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Home , Hypokalemia

Original Article

Association between hypokalemia, and mortality in Peritoneal patients

Authors Abstract daily, thereby reducing the risk of ma- 1 Ana Maria Vavruk jor hemodynamic changes. On the other Cristina Martins2 Introduction: Hypokalemia is found in hand, PD can cause a significant reduc- Marcelo Mazza Nascimento2 peritoneal dialysis (PD) patients. The 1-6 Shirley Yumi Hayashi2 problem may be severe and promote tion in the serum levels of . Miguel Carlos Riella1,3 mortality. Several factors may trigger The daily removal of potassium by the hypokalemia in PD patients, such the dialysate in PD is approximately as preexisting malnutrition and the low 30-40 mmoL.7 The loss of this 1 protein and potassium food intake. Center for Biological and significantly increases with the use of Health Sciences, Pontifical Objectives: To verify the prevalence of Catholic University of Paraná ; presence of ; vomit- (PUCPR). hypokalemia and its association with 2 Renal, Diabetes and mortality, nutrition status, clinical, lab- ing; or other conditions, such as fistula research center (RDH). Pro-Renal Foundation oratory and electrocardiographic vari- and drains. Moreover, patients may Brazil. Foundation for ables in PD patients. Methods: Serum K+ have low intake of protein and foods Support to Research on Renal levels were evaluated retrospectively in and Metabolic Diseases. rich in potassium, preexisting malnu- 3 Pro-Renal Foundation Brazil. PD patients. Hypokalemia was defined trition, and comorbid conditions. The when the average of serum K+ was < 3.5 mEq/L in six consecutive measurements. intake of dietary potassium can vary Other available biochemical tests were significantly between individuals and also evaluated. Subjective Global Assess- on different days for the same person.8 ment (SGA) and body mass index (BMI) The combination of high loss and low were used to assess the nutrition status. A reserve or intake may contribute to the questionnaire was applied to identify the severe hypokalemia in PD patients. most common symptoms and signals as- Increased blood levels of ac- sociated to hypokalemia. An electrocar- diogram was performed. Demographic company the constant absorption of data, dialysis characteristics and survival glucose from PD. Consequently there rate were collected. Results: Hypokale- is a constant flow of potassium into the mia was present in 15 out of 110 patients cells.9-12 However, possibly due to a tem- (13.6%). The survival rate was lower in porary equilibrium in serum, it can be the hypokalemic group (p = 0.002). Hy- difficult to detect the blood electrolyte pokalemia was only associated with se- deficit. Thus, hypokalemia may not be rum levels of albumin and urea, and with the SGA results. Conclusion: Low lev- easily detected in the routine laboratory els of serum potassium were associated assessment of PD patients. to lower survival in PD patients and it Hypokalemia is defined as a serum Submitted on: 06/19/2012. seems to be related to malnutrition. Approved on: 08/16/2012. potassium concentration below 3.5 Keywords: hypokalemia, malnutrition, mEq/L.13 When the deficit is small, the mortality, peritoneal dialysis, potassium. patient may be asymptomatic or show Correspondence to: Cristina Martins. mild symptoms. In this case, the main Fundação Pró-Renal Brasil - Fundação de Amparo à Pesquisa symptoms of hypokalemia are general- em Enfermidades Renais e Introduction Metabólicas. ized ; muscle ; apathy; Rua General Aristides Athayde malaise; ; ; and, some- Jr., nº 208, Bigorrilho, Curitiba, Compared to , peritoneal Paraná, Brasil. CEP: 80730-340. times, abdominal distension. However, E-mail: [email protected] dialysis (PD) has the advantage of re- Tel: 41 3013-5322. Fax: 41 3568-1098. moving plasmatic fluid and metabolites in cases of significant reduction of serum DOI: 10.5935/0101-2800.20120024

