Kidney Failure in the Court of Chronic Diseases

Related Article, p. ∗∗∗ Related Article, p. ∗∗∗ In the title of an award-winning book published in 2010, cancer is characterized as “the emperor of all maladies,” to borrow a surgeon’s epithet from the 1800s. One could appeal to ubiquitous marketing campaigns during October, Breast Cancer Awareness Month, for proof that cancer is popularly regarded as the most fearsome of chronic diseases. However, many studies in nephrology literature suggest that survival after kidney failure is worse than survival with several common types of cancer, as well as with other chronic diseases. In both Italy and Ontario, 5-year survival after dialysis initiation is worse than after diagnosis of breast, colorectal, or prostate cancer.1Nordio M. Limido A. Maggiore U. Nichelatti M. Postorino M. Quintaliani G. Survival in patients treated by long-term dialysis compared with the general population.Am J Kidney Dis. 2012; 59: 819-828https://doi.org/10.1053/j.ajkd.2011.12.023Google Scholar,2Naylor K.L. Kim S.J. McArthur E. Garg A.X. McCallum M.K. Knoll G.A. Mortality in incident maintenance dialysis patients versus incident solid organ cancer patients: a population-based cohort.Am J Kidney Dis. 2019; 73: 765-776https://doi.org/10.1053/j.ajkd.2018.12.011Google Scholar In the United States, death rates among prevalent dialysis patients aged ≥66 years are higher than among similarly aged patients with diagnoses of cancer (all types), diabetes, heart failure, myocardial infarction, and stroke.3Johansen K.L. Chertow G.M. Foley R.N. et al.US Renal Data System 2020 annual data report: epidemiology of kidney disease in the United States.Am J Kidney Dis. 2021; 77: A7-a8https://doi.org/10.1053/j.ajkd.2021.01.002Google Scholar Is kidney failure the true emperor? In this issue of AJKD, Stedman et al4Stedman MR, Tamura MK, Chertow GM. Using relative survival to estimate the burden of kidney failure. Am J Kidney Dis. Published online September 9, 2023. doi:10.1053/j.ajkd.2023.05.015Google Scholar add a methodologically unique analysis, using data from the United States Renal Data System (USRDS). The analysis compares 5-year survival in elderly (aged ≥66 years) people with incident kidney failure in 2009 and contemporaneous elderly people with traditional Medicare coverage. The 2014 USRDS Annual Data Report indicates that among elderly (aged ≥65 years) people with incident kidney failure in 2008-2010, 1.0% of patients received a preemptive kidney transplant, while 6.1% of patients who initiated dialysis did so at home.5Saran R. Li Y. Robinson B. et al.US Renal Data System 2014 annual data report: epidemiology of kidney disease in the United States.Am J Kidney Dis. 2015; 66: S1-S305https://doi.org/10.1053/j.ajkd.2015.05.001Google Scholar Furthermore, the 2-year cumulative incidence of kidney transplant among patients who initiated dialysis in any setting was 1.1%.5Saran R. Li Y. Robinson B. et al.US Renal Data System 2014 annual data report: epidemiology of kidney disease in the United States.Am J Kidney Dis. 2015; 66: S1-S305https://doi.org/10.1053/j.ajkd.2015.05.001Google Scholar Thus, the analysis essentially compared survival in elderly people undergoing in-center hemodialysis in 2009-2014 and contemporaneous Medicare beneficiaries without kidney failure. Unsurprisingly, the relative 5-year survival of patients with kidney failure was dismal, at just 36% of what was expected, conditional upon adjustment for age, sex, race, comorbidity, and calendar year. The displayed data suggest heterogeneity in relative survival among subgroups, with lower relative survival in kidney failure patients with a higher burden of comorbidity (a phenotype with 71% prevalence), advancing age, and White race. However, this heterogeneity is arguably artifactual, reflecting the chosen definition of relative survival as the quotient of 5-year survival proportions. If relative survival were instead defined by the quotient of 5-year survival odds, only kidney failure patients with Black race would exhibit relative survival outside a narrow numerical range (Table 1). Indeed, both of these statistical definitions of relative survival are reasonable, but only 1 suggests heterogeneity in relative survival among subgroups. The analysis also estimated that relative 5-year survival of patients with kidney failure was lower than the corresponding relative survival of Medicare beneficiaries with documented diagnoses of dementia (50%), heart failure (61%), stroke (78%), pulmonary disease (79%), or peripheral vascular disease (83%).Table 1Relative Survival in Patients With Kidney Failure, Overall and Within Subgroups5-Year Survival (%)Relative SurvivalObservedExpectedRatio of ProportionsRatio of OddsOverall23%63%0.360.18Comorbidity score Low40%84%0.470.13 Medium34%78%0.430.15 High17%55%0.320.17Age 66-7036%78%0.460.16 71-7528%72%0.390.15 76-8020%61%0.330.15 81-8513%48%0.270.16 89-908%33%0.260.18 