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Recurrent renal stone disease—advances in pathogenesis and clinical management
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Seminar
Recurrent renal stone disease—advances in pathogenesis and clinical management Geoffrey Bihl, Anthony Meyers Kidney stones are common in industrialised nations: up to 15% of white men and 6% of all women will develop one stone, with recurrence in about half these people. Risk factors for formation of stones include urinary promoters (calcium, urate, cystine, and sodium) and urinary inhibitors (magnesium, citrate, and nephrocalcin). Acute renal colic can be precipitated by dehydration and reduced urine output, increased protein intake, heavy physical exercise, and various medicines. Such colic manifests as severe loin pain and can be accompanied by frequent urination, dysuria, oliguria, and haematuria. Documentation of stone characteristics is extremely important: type, size, location, and underlying metabolic abnormalities. Such details can be obtained with a combination of biochemical investigations, microscopic examination of urine under polarised light, and an intravenous pyelogram. Ultrasonography and plain abdominal radiographs are also useful, especially for patients unable to tolerate an intravenous pyelogram. Acute therapy includes complete pain relief, rehydration, and encouragement of diuresis. Long-term management encompasses education of patients with regard to diet and fluid intake, control of calciuria, citrate replacement, and treatment of any underlying urinary-tract infection or metabolic abnormality. Stones smaller than 5 mm normally pass spontaneously, whereas larger stones, as big as 2 cm, are best treated with extracorporeal shock-wave lithotripsy. All physicians should have a clear understanding of the pathogenesis and clinical management (acute treatment and prevention of recurrence) of renal stone disease. Renal stone disease is an ancient and common affliction, whose clinical occurrence and presentation is described in the Aphorisms of Hippocrates.1 Renal stones occur once in a lifetime in 15% of white men and 6% of all women, and recur in about half these people. Despite urbanisation of black South Africans, renal stones have been reported in less than 1% of this population.2,3 Up to 75% of stones are calcium oxalate, the others are struvite (magnesium ammonium phosphate, 10–20%), uric acid (5%), 5% contain more than 50% brushite (calcium monohydrogen phosphate) or hydroxyapatite, and less than 1% are composed of cystine.4 Because the treatment for every stone type is different, stone composition should be analysed by polarisation microscopy.5 Although much progress has been made in understanding the pathophysiological mechanisms of stone disease, allowing for more effective diagnosis and treatment, stones still cause substantial morbidity from pain, urinary-tract obstruction, and infection.
Pathogenesis The mechanisms of crystallisation need to be understood to outline the basis of stone formation. The states of saturation of ions in a solution are governed by their concentrations. For example, when concentrations of calcium and oxalate reach saturation (the saturation product), stone formation begins with association of small amounts of crystalloid to form nuclei (nucleation). These nuclei normally grow and aggregate on surfaces Lancet 2001; 358: 651–56 Addenbrookes Renal and Dialysis Centre, Addenbrookes Hospital, Cambridge, UK (G Bihl FCP[SA]); and Stone Clinic, Johannesburg Hospital, Johannesburg, South Africa (Prof A Meyers FCP[SA], G Bihl) Correspondence to: Dr Geoffrey Bihl, Renal Unit, Department of Internal Medicine, University of Stellenbosch, Tygerberg Hospital, PO Box 19161, Tygerberg, Cape Town, South Africa (e-mail: [email protected])
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such as collecting ducts and renal papillary epithelium.6 Renal epithelial cells specifically bind and internalise calcium oxalate monohydrate crystals. Events that occur after crystal binding could be important in pathogenesis of stones—ie, cellular responses might be essential for initiation of stone formation.7,8 Fortunately, stone formation is inhibited in urine of mammals by substances that prevent crystallisation, and will only take place once the formation product (the metastable limit) has been exceeded. Therefore, crystallisation in undiluted human urine will begin only in a supersaturated solution of calcium and oxalate. Estimates of urine saturation with stone-forming salts such as calcium, phosphate, urate, and oxalate are important in calculation of overall propensity to crystal formation. Urinary saturation with calcium oxalate is common in the general population so the role of other factors in stone formation must be crucial. However, before discussion of inhibitory and promoting substances, other important factors need to be stressed. First, uric acid can precipitate in persistently acid urine, even in the absence of hyperuricaemia or hyperuricosuria. Second, uric acid can cause formation of calcium oxalate stones without being incorporated into the crystals. This catalyst-like ability is known as salting out, and is enhanced in acid urine.9 Finally, urinary pH has an essential role in many other inhibitor or promoter reactions. Lithogenic risk factors include stone promoters and inhibitors (panel 1). Effects of inhibitors on stone formation have been most studied in calcium oxalate stones. Most inhibitors are anionic and seem to exert their effects by binding to the calcium oxalate surface, although the specific structural mechanisms of this process are not known.10 The many proteins found in stones could cause, be the result of, or have no role in their formation. Nephrocalcin is an acidic protein of renal tubular origin, and in some people who form stones this protein lacks the aminoacid, ␥-carboxyglutamic acid, which reduces 651
