Controversies of Sodium Alkalizers

Urinary alkalinization is defined as increasing urinary pH to >7.5.¹Proudfoot AT, Krenzelok EP, Vale JA. Position paper on urine alkalinization. J Toxicol Clin Toxicol. 2004;42(1):1-26.   Urine alkalization is a method of neutralizing the acids present in the urine by adding base. The normal range of urine pH is from 4.6 to 8.0. When urine pH rises above 7, cystine becomes much more soluble, so achieving urine pH of 7.5-8 for a good part of the day is desirable.

Indications for urine alkalization

• Urinary tract infections
• Cystitis
• Cystinuria
• Nephrolithiasis
• Drug overdose with weak acid ¹Proudfoot AT, Krenzelok EP, Vale JA. Position paper on urine alkalinization. J Toxicol Clin Toxicol. 2004;42(1):1-26.  
  • Phenobarbital or barbiturate overdose
  • Class I antidysrhythmic drug overdose
  • Tricyclic antidepressant overdose
  • Antihistamine overdose
  • Cocaine overdose
  • Salicylates
  • Chlorpropamide
  • Chlorophenoxy herbicides
  • Sulfonamides
  • Methotrexate
  • Fluoride
  • Diflunisal

Contraindications

• Established or incipient renal failure is a contra indication to urine alkalinization. Significant preexisting heart disease is a relative contraindication.

Methods of alkalizing the urine

• Diet modification
• Increase intake of fluids
• Drug therapy
  • Potassium citrate
  • Sodium citrate/dihydrogenase sodium citrate
  • Sodium bicarbonate
  • Herbal therapy

Diet modifications

The goal is to maintain the balance between the acidic and alkaline diet intake. To maintain health, the diet should consist of 80% alkaline forming food and 20% acid forming food. When the pH balance is maintained, the body has a strong resistance against disease. This is best done with mineral-rich vegetables, especially green leaf-vegetables and green protein powders such as spirulina, chlorella, and wheat grass or barley grass powder.

Increase intake of fluids

• Fluid intake has to be increased. Alcohol and other carbonated beverages should be avoided.

Drug therapy
Sodium alkalizer

Potassium citrate, sodium citrate and sodium bicarbonate have been used in urine alkalization since very long. These medications change the pH of urine from acidic to alkaline. These drugs increase the excretion of free bicarbonate ions in the urine, thus effectively raising the urinary pH. By maintaining alkaline urine, the actual dissolution of uric acid stones may be accomplished. The herbal therapy has also been tried for the urine alkalization.

Sodium bicarbonate is indicated in metabolic acidosis, in the treatment of certain drug intoxications and severe diarrhea. Intravenous sodium bicarbonate has been used for this purpose to treat toxicity from phenobarbital, salicylates, methotrexate, and chlorophenoxy herbicides.^1-5Proudfoot AT, Krenzelok EP, Vale JA. Position paper on urine alkalinization. J Toxicol Clin Toxicol. 2004;42(1):1-26.
Roberts DM, Buckley NA. Urinary alkalinization for acute chlorophenoxy herbicide poisoning. Cochrane Database Syst Rev. 2007(1):CD005488.
Wax P. Antidotes in Depth: Sodium Bicarbonate. New York, NY:McGraw Hill; 2006.
Zimmerman JL. Poisonings and overdoses in the intensive care unit: general and specific management issues. Crit Care Med. 2003;31(12):2794-2801.
Shamash J, Earl H, Souhami R. Acetazolamide for alkalinization of urine in patients receiving high-dose methotrexate. Cancer Chemother Pharmacol. 1991;28(2):150-151.   Historically sodium bicarbonate was the first line alkalizing agent, however the sodium load may actually increase the amount of cystine excreted. Concerns have been expressed about increased risk of hypertension following long-term sodium bicarbonate therapy, and some patients will not tolerate the gaseous side effects of the drug.⁶Chandra S. Biyani A, Jon J. Cartledge; Cystinuria-Diagnosis and Management; EAU-EBU updateseries 4(2006):175-183.  