349 Hypokalemia and mortality in DP

potassium concentrations (below 3.0 mEq/L), presence of and the results of Kt/V and symptoms such as muscle contractions and paraly- PET, when available. The most recent values were sis may occur. Individuals, especially those with a recorded for each patient. history of heart disease, may have cardiac arrhyth- Patients were interviewed once by the research- mias. When serum potassium decreases below 2.5 ers for assessment of whether they had any of the mEq/L, the clinical manifestations may progress to 6 common symptoms in PD: , vomiting, severe , paralytic , respiratory muscle aches, breathing difficulties, confusion, and paralysis, and atrial and ventricular arrhythmias13. hypotension. For this part of the study, only subjec- Therefore, patients with severe hypokalemia have tive information was used. a high risk of sudden death due to respiratory or Regarding food intake, patients were asked . about the overall quality and quantity of the food The aim of this study was to determine the fre- eaten. They were asked about how many meals quency of hypokalemia in patients on PD and to they had, with options of 1 to 6. They were also study its associations with mortality, symptoms, questioned about the practice of physical exercises. nutritional markers, and other laboratory tests. It was considered regular when physical exercise was done 3 or more times per week, considering Methods even mild exercises, such as hiking, with duration The study was approved by the Ethics Committee equal to or more than 30 minutes. Data on the use of the Pontifical Catholic University of Parana, and frequency of medication were also collected. Brazil. All patients included in the study signed a A pre-established list was used for this data col- free and informed consent form. lection. The drugs included were as follows: an- The study was qualitative and quantitative. The tihypertensive calcium antagonists, angiotensin II recruited patients were involved in the chronic PD receptor antagonists, antihypertensive angiotensin- program of the Pro-Renal Foundation, located in converting enzyme (ACE) inhibitors, antihyperten- Curitiba, Paraná, Brazil. The study was conducted sive α-2 agonists, antihypertensive β-blockers, an- between November 2004 and October 2007. tihypertensive direct vasodilators, antiarrhythmic, The total study population consisted of all ac- loop diuretics, potassium-sparing diuretics, iron tive patients in a PD program, including those supplements, folic acid, erythropoietin, multivita- undergoing continuous ambulatory peritoneal di- mins, and . The weight (with the alysis (CAPD) and in automated peritoneal dialysis peritoneal cavity empty) and height of the patients (APD). The inclusion criteria used were as follows: were also recorded, and the body mass index (BMI 2 outpatients, aged above18 years, and receiving di- = kg/m ) calculated. Subjective Global Assessment alysis for over 3 months. (SGA) scale was also applied. Data was collected from patients’ records. Data In addition, was performed were collected in factors including age, gender, un- on a sample of 85 patients. The electrocardio- derlying disease, dialysis program, volume and con- graphs were evaluated for non-ST-segment eleva- centration of glucose in the dialysis bags, number of tion signals, ventricular repolarization change, and exchanges, urine volume, laboratory tests routinely T-wave inversion. The electrocardiographic (ECG) performed at the treatment centers, and medica- assessment was not performed in all patients be- tions used by the patients. For laboratory results, cause 18 of them died and 7 changed their facility the average of the previous 6 blood collections from and/or dialysis modality. At the end of the study, the date of interview of the subject was considered. data were collected from the date of initial treat- Serum concentrations of potassium less than 3.5 ment with PD and death, where relevant. mEq/L; phosphorus, less than 3.5 mEq/L; calcium, The results were expressed as frequencies and less than 8.4 mg/dL; and urea, less than 100 mg/ percentages or averages, minimum and maximum, dL were defined as low levels. Likewise, the serum and standard deviation values. For intergroup com- concentration results for albumin less than 3.5 g/dL parison defined for dichotomous variables on the and creatinine less than 7.0 mg/dL were considered probability of having hypokalemia, the Fisher exact low levels. Other data collected were regarding the test was used. For this assessment, the odds ratios