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Panel 1: Urinary stone promoters and inhibitors6,10 Promoters ● ● ● ● ● ● ● ● ●
Calcium Sodium Oxalate Urate Cystine Low urine pH Tamm-Horsfall protein Low urine flow Bacterial products
Inhibitors Inorganic ● Magnesium ● Pyrophosphate ● Citrate Organic ● Nephrocalcin ● Tamm-Horsfall protein ● Urinary prothrombin fragment 1 ● Protease inhibitor: inter-␣-inhibitor ● Glycosaminoglycans ● High urine flow
its ability to inhibit nucleation. Additionally, nephrocalcin inhibits calcium oxalate aggregation, which some believe is a crucial step in initiation of stone formation.11 Nephrocalcin might also affect calcium phosphate crystallisation. Tamm-Horsfall protein (THP) is the most abundant protein in human urine, and is synthesised and secreted by epithelial cells of the thick ascending limb of the loop of Henle and early distal convoluted tubule. THP remains at crystal surfaces, and thus mainly affects aggregation of preformed crystals. Controversy still exists about whether this protein is a promoter or inhibitor of crystallisation.12,13 Glauser and colleagues14 measured THP in 24 h urine samples from people who formed stones and from healthy individuals. They showed that a rise in THP excretion correlated with increasing urinary calcium and oxalate excretion in healthy people but not in those who formed stones. This result could indicate that THP has an inhibitory role that prevents lithogenesis. Of considerable interest is the role of proteins that are incorporated in substantial amounts in renal stones, and their effects on stone formation. One such protein, crystal matrix protein or prothrombin fragment 1, is a peptide generated from sequential cleavage of prothrombin by factor Xa and thrombin. This peptide is present in epithelial cells of the thick ascending limb of the loop of Henle and the distal convoluted tubule in greater quantities in people who form stones than in healthy individuals.15 The peptide inhibits calcium oxalate crystal aggregation and growth in rats,16 and might be excreted by the kidney to protect against stone formation, but further research is required to show that this process occurs in people. The peptide chain of inter-␣-inhibitor has been isolated from urine, and has been reported to inhibit calcium oxalate crystallisation.17 Although research on this protein continues, Dean and colleagues18 concluded that inter-␣-inhibitor does not have a substantial inhibitory role in crystallisation, which emphasises the point that some proteins associated with stones could
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have no active involvement in their formation. Lastly, glycosaminoglycans, or urinary polyanions, are potent inhibitors of growth of calcium oxalate in urine, and block adhesion of uric acid crystals.19,20
Different stone types Calcium stones Most stones contain calcium combined with oxalate, phosphate, or occasionally uric acid. All calcium stones are radio-opaque, and calcium oxalate and calcium phosphate stones are black, grey, or white and small (⬍1 cm in diameter), dense, and sharply circumscribed on radiographs. Different conditions contribute to calcium stones. Hypercalciuria (defined as ⬎0·1 mmol/kg bodyweight of patient per day, calculated for ideal bodyweight) can be idiopathic or result from any disorder that induces even mild hypercalcaemia. Such disorders include: (1) primary hyperparathyroidism, which results from an adenoma in 85% of cases, and is associated with mild to moderate hypercalcaemia. People who form stones and have hypercalcaemia are almost certain to have this parathyroid problem. Hypercalciuria is a result of excess parathyroid hormone, which causes overproduction of 1,25–dihydroxyvitamin D in the kidney; both factors promote bone resorption, increasing the filtered load of calcium and hence calciuria. (2) Other disorders that induce hypercalcaemia can also result in hypercalciuria: malignancies, granulomatous diseases, sarcoidosis, thyrotoxicosis, and immobilisation. (3) Idiopathic hypercalciuria is a familial disorder affecting both sexes equally, in which urinary calcium concentration is raised despite normal concentrations of blood calcium. The primary mechanisms for such hypercalciuria can occur individually or in combination21 and include high intestinal calcium absorption (the commonest mechanism), with a normal or slightly raised serum calcium, suppressed parathyroid hormone, and increased renal filtered load; increased bone resorption; defective renal-tubular calcium reabsorption, with an inappropriately high phosphate excretion for any given calcium concentration, which might induce increased activation of 1,25–dihydroxyvitamin D; and raised phospholipid-arachidonic acid concentration in serum and erythrocytes, with raised urinary prostaglandin E2 concentrations.22 (4) Mutations in the CLCN5 chloride channel in Japanese patients resulted in low-molecular-weight proteinuria, hypercalciuria, and calcium stone formation.23 (5) Other causes of hypercalciuria are inherited syndromes of familial benign and autosomal dominant hypercalciuric hypocalcaemia. These disorders are the result of a mutation in the calcium receptor gene. The calcium receptor facilitates regulation of parathyroid hormone secretion and renal-tubular calcium reabsorption in response to changes in extracellular calcium concentrations.24 Another condition associated with renal stone formation is hyperoxaluria. Oxalate is an end-product of metabolism, is largely derived from endogenous sources, and is excreted unchanged in urine. Foods rich in oxalate—rhubarb, standard teas, nuts, beans, spinach, coffee, and chocolates—can increase concentrations in urine to 670 mol/day (normal value 440 mol/day). However, concentrations of more than 890 mol/day indicate enteric oxaluria (associated with malabsorptive small-bowel diseases), mild metabolic hyperoxaluria, or primary hyperoxaluria.
