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Therapeutic Apheresis and Dialysis 13(3):220–224 doi: 10.1111/j.1744-9987.2009.00659.x © 2009 The Authors Journal compilation © 2009 International Society for Apheresis

Ionized Alkaline Water: New Strategy for Management of Metabolic Acidosis in Experimental Animals Hassan Abol-Enein, Osama A Gheith, Nashwa Barakat, Eman Nour, and Abd-Elhameed Sharaf Department of Urology, El Mansoura Urology and Nephrology Center (MUNC), Mansoura University, Mansoura, Egypt

Abstract: Metabolic acidosis can occur as a result of either the accumulation of endogenous acids or loss of bicarbonate from the gastrointestinal tract or the kidney, which represent common causes of metabolic acidosis. The appropriate treatment of acute metabolic acidosis has been very controversial. Ionized alkaline water was not evaluated in such groups of patients in spite of its safety and reported benefits. So, we aimed to assess its efficacy in the management of metabolic acidosis in animal models.Two models of metabolic acidosis were created in dogs and rats. The first model of renal failure was induced by ligation of both ureters; and the second model was induced by urinary diversion to gut (gastrointestinal bicarbonate loss model). Both models were subjected to ionized alkaline water (orally and by hemodialysis). Dogs with renal failure were assigned to two groups according to the type of dialysate utilized during hemodialysis sessions, the first was utilizing

alkaline water and the second was utilizing conventional water. Another two groups of animals with urinary diversion were arranged to receive oral alkaline water and tap water. In renal failure animal models, acid-base parameters improved significantly after hemodialysis with ionized alkaline water compared with the conventional water treated with reverse osmosis (RO). Similar results were observed in urinary diversion models as there was significant improvement of both the partial pressure of carbon dioxide and serum bicarbonate (P = 0.007 and 0.001 respectively) after utilizing alkaline water orally. Alkaline ionized water can be considered as a major safe strategy in the management of metabolic acidosis secondary to renal failure or dialysis or urinary diversion. Human studies are indicated in the near future to confirm this issue in humans. Key Words: Acidosis, Alkaline ionized water, Hemodialysis.

Metabolic acidosis can occur as a result of either the accumulation of endogenous acids that consume bicarbonate (high anion gap metabolic acidosis) or loss of bicarbonate from the gastrointestinal tract or the kidney (hyperchloremic or normal anion gap metabolic acidosis).The cause of high anion gap metabolic acidosis includes lactic acidosis, ketoacidosis, renal failure and intoxication with ethylene glycol, methanol or salicylate. The most common causes of hyperchloremic metabolic acidosis are gastrointestinal bicarbonate loss, renal tubular acidosis, druginduced hyperkalemia, early renal failure and administration of acids (1).

The use of intestinal segments in the urinary tract can cause metabolic changes that depend on the intestinal segment utilized. The severity of these changes basically depends on the area of the intestinal mucosa in contact with urine, the duration of exposure to urine and renal function. The length of time the intestinal mucosa is in contact with urine largely depends on the surgical technique employed. Mild chronic acidosis is neutralized via the respiratory system and by the bone buffers, which leads to bone remodelling manifested by the significant increase of serum alkaline phosphatase levels and increased calciuria (2,3). Metabolic acidosis is the most common metabolic abnormality seen. The rates and severity of these complications vary, though they may have a profound impact on a patient’s quality of life after enterocystoplasty. The metabolic consequences and long-term complications associated with enterocystoplasty are

Received May 2008; revised August 2008. Address correspondence and reprint requests to Dr Osama A Gheith, Urology and Nephrology Center, Mansoura University, 72 Gomhoria Street, Mansoura 35516, Egypt. Email: ogheith@ yahoo.com

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Alkaline Water and Metabolic Acidosis important clinical features of this intervention, and careful consideration should be given to them before pursuing enterocystoplasty (4). Increased oxidative stress in end-stage renal disease (ESRD) patients may oxidize macromolecules and consequently lead to cardiovascular events during chronic hemodialysis. Hemodialysis with electrolyzed reduced water (ERW) administration may efficiently increase the H2O2- and HOCldependent antioxidant defense and reduce H2O2and HOCl-induced oxidative stress (partly restored total antioxidant status during 1-month treatment) (5). Electrolyzed reduced water treatment administration is effective in palliating HD-evoked oxidative stress, as indicated by lipid peroxidation, hemolysis, and overexpression of proinflammatory cytokines in HD patients (6). The appropriate treatment of acute metabolic acidosis, in particular organic form of acidosis such as lactic acidosis, has been very controversial. The only effective treatment for organic acidosis is cessation of acid production via improvement of tissue oxygenation. Treatment of acute organic acidosis with sodium bicarbonate failed to reduce the morbidity and mortality despite improvement in acid-base parameters. Further studies are required to determine the optimal treatment strategies for metabolic acidosis (1). Until now ionized alkaline water has not been evaluated in such a group of patients despite its safety and reported benefits such as antioxidant effects (5,6); its beneficial effects on ionized calcium (7), and alleviation of some symptoms related to acidosis as low back ache (8). We aimed to assess the efficacy of ionized alkaline water in the management of metabolic acidosis consumed by oral route and/or by hemodialysis among experimental animals.

