TY - JOUR
AU - Chang,, Anthony
AB - Abstract Objectives To determine how often end-stage kidney disease (ESKD) is implicated as a cause of death (COD) at autopsy. Methods We searched our autopsy database (2007-2017) using queries “end-stage renal disease,” “end-stage kidney disease,” “ESRD,” “chronic renal disease,” and “chronic kidney disease.” Final diagnosis and summaries were reviewed to determine if ESKD was appropriately correlated with the COD. Cases in which the COD was unrelated to kidney function were excluded. Results Eighty-five patients with a history of ESKD and histologic confirmation thereof were identified. Their CODs were cardiovascular (36%), infection/sepsis (41%), pulmonary (6%), gastrointestinal/hepatic (2%), central nervous system (3%), other systemic disease (7%), and unspecified (5%). ESKD was implicated as a contributing COD in 24 (28%) cases. Conclusions ESKD is often overlooked at autopsy, particularly in patients with cardiovascular or infectious disease. Accurate documentation of ESKD contributing to mortality is important for education, counseling, record maintenance, and directing research efforts. Before the advent of dialysis as a therapeutic option, end-stage kidney disease (ESKD) was universally fatal. This harsh consequence continues to fade into the past and has been replaced by a false sense of security and a general underappreciation regarding the importance of renal function among both physicians and the general public. Patients with ESKD requiring dialysis currently have a 1-year mortality rate of 20% to 25% with a 5-year survival rate of 35%.1 Furthermore, the Centers for Disease Control and Prevention lists “nephritis, nephrotic syndrome, and nephrosis” as the ninth leading cause of death in the United States in 2016,2,3 which likely does not include deaths from ESKD due to diabetes (the seventh leading cause of death).2 According to Matshes and Dolinak,4 cause of death is defined as “the injury, disease, or combination of the two that initiates a train of physiological disturbances that, no matter how brief or prolonged, resulted in the fatal termination of the individual’s life” and is further subcategorized into a proximate cause and an immediate cause of death. The proximate cause of death is “the original natural disease process, injury, or event that led to a string or unbroken train of events over an unlimited time that eventually led to the individual’s death,” while the immediate cause is defined as “the disease or injury present at the time of death that caused the person’s death.” 4 This differs from mechanism of death, which is, by definition, “the physiologic or biochemical process by which death came about.” 4 At autopsy, there is a natural tendency to focus on the identification of the immediate cause of death and/or mechanism of death but not necessarily the proximate cause. We conducted this study to determine the spectrum of causes of death in the setting of ESKD at a single academic medical center and the frequency that ESKD is implicated as a proximate cause of death at autopsy. Materials and Methods We searched the electronic autopsy database (2007-2017) at the University of Chicago Medical Center using queries that included the following terms: end-stage renal disease (ESRD), end-stage kidney disease, ESRD, chronic renal disease, and chronic kidney disease (CKD). Gross and microscopic descriptions were reviewed to assess the severity of the kidney disease. The final diagnosis and autopsy summaries were reviewed with particular attention to whether a history of kidney disease was mentioned in the autopsy summary and if the kidney disease was explicitly identified as contributing to the patient’s ultimate demise. Cases in which the cause of death was clearly unrelated to kidney function (eg, metastatic cancer) or in which the kidneys were not examined at the time of autopsy (ie, restricted autopsies limited to only heart, brain, etc) were excluded. Results Eighty-five patients with a clinical history of ESKD receiving dialysis and gross and microscopic confirmation at autopsy were identified Table 1. Premortem renal diagnoses were identified Table 2; 37 (46%) cases had multiple renal comorbidities. Gross findings included decreased weight of the kidneys, capsules