Metabolic Risk Factors and Nephrolithiasis

EPIDEMIOLOGY OF NEPHROLITHIASIS – AN OVERVIEW

Nephrolithiasis/urolithiasis or calculus in the urinary tract is a frequently encountered medical condition in the emergency department which generally presents as renal colic. Historical evidence for renal calculi in humans can be traced as far back as 4800 BC, the Egyptian mummies around which time have been found to have calculus in the urinary tract. Additionally, various ancient texts also depict the excruciatingly painful nature of renal colic due to urinary stones, with some literature, especially from India, even mentioning different techniques of stone extraction to provide relief. While archaeological evidences suggest its prevalence to be low during that era, contemporary estimates conclusively indicate a steady escalation in the prevalence of urolithiasis globally. This change in prevalence trend, which cuts across age, race and gender, has been ascribed to changes in dietary habits, and increasing prevalence of cardiometabolic disorders, including obesity, hypertension, diabetes, chronic kidney disease and cardiovascular diseases, which have been closely linked with the risk of renal stone formation. These cardiometabolic risk factors and specific dietary habits induce various lithogenic metabolic alterations in the body – hypercalciuria, hyperoxaluria, hyperuricosuria, and hypocitraturia. Furthermore, various climatic, dietetic and genetic factors by modulating these metabolic changes also influence the risk of lithogenesis. Since these factors differ from one region to another, an inter-regional variation in the prevalence of urolithiasis is expected and is accordingly observed. On an average, the lifetime risk of renal stone formation is 5-10%, which however varies across the globe, being 1-5% in Asia, 5-9% in Europe, 13% in North America, and 20% in Saudi Arabia. Although from these estimates it may be inferred that affluent nations bear the maximum brunt of urolithiasis, it is noteworthy that the developing and not so affluent nations of the world are rapidly catching up with these nations. This is credited to socioeconomic development and globalization in these regions. In fact, in certain regions of Southeast Asia, such as northeast Thailand and northeast India, the prevalence of urinary stones has been reported as high as 16.9% and 22.4%, respectively; figure 1.¹Stewart A, Joyce A. Modern management of renal colic. Trends in Urology Gynaecology & Sexual Health. 2008.   ²Lopez M, Hoppe B. History, epidemiology and regional diversities of urolithiasis. Pediatr Nephrol. 2010;25:49-59.   ³Romero V, Akpinar H, Assimos DG. Kidney Stones: A Global Picture of Prevalence, Incidence, and Associated Risk Factors. Rev Urol. 2010;12(2/3):e86-e96.   ⁴Ramello A, Vitale C, Marangella M. Epidemiology of nephrolithiasis. J Nephrol. 2000 Nov-Dec;13 Suppl 3:S45-50.   ⁵Yanagawa M, Kawamura J, Onishi T, et al. Incidence of urolithiasis in northeast Thailand. Int J Urol. 1997 Nov;4(6):537-40.   ⁶Marak A, Shantibala K, Singh A, et al. Urolithiasis prevalence and related factors in a rural area of Manipur. Int J Med Sci Public Health. 2013;2(4):956-959.   ⁷Qadami E, Ampoon A, Manansala NH. The prevalence and clinical profile of patients diagnosed with renal calculi at the American Mission Hospital in the Kingdom of Bahrain. J Bahrain Med Soc. 2013;24(2):62-65.   ⁸Rao TV, Bano S, Das M. Epidemiology of Urolithiasis and Chemical Composition of Urinary Stones in Purnia Division of Bihar. Indian Journal of Community Medicine. 2006;31(2):76-77.   ⁹Qaader DS, Yousif SY, Mahdi LK. Prevalence and etiology of urinary stones in hospitalized patients in Baghdad. Eastern Mediterranean Health Journal. 2006;12(6):853-861.  

The prevalent dietary habits in a given geographic region also influence the stone composition and its location in the urinary tract (figure 2). Predominantly, the renal stones are calcareous in composition, and unequivocally the upper urinary tract stones are more common than the lower urinary tract stones in both genders and all age groups; prevalence of upper and lower urinary tract stones is estimated to range between 60.8%-84.6% and 15.4%-39.2%, respectively. Table 1 provides composition of urinary stones and their prevalence.¹Stewart A, Joyce A. Modern management of renal colic. Trends in Urology Gynaecology & Sexual Health. 2008.  
 ⁴Ramello A, Vitale C, Marangella M. Epidemiology of nephrolithiasis. J Nephrol. 2000 Nov-Dec;13 Suppl 3:S45-50.   ⁸Rao TV, Bano S, Das M. Epidemiology of Urolithiasis and Chemical Composition of Urinary Stones in Purnia Division of Bihar. Indian Journal of Community Medicine. 2006;31(2):76-77.   ⁹Qaader DS, Yousif SY, Mahdi LK. Prevalence and etiology of urinary stones in hospitalized patients in Baghdad. Eastern Mediterranean Health Journal. 2006;12(6):853-861.   ¹⁰Evan AP. Physiopathology and etiology of stone formation in the kidney and the urinary tract. Pediatr Nephrol. 2010;25:831-841.   ¹¹Singh KB, Sailo S. Understanding epidemiology and etiologic factors of urolithiasis: an overview. Sci Vis. 2013;13(4):ISSN (print) 0975-6175.  

