Part 1: Recovery Of Kidney Function After Dialysis Initiation in Children And Adults in The US: A Retrospective Study Of United States Renal Data System Data
Mar 04, 2022
Contact: emily.li@wecistanche.com
Elaine Ku, et al
1 University of California San Francisco, Division of Nephrology, Department of Medicine, San Francisco, California, United States of America, 2 University of California San Francisco, Division of Pediatric Nephrology, Department of Pediatrics, San Francisco, California, United States of America, 3 University of California San Francisco, Department of Epidemiology and Biostatistics, San Francisco, California, United States of America, 4 Hennepin Healthcare and University of Minnesota, Department of Medicine, Division of Nephrology, Minneapolis, Minnesota, United States of America, 5 Cincinnati Children’s Hospital Medical Center, Department of Pediatrics, Division of Pediatric Nephrology and Hypertension, Cincinnati, Ohio, United States of America, 6 University of California San Francisco, Department of Anesthesia and Perioperative Care, San Francisco, California, United States of America
Keywords: Cistanche, Cistanche benefits, kidney function, kidney disease
Abstract
Background
Little is known about factors associated with recovery of kidney function—and return to dialysis independence—or temporal trends in recovery after starting outpatient dialysis in the United States. Understanding the characteristics of individuals who may have the potential to recover kidney function may promote better recognition of such events. The goal of this study was to determine factors associated with recovery of kidney function in children compared with adults starting dialysis in the US.
Methods and findings
We determined factors associated with recovery of kidney function—defined as survival and discontinuation of dialysis for 90-day period—in children versus adults who started maintenance dialysis between 1996 and 2015 according to the United States Renal Data System (USRDS) followed through 2016 in a retrospective cohort study. We also examined temporal trends in recovery rates over the last 2 decades in this cohort. Among 1,968,253 individuals included in the study, the mean age was 62.6 ± 15.8 years, and 44% were female. Overall, 4% of adults (83,302/1,953,881) and 4% of children (547/14,372) starting dialysis in the out-patient setting recovered kidney function within 1 year. Among those who recovered, the median time to recovery was 73 days (interquartile range [IQR] 43–131) in adults and 100 days (IQR 56–189) in children. Accounting for the competing risk of death, children were less likely to recover kidney function compared with adults (sub-hazard ratio [sub-HR] 0.81; 95% CI 0.74–0.89, p-value <0.001; point estimates <1 indicating increased risk for a negative outcome). Non-Hispanic black (NHB) adults were less likely to recover compared with non-Hispanic white (NHW) adults, but these racial differences were not observed in children. Of note, a steady increase in the incidence of recovery of kidney function was noted initially in adults and children between 1996 and 2010, but this trend declined thereafter. The diagnoses associated with the highest recovery rates of recovery were acute tubular necrosis (ATN) and acute interstitial nephritis (AIN) in both adults and children, where 25%– 40% of patients recovered kidney function depending on the calendar year of dialysis initiation. Limitations to our study include the potential for residual confounding to be present given the observational nature of our data.
Conclusions
In this study, we observed that discontinuation of outpatient dialysis due to recovery occurred in 4% of patients with end-stage kidney disease (ESKD) and was more common among those with ATN or AIN as the cause of their kidney disease. While recovery rates rose initially, they declined to start in 2010. Additional studies are needed to understand how to best recognize and promote recovery in patients whose potential to discontinue dialysis is high in the outpatient setting.
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Author summary
Why was this study done?
•Factors that predict a high potential for recovery of kidney function in dialysis patients are important to identify so that individuals who have the potential for recovery can be closely followed and their recovery recognized.
•The aim of this study was to determine the likelihood of recovery of kidney function following the start of maintenance dialysis in children and adults.
What did the researchers do and find?
•We found that 4% of children and adults recovered kidney function after starting dialysis, but children were not more likely to recover kidney function compared with adults.
•Recovery rates improved initially over time in both children and adults but began to decline around 2010 and varied depending on age, race, and cause of kidney disease.
What do these findings mean?
