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REVIEW ARTICLE |
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| Year : 2002 | Volume
: 19
| Issue : 1 | Page : 20-28 |
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Current approaches in the medical management of urolithiasis: A review article
NP Gupta, Pawan Kesarwani
Department of Urology, All India Institute of Medical Sciences, New Delhi, India
Correspondence Address:
N P Gupta
Department of Urology, AIIMS, Ansari Nagar, New Delhi - 110 029
India
 Source of Support: None, Conflict of Interest: None  | Check |
 Abstract | | |
The medical management of urolithiasis has undergone a great change. In the present time the management of urolithiasis is not only stone removal but also to prevent its recurrence. With the recent advances in the knowledge of pathogenesis of urolithiasis, the medical management is not only restricted to increased fluid intake, but to determine the cause of urolithiasis by a battery of investigation, the use of a particular drug to prevent urolithiasis if required and then to check the effectiveness of the drug by the application of investigations. This article has taken into consideration the various aspects of the etiopathogenesis of urolithiasis and its application towards the prevention of urolithiasis.
Keywords: Urolithiasis; Medical Management; Renal Calculus; Pathophysiology
How to cite this article:
Gupta N P, Kesarwani P. Current approaches in the medical management of urolithiasis: A review article. Indian J Urol 2002;19:20-8 |
| Introduction | |  |
The prevalence of urinary tract stone disease is estimated to be around 2-3% with the likelihood of a man developing stone disease by the age of 70 being 1 in 80. [1] The recurrence rate without treatment for calcium oxalate stone is about 10% at one year, 35% at five years and 50% at ten years. [2] The objective of medical approach in stone managmenent differs fundamentally from that of the surgical approach. [3]
In the last two decades there have been great advances in the field of removal of stones which includes extracorporeal shock wave lithotripsy, percutaneous nephrolithotomy and ureteroscopy. Taking into consideration the incidence of recurrence, surgical treatment of the urinary tract stone is an incomplete procedure. The goal of the surgical treatment is the removal of existing stones while that of the medical treatment is prevention of recurrent stone formation. Equally important progress has been made in the medical arena, continued medical diagnosis and treatment. The combined application of surgical and medical approaches is mandatory for the full control of the disease.
The importance of a medical prophylactic program is emphasized by the findings that urolithiasis is a disease with a high probability of recurrence [4] and the removal of stones is not likely to prevent new stone formation. While the medical approach potentially offers effective prevention of stone recurrence, [5],[6],[7] its application requires pathophysiological elucidation and diagnostic assessment. This article reviews and updates the progress made in the areas of pathophysiology and medical management of urolithiasis.
A. PATHOPHYSIOLOGY
| Hypercalciuria | | |
The association between increased urinary calcium excretion and calcium oxalate renal stones has been reported [8],[9],[10] and about 30-60% of patients with calcium oxalate stones have increased urinary calcium excretion in the absence of raised serum calcium levels. Urinary calcium excretion depends on dietary calcium intake, which varies between 400-2000 mg/day. Thus, the diagnosis of hypercalciuria requires a strict definition:
- Excretion of greater than 200 mg of calcium/24 hrs after one week adherence to a 400 mg of calcium and 100 mg of sodium diet. [11]
- Excretion of greater than 4 mg of calcium/kg body weight or greater than 7 mmol in men and 6 mmol in women. [12]
- Excretion of urinary calcium of greater than 0.11 mg/100 ml of glomerular filtrate. [13]
For the purpose of diagnosis and management hypercalciuria is divided into three types:
1. Absorptive hypercalciuria - Where the primary abnormality involves the increased intestinal absorption of calcium. This is further divided into three types:
Type 1 - the intestinal hyperabsorption of calcium exists irrespective of calcium restricted diet.
Type 2 - a variant where the patients exhibit increased urinary calcium excretion while on their normal diet but normal calcium excretion on a low calcium, low sodium diet.
Type 3 - a variant with renal phosphate leak causing hypophosphatemia which leads to increased renal synthesis of 1, 25 (OH)2 D resulting in hyperabsorption of calcium and the syndrome of hypercalciuria.
2. Renal hypercalciuria characterized by primary renal leak of calcium.
This involves primary renal wasting of calcium with consequent reduction in serum calcium stimulating parathyroid production. The increased parathyroid results in hydroxylation of 25 hydroxy Vit D to 1,25 dihydroxy Vit D3 increasing intestinal calcium absorption. These effects restore the serum calcium to normal at the expense of increased parathormone and 1,25 dihydroxy Vit D3.