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Mild metabolic hyperoxaluria does not seem to represent a substantial fraction of hyperoxalurias, although in one study from South Africa, 20% of patients with recurrent renal stones had this disorder.3 Cytosolic enzyme perturbations are thought to result in mild hyperoxaluria and recurrent calcium oxalate stones, but the exact pathogenic mechanisms have not been identified. Pyridoxine, which is a cofactor in shunting glyoxalate to glycine and pyruvate (ie, away from oxalate), has been successfully used to treat these patients. Primary hyperoxaluria type 1 disease is caused by lack of the liver enzyme alanine:glyoxylate aminotransferase, and type 2 disease by lack of D-glycerate dehydrogenase.25 The defective genes that cause these diseases and their abnormal liver enzyme products cause excessive oxalate metabolism, which results in systemic calcium-oxalate deposition from a young age. Finally, hypocitraturia is also associated with renal lithogenesis. Citrate forms a highly soluble complex with calcium, and thus acts as an inorganic inhibitor of stone formation and interferes with surface-controlled crystallisation. Hypocitraturia could result from causes of intracellular acidosis such as renal failure, potassium deficiency, distal renal tubular acidosis, chronic diarrhoeal states, and drugs such as acetazolamide. Many patients with stones have unexplained low urinary citrate, dysfunction of the renal sodium-citrate cotransporter has been proposed as a possible mechanism.26 Uric acid stones Uric acid stones are smooth, round, yellow-orange and nearly radiographically transparent—unless mixed with calcium crystals or struvite. They are typically seen as filling defects on intravenous pyelograms, and computed tomography scanning can distinguish them from kidney tissue or blood clots. Diets high in purines, especially those containing organ meats and fish, result in hyperuricosuria, and, in combination with low urine volume and low urinary pH (as a result of impaired renal ammonia production), can exacerbate uric-acid stone formation. Uric acid salts out calcium oxalate, and can precipitate out in acid urine even in the absence of raised serum or urinary uric-acid concentrations. Furthermore, hyperuricaemic disorders including gout (about 20% of patients with gout are hyperuricosuric), myeloproliferative disorders, tumour lysis syndrome, and inborn errors of metabolism (such as Lesch-Nyhan syndrome and glucose6–phosphatase deficiency) result in an increased filtered load of uric acid and thus, hyperuricosuria.27 As with all stones, certain drugs may enhance stone formation, and in the case of uric acid stones, hyperuricosuric agents include low dose salicylates, probenecid, and thiazides. Struvite or triple phosphate stones Radiographs show struvite stones as large, gnarled, and laminated. They are associated with substantial morbidity including bleeding, obstruction, and urinarytract infection. Signs of struvite stones include urinary pH greater than 7, staghorn calculi, and urease that grows bacteria on culture (proteus, klebsiella, pseudomonas). Stones develop if urine is alkaline, has a raised concentration of ammonium, contains trivalent phosphate, and contains urease produced by bacteria. Cystine stones Cystine stones should be suspected in patients with a history of childhood stones or a strong family history.