METHODS Induction of metabolic acidosis in experimental animals Fifteen mongrel dogs were selected with average weight of 20 kg and 6 dogs were subjected to open ligation of both ureters to induce state of irreversible renal failure while the remaining 9 dogs were subjected to urinary diversion (ureterosigmoidostomy) aiming at inducing metabolic acidosis. All dogs developed metabolic acidosis and only dogs with bilateral ureteric ligaton developed chronic renal failure and were supported with hemodialysis. All dogs were hemodialyzed for four © 2009 The Authors Journal compilation © 2009 International Society for Apheresis

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hours, three times per week, against acetate based dialysate, under general anesthesia, using an F3 hemoflux filter with an AK10 Gambro machine (Gambro, Lund, Sweden), at a blood pump rate of less than 200 mL per minute and average transmembrane pressure of 120 mm Hg. Double lumen catheter was inserted in the right internal jugular vein as a second step of preparation for hemodialysis. Hemodiaslysis sessions were started on the next day after ligation of ureters. Ionized alkaline water was used randomly in some hemodialysis sessions (9 out of 21 sessions). The hemodialysis program was continued as long as the dog remained alive. We classified dialysis sessions into two groups; group 1 referred to dialysis sessions (12) that utilized acetate based solution, while group 2 referred to dialysis sessions that utilized ionized alkaline water based solution. Five rats were selected with an average weight 250 grams and were subjected to augmentation ileocystoplasty with the aim of induction of hyperchloremic metabolic acidosis. The rats fasted for 12 h preoperatively and then were anesthetized by intraperitoneal injection of ketamine HCL 75 mg/kg and diazepam 5 mg/kg. Cystoplasty was done under sterile conditions with the aid of a microscope/ magnifying loop of 25¥ magnification. The technique of ileocystoplasty has been described previously in the literature by Guan et al. (9) A midline abdominal incision was made. Right sided nephrectomy was done taking care of the vascular pedicle. Working 5 mm away from the cecum, according to the group the length of the distal ileal segment was taken with the mesenteric pedicle, making sure of good arterial pulse and adequate vessel length. The ileal segment was opened along its antimesenteric border and was anastomosed to the longitudinally opened urinary bladder using 7/0 PDS. Continuity of the bowel was restored with end to end anastomosis using simple interrupted sutures (7/0 vicryl/PDS). Closure was done with 5/0 silk. Postoperatively the rats were observed for 30–45 min in the incubator and then they were returned to their respective cages. All animals were evaluated twice per week for the acid-base status using capillary blood sampling. All animals became acidotic by the second week, and cases with bicarbonate levels less than 18 mEq/liter were given alkaline water per mouth daily according their thirst sensation. They were given alkaline water orally for one week and continued for one month then shifted to tap water for another one month and were followed up by blood gases.

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PREPARATION OF IONIZED WATER FOR DIALYSIS AND FOR DRINKING Water electrostatic ionizer (ITen Company, Cairo, Egypt) was used to generate the required amount of water used for both drinking and hemodialysis. When alkaline water was used in dialysis we connected the ionizer distal to a tank full of water previously treated with a reverse osmosis (RO) unit. Total dissolved solids (TDS) of the RO water were adjusted between 200 to 250 ppm, and the ionizer was allowed to work for 24 h prior the first session of dialysis with a target pH between 8 and 9. Clinical evaluation of each dog before each dialysis session was performed with special focus on hemodynamic stability, drinking, feeding, activities, gait and clotting of lines. At the start of the study before induction of renal failure, laboratory evaluation included assessment of kidney function (creatinine and blood urea nitrogen [BUN]); liver function (bilirubin, albumin, alanine aminotransferase) and complete blood count (CBC). Before each dialysis session we performed CBC, creatinine, blood urea nitrogen, blood gases and plasma electrolytes and post-dialysis the same parameters were repeated. Of course assessment of dialysis efficacy using urea kinetic modeling (single pool) was performed. Statistical analysis Statistical analysis was carried out using IBMcompatible SPSS for windows version 11.5 (SPSS Inc., Chicago, IL, USA). All values were expressed as means ⫾ SD for continuous parametric data, median for continuous nonparametric data, and frequencies for categorical data. Values of P < 0.05 were considered significant.