Two factors which differentiate renal hypercalciuria from absorptive type hypercalciuria are elevated fasting urinary calcium and stimulated parathyroid function.
There is a more generalized disturbance is renal tubular function with renal hypercalciuria as shown by an exaggerated natriuretic response to thiazide [16] and exaggerated calciuric response to carbohydrate load. [17]
3. Resorptive hypercalciuria characterized by increased bone demineralization. [15]
Hypercalciuria results from excess PTH dependent bone resorption as well as enhanced intestinal absorption of calcium caused by PTH itself or by a PTH dependent synthesis of 1,25 OH2 Vit D3. Although PTH causes increased tubular absorption of calcium, the increase in the filtered load of calcium overwhelms this and results in excessive urinary calcium excretion.
| Hyperoxaluria | | |
Hyperoxaluria is related to calcium oxalate nephrolithiasis and is usually of three types.
- Increased oxalate production
- primary hyperoxaluria
- increased hepatic conversion
- Increased oxalate absorption
- Hyperoxaluria in idiopathic calcium oxalate stone disease.
Primary hyperoxaluria
It is of two types.
Type 1 - an autosomal recessive inborn error of metabolism characterized by nephrolithiasis, tissue deposition of oxalate and death from renal failure before the age of 20 in untreated patients. [18] There is increased excretion of oxalic, glycolic and glyoxalic acids due to the defect of enzyme alanine glyoxalic acid aminotransferase (AGT) in the liver. [19]
Type 2 - a rare variant occurs due to the deficiency of hepatic enzyme D-glycerate dehydrogenase and glyoxylate reductase, which leads to increase in urinary oxalate and glycerate excretion. [20]
Increased hepatic conversion occurs due to the pyridoxine deficiency, ethylene glycol ingestion and methoxyflurane anesthesia.
Increased Oxalate Absorption
Conditions causing increased oxalate absorption leading to hyperoxaluria are malabsorption occurring from bowel resection, intrinsic disease or jejunoileal bypass, which leads to increased colonic permeability of oxalate as a result of exposure of the colonic epithelium to bile salts; further the unabsorbed fats bind with the calcium making the dietary oxalate free for absorption.
Mild Metabolic Hyperoxaluria
Increased urinary oxalate excretion is seen in 0.3-0.5% of patients with calcium stones. [21] Increased dietary protein intake and altered renal excretion of oxalate have been predicted as an important cause for increased oxalate excretion. [22]
| Hyperuricosuria | | |
Patients with gout or hyperuricosuria form calcium oxalate stones apart from the uric acid stones. The most important cause for hyperuricosuria is excessive purine intake. Apart from this some patients have tendency to excrete more uric acid in the urine than do the normal subjects even on purine-free diet due to the increased uric acid production from endogenous purine metabolism.[23]
Factors leading to uric acid lithiasis in these patients are
(i) Excessive excretion of acid urine at relatively fixed low urinary pH;
(ii) Absorb, produce and excrete more uric acid than patients without gout to uric acid stones;
(iii) Diminished urine volumes.
All these factors serve as an ideal mechanism for the crystallization of uric acid in the urine. Uric acid further promotes calcium oxalate crystallization by facilitating the formation of nuclei. Addition of crystal:; of uric acid to the supersaturated calcium oxalate solution induces the deposition of well-oriented crystals of calcium oxalate over the uric acid. Sodium acid urate also nullifies the effectiveness of naturally occurring inhibitors of calcium oxalate crystal growth.
Hyperuricosuria may be seen in patients with specific enzyme defects such as increased activity of 5 phosphoribosyl 1-pyrophosphate synthetase, the enzyme that initiates purine metabolism and Lesh-Nyhan syndrome, with deficiency or complete lack of hypoxanthine guanine phosphoribosyl transferase resulting in shunting of hypoxanthine to xanthine/uric acid pathway leading to hyperuricosuria and hyperuricimea. Myeloproliferative disorders such as acute leukemia are important causes in childhood.
| Hypomagnesuria | | |
Decreased magnesium excretion is also a known fact for increased stone formation. [24] The most common cause of overt hypomagnesuria is inflammatory bowel disease associated with malabsorption. Patients with hypomagnesuria also have hypocitraturia.[25] The loss of inhibitory or complexing activity of magnesium or citrate is responsible for calcium oxalate crystallization.