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Panel 2: Drugs associated with renal stone formation Drugs that promote calcium stone formation: ● ● ● ● ● ●
Loop diuretics Antacids (calcium and non-calcium) Acetazolamide Glucocorticoids Theophylline Vitamins D and C
Drugs that promote uric acid stone formation: ● Thiazides ● Salicylates ● Probenecid ● Allopurinol Drugs that precipitate into stones: ● Triamterine ● Aciclovir ● Indinavir (Adapted with permission from Monk).27
They are greenish-yellow, flecked with shiny crystallites, and are moderately radio-opaque with a rounded appearance. Calcium stones are denser than vertebral bodies, whereas cystine stones are less dense. People who are homozygous for cystinuria (an autosomal recessive disorder) excrete more than 600 mg per day of insoluble cystine. More than half the stones in cystinuria are of mixed composition, and many patients have associated physiological problems such as hypercalciuria (19% of patients), hyperuricosuria (22%), and hypocitraturia (44%).28
Clinical presentation of acute stone episode When a urinary stone moves into the renal collecting system, the resulting increase in intraluminal pressure stretches nerve endings in the mucosa, and produces a severe and often colicky pain. This pain radiates downward on the anterior from the flank toward the groin, and is often accompanied by frequent urination, dysuria, oliguria, haematuria, acute nausea, and hypotension. In the acute setting, stones can obstruct the urinary tract producing serious symptoms, or obstruction can be a relatively slow and painless process resulting from slow stone growth and presenting with advanced renal parenchymal damage. Precipitants of acute stone episodes include dehydration and reduced urine output, increased protein intake, heavy physical exercise, and various drugs (panel 2).
Investigations Acute setting Documentation of stone characteristics is extremely important (type, size, and location). Although there is a risk of allergy and contrast nephropathy, intravenous pyelography remains the gold standard for such identification. Ultrasonography can indicate whether a stone is in the kidney or ureter, the degree of any obstruction, and quality of renal parenchyma. Plain abdominal radiography is useful for stones above the pelvic brim, and, with ultrasonography, is the investigation of choice in patients unable to tolerate an intravenous pyelogram (for reasons such as allergy to iodine or renal insufficiency). Medical management of a stone depends on the type of stone, and includes correction of dietary aberrations, metabolic defects, or both. Panel 3 shows recommended investigations.
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Panel 3: Investigations for a renal stone Blood ● ● ● ● ● ● ● ● ●
Full blood count Urea and electrolytes Calcium Phosphate Bicarbonate or carbon dioxide Uric acid Parathyroid hormone Alkaline phosphatase Cholesterol
Urine ● Spot pH (include an acid load test if pH >5·4) ● Specific gravity ● Culture ● 24-h analysis of urinary: volume, calcium, sodium, urate, creatinine, phosphate, citrate, and oxalate ● Polarisation microscopy (after fracture of calculi) ● Urinary calcium: creatinine ratios ● Infrared spectrometry
Classification of hypercalciurias is of limited use in management patients with calcium stones, and the calcium-loading test has become obsolete.29 Chronic setting All kidney stones should be investigated30 and assessment needs to include a thorough medical history, drugs taken, family history, lifestyle and diet, fluid intake, and a clinical examination. Investigations outlined in panel 3 should be done. Saturation with stone-forming salts can be calculated from these measurements with commercially available computer software. More than one 24 h urine sample might be needed, especially to be able to define a stone as idiopathic if all results are negative. Optimum values of 24 h urine sample constituents are shown in panel 4.
Management of acute stones Pain relief Renal colic is one of the most intense forms of pain and requires prompt symptomatic treatment. Non-steroidal anti-inflammatory drugs given orally or intravenously have good analgesic properties,31 although they also have serious gastrointestinal and renal side-effects. Renal side-effects are especially important in dehydrated patients and those at risk of allergy to these drugs.
Panel 4: Optimum values of 24 h urine sample constituents ● Volume ● pH ● Calcium ● ● ● ● ●
Oxalate Uric acid Citrate Sodium Phosphate
>2–2·5 L >5·5 and <7·0 (a spot urine specimen will suffice) <0·1 mmol/kg, or <7·5 mmol in men, <6·3 mmol in women 180–350 mol 1·5–4·4 mmol 2·4–5·1 mmol <200 mmol <35·2 mmol
To ensure adequacy of collection, urine creatinine should be: 7·1–15·9 mmol in men 5·2–14·1 mmol in women (Adapted with permission from Monk).27
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Cyclo-oxygenase-II inhibitors have been developed to reduce gastrointestinal effects, but they also inhibit renal vasoactive substances and are contraindicated in patients with renal insufficiency.32 Paracetamol given every 4 h is well tolerated, but pain relief is often inadequate with this agent alone. Narcotic analgesics including morphine (given intramuscularly or intravenously) and pethidine offer excellent pain relief and are the drugs of choice for acute renal colic. However, they are sedative and have the risk of dependence if used for a long time. Their emetogenic side-effects can be counteracted with antihistamines such as hydroxyzine, which has additive analgesic properties in combination with narcotic agents. Codeine is physiologically related to morphine, and, when combined with paracetamol or aspirin, is effective for moderate pain. Dextropropoxyphene combined with paracetamol has been used in the acute setting, and offers fair pain relief if other opiates are contraindicated. Fluids An increase in diuresis will help patients to pass stones, and stone and urinary supersaturation can be reduced by judicious fluid management. Patients should drink 2–3 L of water daily, or be given water by intravenous infusion if nauseous. However, an increase in diuresis can worsen pain, hydronephrosis, and ureteral function, in which case ureteral stenting might be necessary. General therapies A regular catharsis should be encouraged, and although uncommon in the acute setting, urinary-tract infection should be investigated and treated if found. Education of patients about maintenance of adequate hydration, and avoidance of precipitating drugs and foods should begin as soon as possible after an acute event.