Although renal stones are encountered in both genders and all age groups, it is noteworthy that they show predilection for male gender, with the average male-to-female ratio being 1.5-2.5:1. However, the current statistical analyses suggest that by the end of this millennium the prevalent gender disparity will disappear. With regards to the influence of age, the peak age of renal stone occurrence is between 20-50 years, after which the incidence declines drastically.⁷Qadami E, Ampoon A, Manansala NH. The prevalence and clinical profile of patients diagnosed with renal calculi at the American Mission Hospital in the Kingdom of Bahrain. J Bahrain Med Soc. 2013;24(2):62-65.   ⁹Qaader DS, Yousif SY, Mahdi LK. Prevalence and etiology of urinary stones in hospitalized patients in Baghdad. Eastern Mediterranean Health Journal. 2006;12(6):853-861.   ¹²Smith RD, Shah M, Patel A. Recent advances in management of ureteral calculi. F1000 Medicine Reports. 2009;1:53.   ¹³Lieske JC, Peña de la Vega LS, Slezak JM, et al. Renal stone epidemiology in Rochester, Minnesota: an update. Kidney Int. 2006 Feb;69(4):760-4.  

Overall, it may be summed up that prevalence of urolithiasis is increasing globally, and this is ascribable to a rise in lithogenic metabolic risk factors.

METABOLIC RISK FACTORS FOR RENAL STONES

Calculus in the urinary tract is a multifactorial disorder, with various metabolic alterations playing a central role in its development. These include hypercalciuria, hyperoxaluria, hyperuricosuria, hyperphosphaturia, and hypocitraturia. Table 2 describes metabolic alterations predisposing to the formation of 3 major types of renal stones.¹⁴Nouvenne A, Meschi T, Guerra A, et al. Dietary treatment of nephrolithiasis. Clinical Cases in Mineral and Bone Metabolism. 2008;5(2):135-141.  

Concentrated urine is an established risk factor for urinary stone formation, since it increases crystallization of lithogenic minerals in the urine. Appropriately, increasing fluid intake to ≥2 L/day is a traditional, economical and effective therapy to prevent the formation of urinary stones and their recurrence. Increased fluid intake promotes mechanical diuresis and prevents crystallization of lithogenic minerals. Apart from water, increased consumption of coffee, tea, beer and wine has also been recognized to prevent urolithiasis. Citrates also impart protective effects against the development of nephrolithiasis. However, counterintuitively, not all citrus juices render protection against urolithiasis. Lime and lemon juices are perfect examples, which despite their high citrate content do not protect against the formation of renal stones, primarily owing to their acidic nature. Contrarily, orange juice, notwithstanding its low citrate content, offers protection against stone formation by raising urinary pH by approximately 0.6-0.8 points. Overall, it may be summated that various factors, such as fluid intake, urine pH, and metabolic alterations act in tandem to influence the risk of lithogenesis.¹⁵Nouvenne A, Meschi T, Guerra A, et al. Dietary treatment of nephrolithiasis. Clinical Cases in Mineral and Bone Metabolism. 2008;5(2):135-141.   ¹⁶Prasetyo T, Birowo P, Rasyid N. The influence of increased fluid intake in the prevention of urinary stone formation: a systematic review. Acta Med Indones. 2013 Oct;45(4):253-8.   ¹⁷Ferraro PM, Taylor EN, Gambaro G, et al. Soda and other beverages and the risk of kidney stones. Clin J Am Soc Nephrol. 2013 Aug;8(8):1389-95.  

Hypercalciuria

Hypercalciuria is an established prolithogenic metabolic risk factor. It is defined as greater than 200 mg of urinary calcium excretion in 24 hours. It can develop as absorptive hypercalciuria, renal hypercalciuria or resorptive hypercalciuria. Increased consumption of calcium-containing diet which is poor in oxalate generally results in absorptive hypercalciuria, since increased absorption of calcium from the gut increases the renal burden of calcium greater than its absorptive capacity. On the other hand, impaired renal tubular absorption of calcium would result in renal hypercalciuria. Resorptive hypercalciuria is due to primary hyperparathyroidism which increases calcium resorption from bones which in turn increases its load on the renal tubules and thus hypercalciuria.¹⁸Parmar MS. Kidney stones. BMJ 2004;328:1420-4.  

