen. Given that CKD is best avoided, primary prevention by encouraging healthy lifestyles (weight control, exercise, and smoking cessation) and the detection and treatment of hypertension should already be in place.
      The authors point out differences and similarities for transition rates by race and sex. These differences in transition rates might help us understand mechanisms, as well as direct future screening strategies. Stage 3+ CKD is uncommon prior to age 40 years in all groups, whereas the cumulative incidence in all groups increases dramatically from ages 60-80 years with relatively small differences between groups. Accordingly, screening the general population before age 40 would have a low yield. Women of both races show higher and a nearly identical cumulative incidence of stage 3+ compared with men of both races. Paradoxically, black men consistently have the highest transition rates at all ages, which suggests that their lower cumulative incidence can only be due to their shorter life expectancy. Correspondingly, the higher cumulative incidence of stage 3+ CKD in women in large part may be from longer life expectancy.
      Black men and women develop stage 4+ CKD at nearly identical ages with similar cumulative incidences. White men and women also develop stage 4+ CKD at nearly identical ages and with nearly identical cumulative incidences; however, they do so 10-15 years later than blacks and with less cumulative incidence compared with blacks. The analysis estimates the transition rates to stage 4+ CKD to be 4-5 times faster in blacks than whites at most ages. These rate differences could be due to differences in diabetes mellitus rates, access to health care, healthy behaviors, and genetics. Given the more rapid rise and the consequences of transitioning to higher CKD stages, blacks ideally would need to be screened more frequently after age 40 years than whites. Although the utility of screening for CKD in the general population is inconclusive at the present time, screening in blacks should be reconsidered.
      • Moyer V.A.
      US Preventive Services Task Force
      Screening for chronic kidney disease: US Preventive Services Task Force recommendation statement.
      For the final transition from stage 4 CKD to ESRD, the rates are higher for men compared with women. Although this difference appears to be influenced by sex, most transitions to ESRD occur at a time when women are postmenopausal (aged >50 years). A closer examination of the cumulative incidence of stage 4+ CKD and ESRD bears comment. There is almost no difference in the cumulative incidence (slope and magnitude) for stage 4+ CKD and ESRD from ages 40 to 60 years. One explanation is that the time individuals remain in the stage 4 CKD health state is extremely short due to greater mortality and possible rapid transition to ESRD. However, part of the problem is that the ability to detect low disease prevalence accurately is limited by the relatively small numbers sampled in NHANES. After age 60 years, the rate of increase in the cumulative incidence of ESRD for all groups is much less than the sustained growth in stage 4+ CKD, especially for women. These findings are consistent with 2 recent publications that suggest many elderly individuals with stage 5 CKD are either not treated for kidney failure or simply have very high competing risks of death.
      • Hemmelgarn B.R.
      • James M.T.
      • Manns B.J.
      • et al.
      Rates of treated and untreated kidney failure in older vs younger adults.
      • Sparke C.
      • Moon L.
      • Green F.
      • et al.
      Estimating the total incidence of kidney failure in Australia including individuals who are not treated by dialysis or transplantation.
      Better understanding of these observations is worthy of further study.
      What is most interesting is what this study missed. For black men and women, there is a small but detectable prevalence of stage 3+ CKD in the 30- to 40-year age range (see Figs 3, S1, and S2 from Grams et al
      • Grams M.E.
      • Chow E.K.H.
      • Segev D.L.
      • Coresh J.
      Lifetime incidence of CKD stages 3-5 in the United States.
      ). The model ignored this small blip in prevalence. Figure 2 (from Grams et al
      • Grams M.E.
      • Chow E.K.H.
      • Segev D.L.
      • Coresh J.
      Lifetime incidence of CKD stages 3-5 in the United States.
      ) shows that the cumulative risk of ESRD (by the USRDS) is greater than the cumulative risk of stage 3 CKD in black men and women at age 40 (by NHANES). What likely happens is that 1 of every 8 blacks who are destined to reach ESRD have an early and accelerated course prior to age 40 that would not be detected by population screening initiated after age 40 unless this CKD was primarily from diabetes mellitus. It would be very interesting to know the diagnosis and genetics of this group compared with other blacks in the general population who live to older ages with preserved kidney function and compared with those who have slower rates of progression.