| Ammonium Acid Urate Stones | | |
The stones are commonly found in children of developing countries and females with a history of laxative abuse. Conditions giving rise to these stones are [26],[27]
- low fluid intake;
- urealytic infection in the presence of excessive uric acid excretion;
- urinary phosphate deficiency.
| Cystinuria | | |
It is an autosomal recessive disorder of transmembrane cystine transport manifested as disease in absorption in the intestine and reabsorption in the proximal tubule. [28] The cystine excreted in the urine is poorly soluble within the range of normal pH and thus crystallizes to form the stone.
| Hypocitraturia | | |
Hypocitraturia has been reported in 19-63% of patients with nephrolithiasis. [29] There is wide range of variation for the normal level of citrate in urine. According to Dallas the low normal limit of citrate in urine is 320 mg/day for both men and women, irrespective of age and this limit provides a good empirical definition of hypocitraturia, since patients with urinary citrate below this level often show a clinical response to potassium citrate therapy superior to those whose citrate exceeds 320 mg/day. [30]
Hypocitraturia results from acidosis owing to a variety of disturbances, including distal renal tubular acidosis (complete and incomplete), [31] acidosis of chronic diarrhoea) state [32],[33] and potassium loss occurring from thiazide therapy.
In some patients, the exact cause of hypocitraturia is not known. [34],[35] In these patients, it is usually related to the consumption of a diet rich in animal proteins consisting of sulphur-containing amino acids (producing acid load),[36] strenuous physical exercise [30] and high sodium intake in the setting of low potassium intake (resulting in intracellular acidosis). Hypocitraturia is also encountered in patients with active urinary tract infection, presumably from the degradation of citrate by bacterial enzymes.
Pathogenic Role of Citrate in Calcium Nephrolithiasis
Citrate retards the crystallization of stone forming calcium salts by two mechanisms:
- The principal action is the complexation of calcium causing a reduction in ionic calcium concentration and in the urinary saturation of stone-forming calcium salts. [37],[38]
- Citrate directly inhibits the crystallization of calcium oxalate and calcium phosphate by agglomeration of calcium oxalate. It has a modest inhibitory role on the growth of calcium oxalate crystal. [39] Citrate acts as a potent inhibitor of crystal growth of calcium phosphate. In addition citrate has the ability to impair urate induced crystallization of calcium oxalate. [40]
When expressed relative to molecular weight, the inhibitory activity is much less than that of other inhibitors such as pyrophosphate, glycosaminoglycans, glycoproteins or Tamm-Horsfall protein but the amount of citrate normally present in the urine is many times that of other inhibitors.
Due to these inhibitors of citrate, the urinary environment of patients with hypocitraturic nephrolithiasis is characterised by an increased propensity for the crystallization of calcium salts.
Physiologic Basis For Hypocitraturia: Normal Physiology
Citrate is a key component of the citric acid cycle constituting an important source of energy. Only a small fraction of the large amount of citrate metabolized by the whole organism appears in the urine. Dietary citrate is a poor source of citrate since only 0.7% of it appears in the urine. [41]
In the circulation, citrate is present as a trivalent anion at a concentration of about 0.14 mM. Of the 9 micromoles of the citrate filtered by the kidney each minute 75% of it is reabsorbed in the proximal tubule and the rest 25% appears in the urine. [42] The proximal tubule also extracts citrate from the post glomerular blood at a rate of 1.5 micro mol./mt. making it to a total of 8.25 micro mol./mt.
The subsequent citrate oxidation to carbon dioxide and water via the citric acid cycle in the mitochondria of the tubular cell provides an important source of energy for the kidney. The tubular uptake of citrate alone accounts for the fact that citrate concentration in the renal cortex often exceeds that of peripheral blood.
Alternation in RenalCitrate Handling by Change in Acid Base Status
An alteration in acid base status profoundly influences the renal handling of citrate making it a major determinant of urinary citrate excretion. Metabolic acidosis facilitates the influx of citrate to the renal mitochondria, promoting citrate oxidation. A subsequent fall in the cytosolic citrate concentration leads to enhanced citrate uptake by the tubular cells, involving the sodium citrate cotransporter in the brush border basement membrane and the peritubular uptake. The increased tubular reabsorption of citrate reduces urinary citrate excretion, while stimulated mitochondrial citrate oxidation lowers the tissue content of citrate. Thus reduced citrate clearance parallels the fall in citrate concentration in the renal cortex.