Sodium bicarbonate is contraindicated in patients:

• losing chloride by vomiting or from continuous gastrointestinal suction
• receiving diuretics known to produce a hypochloremic alkalosis
• with metabolic and respiratory alkalosis
• with hypocalcemia in which alkalosis may produce tetany.

Potassium citrate alkalizers

Potassium is a mineral, which is needed for many functions of the body. In addition to a role in maintaining cell membrane electrical gradients, potassium plays a role in energy metabolism and fluid and acid-base balance. It is required for optimal cardiac, adrenal, and renal function, and promotes muscular and neurological function.⁷Schuster VL. Potassium deficiency: pathogenesis and treatment. In: Seldin DW, Giebisch G, eds. The Regulation of Potassium Balance. New York, NY: Raven Press; 1989:241-267.   Potassium citrate supplements are used to treat many diseases. Examples are as follows:

• Urinary alkalization
• Hypokalemia
• Nephrolithiasis
• Renal tubular acidosis
• Metabolic acidosis

Potassium citrate scores over sodium alkalizers
Nephrolithiasis

It has been theorized that potassium salts (bicarbonate or citrate) are preferable to sodium salts for oral alkalinization, because sodium loading may promote calcium excretion, hence a risk of calcium stones.

According to a study of contrasting effects of potassium citrate and sodium citrate therapies on urinary chemistries and crystallization of stone-forming salts.8 The results indicate that (1) both alkali therapies are equally effective in preventing uric acid stone formation because of their ability to increase urinary pH, and (2) potassium citrate may prevent the complication of calcium nephrolithiasis in patients with uric acid stones, whereas sodium citrate may not (Table 1).⁸Sakhaee K, Nicar M, Hill K, Pak CY; Contrasting effects of potassium citrate and sodium citrate therapies on urinary chemistries and crystallization of stone-forming salts; Kidney Int. 1983;24(3):348-52.  

Sodium-containing products are not recommended for patients in whom sodium intake should be restricted,e.g. hypertensive patients, those with heart disease and pregnant women.

In the treatment of nephrolithiasis alkalization can be achieved with sodium bicarbonate, sodium citrate or potassium citrate.12 Due to better gastrointestinal tolerance, citrate salts are often preferred.⁹Dipiro JT, Talbert RL, Yee GC, et al. Pharmacotherapy: a pathophysiologic approach. 3rd ed. Appleton and Lange; 1997.   Potassium citrate may be preferable to sodium citrate, because of a reduced potential for the development of calcium stones that may arise from sodium citrate or sodium bicarbonate therapy.⁹Dipiro JT, Talbert RL, Yee GC, et al. Pharmacotherapy: a pathophysiologic approach. 3rd ed. Appleton and Lange; 1997.  

Cystine stones

Potassium citrate has a role in the treatment of cystine stones as well. Patients with cystine stones should be instructed to increase their fluid intake to maintain a urine volume greater than 4 L/day. In addition, potassium citrate should be prescribed to maintain urinary pH between 6.5 and 7.0. Alkalization of urine with sodium bicarbonate or sodium citrate is not recommended because the sodium salts will increase calcium excretion, which increases the tendency to form calcium oxalate stones.¹⁰Hall P. Nephrolithiasis. Cleveland clinic Journal of Medicine 2009; 76(10):683-591.  

The administration of sodium bicarbonate shifts potassium into cells, thus hypokalemia potentially may be observed during urine alkalization. To avoid this potassium citrate may be preferred.

Cystine stones

Potassium citrate is used to prevent recurrent calcium kidney stones. It works by increasing urinary pH, which enhances urinary citrate excretion; high urinary citrate concentrations increase the solubility of stone-forming salts. Modern lifestyle, dietary habits and obesity emerge to be the promoters of idiopathic stone disease. Modern diets containing a lot of animal protein, refined carbohydrates and salt act on the metabolism like an acid load. To overcome these disadvantageous effects, a sufficient supply of potassium and alkali is required.¹¹Straub M, Hautmann RE .Developments in stone prevention. Curr Opin Urol. 2005;15(2):119-26.  

