ORIGINAL ARTICLE

Outcome of End-Stage Renal Disease Patients with Advanced Uremia and Acidemia Iqbal Ur Rehman, Muhammad Khalid Idrees and Shoukat

ABSTRACT Objective: To determine the outcome of End-Stage Renal Disease (ESRD) patients presenting with advanced uremia and acidemia requiring and adverse events seen within 72 hours of admission. Study Design: Cross-sectional study. Place and Duration of Study: Sindh Institute of Urology and Transplantation, Karachi, Pakistan, from October 2010 to March 2011. Methodology: ESRD patients with advanced uremia and acidemia were included in the study. History, , complete blood count, serum , , electrolytes, arterial blood gases analysis, and ultrasound of kidneys were done in each patient. Adverse events and outcome were recorded for the next 72 hours. Data was analyzed by SPSS version (10). Mean value and standard deviation of quantitative measurements were calculated and statistical significance computed by t-test. A p-value ≤ 0.05 was taken as significant. Statistical significance of categorical variables was determined by chi-square test. Results: Out of the 194 ESRD patients (mean age 46.54 ±14.07 years), 28 (14%) expired and 166 (86%) survived within 72 hours of admission. requiring inotropic support was the commonest adverse event observed in 40 (20.6%) cases followed by fits in 31 (16%); and 25 (12.9%) patients required ventilatory support. Mortality was high in patients above 50 years of age. There was no statistically significant difference between two genders regarding adverse events and mortality. Conclusion: The morbidity and mortality of patients with ESRD are serious concerns. Early referral of patients with ESRD, before they develop severe acidosis, can prevent significant morbidity and mortality.

Key Words: Uremia. Acidosis. . Inotropic. Mortality. Renal failure.

INTRODUCTION with each passing year. Only 10% of renal failure patients 4 The global burden of End-Stage Renal Disease (ESRD) receive renal replacement therapy. is rapidly rising and increasing number of patients is ESRD patients have a high mortality rate during the first entering in the pool of those on renal replacement year of initiation of dialysis and at least 6% patients die therapy (dialysis or transplant). Approximately 1.9 million within first 90 days.5 Late referral has been ESRD patients are undergoing hemodialysis worldwide. associated with adverse outcomes among ESRD Access to the facility of Renal Replacement Therapy patients. In Pakistan, till few years ago, almost 100% (RRT) correlates directly with socioeconomic develop- patients presented in emergency department with ment and regional income.1 The initiation of RRT in uremia and required urgent dialysis.6 A recent survey developing world is restricted to fewer than a quarter of from Karachi (the largest metropolis of Pakistan) found ESRD patients.1 In 2010, only 58.9% of ESRD patients that 41% of family physicians did not know when to refer received dialysis or had . There a renal failure patient to nephrologist.7 was disparity among different parts of the world In late referral patients with ESRD, is regarding access to renal replacement therapy, ranging present which is in most cases mild and partially or fully from less than 2% in most of sub-Saharan Africa to over compensated with pH > 7.2 and may not be life 70% in high-income North America, high-income Asia threatening. However, more severe acidosis i.e. pH Pacific, and East Asia.2 The annual incidence of End- < 7.2 can cause hemodynamic instability (hypotension, Stage Renal Disease (ESRD) in Pakistan is estimated at cardiac arrhythmias),8 especially in patients with about 100 per million populations,3 and it is increasing advanced uremia. Metabolic acidosis, however, is not the sole culprit for early mortality and morbidity whereas Department of Nephrology, Sindh Institute of Urology and other factors may also contribute.9 During the first year Transplantation (SIUT), Karachi. of dialysis, mortality is lowest during the first month and Correspondence: Dr. Iqbal Ur Rehman, Department of at peak during the second and third month.10 Analysis of Nephrology, SIUT, Dewan Farooq Medical Complex, patients record from the authors institution revealed that Off M.A. Jinnah Road, Karachi. patients were received with advanced uremia and E-mail: [email protected] metabolic acidosis requiring urgent hemodialysis via Received: July 18, 2014; Accepted: October 16, 2015. temporary vascular access and frequently need