350 J Bras Nefrol 2012;34(4):349-354 Hypokalemia and mortality in DP and 95% confidence intervals were estimated. For The SGA score was also significantly associ- the joint assessment on the association of the vari- ated with death (p < 0.01). According to the SGA ables with the presence of hypokalemia, a logistic score, patients classified as malnourished had the regression model was adjusted. Explanatory vari- worst survival rate (p = 0.002, HR: 3.5, with 95% ables were considered when showing p < 0.05 in CI: 1.6 to 7.6). There was also a significant as- the univariate analysis and having at least 1 case sociation between death and low levels of serum of a patient with hypokalemia in both classifica- albumin (p < 0.05). tions of the variable. To assess the association of As for the practice of physical exercise, there hypokalemia with the survival curve, a Cox regres- was a significant inverse association with mortal- sion model was adjusted, which included variables ity (p = 0.003). That is, regular exercise was pro- presenting a p-value < 0.05 in the univariate assess- tective for survival (p = 0.029, HR: 2.3 with 95% ment (Log-rank test). The results were expressed CI:1, 1-4, 9). by the Kaplan-Meier method. P values of < 0.05 Regarding drugs, the following was the fre- were considered statistically significant. Data were quency of use: calcium antagonists, n = 23; angio- analyzed using the SPSS v.11 software program. tensin receptor antagonists, n = 12; ACE inhibi- tors, n = 59; centrally-acting α-2 agonist, n = 6; Results β-blocker, n = 20; direct-acting vasodilators, n = 1; The sample comprised 110 patients. Of these, antiarrhythmic drugs, n = 3; loop diuretics, n = 69; 53.6% (n = 59) were female patients. Regarding potassium-sparing diuretics, n = 2; ferrous sulfate, PD treatment, 60% (n = 66) of individuals under- n = 43; folic acid, n = 2; erythropoietin, n = 79; went CAPD, and all others underwent APD. The supplements, n = 79; potassium chloride, age group ranged from 22 to 91 years (median, n = 3; and insulin, n = 42. Regarding this subject, an 62 years). The average time for dialysis was 43.82 interesting result was that the use of multivitamin months (± 28.11). supplements significantly increased patient survival Regarding the etiology of chronic kidney dis- (p < 0.05). Further, the reverse occurred with the ease, diabetic nephropathy was the most prevalent use of a potassium-sparing (p < 0.05). It cause (40.9%), followed by hypertensive nephro- was observed that none of the study subjects took sclerosis (26.4%). About 28% of patients had oth- multivitamin supplements concomitantly with a er causes, 6.4% had no established etiology. potassium-sparing diuretic. However, there was no The serum potassium levels varied from 2.7 to association between multivitamin use and hypo- 5.6 mEq/L (4.35 ± 0.75). Hypokalemia was ob- kalemia. The patients who were taking antihyper- served in 13.6% (n = 15). A significant association tensive drugs, such as calcium antagonists and/or was observed between hypokalemia and SGA score potassium-sparing diuretics, were significantly less (p < 0.05, OR 4.1) and blood urea nitrogen level affected by hypokalemia (p < 0.05). Hypokalemia (p < 0.01) (Table 1). was not associated with the other drugs used by Of the 110 subjects studied, 46.8% (n = 51) patients. died. Deaths related to infectious causes and No significant association was found be- cardiovascular disease had the same distribu- tween serum potassium and age; gender; BMI; tion (43.1%, n = 22), followed by cancer (2.0%, physical activity patterns; occurrence of symp- n = 1). Other causes of death were unknown toms; presence of diabetes or insulin therapy; (11.8%, n = 6). type of dialysis; urine volume; test results of PET A significant association was observed be- and Kt/V; peritonitis episodes; number of meals tween death and low levels of serum potassium per day; and serum levels of creatinine, phos- (p = 0.002). It was observed that 80% (n = 12) phorus, and calcium. There was no significant of the patients died hypokalemic and half of them, association between these variables and death. due to cardiovascular disease. The other causes ECG abnormalities occurred in 5.1% of hypo- of deaths of hypokalemic patients were infection kalemic patients when the non-ST-segment eleva- (25%, n = 3) and unknown reasons (25%, n = 3). tion variable (p = 0.683, OR 0.6) was evaluated.

J Bras Nefrol 2012;34(4):349-354 351 Hypokalemia and mortality in DP

Table 1 association between hypokalemia and subjective global assessment (SGA) and biochemical variables Without With hypokalemia Variables Classification hypokalemia p-value* HR (CI 95%) n (%) n (%) Mild/moderate 9 (22%) 32 (78%) SGA malnutrition 0.031 4.1 (1.2-4.5) 4 (6%) 59 (93.7%) Nourished Serum albumin < 3.5 13 (20.3%) 51 (79.7%) 0.023 5.3 (1.1-5.1) (g/dL) Serum urea < 100 15 (22.7%) 51 (77.3%) < 0.001 - (mg/dL) Serum creatinine < 7.0 9 (19.1%) 38 (80.9%) 0.172 2.2 (0.7-6.7) (mg/dL) Serum phosphorus < 3.5 2 (16.7%) 10 (83.3%) 0.667 1.3 (0.3-6.6) (mg/dL) Serum calcium < 8.4 3 (20%) 12 (80%) 0.428 1.7 (0.4-7.0) (mg/dL) * p value based on Fisher’s exact test.