•Discontinuation of outpatient dialysis due to the recovery of kidney function was observed in approximately 4% of patients with end-stage kidney disease (ESKD) but was especially common among those with acute tubular necrosis (ATN) or acute interstitial nephritis (AIN) as the cause of their kidney disease.
•Additional studies are needed to understand how to best recognize and promote recovery in patients whose potential to discontinue dialysis is high in the outpatient setting.
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Introduction
Patients with acute kidney injury (AKI) in the setting of illnesses or hospitalization may often require dialysis initiation acutely [1–3]. A substantial proportion of these patients will survive their initial hospitalizations and be discharged to the outpatient setting with continued dialysis requirements [4–7]. However, subsets of these outpatients may have the potential to recover sufficient kidney function to eventually discontinue maintenance dialysis. Prior studies have reported that approximately 40% of patients who started dialysis after AKI and continued out-patient dialysis following hospital discharge had adequate recovery within 1 year [8]. Even in patients with progressive chronic kidney disease (CKD) who do not appear to suffer any acute insults prior to dialysis initiation, the decision to start dialysis may be based on factors that are not permanent (such as poor adherence to dietary restrictions or unreliable transportation to providers for close monitoring), so that even patients not thought to have an acute deterioration in kidney function may recover enough residual kidney function to maintain homeostasis and discontinue dialysis despite the disease that was deemed consistent with end-stage kidney disease (ESKD) [9].
Given the growing incentives to shorten the length of hospitalizations [10] and payer policy changes over the last decade surrounding AKI and ESKD care [11,12], temporal changes in renal recovery rates in the outpatient dialysis population have likely occurred [11,13]. In addition, the trend toward initiation of dialysis at progressively higher estimated glomerular filtration rate (eGFR; and potentially before dialysis is absolutely indicated) over the last 2 decades in the United States [14–17] may have led to a phenomenon in which subsets of patients who start dialysis subsequently“recover”from dialysis dependency; this phenomenon may also affect patients with dialysis-requiring AKI. The trend toward earlier dialysis initiation has been observed despite the publication of a large landmark trial in 2010 which demonstrated no survival benefit from earlier initiation of dialysis [14]. However, aside from single-center studies focused primarily on adult patients [3,18,19], the prevalence and predictors of recovery of kidney function after outpatient dialysis initiation for adults and children have not been well described on a national level.
The objective of this study was to determine the characteristics of adults (18 years or older) or children (<18 years) who recovered sufficient kidney function to discontinue dialysis for at least 90 days after starting outpatient maintenance dialysis treatment according to the UnitedStates Renal Data System (USRDS), the national ESKD registry that captures all patients undergoing maintenance dialysis in the US. We also examined temporal trends in the discontinuation of maintenance dialysis over time and compared these trends in adults and children. We chose to include both adults and children to enhance our understanding of how differences in disease etiology, practice patterns, and the competing risk of death (which is rare in children with ESKD) may be associated with the likelihood of discontinuing maintenance dialysis within 1 year of therapy initiation in outpatient facilities.
Methods
Study population and data source
We performed a retrospective study of all persons who started outpatient dialysis between January 1, 1996, and December 31, 2015, using data from the USRDS, the national ESKD registry. Demographic characteristics, the attributed cause of ESKD, insurance, zip code, date of ESKD onset, and race and ethnicity (categorized as non-Hispanic white [NHW], Hispanic, non-His- panic black [NHB], Asian, or other) at incident ESKD were abstracted from the Centers for Medicare & Medicaid Services 2728 (CMS-2728) Medical Evidence Form (MEDEVID) and PATIENTS file in the USRDS. Zip code was used to determine the median household income of patients' neighborhoods using values from the American Community Survey between 2006 and 2010 [20]. Initial ESKD treatment modality (peritoneal dialysis versus hemodialysis) was determined at the first ESKD service date according to the RXHIST (treatment history) file. We examined the temporal relation between the calendar year of dialysis initiation and recovery of kidney function using cubic splines.