Journal of the College of Physicians and Surgeons Pakistan 2016, Vol. 26 (1): 31-35 31 Iqbal Ur Rehman, Muhammad Khalid Idrees and Shoukat ventilatory and inotropic support with high (very early, , and pH. Statistical significance of within 72 hours) mortality. As this type of presentation is these variables was determined by t-test and value of p now rare in developed and Western countries, this equal or less than 0.05 was taken as statistically phenomenon is not reported in the literature and its significant. Similarly, the statistical significance of prognostic factors are not well studied. categorical data was determined by chi-square test. There is lack of data regarding the outcome of patients Stratification was done with regard to age, gender and with advanced uremia and acidemia in our population. number of dialysis to observe the effect on outcomes. This study was conducted to study the patients’ demographics, occurrence of adverse events (fits, RESULTS hypotension requiring inotropic support and requirement This study included 194 ESRD patients (130 males and of ventilatory support) and their impact on outcome 64 females) having advanced uremia and acidemia. The (survival/expiry) of the patients who presented with average age of the patients was 46.54 ±14.07 years and advanced uremia and acidemia. most of the patients were above 50 years of age. Patients who expired were older as compared to those METHODOLOGY who survived (52.29 ±12.77 vs. 45.57 ±14.09 years) and This cross-sectional study was conducted at Sindh this difference was statistically significant (p= 0.019). All Institute of Urology and Transplantation (SIUT), Karachi, the patients had fairly advanced uremia with a mean Pakistan, from October 2010 to March 2011. Patients serum urea of 349.04 ±77.6 mg/dl and mean serum between 15 - 60 years of age, presenting first time to creatinine of 14.44 ±4.41 mg/dl respectively. About 40% emergency department of SIUT having advanced patients had hyperkalemia. The patients who expired uremia (arbitrarily defined as serum urea level ≥ 250 had lower pH (7.01 ±0.11) as compared to those who mg/dl at first presentation at SIUT) and diagnosed ESRD survived (7.14 ±0.09) and this difference was statistically on the basis of clinical features, serum biochemistry and significant (p=0.0005). Table I shows the descriptive ultrasound kidneys, were included in the study by statistics of study variables. convenience sampling technique. Patients with acute or Table I: Descriptive statistics of study variables (n=194). chronic renal failure and those already on dialysis were Variables Mean ±SD Max - Min excluded from the study. The study was approved by the Age (years) 46.54 ±14.07 65 - 15 Ethical Review Committee (ERC) of the institution. Temperature* 98.59 ±0.96 103 - 98 Informed consent was obtained. Hemoglobin 7.87 ±1.82 11 - 3 History was taken and physical examination done. Blood Mean arterial pressure 88.06 ±20.51 122 - 47 samples for Complete Blood Count (CBC) and serum TLC 15.48 ±8.23 56 - 1 biochemistry (serum urea, creatinine, electrolytes) sent 246.78 ±139.95 716 - 5 along with a separate heparinized sample of arterial Potassium** 5.41 ±1.35 9 - 2 Sodium 134.66 ±8.48 168 - 107 blood for pH, PO2, PCO2, O2 saturation and bicarbonate measurement. Ultrasound of kidneys was done to see pH 7.12 ±0.13 7.29 - 6.84 the size of the kidneys and exclude obstruction. H.ion (nmol/L) 79.15 ±21.94 144 - 52 Outcome of patients (whether the patient expired or Urea mg/dl 349.04 ±77.6 594 - 251 survived) was observed for the next 72 hours after Creatinine mg/dL 14.44 ±4.41 36.9 - 8.0 *Out of 194 patients, 66 (34%) had temperature more than 100°F admission. Additionally, adverse events (fits, need of ** Out of 194 patients, 78 (40.2%) had hyperkalemia mechanical ventilation and hypotension) were observed. During this period, hemodialysis was done in supervision Hypotension requiring inotropic (vasopressor) support of trained physician. The dialysis was of short duration was the commonest adverse event that was observed in (90 - 120 minutes), with low flux hollow fibre 40 (20.6%) patients followed by fits () in 31 (polysulphone) dialyzer, without any anticoagulation (16%) patients while 25 (12.9%) patients required (saline flushes to prevent clotting of dialyzer), ventilatory support. Fits and ventilatory support were bicarbonate dialysate, blood flow of 250 ml/minute and more common in patients below 30 years of age while dialysate flow of 500 ml/minute. Ultrafiltration was done hypotension was observed in patients above 50 years of in patients having fluid overload. All the relevant age. Frequency of fits and ventilatory support was nearly information (survival, death and adverse outcome) were same in male and female (p=0.46 and p=0.90, recorded on the proforma. respectively) while hypotension was more common in Data was entered and analyzed in statistical software females than males (28.1% vs. 16.9%); but this (SPSS version 10). Frequency and percentage were difference did not reach statistical significance (p=0.07). computed for categorical (qualitative) variables like age Frequency of hypotension and ventilatory support was group, gender, outcome of end stage of renal disease high in those cases who had only one session of dialysis patients and adverse event. Mean and standard as compared to those who required 2 and 3 dialysis deviation were computed for quantitative measurement sessions during the period of 72 hours (p=0.001 and like age, temperature, hemoglobin, TLC, platelet, 0.0001 respectively) while there was no statistically