High protein diet, especially rich in animal proteins, has been determined as an important harbinger of hypercalciuria. Animal proteins are rich in sulfurcontaining amino acids (cystine and methionine). The sulfate released upon oxidation of these proteins increases the systemic acidic load which is buffered by the bones, resulting in bone resorption and increased calcium load on the renal tubules. The sulfate derived from these animal proteins also forms soluble salts with calcium which further limit renal calcium reabsorption. Additionally, animal proteins increase the renal mass which in turn upregulates calcitriol or bioactive vitamin D production and attendant increase in calcium absorption from the gut. Concurrently, feedback inhibition of parathyroid hormone (PTH) reduces renal reabsorption of calcium, resulting in hypercalciuria.²Lopez M, Hoppe B. History, epidemiology and regional diversities of urolithiasis. Pediatr Nephrol. 2010;25:49-59.  

Apart from high-protein diet, a diet abundant in refined carbohydrates also induces hypercalciuria by increasing intestinal calcium absorption and decreasing distal renal tubular calcium reabsorption. Moreover, it is a risk factor for obesity and metabolic syndrome, which are established promoters of hypercalciuria. The acidogenic high-fat diet also promotes hypercalciuria by increasing the risk of obesity.²Lopez M, Hoppe B. History, epidemiology and regional diversities of urolithiasis. Pediatr Nephrol. 2010;25:49-59.   ¹⁵Nouvenne A, Meschi T, Guerra A, et al. Dietary treatment of nephrolithiasis. Clinical Cases in Mineral and Bone Metabolism. 2008;5(2):135-141.   ¹⁹Zerifi R, Bahlous A, Marakchi O, et al. Metabolic syndrome: pathophysiology and impact on lithogenesis. Ann Biol Clin (Paris). 2008 Jan-Feb;66(1):9-17.  Besides this indirect role, the available evidence also indicates that arachidonic acid (a type of fat) increases the production of prostaglandin E2 (PGE2), which promotes hypercalciuria. Appropriately, omega-3 fatty acids which reduce the production of PGE2 inhibit hypercalciuria and hyperoxaluria.¹⁴Nouvenne A, Meschi T, Guerra A, et al. Dietary treatment of nephrolithiasis. Clinical Cases in Mineral and Bone Metabolism. 2008;5(2):135-141.   ¹⁵Nouvenne A, Meschi T, Guerra A, et al. Dietary treatment of nephrolithiasis. Clinical Cases in Mineral and Bone Metabolism. 2008;5(2):135-141.  

High sodium in the diet and the resultant natriuria has also been posited to induce hypercalciuria. Natriuria increases urinary bicarbonate excretion and increases urine pH, which in turn increases crystallization of calcium and phosphate in the urine. Additionally, expansion of extracellular volume due to increased sodium reduces renal reabsorption of calcium and produces hypercalciuria. It is estimated that every 100 mmol/day increase in dietary sodium results in 25 mg/day increase in calciuria. Additionally, hypertension due to high sodium intake further contributes to hypercalciuria (see the trailing section for further elaboration).²Lopez M, Hoppe B. History, epidemiology and regional diversities of urolithiasis. Pediatr Nephrol. 2010;25:49-59.   ¹⁵Nouvenne A, Meschi T, Guerra A, et al. Dietary treatment of nephrolithiasis. Clinical Cases in Mineral and Bone Metabolism. 2008;5(2):135-141.   ²⁰Wagner CA, Mohebbi N. Urinary pH and stone formation. J Nephrol. 2010 Nov-Dec;23 Suppl 16:S165-9.   ²¹Taylor EN, Fung TT, Curhan GC. DASH-Style Diet Associates with Reduced Risk for Kidney Stones. J Am Soc Nephrol. 2009;20:2253-2259.   ²²Türk C, Knoll T, Petrik A. Guidelines on Urolithiasis. European Association of Urology 2013. Available at http://www.uroweb.org/gls/pdf/21_Urolithiasis_LR.pdf. Accessed on 25/02/2015.   ²³Gillen DL, Coe FL, Worcester EM. Nephrolithiasis and Increased Blood Pressure Among Females With High Body Mass Index. Am J Kidney Dis. 2005;46:263-269.   ²⁴Borghi L, Meschi T, Guerra A, et al. Essential arterial hypertension and stone disease. Kidney Int. 1999 Jun;55(6):2397-406.  Contrary to prolithogenic effects of natriuria, increased renal excretion of potassium imparts antilithogenic effects by reducing calciuria. This may be explained by increased renal tubular phosphate absorption that occurs concomitantly with potassium excretion which in turn inhibits the synthesis of calcitriol, and therefore reduces the intestinal absorption of calcium and its net urinary excretion.²Lopez M, Hoppe B. History, epidemiology and regional diversities of urolithiasis. Pediatr Nephrol. 2010;25:49-59.  