These changes often occur without a substantial alteration in serum citrate concentration, moreover negligible citrate is secreted or synthesized during metabolic acidosis. The citrate finally appearing in the urine is that small fraction of citrate that escapes reabsorption. Metabolic acidosis reduces citrate excretion by augmenting citrate reabsorption.
Exactly the opposite sequence prevails in metabolic alkalosis; mitochondria) uptake of citrate is reduced retarding citrate oxidation while cytosolic concentration rises leading to reduced tubular reabsorption and peritubular uptake of citrate. Urinary citrate increases since a smaller fraction of filtered citrate is reabsorbed.
Other Determinants Of Citrate Excretion
Hypokalemia causes an intracellular metabolic acidosis in the renal cortex[43] leading to reduced citrate excretion by the same mechanism as in metabolic acidosis.
Organic acids (malate, succinate and furnerate) stimulate intrarenal citrate synthesis by providing substrate. [44] In addition, they provide an alkali load. These compounds enhance citrate excretion mostly through the effect of alkali on renal citrate handling and partly from the escape into the urine of synthesized citrate.
The ingestion of tamarind, a food item rich in tartaric acid, is believed to be useful in preventing stone formation. [45] The ability of tartaric acid to stimulate citrate excretion may explain this action.
Certain hormones may affect renal citrate excretion by a mechanism still poorly defined. Urinary citrate excretion is higher during the latter half of the normal menstrual cycle than the first half (by 100-200m-/day). [46] During pregnancy, urinary citrate excretion increases by 500 - 1000mg/ day. These results have been attributed to the action of oestrogen or progesterone or both. Parathyroid hormone also augments citrate excretion [47] as seen in patients suffering from primary hyperathyroidism. Vitamin D and calcitonin augment while androgen reduces citrate excretion.
B. MEDICAL MANAGEMENT
With time, there have been notable advances in the management of urolithiasis. The aim of the medical management is prevention of recurrent stones and if possible dissolution of the stone. The medical management of urolithiasis is a multistep approach that involves a detailed history and complete investigation. The institution of the medical therapy depends on the conclusion derived from the detailed workup.
The workup involves a detailed history to predict any causative factor for urolithiasis followed by the investigation which includes urine examination, serum investigations, stone analysis and if required twenty-four hours urine analysis on customary and controlled diet to detect any pathological factor (environmental, metabolic, physiochemical) which may lead to further stone formation.
The medical therapy consist of two parts:
- dietary modification;
- treatment of individual abnormal stone risk factors.
| Dietary Modification | | |
All patients of stone disease are advised to follow the dietary modification irrespective of their normal investigations.
High fluid intake
Patient is informed to measure urine output once a week and then adjust the fluid intake to maintain urine output more than two litres per day. They are also advised to take maximum intake of fluid within three hours after taking the meals, during periods of physical exercises, bedtime and once at midnight. Plain water is good enough but potassium rich citrus fruit juices such as orange, grape fruit and cranberry are preferable to low potassium citrus fruits such as lime and lemon. Orange juice, for example, represents a natural form of potassium citrate and possesses alkalinizing and citraturic action. [48] Lime juice, on the other hand, is composed largely of citric acid, and does not affect acid base balance appreciably, so it does not alter urinary pH and only modestly increases urinary citrate. [49] Increasing fluid intake actually has been demonstrated to have positive effect on two urinary inhibitors, citrate and Tamm-Horsfall protein. Hydration augments urinary citrate excretion, which is thought to result from an increased fluid flux in the proximal tubule resulting in the delivery of more bicarbonate to the cells of this portion of the nephron. [50],[51],[52] Urinary dilution has been found to increase the inhibitory activity of Tamm-Horsfall protein on the calcium oxalate monohydrate crystal aggregation in the urine of the stone formers. [53]
Restriction of animal proteins
Patient is informed to avoid nonvegetarian diet and the recommendation is of 8 oz or less of dry meat per day. Animal proteins are rich in sulphur-containing amino acids such as cystine and methionine, which on oxidation produces sulphate which forms a soluble complex with calcium in the nephron and limits the reabsorption of this cation. Bone serves as a buffer and the resultant osseous dissolution provides more calcium to be excreted. [54],[55],[56] Chronic metabolic acidosis decreases calcium reabsorption within the nephron, which further augments excretion of this mineral. Increased protein consumption also augments glomerular filtration, thus delivering more calcium to the nephron, which promotes its excretion. [57] Animal protein has a high purine content, which leads to increase in uric acid excretion. The associated acidosis results in a decrease in urinary pH that could potentiate uric acid urolithiasis. Acidosis also enhances citrate reasbsorption in the proximal tubule, thus decreasing the excretion of citrate in the urine.