91-954%18%0.220.19Race White21%63%0.330.16 Black31%64%0.480.25 Other32%71%0.440.19Sex Male22%61%0.360.18 Female24%67%0.360.16Relative survival is estimated as the ratio of observed versus expected survival (as presented in Table 1 by Stedman et al4Stedman MR, Tamura MK, Chertow GM. Using relative survival to estimate the burden of kidney failure. Am J Kidney Dis. Published online September 9, 2023. doi:10.1053/j.ajkd.2023.05.015Google Scholar) and alternatively as the ratio of observed versus expected odds of survival. Open table in a new tab Relative survival is estimated as the ratio of observed versus expected survival (as presented in Table 1 by Stedman et al4Stedman MR, Tamura MK, Chertow GM. Using relative survival to estimate the burden of kidney failure. Am J Kidney Dis. Published online September 9, 2023. doi:10.1053/j.ajkd.2023.05.015Google Scholar) and alternatively as the ratio of observed versus expected odds of survival. The accuracy of these statistics is questionable, principally because of the nature of the underlying data. The USRDS is not a registry of United States residents with kidney failure. Instead, it is a registry of residents with registered kidney failure, owing to submission of Centers for Medicare and Medicaid Services form 2728 (“End Stage Renal Disease Medical Evidence Report”). Almost a decade ago, Foley et al6Foley R.N. Chen S.C. Solid C.A. Gilbertson D.T. Collins A.J. Early mortality in patients starting dialysis appears to go unregistered.Kidney Int. 2014; 86: 392-398https://doi.org/10.1038/ki.2014.15Google Scholar argued that a nonmonotonic pattern of weekly death rates during the first 20 weeks after dialysis initiation, as recorded in the USRDS database, was circumstantial evidence that early mortality after dialysis initiation appears to go “unregistered.” If a patient initiates dialysis in the hospital (for the treatment of kidney failure, not acute kidney injury) and dies there, it is highly unlikely that form 2728 is submitted. From this perspective, aggregate survival after all-setting dialysis initiation may be much worse than what Stedman et al reported. A recent analysis of insurance claims data from Germany offers a tantalizing clue. The German modification of the International Classification of Diseases, Tenth Revision (ICD-10) taxonomy includes diagnosis code N18.5 (“chronic kidney disease, stage 5”), but not N18.6 (“end stage renal disease”), which is widely used in the United States. Among elderly patients whose 2016-2017 claims history included diagnosis code N18.5 and initiation of hemodialysis, hemodiafiltration, or peritoneal dialysis, 1-year survival was 60.6%.7Kolbrink B. Schüssel K. von Samson-Himmelstjerna F.A. et al.Patient-focused outcomes after initiation of dialysis for ESRD: mortality, hospitalization, and functional impairment.Nephrol Dial Transplant. 2023; https://doi.org/10.1093/ndt/gfad099Google Scholar Corresponding statistics from the USRDS indicate 1-year survival ranging from 81.7% in contemporary patients aged 65-69 years to 59.8% in those aged ≥85 years.8Johansen K.L. Chertow G.M. Gilbertson D.T. et al.US Renal Data System 2022 annual data report: epidemiology of kidney disease in the United States.Am J Kidney Dis. 2023; 81: A8-a11https://doi.org/10.1053/j.ajkd.2022.12.001Google Scholar Thus, the relative survival reported by Stedman et al may be positively biased (ie, overly optimistic). Regarding the comparisons of relative survival with kidney failure versus other chronic diseases, additional caution is warranted. Other chronic diseases were defined by diagnosis codes in claims, not a national registry built with a standard intake form, itself a physician attestation of irreversible disease. Imperfect sensitivity and specificity of diagnosis codes may bias estimates of relative survival associated with diseases other than kidney failure; the direction of such bias is speculative. Furthermore, disease severity was ignored, despite that kidney failure is the most severe form of chronic kidney disease (CKD). Bias aside, the analysis reflects survival in a dated cohort of patients with incident kidney failure. From 2009 to 2019, the adjusted rate of all-cause mortality in patients undergoing hemodialysis in the United States fell from 193 to 159 deaths per 1,000 person-years, a decline exceeding 17%.9Johansen K.L. Chertow G.M. Gilbertson D.T. et al.US Renal Data System 2021 annual data report: epidemiology of kidney disease in the United States.Am J Kidney Dis. 2022; 79: A8-a12https://doi.org/10.1053/j.ajkd.2022.02.001Google Scholar Although the COVID-19 pandemic increased the rate of all-cause mortality,10Salerno S. Messana J.M. Gremel G.W. et al.COVID-19 risk factors and mortality outcomes among medicare patients receiving long-term dialysis.JAMA Netw Open. 2021; 4e2135379https://doi.org/10.1001/jamanetworkopen.2021.35379Google Scholar a recent calculation by a global dialysis provider suggested that