Hot climate in tropical countries, such as India, also predisposes to hypercalciuria by increasing the cutaneous synthesis of vitamin D, which increases intestinal absorption of calcium and its renal excretion. ⁹Qaader DS, Yousif SY, Mahdi LK. Prevalence and etiology of urinary stones in hospitalized patients in Baghdad. Eastern Mediterranean Health Journal. 2006;12(6):853-861.  

Hypertension also promotes formation of renal stones by increasing calciuria. Although the causal mechanisms by which hypertension promotes hypercalciuria remain incompletely deciphered, it is suggested that increase in intestinal calcium absorption and secondary activation of parathyroid gland in hypertensive individuals culminate in hypercalciuria. Moreover, increased salt intake and consumption of lithogenic diet (a diet rich in proteins fat and carbohydrates) by hypertensive individuals promote hypercalciuria in them. Irrespective of the mechanisms, it is notable that clinical trials have established beyond doubt that hypertension is a risk factor for hypercalciuria by documenting hypertensive individuals to exhibit far greater urinary calcium excretion than their normotensive counterparts; refer to table 3 for urine levels of various lithogenic minerals in hypertensive vs normotensive individuals.²⁴Borghi L, Meschi T, Guerra A, et al. Essential arterial hypertension and stone disease. Kidney Int. 1999 Jun;55(6):2397-406.   ²⁵Cappuccio FP, Kalaitzidis R, Duneclift S, et al. Unravelling the links between calcium excretion, salt intake, hypertension, kidney stones and bone metabolism. J Nephrol. 2000;13:169-177.  

Obesity and insulin resistance have also been associated with hypercalciuria and increased risk of calcium-containing urinary stones. Individuals with insulin resistance and higher body mass index (BMI) show increased urinary calcium excretion.²⁶Libório AB, Figueiredo PR, Montenegro RM, et al. Urinary calcium excretion and insulin resistance in patients with acromegaly. International Urology and Nephrology. 2012;44(5):1473-1477.  Although the mechanisms of association remain incompletely elucidated, it is suggested that impaired renal tubular calcium reabsorption in these patients potentially contributes to increased calciuria.²⁷Yüksel H, Darcan S, Kabasakal C, et al. Effect of enalapril on proteinuria, phosphaturia, and calciuria in insulin-dependent diabetes. Pediatr Nephrol. 1998 Oct;12(8):648-50.  Experimental trials have upheld these observations by noting the models of human type 2 diabetes and metabolic syndrome to demonstrate increased calcium excretion than their control counterparts.²⁷Iba A, Kohjimoto Y, Mori T, et al. Insulin resistance increases the risk of urinary stone formation in a rat model of metabolic syndrome. BJU Int. 2010 Nov;106(10):1550-4.  Furthermore, the results from clinical trials have strengthened the veracity of these findings by showing obese individuals weighing >120 kg to excrete increased amounts of urinary calcium compared to those weighing <100 kg.²⁹Powell CR, Stoller ML, Schwartz BF, et al. Impact of body weight on urinary electrolytes in urinary stone formers. Urology. 2000 Jun;55(6):825-30.  Collectively, these findings authenticate the supposition that obesity and insulin resistance induce hypercalciuria. Overall, figure 3 elaborates various mechanisms of hypercalciuria.

Hyperoxaluria

Hyperoxaluria is also an important metabolic risk factor which promotes lithogenesis. It is defined as urinary oxalate excretion greater than 45 mg in 24 hours. It can develop as enteric hyperoxaluria or primary hyperoxaluria. Enteric hyperoxaluria is due to low calcium and increased oxalate intake, ileal diseases or decolonization of oxalobacter. Low dietary calcium intake is particularly important for the development of hyperoxaluria, since dietary oxalates bind with calcium in the small and large intestines and form non-absorbable calcium oxalate salts, and thus regulate serum oxalate levels. However, reduced intake of calcium compels the oxalates in the intestines to bind with either sodium or potassium, resulting in the formation of absorbable salts which leads to increase in the serum oxalate levels and hence their excretion in the urine. Another important reason for hyperoxaluria is gut decolonization. Normally, the gut microflora is rich in oxalobacter, which limits oxaluria by degrading dietary oxalates. Understandably, gut decolonization would increase oxaluria. Apart from these environmental factors which promote hyperoxaluria and risk of urolithiasis, primary hyperoxaluria, an inborn error of metabolism, also increases the risk of renal stones. However, it is relieving that this disorder is a rarity.¹⁴Nouvenne A, Meschi T, Guerra A, et al. Dietary treatment of nephrolithiasis. Clinical Cases in Mineral and Bone Metabolism. 2008;5(2):135-141.   ¹⁵Nouvenne A, Meschi T, Guerra A, et al. Dietary treatment of nephrolithiasis. Clinical Cases in Mineral and Bone Metabolism. 2008;5(2):135-141.   ¹⁸Parmar MS. Kidney stones. BMJ 2004;328:1420-4.  