that stripped with difficulty, granular surface, and effacement of corticomedullary junctions. Microscopically, all reviewed cases had advanced glomerular and tubulointerstitial scarring characteristic of end-stage kidneys. Thirty-two (40%) cases demonstrated advanced diabetic nephropathy. The causes of death were reported as cardiovascular disease (36%), infectious disease/sepsis (41%), pulmonary disease (acute respiratory distress syndrome, pulmonary embolism, interstitial lung disease, and pulmonary hemorrhage; 6%), gastrointestinal/hepatic disease (nonalcoholic steatohepatitis cirrhosis and bleeding ulcer; 2%), central nervous system disease (brain hemorrhage; 3%), and other systemic disease (systemic lupus erythematosus, multiple myeloma, and amyloidosis; 7%). The immediate cause of death was undetermined or unspecified in four (5%) cases. Of total cases, ESKD was neglected entirely in the autopsy summary in three. ESKD was identified as a proximate cause of death in only 24 (28%) cases Figure 1. Of these 24 cases, the most common immediate causes of death were infection/sepsis (40%) and cardiovascular disease (37%). Table 1 Demographics of Study Patients (n = 85) Patient Demographic . No. . Sex  Male 31  Female 54 Age, y  <25 3  26-50 16  51-75 54  >76 12 Race/ethnicity  Black/African American 66  White 6  Unknown/unspecified 13 Duration of dialysis  1 month to 1 year 19  2-5 years 19  6-10 years 7  >11 years 5  Unknown 35 Patient Demographic . No. . Sex  Male 31  Female 54 Age, y  <25 3  26-50 16  51-75 54  >76 12 Race/ethnicity  Black/African American 66  White 6  Unknown/unspecified 13 Duration of dialysis  1 month to 1 year 19  2-5 years 19  6-10 years 7  >11 years 5  Unknown 35 Open in new tab Table 1 Demographics of Study Patients (n = 85) Patient Demographic . No. . Sex  Male 31  Female 54 Age, y  <25 3  26-50 16  51-75 54  >76 12 Race/ethnicity  Black/African American 66  White 6  Unknown/unspecified 13 Duration of dialysis  1 month to 1 year 19  2-5 years 19  6-10 years 7  >11 years 5  Unknown 35 Patient Demographic . No. . Sex  Male 31  Female 54 Age, y  <25 3  26-50 16  51-75 54  >76 12 Race/ethnicity  Black/African American 66  White 6  Unknown/unspecified 13 Duration of dialysis  1 month to 1 year 19  2-5 years 19  6-10 years 7  >11 years 5  Unknown 35 Open in new tab Table 2 Premortem Renal Diagnoses of Cases Undergoing Microscopic Review (n = 80) Premortem Renal Diagnoses . No. . Diabetes mellitus 45 Hypertension 57 Systemic lupus erythematosus 2 Sickle cell disease 2 Autosomal dominant polycystic kidney disease 3 Drug toxicity (ibuprofen, calcineurin inhibitor) 4 Paraproteinemia (amyloid, multiple myeloma) 3 Focal segmental glomerulosclerosis 2 Hydronephrosis 1 Cases with multiple comorbidities 37 Premortem Renal Diagnoses . No. . Diabetes mellitus 45 Hypertension 57 Systemic lupus erythematosus 2 Sickle cell disease 2 Autosomal dominant polycystic kidney disease 3 Drug toxicity (ibuprofen, calcineurin inhibitor) 4 Paraproteinemia (amyloid, multiple myeloma) 3 Focal segmental glomerulosclerosis 2 Hydronephrosis 1 Cases with multiple comorbidities 37 Open in new tab Table 2 Premortem Renal Diagnoses of Cases Undergoing Microscopic Review (n = 80) Premortem Renal Diagnoses . No. . Diabetes mellitus 45 Hypertension 57 Systemic lupus erythematosus 2 Sickle cell disease 2 Autosomal dominant polycystic kidney disease 3 Drug toxicity (ibuprofen, calcineurin inhibitor) 4 Paraproteinemia (amyloid, multiple myeloma) 3 Focal segmental glomerulosclerosis 2 Hydronephrosis 1 Cases with multiple comorbidities 37 Premortem Renal Diagnoses . No. . Diabetes mellitus 45 Hypertension 57 Systemic lupus erythematosus 2 Sickle cell disease 2 Autosomal dominant polycystic kidney disease 3 Drug toxicity (ibuprofen, calcineurin inhibitor) 4 Paraproteinemia (amyloid, multiple myeloma) 3 Focal segmental glomerulosclerosis 2 Hydronephrosis 1 Cases with multiple comorbidities 37 Open in new tab Figure 1 Open in new tabDownload slide Correlation of end-stage kidney disease (ESKD) with cause of death in autopsy summary. Of 86 total cases, ESKD was appropriately correlated in 24 (28%). Figure 1 Open in new tabDownload slide Correlation of end-stage kidney disease (ESKD) with cause of death in autopsy summary. Of 86 total cases, ESKD was