Management of chronic stones General measures Non-pharmacological interventions reduce 5 year rate of stone recurrence by up to 60%33 in people who adhere to a sensible diet. Patients should be encouraged to increase their basic intake of water to at least 2 L daily, and especially so during heavy exercise, pyrexial episodes, and when travelling long distances. Maximum urine output should be encouraged in patients with renal insufficiency, with careful monitoring of volume status and weight gain. A non-animal low protein diet (0·8–1·0 g/kg per day) prevents the mild acidosis induced by animal protein breakdown, and improves calcium homoeostasis. Severe protein restriction results in malnutrition and muscle breakdown and should be discouraged.34 Measurement of urea and, if possible, inorganic sulphate excretion are easy ways to assess total and animal protein intakes. Calcium binds oxalate in the gut, thus people who form stones and are on a high calcium diet paradoxically have a lower occurence of stone formation than those not on such a diet. Dietary calcium should be limited to about 1 g/day in patients who remain hypercalciuric despite pharmacological treatment. An increased tubular sodium load results in reduced tubular reabsorption of calcium, therefore a low sodium diet (2–3 g/day) is recommended for hypercalciuric patients. Specific therapies These therapies are designed for metabolically active stone disease.
patients with After general
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measures have been instituted, further treatment is based on stone composition and abnormalities noted from the 24 h urine sample analyses. Calcium stones—hypercalciuria Thiazide diuretics such as hydrochlorothiazide (at doses of 25–50 mg/day) increase distal tubular reabsorption and reduce intestinal calcium reabsorption. Indapamide (2·5–5·0 mg/day) has been shown to be best for treatment of recurrent stones associated with idiopathic hypercalciuria. This agent has fewer untoward metabolic effects than other thiazides if used in high doses.35 Addition of potassium citrate maintains potassium concentration at the ideal of 3·5–4·0 mmol/L and this, together with citrate, improves citrate excretion in the tubules thereby reducing crystal agglomeration.36 Persistent hypercalciuria can respond to potassium-sparing diuretics, calcium restriction (800–1000 mg/day), and reassessment of compliance. Phosphate rarely needs to be replaced even in patients with phosphate-losing tubular defect. In patients with intractable stone recurrence and idiopathic hypercalciuria, Coe and colleagues37 recommend a calcium-binding resin (sodium cellulose phosphate) with a thiazide diuretic, although no controlled clinical studies in support of such treatment have been done. Use of ethyl icosapentate (a polyunsaturated fatty acid) has yielded disappointing results with regard to urinary calcium and oxalate excretion, although calciuria was reduced in some patients and further research is advocated.38 Calcium stones—hyperoxaluria First principles of treatment include increased fluid intake and urinary alkalinisation, treatment of the underlying cause of disease, dietary restriction of foods high in oxalate, and an increase in dietary calcium. Calcium carbonate (500–650 mg tablets, two or three to be taken with every meal) binds dietary oxalate, and potassium citrate (450 mg capsules taken two to three times per day) in combination with magnesium gluconate (0·5–1·0 g/day) is a useful adjunct.39 Mild metabolic hyperoxaluria can be treated with pyridoxine, but not very successfully. Primary hyperoxaluria can be cured only by liver transplantation, although pyridoxine supplementation may reduce endogenous oxalate production. Calcium stones—hypocitraturia Because citrate forms a soluble complex with calcium, citrate is an effective treatment for most calcium stones, irrespective of their cause. Urinary citrate concentrations should be maintained above 2·4–5·1 mmol/day, and an initial dose of 450 mg of potassium citrate two to three times daily might have to be increased to achieve this level. Potassium citrate must be used rather than sodium bicarbonate, because sodium bicabonate increases delivery of sodium to the renal tubules, which results in an increase in urinary calcium.
