Clinical Kidney Journal, 2021, vol. 14, no. 3, 998–1003 doi: 10.1093/ckj/sfaa056 Advance Access Publication Date: 22 June 2020 Original Article ORIGINAL ARTICLE Effect of altitude on mortality of end-stage renal disease patients on hemodialysis in Peru Downloaded from https://academic.oup.com/ckj/article/14/3/998/5860802 by guest on 13 March 2023 Katia Bravo-Jaimes 1, Viky Y. Loescher2, Carlos Canelo-Aybar3, Jose Rojas-Camayo4, Christian R. Mejia5, Sandra Schult6, Ruben Nieto7, Kyra Singh8, Susan Messing8 and Juana Hinostroza9 1 Division of Cardiovascular Medicine, University of Texas Health Science Center at Houston, Houston, TX, USA, 2Department of Radiology, Mount Sinai Hospital, Miami, FL, USA, 3Institut d’Investigacions Biomèdiques Sant Pau (IIB- Sant Pau), Cochrane Iberoamerican Center, Barcelona, Spain, 4Instituto de Investigaciones de la Altura, Universidad Peruana Cayetano Heredia, Lima, Peru, 5School of Health Sciences, Universidad Continental, Huancayo, Junin, Peru, 6Instituto Nacional de Salud del Nin ~ o, Lima, Peru, 7Division of Nephrology, 8 EsSalud Cusco, Cusco, Peru, Department of Biostatistics and Computational Biology, University of Rochester Medical Center, Rochester, NY, USA and and 9EsSalud, Centro Nacional de Salud Renal, Lima, Peru Correspondence to: Katia Bravo-Jaimes; E-mail: katia.m.bravojaimes@uth.tmc.edu ABSTRACT Background. In Latin America, the prevalence of end-stage kidney disease (ESKD) has risen tremendously during the last decade. Previous studies have suggested that receiving dialysis at high altitude confers mortality benefits; however, this effect has not been demonstrated at >2000 m above sea level (masl) or in developing countries. Methods. This historical cohort study analyzed medical records from six Peruvian hemodialysis (HD) centers located at altitudes ranging from 44 to 3827 masl. Adult ESKD patients who started maintenance HD between 2000 and 2010 were included. Patients were classified into two strata based on the elevation above sea level of their city of residence: low altitude (<2000 masl) and high altitude (2000 masl). Death from any cause was collected from national registries and Cox proportional hazards models were built. Results. A total of 720 patients were enrolled and 163 (22.6%) resided at high altitude. The low-altitude group was significantly younger, more likely to have diabetes or glomerulonephritis as the cause of ESKD and higher hemoglobin. The all-cause mortality rate was 84.3 per 1000 person-years. In the unadjusted Cox model, no mortality difference was found between the high- and low-altitude groups fhazard ratio [HR] 1.20 [95% confidence interval (CI) 0.89–1.62]g. After multivariable adjustment, receiving HD at high altitude was not significantly associated with higher mortality, but those with diabetes as the cause of ESKD had significantly higher mortality [HR 2.50 (95% CI 1.36–4.59)]. Conclusions. In Peru, patients receiving HD at high altitudes do not have mortality benefits. Keywords: altitude, anemia, chronic hemodialysis, chronic hypoxia, mortality Received: 25.9.2019; Editorial decision: 17.3.2020 C The Author(s) 2020. Published by Oxford University Press on behalf of ERA-EDTA. V This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/ licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com 998 Altitude affects mortality in Peruvian HD patients | 999 INTRODUCTION Patients were classified into two strata based on the eleva- tion above sea level of their city of residence: low altitude Chronic noncommunicable diseases, including chronic kidney (<2000 masl) and high altitude (2000 masl). A sensitivity disease (CKD), are the leading cause of death in developed coun- analysis using a lower altitude cutoff (1828 masl) was per- tries and impose an enormous cost on countries of Latin formed. Medians and frequencies of patient characteristics America (LA) [1–3]. Data on the CKD burden in LA are scarce; were calculated by elevation group. Pearson chi-squared and however, some studies have found CKD prevalence to be as Wilcoxon rank-sum tests were used for univariate analyses of high as 8% in Mexico [4], 12% in Chile [5] and 16.8% in Peru [6]. baseline characteristics. Cox proportional hazards models Similarly, the prevalence of end-stage kidney disease (ESKD) assessed the time from first HD to death from any cause, strati- patients under renal replacement therapies (RRTs) in LA has fying for each year and following