32 Journal of the College of Physicians and Surgeons Pakistan 2016, Vol. 26 (1): 31-35 Outcome of ESRD with advanced uremia and acidemia significant difference in case of fits (p=0.172). These DISCUSSION patients had more severe metabolic acidosis and The authors specifically studied outcome of uremic consequent highest mortality as shown in Table II. patients who were acidotic and in need of emergency Dialysis prescription varied very little from patient to dialysis, which is a common scenario in Pakistan due to patient as all the patients had short duration dialysis and late diagnosis or referral. Most of those patients, who dialysate flow (500 ml/minute) whereas dialysate have an uneventful course within few days after starting compositions (prepared in the institution in bulk) were 2 dialysis, usually do well subsequently. The total number fixed and dialyzer used was of the same size (1.4 m ) for of patients with a span of 6 months, suggests that this is all the patients. still a frequent mode of presentation in Pakistan. The Fourteen percent (28/194) patients expired and 86% average age of these patients (46.54 ±14.07 years) is (166/194) survived within 72 hours after admission. much less than that reported from USA11 but close to Mortality/expiry rate was highest (20.8%) among those that in other South Asian countries.12 The number of above 50 years of age while it was about 8% (8 out of males was almost twice that of females in this study. 98) in those below 50 years of age. Mortality was This is contrary to the finding from community based statistically significantly higher in those above 50 years study from Karachi13 which did not find gender of age as compared to those below 50 years (p=0.029). difference in occurrence of among There was no difference in both genders regarding general population. The lesser number of females in this mortality (p=0.918). Similarly, mortality/expiry rate was study is probably due to gender bias and social 100% in those cases who had only one dialysis session. deprivation of females. Frequencies of adverse events and mortality are This study included patients with severe acidosis i.e. summarized in Table III. pH < 7.3. The patients who eventfully expired had more severe acidemia compared to those who survived. Table II: Comparison of characteristics between survived and expired patients. Acidosis of such severity may lead to adverse Variables Survive group Expired group p-value hemodynamic effects such as arteriolar dilatation and 8 (n=166) (n=28) depression of myocardial contractility. In an Gender experimental study, the effect of metabolic acidosis Male 111 (66.9%) 19 (67.9%) 0.918 induced by infusion of hydrochloric acid in pigs was Female 55 (33.1%) 09 (32.1%) studied which showed that lowering of pH to 7.1 resulted Age (years) 45.57 ±14.09 52.29 ±12.77 0.019 in diminished cardiac contractility and increased the Temperature (F) 98.49 ±0.78 99.16 ±1.60 0.001* ventricular stroke work per minute.14 Numerous studies Mean arterial pressure on patients with lactic acidosis in critical care setting (mmHg) 91.62 ±18.25 66.94 ±20.71 0.0005* have highlighted the adverse effects of profound Hemoglobin (gm/dl) 7.88 ±1.83 7.76 ±1.79 0.734 acidemia.15 The authors were unable to find any study 3 TLC (1000/mm ) 14.63 ±7.39 20.46 ±11 0.0005* where effect of such profound metabolic acidosis in 3 (100,000/mm ) 247.21 ±136.7 244.25 ±147.68 0.917 uremic patients has been studied. Urea (mg/dl) 344.39 ±74.09 376.64 ±92.67 0.042 Creatinine (mg/dl) 14.45 ±4.51 14.04 ±4.07 0.649 It is difficult to compare these patients (whose acidosis Bicarbonate (mmol/L) 7.62 ±2.85 5.89 ±2.03 0.002* is rapidly corrected by dialysis) with non-uremic patients