appropriately correlated in 24 (28%). Discussion The complete absence of renal function is incompatible with life, yet the clinical history and detrimental impact of ESKD are often overlooked postmortem at our institution. This oversight is not limited to autopsies and also occurs for both death certificates and other data registries.5 As early as the turn of the 20th century, uremia was recognized as a poorly documented cause of death; in 1912, Cabot6 emphasized the importance of careful clinicopathologic correlation at autopsy in patients with kidney disease. Before the widespread availability of therapies for ESKD, only 67% of death certificates listed renal disease as a cause of death in uremic patients.5 A review of death certificates and US Renal Data System registry reports by Perneger et al5 revealed a striking discrepancy: the most frequent cause of death reported on death certificates was renal disease, whereas cardiovascular disease was the most frequent cause of death in registry reports, with renal disease reported as an underlying cause of death in only 8% of cases. This is troubling, as the burden of CKD in the United States is 13% to 16% among adults, with over 450,000 patients receiving hemodialysis each year.7 The prevalence of CKD in Americans older than 30 years is predicted to increase from 13.2% (1999-2010) to 16.7% by 2030,8 at which point an estimated 2 million patients may require dialysis.7 Furthermore, the global burden of CKD has increased in prevalence by 19.6% from 2003 to 2013.9 There is a lack of awareness of CKD and its ramifications in both high- and low-risk populations, even among health care workers, resulting in delays in diagnosis and appropriate management.9 Accurate quantification of the impact of kidney disease, particularly ESKD, requires proper determination of the cause of death so that the correct prioritization of medical research and public health efforts can be made regarding early detection of CKD and reducing long-term costs associated with caring for patients with renal disease.1 Since the advent of dialysis, the lives of millions of people have been extended. However, dialysis is not the perfect replacement for one’s kidneys, and cardiovascular disease and infectious diseases are the most common immediate causes of death in patients with ESKD.3,5,10 ESKD in and of itself is a predictor of cardiovascular death and for a large spectrum of cardiovascular diseases,11-13 and this link between increased risk of cardiovascular deaths exists at even lesser degrees of CKD.1 Most cardiovascular deaths in patients receiving dialysis are presumed to be due to dysrhythmias, potentially secondary to dynamic changes in electrolytes (eg, K+, Ca2+, PO4, HCO3–), blood pH, volume status, and blood pressure associated with renal dysfunction and dialysis itself.7 In particular, hyperkalemia is common among patients with ESKD in the hours prior to receiving dialysis, and the dialysis itself can cause rapid K+ removal and resultant hypokalemia and arrhythmias.14 In the setting of uremia and ESKD, there is also substantial dysfunction of endothelial and immune cells and platelets, which all may contribute to the demise of a patient with ESKD.1,15,16 However, the precise mechanisms are not well understood, and no objective pathologic findings can connect the proximate cause (CKD or ESKD) to the immediate causes of death. This current knowledge gap remains a major impediment. The autopsy summation often focuses on the immediate cause or mechanism of death, which is analogous to watching the last domino fall without seeing the first domino. An immediate cause of death can be difficult to identify in patients with numerous complex medical conditions, but the proximate cause of death (analogous to the first domino) in the setting of ESKD is incontrovertible. Among pathologists, formal education and exposure to renal pathology during residency training are limited. In 2007, in a survey of US pathology residency programs, we found that only 36% required any renal pathology education, so most pathology trainees can graduate without any guidance regarding the evaluation of the nonneoplastic kidney.17 Our 2018 autopsy study discovered that 60% of renal pathology diagnoses, including from diabetic