Apart from a diet rich in oxalates (spinach, rhubarb, beets, nuts, chocolate, tea, wheat bran, and strawberries), increased intake of animal proteins and fructose/glucose also augment oxaluria by increasing the production of glycolate (an oxalate precursor).²Lopez M, Hoppe B. History, epidemiology and regional diversities of urolithiasis. Pediatr Nephrol. 2010;25:49-59.   ¹⁵Nouvenne A, Meschi T, Guerra A, et al. Dietary treatment of nephrolithiasis. Clinical Cases in Mineral and Bone Metabolism. 2008;5(2):135-141.   ³⁰Massey LK, Roman-Smith H, Sutton RA. Effect of dietary oxalate and calcium on urinary oxalate and risk of formation of calcium oxalate kidney stones. J Am Diet Assoc. 1993 Aug;93(8):901-6.  Certain vitamins also modulate the risk of urolithiasis by influencing renal oxalate excretion. In this regard, it has surfaced that increased intake of vitamin C (its metabolism yields oxalates), particularly >1500 mg/day, is associated with hyperoxaluria.³¹Assimos DG. Vitamin C Supplementation and Urinary Oxalate Excretion. Rev Urol. 2004;6(3):167.  On the other hand, intake of vitamin B6 or pyridoxine, within permissible ranges, has been noted to mitigate the risk urinary stones by inhibiting the synthesis of oxalates and their excretion in urine.¹⁴Nouvenne A, Meschi T, Guerra A, et al. Dietary treatment of nephrolithiasis. Clinical Cases in Mineral and Bone Metabolism. 2008;5(2):135-141.   ³²Mitwalli A, Ayiomamitis A, Grass L, et al. Control of hyperoxaluria with large doses of pyridoxine in patients with kidney stones. Int Urol Nephrol. 1988;20(4):353-9.  

Additionally, metabolic factors such has increased BMI, also contribute to increased urinary excretion of oxalate in both men and women.³³Negri AL, Spivacow FR, Del Valle EE, et al. Role of overweight and obesity on the urinary excretion of promoters and inhibitors of stone formation in stone formers. Urol Res. 2008 Dec;36(6):303-7.  Increased urinary excretion of oxalate has been noted in obese (>120 kg) and hypertensive individuals compared to their control counterparts (Table 3).²⁴Borghi L, Meschi T, Guerra A, et al. Essential arterial hypertension and stone disease. Kidney Int. 1999 Jun;55(6):2397-406.   ²⁹Powell CR, Stoller ML, Schwartz BF, et al. Impact of body weight on urinary electrolytes in urinary stone formers. Urology. 2000 Jun;55(6):825-30.   Sex-steroid hormones have also been posited to influence renal excretion of oxalates. Findings from experimental studies indicate that while estrogens decrease oxaluria, testosterone may serve as prolithogenic factor by increasing oxaluria. These findings possibly explain the inherent increased risk of renal stone formation in males compared to females. Summarily, refer to figure 4 for various etiologic factors for hyperoxaluria.³⁴Yagisawa T, Ito F, Osaka Y, et al. The influence of sex hormones on renal osteopontin expression and urinary constituents in experimental urolithiasis. J Urol. 2001 Sep;166(3):1078-82.   ³⁵Li X, Liu K, Pan Y, et al. Roles of Osteopontin Gene Polymorphism (rs1126616), Osteopontin Levels in Urine and Serum, and the Risk of Urolithiasis: A Meta- Analysis. BioMed Research International. 2015;Volume 2015:Article ID 315043.  

Hyperuricosuria

Increased renal excretion of uric acid is an important prolithogenic factor. Uric acid is the end product of purine metabolism. Therefore, chronic metabolic acidosis which promotes protein/purine metabolism increases uric acid synthesis and thus its renal excretion. Formation of acidic urine (urine pH <5.5) is another harbinger of hyperuricosuria.¹⁸Parmar MS. Kidney stones. BMJ 2004;328:1420-4.  