      There are several limitations to this study. A separate analysis of Hispanics is warranted, but the data from NHANES are not rich enough to detect differences with non-Hispanic whites. This study did not estimate sequential stage progression (stage 3a to 3b to 4 to ESRD); rather, the authors calculated normal to 3a, normal to 3b, normal to 4, etc, and this makes the inferences discussed problematic. There are several more sophisticated CKD population studies that include proteinuria, diabetes mellitus, and hypertension.
      • Manns B.
      • Hemmelgarn B.
      • Tonelli M.
      • et al.
      Population based screening for chronic kidney disease: cost effectiveness study.
      • Boulware L.E.
      • Jaar B.G.
      • Tarver-Carr M.E.
      • Brancati F.L.
      • Powe N.R.
      Screening for proteinuria in US adults: a cost-effectiveness analysis.
      • Hoerger T.J.
      • Wittenborn J.S.
      • Segel J.E.
      • et al.
      A health policy model of CKD: 1. Model construction, assumptions, and validation of health consequences.
      • Kiberd B.A.
      Estimating the long term impact of kidney donation on life expectancy and end stage renal disease.
      Hoerger et al's
      • Hoerger T.J.
      • Wittenborn J.S.
      • Segel J.E.
      • et al.
      A health policy model of CKD: 1. Model construction, assumptions, and validation of health consequences.
      tour de force published in AJKD in 2010 is a very good reference and included an analysis of cardiovascular attributed mortality. As discussed by Grams et al,
      • Grams M.E.
      • Chow E.K.H.
      • Segev D.L.
      • Coresh J.
      Lifetime incidence of CKD stages 3-5 in the United States.
      it is not clear why the estimates for CKD were different between studies, although undoubtedly modeling differences will result in variations in the final estimates. Also, the authors also used the CKD-EPI (CKD Epidemiology Collaboration) creatinine formula rather than the MDRD (Modification of Diet in Renal Disease) Study equation; Although CKD-EPI is the more relevant formula, it results in a lower cumulative incidence for stage 3 CKD, but not for stage 4 or ESRD.
      • Levey A.S.
      • Stevens L.A.
      • Schmid C.H.
      • et al.
      CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration)
      A new equation to estimate glomerular filtration rate.
      All studies have the limitation of unstudied populations, inability to detect low disease prevalence in younger populations, the issues of acute kidney disease, and underestimating untreated chronic kidney failure. As currently estimated, cumulative risks of diabetes mellitus are lower than CKD, whereas the cumulative risk of hypertension is higher.
      • Narayan K.M.
      • Boyle J.P.
      • Thompson T.J.
      • Sorensen S.W.
      • Williamson D.F.
      Lifetime risk for diabetes mellitus in the United States.
      • Vasan R.S.
      • Beiser A.
      • Seshadri S.
      • et al.
      Residual lifetime risk for developing hypertension in middle-aged women and men: the Framingham Heart Study.
      Future studies could be used to calculate the unique population-attributed burden of CKD on reduced life expectancy. However this may be difficult to unravel given that all 3 are closely intertwined.
      Despite these limitations, the availability of Grams et al's transition rates should help future researchers, and the information provided in the study is useful to clinicians. At a patient level, I tell prospective kidney donors that all people are at risk of reaching ESRD, and I quote the risks by age, sex, and race. For example, if I am discussing kidney donation with a 25-year-old white woman, I tell her that she has about a 2% risk of ESRD regardless of whether she donates. I can now also tell her she has a 65% chance of developing a low GFR before death. Both pieces of information are important for informed decision making and may help the prospective donor understand the need to adhere to a healthy lifestyle and regular follow-up recommendations. On a population level, there has always been great interest in ESRD given its high cost in a small population. The knowledge that the cumulative incidence of CKD has surpassed diabetes mellitus should stimulate even greater interest in CKD as a population health problem.

      Acknowledgements

      Support: None.
      Financial Disclosure: The author declares that he has no relevant financial interests.

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