patients for up to 5 years after substantially increased from 119 patients per million people first dialysis. Observations were censored by the end of the data (pmp) in 1991 to 669 patients pmp in 2013 [7, 8]. collection (January 1, 2012) and censure criteria were applied as In Peru, access to RRTs is not universal, mostly benefiting following: loss to follow-up, survival after 5 years of first HD, those with social security (EsSalud) and some with subsidized transference to another HD center outside the city, renal trans- insurance from the Ministry of Health [6]. In 2010, EsSalud pro- plantation or migration to peritoneal dialysis during follow-up. Downloaded from https://academic.oup.com/ckj/article/14/3/998/5860802 by guest on 13 March 2023 vided RRTs to 9814 patients and the Ministry of Health provided Patients living at low altitude served as a reference category for RRTs to 1983 patients in 2014 [9]. These numbers reflect the all analyses. high prevalence of ESKD requiring RRT in this country, which is Cox proportional hazards models were employed to look at similar to developed regions worldwide. Furthermore, they sup- the unadjusted and adjusted associations with mortality; the pose an increasing unmet need that affects a large number of latter included altitude, age, sex and cause of ESKD as well as Peruvians. interactions of cause of ESKD with altitude. A subgroup analysis Peru has 30 million inhabitants and a third of its population looked at the association between hemoglobin and mortality. P- lives at altitudes >2000 m. Prior studies have shown that values <0.05 were considered statistically significant. All analy- patients who receive dialysis at an altitude >1828 m above sea ses were carried out using SAS/STAT software, version 9.4 (SAS level (masl) have 15% lower mortality risk in a 5-year follow-up Institute, Cary, NC, USA) on a Windows 7 platform. compared with similar patients who receive dialysis at sea level [10]. However, this study was carried out in the USA, with 0.4% RESULTS of their sample living at >1828 masl and where the highest he- modialysis (HD) center is located at 2299 masl [11]. Thus, little is Of 2576 patients who started HD between 2000 and 2010 at the known about mortality in patients with ESKD living at higher six HD centers, 720 (39.6%) met inclusion criteria (Figure 1). In altitudes, especially >2000 masl, where arterial oxygenation Trujillo, Lima and Huanuco, 77.4, 81.8 and 84.5% of incident HD saturation starts to decline [12]. Therefore this study was con- patients were enrolled, respectively; whereas in Puno, Cusco and Arequipa, these proportions fell to 34.7, 33.3 and 4.8%, re- ducted to determine the effect of altitude on mortality in ESKD spectively (Figure 2). A total of 557 (77.4%) patients were in the patients receiving HD in Peru. low-altitude group (72 from Trujillo, 436 from Lima and 49 from Huanuco) and 163 (22.6%) were in the high-altitude group (37 MATERIALS AND METHODS from Arequipa, 116 from Cusco and 10 from Puno). Baseline characteristics are shown in Table 1, stratified by elevation This historical cohort study included patients with ESKD from group. Patients in the low-altitude group were significantly six HD centers located at different altitudes: Centro Nacional de younger, more likely to have diabetes or glomerulonephritis as Salud Renal, EsSalud-Lima, Hospital Nivel IV Victor Lazarte the cause of ESKD and had higher hemoglobin. Echegaray, EsSalud-Trujillo (at sea level); Hospital Nivel II Over a median follow-up of 3.6 years, there were 260 (36.1%) Huanuco, EsSalud-Huanuco (at 1894 masl); Hospital Nivel IV deaths (overall mortality rate 84.3 per 1000 person-years). In the Carlos Alberto Seguin Escobedo, EsSalud-Arequipa (at 2335 low-altitude group, 207 (37.2%) patients died, while in the high- masl); Hospital Nivel IV Adolfo Guevara Velasco, EsSalud-Cusco altitude group, 53 (32.5%) died. In an unadjusted Cox propor- (at 3400 masl) and Hospital Nivel III Puno, EsSalud-Puno (at 3827 tional hazards model, the high-altitude group had a trend to- masl). ward higher mortality, although it was not statistically All patients who initiated maintenance HD between 2000 significant fhazard ratio [HR] 1.20 [95% confidence interval (CI) and 2010 in these locations and who were >18 years of age were 0.89–1.62], P ¼ 0.243g (Figure 3). In the sensitivity analysis using included. Patients who died within 90 days of HD initiation or a lower altitude