Calcium stones—hyperuricosuria Recommended therapies are increased fluid intake, treatment of the underlying cause of disease, and a low purine diet with the addition of allopurinol if other measures fail. Uric acid stones Recommended therapies include adequate fluid intake, a low purine diet, and urinary alkalinisation (pH 6·5) with potassium citrate. Such measures should pre-empt use of allopurinol and acetazolamide for urinary uric acid secretion and alkaline pH maintenance. Acetazolamide should not be used in the long term. Struvite stones Because urease-producing bacteria are often embedded in these stones, antibiotics can be ineffective in eradication of the offending pathogen. Early urological intervention is warranted in patients with these stones, as is use of culture-specific antibiotics around the time of operation. Furthermore, once the patient is stone free, Wong and colleagues41 recommend continuation of antibiotics until cultures remain negative for at least 3 months. As an adjunct, oral phosphate binders reduce phosphate content of these stones. Cystine stones Treatment for these stones is aimed at improvement of solubility of cystine in urine, by increase of fluid intake to more than 4 L/day and alkalisation of urinary pH to more than 7·4 with potassium citrate. Treatment also includes restriction of dietary sodium, and occasionally, d-penicillamine can be used as a chelating agent— although occasionally side-effects (agranulocytosis and thrombocytopenia) limit its clinical use.42 Because cystine stones do not disperse well with extracorporeal shock-wave lithotripsy, formal urological procedures might be necessary to remove these stones. Urological intervention43 Advances in urological techniques have drastically altered management of patients with symptomatic stones that require treatment. Most symptomatic upper urinary-tract stones are small, occur in normal kidneys, and pass spontaneously if less than 5 mm in diameter. Up to 85% of stones smaller than 2 cm in diameter that need to be removed are best treated with extracorporeal shock-wave lithotripsy. An endoluminal approach with ureteroscopy or percutaneous nephrolithotomy is best suited for large or complex stones, stones associated with urinary tract abnormalities, those in the lower ureter, or ones that do not fragment after extracorporeal shock-wave lithotripsy. Fortunately, formal surgical lithotomy has been relegated to anecdotal status. We thank Maria Martins for her assistance, advice, and encouragement with the preparation of this manuscript.
References 1
Calcium stones—renal tubular acidosis These patients have a mild metabolic acidosis that results in increased renal tubular reabsorption, metabolism of citrate, and hypercalciuria.40 In patients with type 1 renal tubular acidosis (distal), raised urinary pH promotes calcium phosphate precipitation, and high doses of potassium might be necessary to prevent stone formation.
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Herring LC. Observations on the analysis of ten thousand urinary calculi. J Urol 1962; 88: 545–62. Whalley N, Martins MC, Wandy KRC, Meyers AM. Lithogenic risk factors in normal black volunteers, and black and white recurrent stone formers. BJU Int 1999; 84: 243–48. Lieske JC, Tobock FG. Regulation of renal epithelial cell endocytosis of calcium oxalate monohydrate crystals. Am J Physiol 1993; 264: 800–07. Lieske JC, Walsh-Rietz MM, Tobock FG. Calcium oxalate monohydrate crystals are endocytosed by renal epithelial cells and induce proliferation. Am J Physiol 1992; 262: 622–30. Grover PK, Ryall RL, Marshall VR. Effect of urate on calcium oxalate crystallisation in human urine, evidence for a promotory role of hyperuricosuria in urolithiasis. Clin Sci 1998; 79: 9–15. Worcester EM. Inhibitors of Stone Formation. Semin Nephrol 1996; 16: 474–86. Teselius HG, Bek-Jensen H, Fornander AM, et al. Crystallisation properties in urine from calcium oxalate stone formers. J Urol 1995; 154: 940–46. Hess B, Nakagawa Y, Parks JH, et al. Molecular abnormality of Tamm-Horsfall glycoprotein in calcium oxalate nephrolithiasis. Am J Physiol 1991; 260: 569–78. Hess B, Zipperle L, Jaeger Ph. Citrate and calcium effects on Tamm-Horsfall glycoprotein as a modifier of calcium oxalate crystal aggregation. Am J Physiol 1993; 265: 784–91. Glauser A, Hochreiter W, Jaeger P, Hess B. Determinants of urinary excretion of Tamm-Horsfall protein in non-selected kidney stone