The therapy with potassium citrate, or magnesium potassium citrate, is commonly prescribed in clinical practice in order to increase urinary citrate and to reduce stone formation rates.

Medullary sponge kidney (MSK) is a renal malformation typically associated with nephrocalcinosis and recurrent calcium stones. A retrospective analytical study was conducted on 97 patients with a radiologic diagnosis of medullary sponge kidney: 65 had at least one stone risk factor (SRF; hypercalciuria, hypocitraturia, hyperuricosuria, hyperoxaluria) and received potassium citrate [29 ± 8 (SD) mEq/d]; 10 patients with SRF and 22 without received only general stone clinic suggestions.¹²Fabris A, Lupo A et al. Long-Term Treatment with Potassium Citrate and Renal Stones in Medullary Sponge Kidney Clin J Am Soc Nephrol. 2010; 5(9): 1663–1668.   The 24-hour urinary excretion of calcium, oxalate, uric acid, citrate, and morning urine pH were investigated at baseline and at the end of follow-up. Results of this study showed that potassium citrate led to a dramatic reduction in the stone event rate (from 0.58 to 0.10 stones/yr per patient). This study concluded that treatment with potassium citrate was effective in preventing renal stones in the typical patient with MSK.

Hypocitraturia

Potassium citrate has been demonstrated to reduce the stone formation rates by 96% in patients with hypocitraturia. The response to potassium citrate has also been shown to be durable. With a median of 41 months follow-up, urinary pH and citrate levels remained significantly higher in patients treated with potassium citrate when compared with pretreatment values. Potassium citrate significantly decreased the stone formation rate in this long-term clinical trial (Figure 1). The dosage should be titrated with a goal of obtaining urinary citrate level greater than 500 mg/day.¹³Lipkin ME et al. Demystifying the Medical Management of Nephrolithiasis. Rev Urol. 2011;13(1):34-38.  

Renal tubular acidosis

A study was conducted to compare the effects of potassium citrate to that sodium citrate in well defined 6 cases of incomplete distal renal tubular acidosis.¹⁴Preminger GM et al. Alkali action on the urinary crystallization of calcium salts: contrasting responses to sodium citrate and potassium citrate. J Urol. 1988;139(2):240-2.   The patients were studied during a control phase, during potassium citrate treatment of 80 m Eq per day and also during sodium citrate treatment of 80 m Eq per day chosen in a random order. Potassium citrate caused the decrease in urinary calcium and a significant increase in urinary citrate that resulted in significant decrease in the urinary saturation of calcium oxalate. Sodium citrate also increased the urinary citrate level, but there was no decrease in the urinary calcium. This study supported the potential clinical advantage of potassium citrate therapy over sodium alkali treatment in patients with incomplete distal renal tubular acidosis.

Hypomagnesuria

This is characterized by low levels (< 50mg/24hr) of magnesium in urine. Most common causes of hypomagnesuria are due to dietary deficiency, inflammatory bowel disease & use of thiazide diuretics. A study was conducted by Pak CY to ascertain whether hypomagnesemia developed during short-term thiazide treatment in normal subjects and if it could be corrected by potassium-magnesium citrate supplementation. In this study hypomagnesemia (< or =1.8 mg/dl) was disclosed in 19.4% of 242 subjects on thiazide alone.¹⁵Pak CY. Correction of thiazide-induced hypomagnesemia by potassium-magnesium citrate from review of prior trials. Clin Nephrol. 2000;54(4):271-5.   After 1-3 weeks of treatment with hydrochlorothiazide 50mg/day, subjects received supplementation with potassium magnesium citrate while continuing on thiazide for 3 weeks. The frequency of hypomagnesemia decreased from 22.9% on thiazide alone to 4.6% after 4 weeks of supplementation.

Another study shows potassium magnesium citrate is effective in reversing hypokalemia and may improve magnesium balance in subjects receiving thiazide diuretics.¹⁶Ruml LA, Pak CY. Effect of Potassium Magnesium Citrate on Thiazide-Induced Hypokalemia and Magnesium Loss. Am J Kidney Dis. 1999;34(1):107-13.   It also increases urinary pH and citrate values, making it an effective drug for the prevention of uric acid and calcium oxalate stones.