cutoff of 1828 masl, the high-altitude group had those who previously received renal transplant or peritoneal di- significantly higher mortality [HR 1.42 (95% CI 1.07–1.90), alysis were excluded. The study was approved by the ethics P ¼ 0.016] (Supplementary data). In the univariate subgroup committees from Universidad Peruana Cayetano Heredia and analysis, increased hemoglobin was not significantly associated EsSalud. All procedures performed in studies involving human with lower mortality [HR 0.95 (95% CI 0.87–1.04), P ¼ 0.274]. participants were in accordance with the ethical standards of An adjusted Cox model (Table 2) with altitude, age, sex and the ethics committees at EsSalud and Cayetano Heredia and cause of ESKD was fit and demonstrated that the high-altitude with the 1964 Helsinki Declaration and its later amendments or group had higher mortality, but this association did not reach comparable ethical standards. Informed consent was waived statistical significance [HR 1.16 (95% CI 0.85–1.58), P ¼ 0.360]. due to the retrospective nature of the study. Similarly, women had a nonsignificant trend toward higher Using a standardized form, medical records were reviewed mortality [HR 1.30 (95% CI 1.00–1.69), P ¼ 0.050]. Additionally, for to gather the following information: age, sex, cause of ESKD, each year of increase in age, the hazard of death increased by date of the first HD session and date of the last follow-up. Death 4% [HR 1.04 (95% CI 1.03–1.05), P < 0.001] over both altitudes. A from any cause was the outcome of interest and it was collected second adjusted Cox model (Table 3) with altitude, age, sex and from national registries. interaction of cause of ESKD and altitude level was fit and 1000 | K. Bravo-Jaimes et al. Downloaded from https://academic.oup.com/ckj/article/14/3/998/5860802 by guest on 13 March 2023 FIGURE 1. Patient inclusion flowchart. showed that patients with diabetes as the cause of ESKD in the Our sample was composed of middle-aged subjects, a popu- high-altitude group experience significantly higher mortality lation relatively younger than that of other studies involving [HR 2.50 (95% CI 1.36–4.59), P ¼ 0.003]. There is also a suggestion maintenance HD [10]. Interestingly, those who started HD at that this is true for hypertension as cause of ESKD. high altitude were significantly older than their low-altitude counterparts. This is in agreement with prior evidence showing that slower CKD progression may be present at high altitude DISCUSSION [15, 16]. However, other factors such as lower survival in older This is the first study, to our knowledge, that has examined the patients living at low altitude due to significant comorbidities or association between altitude and mortality in patients receiving increased availability of healthcare resources with planned HD HD in the Andes. This is important not only due to the altitude initiation in these settings need to be considered. levels seen in these cities, but also because this is an ethnic Substantial mortality rates were found across both altitude group that is very different from others living at high altitude. groups and a nonsignificant trend toward higher mortality was In fact, Andeans have lived at high altitude for >11 000 years, observed in those living at high altitude in the adjusted analy- developing circulatory, respiratory and hematological adapta- sis. Our results differ from prior findings [10, 17, 18] that showed tions; however, when compared with Tibetan populations, the up to 18% mortality reduction in dialysis patients receiving HD former have higher hemoglobin concentrations, lower resting at increased altitudes. Notably, these studies were conducted ventilation, higher oxygen saturation and an absence of genetic mainly in Caucasian populations at altitudes not significantly adaptation [13, 14]. >2000 masl. Our results could potentially be explained by a Altitude affects mortality in Peruvian HD patients | 1001 myriad of factors, including not only the magnitude of altitude them prone to the deleterious effects of anemia in an already level, but also genetic and adaptation variances from our spe- hypoxic environment. cific patient population, comorbid conditions, healthcare- Additionally, our study raises concern for a potential sex dis- associated factors and social disparities. Erythropoietin use parity in Peruvian patients receiving HD across altitude levels, may also differ in different