formers and healthy subjects. Nephrol Dial Transplant 2000; 15: 1580–87. Stapleton AMF, Dawson CJ, Grover PK, et al. Further evidence linking urolithiasis and blood coagulation: urinary prothrombin fragment 1 is present in stone matrix. Kidney Int 1996; 49: 880–88. Grover PK, Dogra SC, Davidson BP, Stapleton AMF, Ryall RL. The prothrombin gene is expressed in the rat kidney: implications for urolithiasis research. Eur J Biochem 2000; 267: 61–67. AtmaniF, Lacour B, Strecker G, Parvy P, Druecke T, Daudon M. Molecular characteristics of uronic-acid-rich protein, a strong inhibitor of calcium oxalate crystallisation in vitro. Biochem Biophy Res Commun 1993; 191: 1158–65. Dean C, Kanellos J, Pham H, et al. Effects of inter-alpha-inhibitor and several of its derivatives on calcium oxalate crystallization in vitro. Clin Sci (Colch) 2000; 98: 471–80. Robertson WG, Scurr DS, Bridge CM. Factors influencing the crystallisation of calcium oxalate in urine. J Crystal Growth 1981; 53: 182–94. Koka RM, Huang E, Lieske JC. Adhesion of uric acid crystals to the surface of renal epithelial cells. Am J Physiol Renal Physiol 2000; 278: 989–98. Monk RD, Bushinsky DA. Pathogenesis of idiopathic hypercalciuria. In: Coe FL, Favus J, Pak CYC, eds. Kidney stones: medical and surgical management. Philadelphia: Lippincott-Raven, 1996: 759–72. Baggio B, Budakovic A, Nassuato MA, et al. Plasma phospholipid arachidonic acid content and calcium metabolism in idiopathic calcium nephrolithiasis. Kidney Int 2000; 58: 1278–84.
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23 Takemura T, Hino S, Ikeda M, et al. Identification of two novel mutations in the CLCN5 gene in Japanese patients with familial idiopathic low molecular weight proteinuria (Japanese Dent’s disease). Am J Kidney Dis 2001; 37: 138–143. 24 Pearce SH. Calcium homeostasis and disorders of the calciumsensing receptor. J R Coll Physicians Lond 1998; 32: 10–14. 25 Rumsby G. Biochemical and genetic diagnosis of the primary hyperoxalurias: a review. Mol Urol 2000; 4: 349–54. 26 Parks JP, Ruml LA, Pak CYC. Hypocitraturia. In: Coe FL, Favus M, Pak CYC, eds. Kidney stones: medical and surgical management. Philadelphia: Lippincott-Raven, 1996: 905–20. 27 Monk RD. Clinical approach to adults. Semin Nephrol 1996; 16: 375–88. 28 Sakhee K, Poindexter JR, Pak CYC. The spectrum of metabolic abnormalities in patients with cystine nephrolithiasis. J Urol 1989; 141: 819–21. 29 Pak CYC, Kaplan R, Bone H, et al. A simple test for the diagnosis of absorptive, resorptive and renal hypercalciuria. N Engl J Med 1975; 275: 497–500. 30 Consensus conference: prevention and treatment of kidney stones. JAMA 1988; 260: 977–81. 31 Kekec Z, Yilmaz U, Sozuer E. The effectiveness of tenoxicam vs isosorbide dinitrate plus tenoxicam in the treatment of acute renal colic. BJU Int 2000; 85: 783–85. 32 Nakada SY, Jerde TJ, Bjorling DE, Saban R. Selective cyclooxygenase-2 inhibitors reduce ureteral contraction in vitro: a better alternative for renal colic? J Urol 2000; 163: 607–12. 33 Hoskins DH, Erickson SB, Vandenberg CJ. The stone clinic effect in patients with idiopathic calcium urolithiasis. J Urol 1983; 130: 1115–18. 34 Martini LA, Wood RJ. Should dietary calcium and protein be restricted in patients with nephrolithiasis? Nutr Rev 2000; 58: 111–17. 35 Martins M, Meyers AM, Whalley MA. Indapamide: the agent of choice in the treatment of recurrent renal calculi associated with idiopathic hypercalciuria. Br J Urol 1996; 78: 176–80. 36 Hamm LL. Renal handling of citrate. Kidney Int 1990; 38: 728–35. 37 Coe FL, Parks JH, Asplin JR. The pathogenesis and treatment of kidney stones. N Engl J Med 1992; 327: 1141–52. 38 Konya E, Tsuji H, Umekawa T, Kurita T, Iguchi M. Effect of ethyl icosapentate on urinary calcium and oxalate excretion. Int J Urol 2000; 7: 361–65. 39 Hanson KA. Management of calcium oxalate stones. Clin Excell Nurse Pract 2001; 5: 21–25. 40 Buchinsky DA. Net calcium efflux from live bone during chronic metabolic, but not respiratory acidosis. Am J Physiol 1989; 256: 836–42. 41 Wong HY, Riedel CR, Griffith DP. Medical management and prevention of struvite stones. In: Coe FL, Favus MJ, Pak CYC, eds. Kidney stones: medical and surgical management. Philadelphia: Lippincott-Raven, 1996: 1007–17. 42 Joly D, Rieu P, Mejean A, Gagnadoux MF, Daudon M, Jungers P. Treatment of cystinuria. Pediatr Nephrol 1999; 13: 945–50. 43 Lingeman JE. Lithotripsy and Surgery. Semin Nephrol 1996; 16: 487–98.