the rate has nearly returned to its pre-pandemic level.11Fresenius Medical Care successfully executes strategic plan and narrows guidance range due to strong operational performance in the first half of 2023 [press release].https://www.prnewswire.com/news-releases/fresenius-medical-care-successfully-executes-strategic-plan-and-narrows-guidance-range-due-to-strong-operational-performance-in-the-first-half-of-2023-301891627.htmlDate accessed: November 7, 2023Google Scholar These limitations create sufficient uncertainty to preclude a strong claim to the crown worn by the disease with poorest survival. Still, the analysis by Stedman et al and predecessor studies consistently support an imperial rank for kidney failure in the court of chronic diseases. How can this rank be positioned in modern democracy, where policy is a function of advocacy? First, if kidney failure has very poor relative survival, then detection of CKD and prevention of disease progression should be prioritized, so that kidney failure might occur less often. This view supports targeted CKD screening12Komenda P. Ferguson T.W. Macdonald K. et al.Cost-effectiveness of primary screening for CKD: a systematic review.Am J Kidney Dis. 2014; 63: 789-797https://doi.org/10.1053/j.ajkd.2013.12.012Google Scholar and wider access to medical therapies that prevent CKD progression,13Rossing P. Caramori M.L. Chan J.C.N. et al.Executive summary of the KDIGO 2022 Clinical Practice Guideline for Diabetes Management in Chronic Kidney Disease: an update based on rapidly emerging new evidence.Kidney Int. 2022; 102: 990-999https://doi.org/10.1016/j.kint.2022.06.013Google Scholar such as sodium/glucose cotransporter-2 inhibitors and mineralocorticoid receptor antagonists. Second, if the incidence of kidney failure cannot be reduced to nil, then treatment of kidney failure ought to be improved, so that relative survival after kidney failure might increase. Options abound. One tactic is to invest in technological improvements to dialytic therapy, with the goals of increasing clearance (eg, hemodiafiltration14Blankestijn P.J. Vernooij R.W.M. Hockham C. et al.Effect of hemodiafiltration or hemodialysis on mortality in kidney failure.N Engl J Med. 2023; 389: 700-709https://doi.org/10.1056/NEJMoa2304820Google Scholar), reducing infection risk (eg, catheter lock solution), and easing access to in-home therapy. Another tactic is to increase the incidence of human kidney transplantation. Yet another tactic is to invest public dollars in “moonshots,” such as a bioartificial kidney or xenotransplantation. These tactics may be commonsensical to nephrology experts, but to elected and appointed officials who are asked to allocate resources to diseases throughout the human body, these tactics may appear to lack sufficient justification unless need is perceived as both high and urgent. Some officials may instinctively respond to the financial outlay for CKD, but for others, poor relative survival after kidney failure may provide clearer justification for action. Future research should assess whether relative survival after kidney failure has changed during past decades, whether owing to decreasing mortality on in-center hemodialysis, increasing utilization of home dialysis, or increasing incidence of deceased-donor kidney transplantation.8Johansen K.L. Chertow G.M. Gilbertson D.T. et al.US Renal Data System 2022 annual data report: epidemiology of kidney disease in the United States.Am J Kidney Dis. 2023; 81: A8-a11https://doi.org/10.1053/j.ajkd.2022.12.001Google Scholar It is also unclear whether relative survival varies among countries. For instance, the rate of death among dialysis patients in Japan is low, but so is the rate in the general population.15Kimata N. Tsuchiya K. Akiba T. Nitta K. Differences in the characteristics of dialysis patients in Japan compared with those in other countries.Blood Purif. 2015; 40: 275-279https://doi.org/10.1159/000441573Google Scholar For now, the analysis by Stedman et al is a useful tool for encouraging investments aimed at banishing kidney failure from the inner court of chronic diseases. None. At the time of submission, Dr Weinhandl was an employee of Satellite Healthcare, a provider of outpatient dialysis services. Dr Weinhandl also serves on the volunteer board of directors of the Medical Education Institute. Received August 3, 2023, in response to an invitation from the journal. Direct editorial input from an Associate Editor and a Deputy Editor. Accepted in revised form August 26, 2023. Using Relative Survival to Estimate the Burden of Kidney FailureAmerican Journal of Kidney DiseasesPreviewEstimates of mortality from kidney failure are misleading because the mortality from kidney failure is inseparable from the mortality attributed to comorbid conditions. We sought to develop an alternative method to reduce the bias in estimating mortality due to kidney failure using life table methods. Full-Text PDF