PCO2 14.86 ±5.31 21.93 ±13.82 0.0005* with lactic acidosis. More than 40% patients had Sodium (mEq/L) 134.76 ±8.49 134.18 ±8.54 0.74 hyperkalemia but it had no effect on mortality. It is pH 7.14 ±0.09 7.01 ±0.11 0.0005* probably because of the rapid removal of potassium in H ion (nmol/L) 75.32 ±19.15 101.82 ±23.98 0.0005* process of hemodialysis. Patients who expired had Adverse event higher temperature and higher TLC as compared to Fits 21 (12.7%) 10 (35.7%) 0.002* those who survived. This could be due to presence of Hypotension 21 (12.7%) 19 (67.9%) 0.0001* some unrecognized infection (such as UTI) or result Ventilatory support 10 (6%) 15 (53.6%) 0.0001* from systemic inflammation due to metabolic acidosis. * Significant Patients with higher PCO2 (respiratory acidosis) had

Table III: Adverse events and mortality. Age groups Number Fits Hypotension Ventilatory support Expired ≤ 30 years 36 7 (19.5%) 6 (16.7%) 5 (13.8%) 3 (8.3%) 31 to 50 years 62 11 (17.8%) 7 (11.3%) 7 (11.3%) 5 (8.1%) > 50 years 96 13 (13.5%) 27 (28.1%) 13 (13.5%) 20 (20.8%) Number of adverse events Males 130 19 (14.6%) 22 (16.9%) 17 (13.1%) 19 (14.6%) Females 64 12 (18.8%) 18 (28.1%) 8 (12.5%) 9 (14.1%) Total - 31 (16%) 40 (20.6%) 25 (12.9%) 28 (14%)

Journal of the College of Physicians and Surgeons Pakistan 2016, Vol. 26 (1): 31-35 33 Iqbal Ur Rehman, Muhammad Khalid Idrees and Shoukat higher mortality. Patients with pure metabolic acidosis new ESRD patients. Bloembergen et al. found that have lower PCO2 due to respiratory compensation but males receiving chronic dialysis had a 22% higher exhaustion of respiratory muscles leads to concomitant mortality than females, mostly because of excess risk of respiratory acidosis (more pronounced among diabetic acute myocardial infarction and malignancies.23 CKD patients) and consequent higher morbidity and However, another study from European cohort showed mortality.16 that young and diabetic women starting dialysis had Hypotension was the commonest adverse event higher non-cardiovascular mortality risk than men while observed in 20.6% cases followed by fits (16%) and females of 45 years old and above had lower 24 12.9% patients required ventilator support. High cardiovascular mortality than men. The authors did not mortality rate (60%) observed in patients who were on find such gender difference in this study. This may be ventilator followed by hypotension (47.5%) and fits because of smaller number of females. Higher (2.3%). Seizures are not uncommon in patients with frequency of hypotension, need of ventilatory support advanced uremia on presentation and are multi-factorial and 100% mortality among patients, who survived to in causation. Seizures in uremic patients can be a have only one dialysis session, reflects that these manifestation of uremia, metabolic derangements or the patients were more seriously sick. The dialysis treatment of these derangements.17 Bergen and prescription was more or less the same among all the colleagues reported the incidence of seizures (fits) of patients and it is not possible to judge the effect of approximately 10% in patients with chronic renal dialysis on survival or mortality in this small single centre failure.18 The lower frequency of seizures among our study. study participants may be due to short period of This study is, to the best of authors' knowledge, the first observation (72 hours). of its kind from this part of the world which highlights the high mortality rate among ESRD patients presenting Mechanical ventilation was required in 12.9% patients with advanced uremia and metabolic acidosis/acidemia which is less than 26% as reported by Rocha19 among during first 72 hours of admission. It highlights the maintenance dialysis patients admitted in ICU. Patients importance of accurate reporting of events during initial with advanced uremia often have , days of start of dialysis. Early referral to nephrologist inability to clear upper airways and exhaustion due to and attendance of pre-dialysis clinics may facilitate the respiratory muscle . Similarly, 20.6% of our avoidance of central venous catheters, timely creation of patients had hypotension and required inotropic support AV fistula, correction of , mineral bone 19 compared to 24% as reported by Rocha. The metabolism and , which ultimately improve difference in the two study populations is that there was survival on dialysis.25 high proportion of patients with sepsis in the study of Rocha while these patients had severe metabolic It is a single center study and observation period was acidosis. only 3 days, so co-morbid conditions other than ESRD could affect the outcome and adverse events. The outcome of ESRD patients with advanced uremia was quite dismal in this study. 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