A diet rich in animal proteins increases acidic load and promotes uric acid production and its renal excretion. Increased consumption of refined carbohydrates also promotes uricosuria.¹⁵Nouvenne A, Meschi T, Guerra A, et al. Dietary treatment of nephrolithiasis. Clinical Cases in Mineral and Bone Metabolism. 2008;5(2):135-141.  Additionally, certain metabolic disorders also increase the risk of hyperuricosuria. Obese individuals particularly show hyperuricosuria. Increased BMI is reportedly associated with formation of acidic urine and increased excretion of ammonium and uric acid. Insulin resistance also promotes hyperuricosuria by facilitating the formation of acidic urine and impairing renal excretion of ammonia, both factors serving as promoters of hyperuricosuria.¹⁸Parmar MS. Kidney stones. BMJ 2004;328:1420-4.   ³⁶Aydogdu O. Urinary stone disease and obesity: Different pathologies sharing common biochemical mechanisms. World J Nephrol. 2012;1(1):12-15.  For reasons incompletely understood, hypertension (refer to table 3), hypercholesterolemia and hypertriglyceridemia also promote urinary excretion of uric acid.²⁴Borghi L, Meschi T, Guerra A, et al. Essential arterial hypertension and stone disease. Kidney Int. 1999 Jun;55(6):2397-406.   ³⁷Torricelli FC, De SK, Gebreselassie S, et al. Dyslipidemia and kidney stone risk. J Urol. 2014;191(3):667-72.  

Hypocitraturia

Excretion of citrate in urine blunts the risk of lithogenesis. Therefore, any reduction in renal excretion of citrate – known as hypocitraturia – would promote urolithiasis. Hypocitraturia is defined as urinary excretion <250 mg citrate in 24 hours. Citrate in urine, which is a component of tricarboxylic acid cycle (TCA) and is excreted by renal tubular cells, forms soluble calcium salts which are passed out in urine. However, acidic diet, metabolic acidosis, distal renal tubular acidosis and hypokalemia promote hypocitraturia and thus formation of renal stones; box 1 enlists various etiologic factors of hypocitraturia.¹⁸Parmar MS. Kidney stones. BMJ 2004;328:1420-4.   ³⁸Zuckerman JM, Assimos DG. Hypocitraturia: Pathophysiology and Medical Management. Rev Urol. 2009 Summer;11(3):134-144.  

High animal protein intake increases acidic load and decreases urinary pH, both factors portending the risk of hypocitraturia.¹⁵Nouvenne A, Meschi T, Guerra A, et al. Dietary treatment of nephrolithiasis. Clinical Cases in Mineral and Bone Metabolism. 2008;5(2):135-141.   Although acidic urine promotes hypocitraturia, it is noteworthy that increased urinary pH associated with increased sodium intake in the diet and resultant natriuria also induces hypocitraturia; it is suggested that increased bicarbonate load in the proximal renal tubules secondary to natriuria induces hypocitraturia. Contrarily, food sources rich in potassium mitigate the risk of stone formation since they are replete in alkali agents, such as bicarbonates, which counter the acidic pH of the urine and hence promote hypercitraturia.²Lopez M, Hoppe B. History, epidemiology and regional diversities of urolithiasis. Pediatr Nephrol. 2010;25:49-59.  ³⁹Le JD, Eisner BH, Tseng TY, et al. Laterality of nephrocalcinosis in kidney stone formers with severe hypocitraturia. BJU Int. 2011 Jan; 107(1): 106-110.  

Various metabolic disorders also induce hypocitraturia. Impaired renal ammonium ion production associated with insulin resistance results in defective renal acid excretion and hypocitraturia.²Lopez M, Hoppe B. History, epidemiology and regional diversities of urolithiasis. Pediatr Nephrol. 2010;25:49-59.  ³⁹Le JD, Eisner BH, Tseng TY, et al. Laterality of nephrocalcinosis in kidney stone formers with severe hypocitraturia. BJU Int. 2011 Jan; 107(1): 106-110.   Hypertension also increases the risk of urolithiasis by inducing hypocitraturia.⁴⁰Kim YJ, Park MS, Kim WT, et al. Hypertension influences recurrent stone formation in nonobese stone formers. Urology. 2011 May;77(5):1059-63.   Additionally, the use of thiazide diuretics in these patients promotes hypokalemia – an important etiologic factor for hypocitraturia.³⁹Le JD, Eisner BH, Tseng TY, et al. Laterality of nephrocalcinosis in kidney stone formers with severe hypocitraturia. BJU Int. 2011 Jan; 107(1): 106-110.  