RESULTS Table 1 showed the demographic features of both groups at the start of the study. We observed that the two groups were comparable regarding pre-and postdialysis creatinine and serum potassium (P > 0.05). The pre-dialysis acid-base parameters suggested higher degree of metabolic acidosis in the sessions utilized ionized alkaline water: significantly higher pH, and lower partial pressure of carbon dioxide, P = 0.032 and 0.024 respectively. The mean respiratory rate in both groups was comparable and also the oxygen saturation in blood gases analyses. However, these parameters improved significantly after dialysis with ionized water compared with the usual water treated with RO. Not only did the post-dialysis bicarbonate improved significantly after dialysis from 13.6 to 17.18 vs. 13.2 to 13.4 in the other group (P = 0.048), but also partial pressure of carbon dioxide improved from 27.2 to 34.3 vs. 31.6 to 32.7 (Table 2). The daily evaluation of the dialyzed dogs after recovery from anesthesia induced during dialysis, and the dialysis free days were recorded and recoded and summarized in Table 3. We could not detect any significant difference between both groups regarding drinking, feeding, daily activities, gait (P > 0.05).Also, the frequency of clotting of blood in the extracorporeal circuit was higher than that observed in humans, so we were obliged to use a higher dose of heparin during dialysis. However, the two groups of dialysis sessions were comparable regarding clotting of blood (P = 0.15). We observed that cases of both groups were comparable regarding basal acid-bases status (P > 0.05) as all of them developed metabolic acidosis after the urinary diversion by average 2 weeks duration. On drinking ionized alkaline water there was no signifi-

TABLE 1. Demographic features of dogs at the start of the study

Basal Hb HCT WBCs Platelets Basal weight (kgm) Basal creatinine (mg/dL) Basal bicarbonate(mEq/L) Basal sodium (mmol/L) Basal potassium (mmol/L) Basal calcium (mg/dL) Basal phosphorus (mg/dL) Basal pH Basal pCO2

Acetate dialysis sessions (N = 12) Group 1

Ionized alkaline water sessions (N = 9) Group 2

P value

14.96 ⫾ 1.6 39 ⫾ 5 12.6 ⫾ 4.1 307 ⫾ 88 20.9 ⫾ 7 1.0 ⫾ 0.25 18.2 ⫾ 2.3 146 ⫾ 5.5 4.6 ⫾ 1.2 9.7 ⫾ 0.0 4.9 ⫾ 0.0 7.36 ⫾ 0.056 32 ⫾ 0.0

14.07 ⫾ 1.9 39.7 ⫾ 4.7 19.6 ⫾ 4.6 368 ⫾ 261 18.5 ⫾ 4.2 1.1 ⫾ 0.3 18.7 ⫾ 1.4 147 ⫾ 4.5 4.8 ⫾ 0.0 11.7 ⫾ 0.7 6.9 ⫾ 0.4 7.23 ⫾ 0.02 41.3 ⫾ 4

0.549 0.848 0.093 0.719 0.702 0.783 0.756 0.951 0.786 0.212 0.162 0.101 0.053

Hb, hemoglobin; HCT, hematocrit; pCO2, partial pressure of carbon dioxide; WBCs, white blood cells.


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TABLE 2. Laboratory evaluation of the studied dogs (pre- and post-dialysis) Acetate dialysis sessions (N = 12) Group 1 Serum creatinine Predialysis Post-dialysis Mean Kt/V

Ionized alkaline water sessions (N = 9) Group 2

P value

11.48 ⫾ 4.59 4.8 ⫾ 2.4 1.15

0.827 0.643 0.24

5.1 ⫾ 0.96 2.75 ⫾ 0.56

4.90 ⫾ 1.0 2.8 ⫾ 0.6

0.757 0.701

7.245 ⫾ 0.036 7.283 ⫾ 0.096

7.2947 ⫾ 0.042 7.27 ⫾ 0.066

0.032 0.778

31.6 ⫾ 2.5 32.7 ⫾ 4.7

27.2 ⫾ 3.5 34.3 ⫾ 5.9

0.024 0.613

13.20 ⫾ 1.9 13.44 ⫾ 4.1

13.60 ⫾ 1.8 17.18 ⫾ 3.3

0.660 0.048

11.09 ⫾ 3.4 4.5 ⫾ 1.1 1.14

Serum potasium Predialysis Post-dialysis Serum pH Predialysis Post-dialysis Serum pCO2 Predialysis Post-dialysis Serum bicarbonate Predialysis Post-dialysis

pCO2, partial pressure of carbon dioxide.