Definition of recovery and discontinuation of maintenance dialysis
Patients are registered within the USRDS after provider certification of their ESKD status via submission of the CMS-2728 MEDEVID file which is required within 45 days of dialysis initiation. The RXHIST file amalgamates data from Medicare Claims, CROWNWeb (a data management system through which Medicare-certified dialysis facilities report metrics to CMS), the CMS-2728 form, the CMS Death Notification Form, and the Organ Procurement Transplant Network Transplant files to update treatment status sequentially over time [21]. We used the RXHIST files to ascertain the initial ESKD treatment modality, date of chronic dialysis initiation, and changes in treatment modality including cessation of dialysis. Any patient who had a CMS-2728 form completed was eligible for inclusion in the study.
Patients were considered to have recovered kidney function if they met all of the following:
(1) they were noted to have recovered kidney function according to the RXHIST file and did not have an episode of restarting dialysis within 90 days of the date of recovery; (2) the patient did not die within 90 days of stopping dialysis treatment (and potentially withdraw from dialysis therapy); and (3) the patient did not receive a kidney transplant within 90 days of stopping dialysis. A 90-day dialysis-free period was required for recovery to remain consistent with definitions according to the USRDS (which also requires a 90-day period of dialysis independence) [21]. Patients who received a transplant at any time were censored since even if recovery of kidney function occurred following kidney transplantation, it would be difficult to distinguish native kidney function from allograft function.
Follow-up began at the first episode of dialysis initiation according to the RXHIST file (and did not require a prespecified duration of dialysis for inclusion in our study) and ended at the date of renal recovery, death, 365 days following dialysis initiation, or administrative censoring date (December 31, 2016). We chose to focus on kidney recovery that occurred within 1 year of outpatient dialysis initiation as rates of recovery of kidney function thereafter were low. However, in sensitivity analyses, we also examined predictors of the outcome of recovery at any time during study follow-up.
Predictors of recovery of kidney function
We first examined the characteristics of patients who recovered kidney function in children compared with adults. Characteristics of interest included age (as a 6-category variable), sex, race, insurance type, the primary cause of ESKD, median neighborhood income, initial outpatient treatment modality (hemodialysis or peritoneal dialysis), calendar period (divided into 5-year intervals), region of the US (West, Northeast, South, and Midwest), and median neighborhood income.
Next, we used Fine and Gray models to examine the predictors of recovery of kidney function including candidate variables listed above in both univariable and multivariable analyses. Multivariable models included the covariates listed above and comorbid conditions including coronary artery disease, malignancy, heart failure, hypertension, diabetes, peripheral vascular disease, stroke, tobacco use, and drug use as reported on the CMS-2728 form. In these models, time was started from the first outpatient dialysis treatment session (and we did not require that patients have at least 90 days of dialysis to be included for study), death was treated as a competing event, and follow-up was censored at transplantation or administratively at 1 year after the first outpatient dialysis treatment. Of note, hazard ratios <1 in these models indicate a negative outcome (lower likelihood of recovery of kidney function) in this study. For these models, we included both adults and children in the same model so that comparisons could be made across the entire age spectrum. We also compared children (<18 years) and adults (18 years or older) as a 2-category predictor to determine the overall risk of recovery in univariable and multivariable analysis, adjusted for the same covariates as described above.
Next, we tested for differences in the associations between various characteristics and hazard of recovery in children versus adults by testing for interaction between sex, race, cause of kidney disease, initial treatment modality, insurance type, median income, calendar year of dialysis initiation, and region of the US with age at the time of dialysis initiation (<18 years versus �18 years) in unadjusted models. For factors where we found statistically significant interactions (p < 0.05), we then repeated our Fine and Gray analyses stratified by whether the patient was a child or adult at the time of dialysis initiation to understand how these factors differed among these populations in their association with recovery. We did not test for interactions between comorbidities given the low prevalence of comorbid conditions in the pediatric population.
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Subgroup analyses among diagnoses with high rates of recovery of kidney function
We identified the attributed causes of ESKD with the highest rates of recovery of kidney function for children and for adults. For each of these diagnoses, we determined the median time to recovery in children and adults separately among those who recovered kidney function and also the proportion who recovered at 30, 90, and 180 days of follow-up.