ROLE OF URINARY ALKALINIZATION IN PREVENTION OF URINARY STONE FORMATION

Urinary alkalinization is an effective method of dissolving urinary stones, particularly which do not warrant urgent surgical intervention for the reasons of pain, obstruction or infection. Struvite stones, however, are an exception since they form only in the settings of infection.⁴¹Bichler KH, Eipper E, Naber K, et al. Urinary infection stones. Int J Antimicrob Agents. 2002 Jun;19(6):488-98.   Urinary alkalinizing agents (e.g., oral potassium citrate) effectively increase urinary pH and/ or citrate excretion and therefore play a therapeutic as well as preventive role in the management of urolithiasis. It should be remembered that the dosage of alkalinizing agents should be such that urinary pH is maintained between 6.5 and 7.0 and does not exceed 7.5. Similarly, dietary modulations should be such that urinary sodium-potassium ratio is maintained at <2.5 in order to prevent stone formation.⁴²Edrees B, Rasheed SA. Urinary Stone Disease. In: Elzouki AY, Harfi HA, Stapleton FB, et al. Textbook of Clinical Pediatrics. 2nd edition. Germany: Springer Science & Business Media; 2012. 2857-2878.  

Benefits of citrate in urine

Benefits of citrate therapy in the management of urolithiasis are well-established. High availability of citrate in urine reduces stone formation by inhibiting crystallization of calcium salts. Citrate in urine binds to urinary calcium and forms a soluble complex which reduces the availability of free ionic calcium to form urinary calcium oxalate or phosphate crystals. Additionally, citrate also acts as a direct inhibitor of calcium crystal aggregation and growth.⁴³Tiselius HG, Berg C, Fornander A-M, Nilsson M-A. Effects of citrate on the different phases of calcium oxalate crystallization. Scanning Microscopy. 1993; 7: 381-91.   ⁴⁴Xu H, Zisman AL, Coe FL, et al. Kidney stones: an update on current pharmacological management and future directions. Expert Opin Pharmacother. 2013;14(4):435-447.  

Benefits of oral potassium citrate over sodium-containing alkali

Oral potassium citrate is mainly used for supplementation due to its documented superior efficacy in urine alkalinization. It is preferred as a first-line urine alkalinizing agent over sodium-containing salts, such as sodium bicarbonate or sodium citrate, since sodium load is known to increase urinary calcium excretion which may blunt the benefits of hypercitraturia.⁴⁴Xu H, Zisman AL, Coe FL, et al. Kidney stones: an update on current pharmacological management and future directions. Expert Opin Pharmacother. 2013;14(4):435-447.  ⁴⁵Vigen R, Weideman RA, Reilly RF. Thiazides diuretics in the treatment of nephrolithiasis: are we using them in an evidence-based fashion? Int Urol Nephrol. 2011;43(3):813-819.   Another important reason for its preference is more solubility of potassium urate compared with sodium urate.⁴⁶Maneesh S, Kumar P, Prasanna V, et al. Results of urinary dissolution therapy for radiolucent calculi. Int. braz j urol. 2013;39(1): Print version ISSN 1677-5538.   Also, potassium citrate therapy repletes the depleted potassium levels secondary to the use of thiazide diuretics; thiazide diuretics are frequently used in the management of urolithiasis.⁴⁵Vigen R, Weideman RA, Reilly RF. Thiazides diuretics in the treatment of nephrolithiasis: are we using them in an evidence-based fashion? Int Urol Nephrol. 2011;43(3):813-819.   Furthermore, oral potassium citrate is quite safe, highly palatable and has pleasant taste and good tolerability profile even after long-term use; all these clinical advantages may improve patient compliance. The safety of sodium-containing alkali, on the other hand, is questionable, especially in patients in whom sodium intake should be restricted, for example, pregnant women, hypertensive patients and patients with heart disease.⁴⁷Sweetman S. Martindale: The Complete Drug Reference. Edition 37; London: pharmaceutical press; 2011.   The aforementioned observations together explain the preference of potassium citrate over sodium-containing salts as a urinary alkalinizer.