Potassium citrate after surgical intervention

Potassium citrate has an important role in clearance of the residual stone fragments after surgical interventions like ESWL and PCNL. It inhibits calcium oxalate aggregation and crystallization which helps in stone fragment clearance. Post-surgical administration of potassium citrate becomes more important because 92% of patients are at risk of stone recurrence following ESWL.

A study was conducted to evaluate the efficacy of potassium citrate treatment in preventing stone recurrences and residual fragments after shockwave lithotripsy (SWL) for lower pole calcium oxalate urolithiasis.¹⁷Soygür T, Akbay A, Küpeli S. Effect of potassium citrate therapy on stone recurrence and residual fragments after shockwave lithotripsy in lower caliceal calcium oxalate urolithiasis: a randomized controlled trial. J Endourol. 2002;16(3):149-52.   This study showed that potassium citrate therapy significantly alleviated calcium oxalate stone activity after SWL for lower pole stones in patients who were stone free.

Urinary tract infection

In a clinical trial of recurrent UTI in 59 children, potassium citrate was prescribed along with salt, protein, and calcium restriction due to hypercalciuria.16 In 95% of the children, no further episodes of UTI occurred once normocalciuria was achieved. The efficacy of citrate in the treatment of calcium oxalate and urate kidney stones has been well documented.¹⁸Pak CY, Sakhaee K, Fuller C. Successful management of uric acid nephrolithiasis with potassium citrate. Kidney Int 1986;30:422-428.  

As a potassium salt, citrate raises the pH of urine and increases uric acid dissociation, thus inhibiting uric acid stone formation. Potassium citrate also decreases urinary excretion of calcium and inhibits growth and precipitation of calcium phosphate and calcium oxalate crystals in the urine.¹³Lipkin ME et al. Demystifying the Medical Management of Nephrolithiasis. Rev Urol. 2011;13(1):34-38.  

A recent study assessed the effect of potassium citrate in preventing recurrences of kidney stones in 64 patients, who were followed 24-60 months after initial incident.¹⁹Lee YH, Huang WC, Tsai JY, Huang JK. The efficacy of potassium citrate based medical prophylaxis for preventing upper urinary tract calculi: a midterm followup study. J Urol 1999;161:1453-1457.   Compared to a control group who received no prophylaxis (46.2% recurrence), or a group with intermittent prophylaxis (30% recurrence), those on potassium citrate had only a 7.8% recurrence rate.

Cystinuria

A study was conducted by Fjellstedt E et al in patients with homozygous cystinuria to compare the effects of potassium citrate and sodium bicarbonate in the alkalinization of urine.²⁰Fjellstedt E, Denneberg T, Jeppsson JO, Tiselius HG. A comparison of the effects of potassium citrate and sodium bicarbonate in the alkalinization of urine in homozygous cystinuria. Urol Res. 2001;29(5):295-302.   The study was conducted on 14 patients. In the first week the study was conducted without any alkalizing agent (Period 0) followed by 2 weeks with sodium bicarbonate (Period 1) and 2 weeks with potassium citrate (Period 2). Urinary pH, volume, excretion of sodium, potassium, citrate and free cystine, as well as the plasma potassium concentration, were recorded. The study supported the effective use of potassium citrate for urine alkalization in homozygous cystinuria.

Conclusion

It can be concluded that sodium bicarbonate is no longer considered as the first line agent for urine alkalization.

Sodium salts have the drawback that they have to be used with caution in patients with cardiac failure, hypertension, impaired renal function, peripheral and pulmonary edema, toxemia and pregnancy. Further, sodium salts are to be used with caution in patients with low urinary output or reduced GFR who are prone to hyperkalemia and alkalosis. Sodium salts may actually increase cystine secretion.