Sodium restriction
Patient is asked to avoid high sodium-containing food with restriction of salt in the diet and salty shakers. Increased sodium intake may promote a variety of metabolic changes that may be detrimental to stone formers, including increase in the urinary pH, calcium and cystine excretion and a decrease in citrate excretion.
Oxalate restriction
Avoidance of nuts, spinachs, dark roughage, chocolate, tea, and vitamin C coupled with the advice to maintain recommended daily intake of calcium and to ensure that calcium consumption accompanies the ingestion of oxalate rich foods to prevent the absorption of oxalate.
Restriction of calcium
Moderate restriction of calcium is recommended and about 250m1 of milk or milk products can be taken daily. In patients who are advised for long-term restriction of calcium intake, measurement of bone density, particularly in the spine is recommended.
| Treatment of Individual Abnormal Stone Risk Factors | | |
Hypercalciuria
The management of hypercalciuria depends on its type.
Absorptive hypercalciuria
Type I - Cellulose phosphate in the dose of 10-15g orally in three divided dosages is to be taken with meals. It is an effective nonabsorbable exchange resin, which binds the calcium in the gut and prevents bowel absorption. It has no impact on the calcium transport mechanism and the urinary calcium excretion returns to normal values with therapy. This therapy is contraindicated in postmenopausal women and in children during the period of active growth. Hydrochlorothiazide is an alternative treatment but the effect on calcium excretion is temporary. It causes a decrease in the renal excretion of calcium. The increased absorbed calcium is deposited in the bone. Gradually the bone reservoir reaches its capacity and the drug becomes ineffective. Hydrochlorothiazide may be alternated with cellulose phosphate for an effective treatment regimen.
Type II - Since this is dietary dependent reduction of the calcium intake to 400-600 mg/day reduces calcium excretion to normal.
Type III - Orthophosphate is administered in the dosage of 250 - 2000 mg 3-4 times/day preferably after meals and before bedtime. It inhibits vitamin D synthesis, which finally decreases absorption of the calcium.
Renal Hypercalciuria
Thiazide diuretics like trichlorthiazide are recommended. They have effect on the proximal and the distal tubules. Acting as a diuretic, it decreases the circulating blood volume and subsequently stimulates proximal tubular absorption of calcium.
Hyperoxaluria
Patients suffering from mild hyperoxaluria (<60 mg/ day) are easily managed on the dietary restriction of oxalate rich foods such as spinach, dark roughage, tea, chocolate and nuts. Vitamin C supplementation should not increase more than 500 mg/day in such patients. Patients suffering from absorptive hypercalciuria maintained on calcium restriction could have mild hyperoxaluria due to insufficient amount of calcium left in the bowel to bind oxalate.
In patients with moderate to severe hyperoxaluria commonly seen in patients suffering from intestinal malabsorption of fat, inflammatory disease or resection of the small bowel, patients with aborptive hypercalciuria taking cellulouse phosphate, a rigid restriction of dietary oxalate is critical. Solublized calcium may further help to lower urinary oxalate by binding oxalate.
In the absence of bowel disease or absorptive hypercalciuria in the patients suffering from moderate to severe hyperoxaluria, mild metabolic hyperoxaluria or primary hyperoxaluria must be suspected and pyridoxine in the dosage of 100 to 200 mg/day is required for suppression of oxalate synthesis in vivo.
Hyperuricosuria
In patients with normouricimea, hyperuricosuria is caused by dietary excess of animal proteins. The general recommendation in these patients is a balanced diet with a reduced intake of animal proteins and increased intake of vegetables and fruits, although the long-term compliance in patients with dietary modification is very poor. Allopurinol (300 mg/day) is indicated in such patients if hyperuricosuria is more than 800 mg/day.