When we assessed the change in ventricular repo- death were cardiovascular disease and peritonitis, larization, the percentages was 4.9% (p = 0.344, which resulted in 14.8% of deaths, each. In that OR 0.4). With regard to T-wave inversion, there study, it was observed that 80% (n = 12) of hy- were 10.5% (p = 0.612, OR 1.8) of abnormalities pokalemic patients died, and half of them, due to on the electrocardiogram. However, no associa- cardiovascular disease. Similarly, in our study, hy- tion was found between hypokalemia and the ECG pokalemic patients had higher mortality rates than findings. There was no significant association be- non-hypokalemic patients. Therefore, the assess- tween mortality and the variables non-ST-segment ment of serum potassium, which is a simple bio- elevation, ventricular repolarization, and chemical test, can be a good indicator for acute risk inversion. of cardiovascular death. Hypokalemia appears to be directly associated Discussion with acute and chronic depletion of the nutritional In this study, hypokalemia was found in 13.6% of status. As in our results, one study showed a signif- the 110 individuals undergoing PD. Previous stud- icant association between malnutrition, as assessed 3 ies have shown similar results. In the study by Kim by SGA score, and hypokalemia. Furthermore, 3,5,6 et al.,6 10.3% (n = 7) of the patients had low lev- in ours as well as other studies, hypoalbumin- els of serum potassium. Szeto et al.3 showed that emia was observed in hypokalemic patients. The 20.3% (n = 54) of the patients were hypokalemic. strong and significant relationship between hypo- The prevalence of the problem was 23.6% in the albuminemia and mortality is already well known. study by Chuang et al.5 In the study by Oreopoulos Excluding etiology, hypoalbuminemia may reflect et al.10, out of the 152 patients studied, 25 had a visceral protein depletion and global malnutrition. history of hypokalemia. Hypokalemic patients Another variable that may reflect the nutritional were divided into 2 groups: Group 1 (n = 20), with status is serum urea. In our study, low serum urea serum potassium > 3 mmol/L, and Group 2 (n = 5), was associated with hypokalemia. The low serum with serum potassium ≤ 3 mmol/L. Therefore, hy- levels of urea in dialysis patients may reflect inad- pokalemia is a problem for people on PD in differ- equate protein and, indirectly, potassium intake. ent locations and deserves special attention in the Low serum creatinine, on the other hand, may clinical routine. reflect the depletion of body muscle mass of pa- 6 In our population, there was no significant dif- tients. In the study by Kim et al. and in that by 5 ference among the causes of mortality. The major Chuang et al., serum levels of potassium were pos- causes were infectious and cardiovascular diseases. itively associated with serum creatinine. However, In the study by Szeto et al.,3 the major causes of in our study, there was no association between