Peruvian centers, as noted by lower since women had a nonsignificant increase in the hazard of hemoglobin levels in the high-altitude group, which may make death of 30%. A similar observation has been documented in Caucasian and Asian populations receiving HD and potential reasons include longer waiting times to HD initiation, greater loss of residual renal function, lower urea clearance adjusted for urea volume (Kt/Vurea) and shorter HD sessions [19]. Moreover, we found higher mortality among those subjects with diabetes receiving HD at high altitude. Regarding the previ- ously described independent association between higher alti- tude, worsening hypoxemia and increased cardiometabolic risk factors [20], it is possible that this higher mortality may be Downloaded from https://academic.oup.com/ckj/article/14/3/998/5860802 by guest on 13 March 2023 strongly influenced by cardiovascular disease. Future studies are needed to explore this association, accounting for potential confounders. Our study was performed in patients who had social security to ensure access to healthcare and guideline uniformity. However, we could not account for specific differences in the way healthcare is delivered in each center, their staffing needs or medication availability. Furthermore, Andeans’ lifestyle and stress levels may be different than their coastal peers, impacting mortality outcomes. Indirect data that support the existence of regional differences include the gross domestic product per cap- ita [in Lima, Arequipa and Trujillo (US$1631–3073) is higher than in Cusco, Puno and Huanuco (US$681–1228)] [21], life expectancy [in Lima, Arequipa and Trujillo (74.1–78.4 years) is higher than in Huanuco, Puno and Cusco (64.3–68.5 years)] [22], human develop- ment index (higher in Lima and Arequipa; intermediate in Trujillo; and lower in Huanuco, Cusco and Puno) [23], number of university hospitals offering nephrology training (nine in Lima, two in Arequipa, one in Cusco and none in Trujillo, Huanuco or Puno) [24] and the proportion of Quechua ethnicity [higher in Cusco, Puno and Huanuco (43.1–74.7%) than in Arequipa, Lima and Trujillo (2.9–31.3%)] [25]. This study has several limitations. Our high-altitude group FIGURE 2. Map of Peru displaying the location and name of the participating cit- size was comparatively small and clustering of altitude levels ies according to altitude level as well as the number of incident HD patients and was performed. The percentage of incident HD patients that number of patients included in our study. Map source: Wikimedia Commons. were enrolled in Arequipa was <10%, mostly due to missing Table 1. Baseline characteristics by elevation group Variable Low altitude (n ¼ 557) High altitude (n ¼ 163) P-value Age (years), median (range)a 51.8 (18.1–94.4) 56.8 (18.2–98.3) <0.001 Sex, n (%)b,c Men 297 (61.2) 104 (63.8) 0.559 Women 188 (38.8) 59 (36.2) Cause of ESKD, n (%)b Hypertension 172 (30.9) 52 (31.9) <0.001 Diabetes 119 (21.4) 24 (14.7) Glomerulonephritis 86 (15.4) 12 (7.4) Other 88 (15.8) 21 (12.9) Undetermined 13 (2.3) 10 (6.1) Mixed 2 (0.4) 12 (7.4) Not filed 77 (13.8) 32 (19.6) Hemoglobin (g/dL), median (range)a,d 9.0 (4.0–16.4) 8.3 (3.6–18.7) 0.009 Follow-up (years), median (range) 3.9 (0.3–5.0) 2.4 (0.2–5.0) < 0.001 a Wilcoxon rank-sum test. b Chi-squared test. c Information available in 648 records. d Baseline hemoglobin was determined in 54% of the patients: 309 patients in the low-altitude group and 86 patients in the high-altitude group. 1002 | K. Bravo-Jaimes et al. ACKNOWLEDGEMENTS Special thanks to the International Society of Nephrology, who supported this research through the Global Outreach and Prevention Program. We also recognize the support from the following nephrologists: Myriam Fiestas, José Taypicahuana, José Figueroa, Raúl Hinojosa, Jhony Paredes Silva and Nancy Garcı́a. FUNDING This study was supported by a grant from International Society of Nephrology, Global Outreach Research and Prevention Program. Downloaded from https://academic.oup.com/ckj/article/14/3/998/5860802 by guest on 13 March 2023 FIGURE 3. Survival plot displays the estimated survival time for patients at low and high altitude, with the number of subjects at risk at 0, 1000, 2000, 3000 and CONFLICT OF INTEREST STATEMENT 4000 days. Patients at high altitude have a nonsignificant trend toward lower The authors have no conflicts of interest. 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