In patients with hyperuricimea e.g., gouty diathesis, allopurinol (300 mg/day) is indicated to reduce serum uric acid. Potassium citrate is also added to alkalinize the urine.
Cystinuria
The main goal of therapy is to lower cystine concentration in the urine below 200 mg/L. Dietary restriction is the primary therapy with the avoidance of diet containing essential amino acid methionine such as meat, poultry, fish, and dairy products. Increasing urine output on 3 L/day allows dissolution of existing stones and prevents new stone formation. The pH of the urine is kept high (>7.5) to allow dissolution of the stone. Sodabicarbonate (15-25 gm/ day) and potassium citrate (15-20 mmol two to three times per day) are commonly used to alkalinize the urine. Acetazolamide 250 mg three times a day augments the alkalinization achieved by the citrate and bicarbonate. Glutamine 2 g/day can further reduce the excretion of the cystine especially if the intake of sodium is very high.
If hydration and alkalinisation is ineffective in reducing the excretion of cystine or cystine formation then complexing agents such as penicillamine or alfa mercaptopurine can be used. These agents bind cystine, forming a complex solution that is soluble in the urine. Captopril has also been used to lower cystine excretion by forming a captopril-cystine disulfide complex.
Hypocitraturia
Citrate is an important inhibitor of crystallization of stone-forming salts and hypocitraturia being common among patients with calcium nephrolithiasis. It is apparent that maneuvers that maintain urinary pH between 6&7 and that raise urinary citrate levels to the normal would be desirable in preventing the formation of calcium oxalate stones.
Potassium citrate taken orally is absorbed mostly under normal circumstances. The citrate after absorption is metabolized to bicarbonate. In absence of a deficit of bicarbonate in plasma, the bicarbonate ions are excreted in urine that is rendered alkaline.
The small amount of absorbed citrate that escapes oxidation in the urine contributes in a minor way to the citraturic action of potassium citrate.[58]In the presence of hypokalemia, the potassium ion augments citrate excretion by correcting intracellular acidosis.
During long-term treatment, potassium citrate has been shown to cause a sustained rise in urinary citrate and pH.[29] In patients with mild to moderate hypocitraturia (100-320 mg/day), potassium citrate (60 meq/day) increases urinary citrate by about 400 mg/day. The urinary pH rises by about 0.5 units and can be maintained at about 6.5. The citraturic action is less prominent in those cases with severe hypocitraturia (e.g., complete renal tubular acidosis and severe chronic diarrhoeal syndrome). The total rise in urinary pH is less marked in renal tubular acidosis in which urinary pH is usually high.
Potassium citrate has a hypocalciuric effect because of enhanced renal calcium absorption and is usually transient. [59] In patients with renal tubular acidosis the hypocalciuric effect is sustained. [31] This is in contrast to sodium citrate where calcium excretion is unaffected since alkali mediated hypocalciuric effect is offset by sodium linked calciuresis. [60],[61]
Physiochemical effects of potassium citrate are associated to its citraturic and alkalinizing action resulting in [29]
- Inhibition of the crystallization of calcium salts in the urine. [5]
- Rise in pH contributes to the retardation of the crystallization of calcium salts and inhibits uric acid crystallization.
- At a high pH more phosphate and citrate ions become dissociated further augmenting the complexation of calcium.
- Dissociation of citrate, pyrophosphate and other macromolecules may accentuate their inhibitor activity against crystallization of calcium salts.
- The rise in urinary pH increases the dissociation of uric acid, reducing the concentration of undissociated uric acid and the propensity for the uric acid lithiasis. [34]
Distal Renal Tubular Acidosis Type 1
Potassium citrate therapy is capable of correcting both metabolic acidosis and hypokalemia. In severe acidosis, large doses (up to 120 mEq/day) may be required to restore normal urinary citrate level. [62] Urinary calcium declines with the correction of acidosis. The overall rise in urinary pH is generally below 7.5 during treatment unless there is a complication by a urinary tract infection.
If there is a substantial renal sodium leak, alkali must be provided as a mixed sodium potassium salt, although renal sodium wasting is not prominent in most patients with renal tubular acidosis who present with stones.
Potassium citrate is contraindicated in patients with moderate to severe renal disease (endogenous creatinine clearance of <40 ml/mt). If it were to be used in those with moderate renal disease, it should be begun at a lower dosage and the serum potassium levels should be carefully monitored.