cant effect on pH (P = 0.575). However, there was significant improvement of both pCO2 and serum bicarbonate (P = 0.007 and 0.001 respectively) irrespective to the cause of metabolic acidosis (Table 4). DISCUSSION In this study we aimed to evaluate the efficacy of ionized alkaline water in the management of metabolic acidosis resulted from two important groups of disorders that we are confronted with in our center. We induced metabolic acidosis in 15 dogs and 5 rats. Fifteen dogs were subjected to either open TABLE 3. Clinical features of the studied dogs during and in between dialysis sessions Score of clinical features

Drinking Group I† Group II‡ Feeding Group I Group II Activities Group I Group II Gait Group I Group II Clotting of lines Group I Group II

Good

Moderate

Poor

P value

5 5

3 2

1 5

0.10

3 3

1 1

5 8

0.93

6 7

2 4

1 2

0.72

7 8

1 3

1 1

0.30

7 6

1 2

1 4

0.15

† Acetate dialysis sessions (N = 12) Group 1. ‡Ionized alkaline water sessions (N = 9) Group 2.


ligation of both ureters (6 dogs) to induce state of irreversible renal failure; or urinary diversion using uretero-sigmoidostomy (9 dogs) aiming at inducing metabolic acidosis in all dogs. Five rats were subjected to augmentation ileo-cystoplasty with the aim of induction of hyperchloremic metabolic acidosis. All dogs with renal failure were supported—from the second day—by hemodialysis. So, we create two groups of hemodialysis sessions, the first utilized conventional water and the second utilized alkaline water. The two groups were comparable regarding demographic features at the start of the hemodialysis program shown in Table 1. We observed that the two groups were comparable regarding pre-and post-dialysis creatinine and serum potassium (P > 0.05). The pre-dialysis acid-base parameters suggested higher degree of metabolic acidosis in the sessions utilizing ionized alkaline water (pH was significantly higher and pCO2 was significantly lower). However, these parameters improved significantly after dialysis with ionized water compared with the usual water treated with RO. The dialyzed dogs were recorded, recoded and summarized in Table 3. We could not detect any significant difference between both groups regarding drinking, feeding, daily activities, gait (P > 0.05).Also, the frequency of clotting of blood in the extracorporeal circuit was higher than that observed in humans, so we were obliged to use higher dose of heparin during dialysis. However, the two groups of dialysis sessions were comparable regarding clotting of blood (P = 0.15).


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H Abol-Enein et al. TABLE 4. Effect of drinking ionized alkaline water for one week on acid-base status of dogs with metabolic acidosis due to urinary diversion or induced renal failure Phase I Drinking Ionized alkaline water

Phase II Drinking tap water after 2 weeks wash out period

Number of dogs (n = 15)

Number of dogs (n = 9)

Mean

SD

Mean

SD

P value

pH: basal After 1 week pCO2: basal After 1 week

7.26 7.28 33.84 44.25

0.06 0.03 6.9 8.8

7.28 7.24 35.5 32

0.03 0.04 6.9 0.3

0.57 0.14 0.62 0.007

Serum bicarbonate Basal After 1 week

14.66 21.12

3.8 3.7

16.2 13.9

3.2 1.6

0.29 0.001

Number of rats (n = 5)

pH: basal After 1 week pCO2: basal After 1 week Serum bicarbonate Basal After 1 week

Number of rats (n = 5)

Mean

SD

Mean

SD

P value

7.24 7.27 33.85 45.25

0.04 0.02 6.9 8.8

7.23 7.26 35.5 31

0.03 0.04 6.9 0.3

0.66 0.22 0.62 0.006

14.66 25.12

3.8 3.7

15.2 14.9

3.2 1.6

0.39 0.001

pCO2, partial pressure of carbon dioxide.

All animals that were subjected to urinary diversion, developed metabolic acidosis after an average 2 weeks duration (bicarbonate < 18, 9 dogs and 5 rats). We observed that animals receiving alkaline water became significantly less acidotic (more bicarbonate and more CO2) compared to the same parameters after 2 weeks of wash out period. On drinking ionized alkaline water, there was no significant effect on serum pH. However, there was significant improvement of both pCO2 and serum bicarbonate. On stoppage of ionized alkaline water and utilization of tap water all dogs and rats developed relapse of metabolic acidosis with significant low bicarbonate and serum CO2 (Table 4). CONCLUSION Alkaline ionized water can be considered as a major safe strategy in the management of metabolic acidosis encountered among animals with either dialysis or urinary diversion. Further studies are indicated in the near future to confirm this issue in humans. Acknowledgments: Abd-Elhameed Sharaf provided the ionizer, which is licensed and available in Egypt.


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