Whereas, potassium citrate is highly beneficial as it is highly palatable, has pleasant taste and is tolerable even with long term use. It does not neutralize gastric juice or disturbs digestion. Potassium citrate has the superior efficacy in urine alkalization for the management of nephrolithiasis, cystinuria, renal tubular acidosis, hypomagnesuria, hypocitraturia, UTI and also in clearing the residual stone fragments after surgical intervention when compared to sodium salts. Various recent studies support the evidence in favour of potassium citrate as the first line urine alkalizing agent.

References

1. Proudfoot AT, Krenzelok EP, Vale JA. Position paper on urine alkalinization. J Toxicol Clin Toxicol. 2004;42(1):1-26.
2. Roberts DM, Buckley NA. Urinary alkalinization for acute chlorophenoxy herbicide poisoning. Cochrane Database Syst Rev. 2007(1):CD005488.
3. Wax P. Antidotes in Depth: Sodium Bicarbonate. New York, NY:McGraw Hill; 2006.
4. Zimmerman JL. Poisonings and overdoses in the intensive care unit: general and specific management issues. Crit Care Med. 2003;31(12):2794-2801.
5. Shamash J, Earl H, Souhami R. Acetazolamide for alkalinization of urine in patients receiving high-dose methotrexate. Cancer Chemother Pharmacol. 1991;28(2):150-151.
6. Chandra S. Biyani A, Jon J. Cartledge; Cystinuria-Diagnosis and Management; EAU-EBU updateseries 4(2006):175-183.
7. Schuster VL. Potassium deficiency: pathogenesis and treatment. In: Seldin DW, Giebisch G, eds. The Regulation of Potassium Balance. New York, NY: Raven Press; 1989:241-267.
8. Sakhaee K, Nicar M, Hill K, Pak CY; Contrasting effects of potassium citrate and sodium citrate therapies on urinary chemistries and crystallization of stone-forming salts; Kidney Int. 1983;24(3):348-52.
9. Dipiro JT, Talbert RL, Yee GC, et al. Pharmacotherapy: a pathophysiologic approach. 3rd ed. Appleton and Lange; 1997.
10. Hall P. Nephrolithiasis. Cleveland clinic Journal of Medicine 2009; 76(10):683-591.
11. Straub M, Hautmann RE .Developments in stone prevention. Curr Opin Urol. 2005;15(2):119-26.
12. Fabris A, Lupo A et al. Long-Term Treatment with Potassium Citrate and Renal Stones in Medullary Sponge Kidney Clin J Am Soc Nephrol. 2010; 5(9): 1663–1668.
13. Lipkin ME et al. Demystifying the Medical Management of Nephrolithiasis. Rev Urol. 2011;13(1):34-38
14. Preminger GM et al. Alkali action on the urinary crystallization of calcium salts: contrasting responses to sodium citrate and potassium citrate. J Urol. 1988;139(2):240-2.
15. Pak CY. Correction of thiazide-induced hypomagnesemia by potassium-magnesium citrate from review of prior trials. Clin Nephrol. 2000;54(4):271-5.
16. Ruml LA, Pak CY. Effect of Potassium Magnesium Citrate on Thiazide-Induced Hypokalemia and Magnesium Loss. Am J Kidney Dis. 1999;34(1):107-13.
17. Soygür T, Akbay A, Küpeli S. Effect of potassium citrate therapy on stone recurrence and residual fragments after shockwave lithotripsy in lower caliceal calcium oxalate urolithiasis: a randomized controlled trial. J Endourol. 2002;16(3):149-52.
18. Pak CY, Sakhaee K, Fuller C. Successful management of uric acid nephrolithiasis with potassium citrate. Kidney Int 1986;30:422-428.
19. Lee YH, Huang WC, Tsai JY, Huang JK. The efficacy of potassium citrate based medical prophylaxis for preventing upper urinary tract calculi: a midterm followup study. J Urol 1999;161:1453-1457.
20. Fjellstedt E, Denneberg T, Jeppsson JO, Tiselius HG. A comparison of the effects of potassium citrate and sodium bicarbonate in the alkalinization of urine in homozygous cystinuria. Urol Res. 2001;29(5):295-302.