Chronic Diarrhoeal Syndrome [29],[32]
In patients with mild to moderate severity of intestinal fluid loss and in whom hypocitraturia is not severe (100-320 mg/day), potassium citrate (40-60 mEq/day in 3-4 divided doses, is effective in restoring normal urinary citrate.
A liquid preparation is usually preferred in such cases rather than a slow release tablet because some of these patients have intestinal adhesion and may be prone to obstruction from a tablet preparation. Furthermore, a slow release medication may be poorly absorbed due to rapid intestinal transit. A frequent dose schedule (3-4 times/day) is advisable for the liquid preparation because of relatively short duration of biological action. Other drugs may be necessary for the treatment of additional disturbances.
If hypomagnesuria is present, magnesium citrate (10 mEq two to four times/day) may raise urinary magnesium and increase urinary citrate and pH.
When hyperoxaluria coexists, dietary oxalate restriction is a must. In patients of hyperoxaluria with hypocalciuria, calcium citrate is useful which lowers renal excretion of oxalate by binding it in the intestinal tract, raises urinary citrate, corrects malabsorption of calcium and averts potential developments of bone disease.
Thiazide Induced Hypocitraturia [63],[64]
Hypokalemia resulting from thiazide leads to hypocitraturia, which may attenuate the beneficial hypocalciuric effects of therapy in urolithiasis. Use of potassium citrate with thiazide raises urinary pH and citrate. It is recommended that potassium citrate (15-20 mEq twice a day) be given to all patients being treated with thiazide for hypercalciuric nephrolithiasis. [65]
Idiopathic Hypocitraturic Calcium Nephrolithiasis [63],[66]
This includes hypocitraturia occurring alone with calcium stones and hypocitraturia occurring in conjunction with absorptive and renal hypercalciuria and hyperuricosuric calcium oxalate nephrolithiasis. [40] In these patients the stones are predominantly calcium oxalate.
Potassium citrate (15-30 mEq twice a day) produces a sustained increase in urinary citrate excretion, maintains pH between 6.5-7.0 and decreases the urinary saturation of calcium oxalate to normal limits.
Uric Acid Nephrolithiasis [34],[67]
Potassium Citrate is recommended in patients with hyperuricosuric (gouty diasthesis) for prevention of both calcium oxalate and uric acid stone formation.
Potassium citrate creates an environment less conducive to the crystallization of uric acid by increasing urinary pH and reducing the amount of undissociated uric acid. It inhibits urinary crystallization of calcium oxalate by reducing urinary saturation and augmenting the inhibitor activity owing to the rise in urinary citrate and pH.
Post Extra Corporeal Shock Wave Lithotripsy Fragments [68],[69]
The natural history of residual stone fragments after ESWL shows growth and persistence of the calculus. In patients with residual fragments <5 mm or clinically insignificant residual fragments (CISF) with calcium oxalate and/or infection stones use of potassium citrate (6-8 gm in 2-3 divided doses) has significantly ameliorated the outcome of these residual fragments by decreasing growth or agglomeration, allowing spontaneous passage and finally improving the clearance rate.
Advantages of Potassium Citrate Compared with other Alkali
Potassium citrate is a better substitute than potassium bicarbonate because of more prolonged rise in urinary citrate and pH. The increment in urinary citrate is more pronounced with potassium citrate due to the renal excretion of small amount of absorbed citrate that has excaped oxidation. [62]
When compared with sodium citrate, potassium citrate reduces calcium excretion by augmenting the renal tubular absorption of calcium. [60] Urinary sodium remains unaltered with potassium citrate but increases during sodium citrate therapy. [62] In patients with hypokalemia, potassium citrate causes a more pronounced rise in citrate excretion than sodium citrate.
| Conclusions | | |
The medical management of urolithiasis is a rational approach based on the abnormal parameters detected on full investigation. However, in clinical practice it is very difficult as the patients may have all normal urinary parameters or multiple deranged parameters. In patients with all normal urinary parameters (idiopathic) the patient is advised dietary restriction and kept on periodic surveillance. In patients with multiple deranged parameters the drug approach in a permutation combination rationale is applied with periodic surveillance of the parameters at repeated intervals for dose modification or temporary discontinuation of the drug therapy. Both surgical and medical treatment is necessary for the complete management of patients of urolithiasis.
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