352 J Bras Nefrol 2012;34(4):349-354 Hypokalemia and mortality in DP these 2 laboratory tests. Furthermore, patients In our opinion, the main limitation of this study who performed regular exercise had lower mortal- was the short follow-up time. An assessment for a ity. Muscle body mass is an important marker of longer time period could generate a more complete nutritional status. Depletion of muscle body mass data set. reflects chronic malnutrition, which may not have been a problem for our patients. Another aspect Conclusion that supports this conclusion is that no difference Our study showed that hypokalemia occurred in was found between hypokalemia or mortality in approximately 14% of PD patients and that it was relation to the BMI of our patients. The hypokale- associated with a high mortality. Acute nutritional mic patients in our study, unlike in other published depletion, probably associated with low food in- studies, apparently had acute nutritional deple- take, was the main factor causing hypokalemia. tion, which was evidenced by the SGA and the low Therefore, serum potassium levels can be used in serum urea levels. the diagnosis of acute malnutrition and for identi- In chronic malnutrition, BMI and serum cre- fying risk of death. atinine levels are expected to be low. These results This study also showed that patients might not were not found in our study. Moreover, unlike show clear of hypokalemia. 3,5 other studies, our results found no relation- Since monthly laboratory tests, unfortunately, do ship between hypokalemia and serum levels of not capture all the instances of hypokalemia, fre- phosphorus and calcium. There was no associa- quent nutritional attention is essential in PD pa- tion between hypokalemia and adequacy of di- tients. The main nutritional focus should be food alysis, volume of urine, or episodes of peritonitis. intake, in addition to identification of the sources Hypokalemia was also not associated with age or of potassium loss. This would help the replacement 6 the presence of diabetes. One study found that of the mineral through food and medication may hypokalemic patients were significantly older and be indicated prematurely, and reduce the risk of had higher prevalence of diabetes mellitus. It is death for these patients. well known that the elderly and patients with diabetes are major risk groups for malnutrition, Acknowledgements particularly of the chronic type. From a practical point of view, our results indicate that a low se- We thank the Pro-Renal Foundation for providing rum level of potassium can be a good marker of the space for research and all those who contrib- acute nutritional depletion and, hence, death. uted directly or indirectly to this study. In hemodialysis, serum potassium levels tend to be high. In PD, they are normal or tend to be low. References When occurs during PD, the prob- 1. Rostand SG. Profound hypokalemia in continuous ambulatory peritoneal dialysis. Arch Intern Med 1983;143:377-8. lem is usually associated with inadequate dialysis. 2. Newman LN. The law of unintended consequences in action: However, for both dialysis modalities, changes in increase in incidence of hypokalemia with improved adequacy of dialysis. Perit Dial Int 1999;19. serum potassium levels do not seem to lead to sig- 3. Szeto CC, Chow KM, Kwan BCH, Leung CB, Chung KY, Law nificant ECG abnormalities. For patients on hemo- MC, et al. Hypokalemia in Chinese peritoneal dialysis pa- 14 tients: prevalence and prognostic implication. Am J Kidney Dis dialysis, Nakamura et al. found no association 2005;46:128-35. between serum potassium levels and ECG results. 4. Spital A, Sterns RH. Potassium supplementation via the dialy- However, to our knowledge, no other study had sate in continuous ambulatory peritoneal dialysis. Am J Kidney Dis 1985;6:173-6. sought this association in PD patients, which was 5. Chuang YW, Shu KH, Yu TM, Cheng CH, Chen CH. Hy- also nonexistent. That is, hypokalemia does not pokalaemia: an independent risk factor of Enterobacteria- ceae peritonitis in CAPD patients. Nephrol Dial Transplant bring significant ECG changes in patients on dialy- 2009;24:1603-8. sis, or the test is not effective for identifying cardiac 6. Kim HW, Chang JH, Park SY, Park JT, Kim EY, Chang TI, et al. Factors associated with hypokalemia in continuous am- changes promoted by changes in serum potassium bulatory peritoneal dialysis patients. Electrolyte Blood Press levels in these patients. 2007;5:102-10.

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7. Musso C, Oreopoulos D. Potassium metabolism in chronic re- 12. Lin SH, Lin YF. Propranolol rapidly reverses paralysis, hypoka- nal failure. 3º Congress of Nephrology in Internet. 2003. lemia, and in thyrotoxic . 8. Constanzo LS. Fisiologia. Rio de Janeiro: Guanabara Koogan; 1999. Am J Kidney Dis 2001;37:620-3. 9. Musso CG. Potassium metabolism in patients with chronic 13. Brooks MJ, Melnik G. The : an approach to kidney disease. Part II: patients on dialysis (stage 5). Int Urol understanding its complications and preventing its occurrence. Nephrol 2004;36:469-72. Pharmacotherapy1995;15:713-26. 10. Tziviskou E, Musso C, Bellizzi V, Khandelwal M, Wang T, 14. Nakamura S, Uzu T, Inenaga T, Kimura G. Prediction of Savaj S, et al. Prevalence and pathogenesis of hypokalemia in coronary artery disease and cardiac events using electrocar- patients on chronic peritoneal dialysis: one center’s experience diographic changes during hemodialysis. Am J Kidney Dis and review of the literature. Int Urol Nephrol 2003;35:429-34. 2000;36:592-9. 11. Teitelbaum I, Burkart J. Peritoneal dialysis. Am J Kidney Dis 2003;42:1082-96.

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