Potassium citrate was approved by the US FDA in 1985 for prevention of calcium stones (including calcium oxalate stones) and uric acid stones.⁴⁸Kidney Stones. Available at http://healthlibrary.epnet.com/GetContent.aspx?token=e0498803-7f62-4563-8d47-5fe33da65dd4&chunkiid=21459. Accessed on 24/07/15.   The dosage of potassium citrate should be titrated with the goal of achieving urinary citrate level > 500 mg/day, which would effectively ameliorate multiple metabolic abnormalities associated with urolithiasis, including hypercalciuria, hypocitraturia, hyperuricosuria and cystinuria, and thus prevent stone recurrence.⁴⁹Singh SK, Agarwal MM, Sharma S. Medical therapy for calculus disease. BJU Int. 2011 Feb;107(3):356-68.  ⁵⁰Suarez M, Youssef RF. Potassium Citrate: Treatment and Prevention of Recurrent Calcium Nephrolithiasis. J Clin Nephrol Res. 2015;2(1):1015.   More specifically, in patients with idiopathic hypercalciuria, potassium citrate therapy offers dual benefits of reducing urinary calcium excretion and increasing urinary citrate excretion. Similarly, in patients with uric acid stones it decreases the undissociated uric acid content in the urine and prevents complication of calcium nephrolithiasis.⁵¹Alon US. Medical treatment of pediatric urolithiasis. Pediatr Nephrol. 2009 Nov; 24(11): 2129-2135.   ⁵²Pak CY, Sakhaee K, Fuller C. Successful management of uric acid nephrolithiasis with potassium citrate. Kidney International. 1986;30:422-428.  Unfortunately, sodium citrate therapy does not decrease urinary calcium excretion, and hence may not be effective in preventing calcium nephrolithiasis in these patients.⁵²Pak CY, Sakhaee K, Fuller C. Successful management of uric acid nephrolithiasis with potassium citrate. Kidney International. 1986;30:422-428.   Also, potassium citrate therapy, either with or without thiazide diuretic, is strongly recommended in patients with renal tubular acidosis (depending upon their relative urinary risk factors) to prevent recurrent urinary stones.⁵³Skolarikos A, Straub M, Knoll T, et al. Metabolic evaluation and recurrence prevention for urinary stone patients: EAU guidelines. Eur Urol. 2015 Apr;67(4):750-63.   Moreover, since patients with multiple stones generally have hypocitraturia and are at heightened risk for stone recurrence, oral potassium citrate therapy should be initiated in them to prevent stone recurrence.⁵⁴Kang HW, Seo SP, Kwon WA, et al. Distinct metabolic characteristics and risk of stone recurrence in patients with multiple stones at the first-time presentation. Urogy. 2014;84(2):274-278.   Figure 5 compositely depicts benefits of oral potassium citrate therapy in urolithiasis.

Documenting the clinical benefits of potassium citrate therapy, a retrospective cohort study of mean 41-month follow up demonstrated 6 months of oral potassium citrate supplementation to increase urinary pH from 5.90 to 6.46 and urinary citrate excretion from 470 to 700 mg/day. These metabolic changes clinically translated into 68% stone remission rate and 93% reduction in stone formation rate (figure 6).⁵⁵Robinson MR, Leitao VA, Haleblian GE, et al. mpact of long-term potassium citrate therapy on urinary profiles and recurrent stone formation. J Urol. 2009 Mar;181(3):1145-50.  

Similarly, a clinical trial by Pak et al which evaluated the long-term effects of potassium citrate therapy, either alone or in combination with thiazide and/or allopurinol, in 53 patients with urolithiasis demonstrated significant increase in urinary pH and citrate excretion, significant decrease in urinary saturation of calcium oxalate and decline in spontaneous nucleation of calcium oxalate. Consequently, new stone formation was reduced, and stone passage rate decreased from 5.14-7.41 stones/patient year at baseline to 0.66-1.33 stones/patient year during the treatment and remission was achieved in 75- 91.7% patients. Also, in approximately 43% patients with radiopaque stones potassium citrate treatment reduced the number of radiographically visible stones.⁵⁶Pak CY, Sakhaee K, Fuller CJ. Physiological and physiochemical correction and prevention of calcium stone formation by potassium citrate therapy. Trans Assoc Am Physicians. 1983;96:294-305.  

In aggregate, oral potassium citrate is a valuable medical therapy for the management of urolithiasis.

CONCLUSION

Nephrolithiasis/urolithiasis has afflicted human beings for millennia and continues to be a significant and recurrent cause of morbidity globally. It is encountered in all age groups and in both genders; however, the peak age of incidence is between 20 and 50 years and unequivocally shows male preponderance. Although considered to be a disease of affluent nations, the changing socioeconomic environment and globalization have led to its emergence as a fairly frequent medical entity even in the less affluent and the developing regions of the world. These changing trends are ascribable to changes in dietary habits, and increasing prevalence of cardiometabolic disorders, including obesity, hypertension, diabetes and chronic kidney disease, which are closely associated with the risk of renal stone formation. These cardiometabolic risk factors and the specific dietary habits induce various lithogenic metabolic alterations in the body, including hypercalciuria, hyperoxaluria, hyperuricosuria, and hypocitraturia. These metabolic risk factors portend the risk of urinary stone formation, especially calciumcontaining stones in the upper urinary tract, which are ubiquitously the predominant stone types encountered in clinical practice.

Since oral potassium citrate therapy can drastically reduce stone formation rates and has durable longterm effects, it is an important cornerstone of medical management of urolithiasis.

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