Temporal trends in the recovery of kidney function
To examine temporal trends in the recovery of kidney function, we modeled time as a cubic spline with knots in 2000, 2004, 2008, and 2012 in linear regression models where the outcome was the average proportion of patients who recovered within 1 year of starting dialysis. We performed these analyses separately for children and adults and for patients with ESKD attributed to either acute tubular necrosis (ATN) or acute interstitial nephritis (AIN) which were the 2 diagnoses with the highest recovery rates in children and adults.
Next, we repeated our linear regression models with time as a cubic spline and recovery as the outcome, but stratified our models by whether the patient started dialysis early (10 mL/ min/1.73 m2) versus late (<10 mL/min/1.73 m2) in adults and children separately. We determined the eGFR at dialysis initiation using the creatinine-based CKD-EPI equation in adults [22] and Schwartz equation [23] in children. Serum creatinine is routinely reported on the CMS-2728 form, which asks providers to certify the latest creatinine value within 45 days prior to the most recent episode of dialysis initiation. For eGFR determination, any serum creatinine reported more than 7 days after dialysis initiation was set as missing.
The University of California San Francisco Institutional Review Board considers this study not human subjects research and waived the requirement for ethical approval. Analyses were conducted in STATA 16 (Stata, Texas, US) and verified by a separate analyst using SAS 9.4 (SAS Institute, North Carolina, US) using USRDS data which authors had full access to and which is available to the public at https://www.usrds.org/for-researchers/simple-data-requests/. Due to extended run times for some analyses, we used a computationally more efficient method to perform the competing risks analyses. This consists of preprocessing the data, calculating time-dependent weights, and using standard Cox proportional hazards routines that incorporate the weights [24,25].
Our analytic plan was specified a priori during a meeting between coauthors with the goal of examining differences in recovery of kidney function within 1 year of starting dialysis in adults and children. Spline-based analyses to examine temporal trends in the recovery of kidney function were added after completion of the main analyses given the recognition that these associations may have changed over time. Originally, the analytic plan was to only examine recovery of kidney function within 1 year of dialysis initiation, but at the request of reviewers during revision, we extended follow-up for recovery to the end of the study period and added this as an additional analysis. This study is reported as per the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guidelines (S1 Checklist).
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Results
Predictors of recovery of kidney function in adults and children
We identified 1,953,881 adults who started outpatient dialysis between 1996 and 2015. Overall, the mean age of the adult cohort was 63±15.2 years, 44% were women, 28% were NHB and 13% were Hispanic. Of these patients, 83,302 (4.3%) recovered sufficient kidney function and were able to gain independence from dialysis within a 1-year period, and an additional 12,360 (0.6%) individuals recovered sufficient kidney function to stop dialysis during longer-term follow-up
through the end of the study. Among those recovering, the median time to recovery of kidney function in the adult cohort was 73 days (interquartile range [IQR] 43 to 132). Approximately 22% died (N=439,552) prior to recovery of kidney function within a 1-year period.
We identified 14,372 children who started dialysis between 1996 and 2015. Overall, the mean age of the pediatric cohort was 10.3±5.9 years, 45% were girls, 25% were NHB and 27% were Hispanic. Of these patients, 547 (3.8%) recovered sufficient kidney function and gained independence from dialysis within a 1-year period. Approximately 4% of children died (N=586) prior to recovery of kidney function within a 1-year period. The median time to recovery of kidney function in the pediatric cohort was 100 [IQR 56 to 189] days if recovery occurred.
Within 3 months of dialysis initiation, 5.8% of children (N=831) and 0.5% of adults (N=8,790) received kidney transplantation. Within 1 year of dialysis initiation, 30.3% of children (N=4,350) and 2.4% of adults (N = 47,201) received kidney transplantation. Approximately 71% (N=1,384,412) of adults and 62% of children (N=8,889) were censored administratively as they did not reach any endpoint of interest by 1 year of follow-up. The proportion of children and adults who recovered within various timeframes are shown in S1 Fig.