nephropathy, amyloidosis, light chain cast nephropathy, and thrombotic microangiopathy, were overlooked.3 In summary, we found that ESKD is often neglected as a proximate cause of death at autopsy. Accurate assessment and documentation of ESKD contributing to mortality are important for educating physicians, counseling surviving kin, maintaining accurate records, and prioritizing future research and policy decisions toward ESKD. Establishing a standardized or consensus approach to the autopsy summation might also be a worthwhile endeavor in the future. References 1. Go AS , Chertow GM, Fan Det al. Chronic kidney disease and the risks of death, cardiovascular events, and hospitalization . N Engl J Med . 2004 ;351: 1296-1305 . OpenURL Placeholder Text WorldCat 2. Heron M . Deaths: leading causes for 2016. Natl Vital Stat Rep. 2018;67(6). 3. Perrone ME , Chang A, Henriksen KJ. Medical renal diseases are frequent but often unrecognized in adult autopsies . Mod Pathol. 2018 ; 31 : 365 - 373 . Google Scholar Crossref Search ADS PubMed WorldCat 4. Matshes EW , Dolinak D. Forensic Pathology: Principles and Practice . Oxford, UK : Academic Press; 2005 . Google Scholar Google Preview OpenURL Placeholder Text WorldCat COPAC 5. Perneger TV , Klag MJ, Whelton PK. Cause of death in patients with end-stage renal disease: death certificates vs registry reports . Am J Public Health . 1993 ; 83 : 1735 - 1738 . Google Scholar Crossref Search ADS PubMed WorldCat 6. Cabot RC. Diagnostic pitfalls identified during a study of three thousand autopsies . JAMA. LIX . 1912 ;59: 2295 . OpenURL Placeholder Text WorldCat 7. Sakhuja R , Shah AJ, Hiremath S, et al. End-stage renal disease and sudden cardiac death . Card Electrophysiol Clin . 2009 ; 1 : 61 - 77 . Google Scholar Crossref Search ADS PubMed WorldCat 8. Centers for Disease Control and Prevention . Chronic Kidney Disease Surveillance System—United States . http://www.cdc.gov/ckd Accessed July 3, 2019. 9. Sharma S , Sarnak MJ. Epidemiology: the global burden of reduced GFR: ESRD, CVD and mortality . Nat Rev Nephrol . 2017 ; 13 : 447 - 448 . Google Scholar Crossref Search ADS PubMed WorldCat 10. Padmanabhan A , Gohil S, Gadgil NM, et al. Chronic renal failure: an autopsy study . Saudi J Kidney Dis Transpl . 2017 ; 28 : 545-551 . Google Scholar Crossref Search ADS PubMed WorldCat 11. Roberts WC , Taylor MA, Shirani J. Cardiac findings at necropsy in patients with chronic kidney disease maintained on chronic hemodialysis . Medicine . 2012 ; 91 : 165 - 178 . Google Scholar Crossref Search ADS PubMed WorldCat 12. Santoro A , Mandreoli M. Chronic renal disease and risk of cardiovascular morbidity-mortality . Kidney Blood Press Res . 2014 ; 39 : 142 - 146 . Google Scholar Crossref Search ADS PubMed WorldCat 13. Chua HR , Lau T, Luo N, et al. Predicting first-year mortality in incident dialysis patients with end-stage renal disease—the UREA5 study . Blood Purif . 2014 ; 37 : 85 - 92 . Google Scholar Crossref Search ADS PubMed WorldCat 14. Pun PH , Herzog CA, Middleton JP. Improving ascertainment of sudden cardiac death in patients with end stage renal disease . Clin J Am Soc Nephrol . 2012 ; 7 : 116 - 122 . Google Scholar Crossref Search ADS PubMed WorldCat 15. Betjes MG . Immune cell dysfunction and inflammation in end-stage renal disease . Nat Rev Nephrol. 2013 ; 9 : 255 - 265 . Google Scholar Crossref Search ADS PubMed WorldCat 16. Kennedy C , Wong L, Sexton DJ, et al. Successful kidney transplantation normalizes platelet function . Clin Kidney J . 2018 ; 11 : 574 - 580 . Google Scholar Crossref Search ADS PubMed WorldCat 17. Henriksen KJ , Meehan SM, Chang A. Non-neoplastic renal diseases are often unrecognized in adult tumor nephrectomy specimens: a review of 246 cases . Am J Surg Pathol. 2007 ; 31 : 1703 - 1708 . Google Scholar Crossref Search ADS PubMed WorldCat © American Society for Clinical Pathology, 2020. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model)
TI - End-Stage Kidney Disease Is Overlooked as a Proximate Cause of Death at Autopsy
JF - American Journal of Clinical Pathology
DO - 10.1093/ajcp/aqz211
DA - 2020-05-05
UR - https://www.deepdyve.com/lp/oxford-university-press/end-stage-kidney-disease-is-overlooked-as-a-proximate-cause-of-death-Ex7Bbf0ZN2
SP - 772
VL - 153
IS - 6
DP - DeepDyve
ER -