Characteristics of adults and children who recovered kidney function are shown in Table 1. Qualitatively, a greater proportion of the adults who recovered were younger, more likely to be NHW, male, and more likely to have started outpatient therapy with hemodialysis (versus peritoneal dialysis) than those who did not recover kidney function. Qualitatively, a greater proportion of the children who recovered were also younger, but more likely to be of NHB or other race, and female (Table 1). Although starting hemodialysis as the initial treatment modality was also associated with more recovery than starting with peritoneal dialysis in children, a higher proportion of children starting outpatient peritoneal dialysis (3.5%, N=243) recovered kidney function compared with adults (1.4%, N=2,115, Table 1).
Subgroup analyses among diagnoses with high rates of recovery of kidney function
The attributed causes of kidney disease with the highest incidence of recovery among adults were AIN (33%, N=1,381) and ATN (29%, N=14,380, Table 1). In adults with these diagnoses, the median time to recovery among those who recovered were 49 [IQR 31 to 83] and 58 [IQR 36 to 98] days, respectively.
The attributed causes of kidney disease among children with the highest incidence of recovery were ATN (18%, N=54), AIN (N<11) followed by glomerulonephritis (5%, N=278, Table 1). The median time to recovery among those who recovered with these diagnoses were 136 days [IQR 48 to 229], 32 days [IQR 17 to 46], and 93 days [IQR 51 to 176], respectively.
Predictors of recovery in adults versus children
Overall, after accounting for the competing risk of death, children were less likely to recover compared with adults (unadjusted analyses: sub-hazard ratio [sub-HR] 0.95; 95% CI 0.87 to 1.03; p=0.24; adjusted analyses: sub-HR 0.81 [95% CI 0.74 to 0.89]; p<0.001). Considering the full age spectrum, recovery was more likely to occur in the 0- to<5-year-old age groups (sub-HR 1.04; 95% CI 0.88 to 1.23, p=0.64), although this did not reach statistical significance, and less likely in the 5- to<13-year-old (sub-HR 0.63; 95% CI 0.52 to 0.76, p<0.001) and 13- to<18-year-old age groups (sub-HR 0.64; 95% CI 0.56 to 0.73, p<0.001) in adjusted analyses (Table 2). Female sex (sub-HR 0.98; 95% CI 0.96 to 0.99, p<0.001), NHB (sub-HR 0.52; 95% CI 0.51 to 0.53, p<0.001), and Hispanic groups (sub-HR 0.66;95% CI 0.64 to 0.67; p<0.001), those starting treatment with peritoneal dialysis (sub-HR 0.34; 95% CI 0.32 to 0.35, p<0.001), those with urologic/cystic/congenital causes of kidney disease (sub-HR 0.08; 95% CI 0.08 to 0.09, p<0.001) or diabetes (sub-HR 0.09; 95% CI 0.09 to 0.10, p<0.001), and residence in the Northeastern part of the US (sub-HR 0.72; 95% CI 0.70 to 0.74, p<0.001) were predictors associated with lower recovery rates in the overall population in multivariable models (Table 2). Similar findings were noted in sensitivity analyses when we extended follow-up to end of the study (S1 Table).
However, some predictors of recovery differed in adults and children (presence of interaction was detected) as shown in Table 3. Whereas women had a lower hazard of recovery than men (sub-HR 0.97; 95% CI 0.96 to 0.99, p < 0.001), girls had a higher hazard of recovery than boys (sub-HR 1.47; 95% CI 1.22 to 1.76, p<0.001; Table 2). Although NHB adults were less likely to recover kidney function than NHW adults (sub-HR 0.52; 95% CI 0.51 to 0.53, p<0.001), there was no statistically significant difference between the recovery rates in NHB and NHW children (sub-HR 1.00; 95% CI 0.79 to 1.27, p=0.98). Starting outpatient dialysis with peritoneal dialysis was associated with a lower hazard of recovery compared with hemodialysis in both children and adults, but the effect size was more pronounced in adults (sub-HR 0.33; 95% CI 0.31 to 0.34, p<0.001) compared with children (sub-HR 0.65; 95% CI 0.54 to 0.79, p<0.001). Similar findings were noted when the outcome of recovery was followed until the end of the study (S2 Table).
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