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Seminar
Recurrent renal stone disease—advances in pathogenesis and clinical management Geoffrey Bihl, Anthony Meyers Kidney stones are common in industrialised nations: up to 15% of white men and 6% of all women will develop one stone, with recurrence in about half these people. Risk factors for formation of stones include urinary promoters (calcium, urate, cystine, and sodium) and urinary inhibitors (magnesium, citrate, and nephrocalcin). Acute renal colic can be precipitated by dehydration and reduced urine output, increased protein intake, heavy physical exercise, and various medicines. Such colic manifests as severe loin pain and can be accompanied by frequent urination, dysuria, oliguria, and haematuria. Documentation of stone characteristics is extremely important: type, size, location, and underlying metabolic abnormalities. Such details can be obtained with a combination of biochemical investigations, microscopic examination of urine under polarised light, and an intravenous pyelogram. Ultrasonography and plain abdominal radiographs are also useful, especially for patients unable to tolerate an intravenous pyelogram. Acute therapy includes complete pain relief, rehydration, and encouragement of diuresis. Long-term management encompasses education of patients with regard to diet and fluid intake, control of calciuria, citrate replacement, and treatment of any underlying urinary-tract infection or metabolic abnormality. Stones smaller than 5 mm normally pass spontaneously, whereas larger stones, as big as 2 cm, are best treated with extracorporeal shock-wave lithotripsy. All physicians should have a clear understanding of the pathogenesis and clinical management (acute treatment and prevention of recurrence) of renal stone disease. Renal stone disease is an ancient and common affliction, whose clinical occurrence and presentation is described in the Aphorisms of Hippocrates.1 Renal stones occur once in a lifetime in 15% of white men and 6% of all women, and recur in about half these people. Despite urbanisation of black South Africans, renal stones have been reported in less than 1% of this population.2,3 Up to 75% of stones are calcium oxalate, the others are struvite (magnesium ammonium phosphate, 10–20%), uric acid (5%), 5% contain more than 50% brushite (calcium monohydrogen phosphate) or hydroxyapatite, and less than 1% are composed of cystine.4 Because the treatment for every stone type is different, stone composition should be analysed by polarisation microscopy.5 Although much progress has been made in understanding the pathophysiological mechanisms of stone disease, allowing for more effective diagnosis and treatment, stones still cause substantial morbidity from pain, urinary-tract obstruction, and infection.
Pathogenesis The mechanisms of crystallisation need to be understood to outline the basis of stone formation. The states of saturation of ions in a solution are governed by their concentrations. For example, when concentrations of calcium and oxalate reach saturation (the saturation product), stone formation begins with association of small amounts of crystalloid to form nuclei (nucleation). These nuclei normally grow and aggregate on surfaces Lancet 2001; 358: 651–56 Addenbrookes Renal and Dialysis Centre, Addenbrookes Hospital, Cambridge, UK (G Bihl FCP[SA]); and Stone Clinic, Johannesburg Hospital, Johannesburg, South Africa (Prof A Meyers FCP[SA], G Bihl) Correspondence to: Dr Geoffrey Bihl, Renal Unit, Department of Internal Medicine, University of Stellenbosch, Tygerberg Hospital, PO Box 19161, Tygerberg, Cape Town, South Africa (e-mail: [email protected])
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such as collecting ducts and renal papillary epithelium.6 Renal epithelial cells specifically bind and internalise calcium oxalate monohydrate crystals. Events that occur after crystal binding could be important in pathogenesis of stones—ie, cellular responses might be essential for initiation of stone formation.7,8 Fortunately, stone formation is inhibited in urine of mammals by substances that prevent crystallisation, and will only take place once the formation product (the metastable limit) has been exceeded. Therefore, crystallisation in undiluted human urine will begin only in a supersaturated solution of calcium and oxalate. Estimates of urine saturation with stone-forming salts such as calcium, phosphate, urate, and oxalate are important in calculation of overall propensity to crystal formation. Urinary saturation with calcium oxalate is common in the general population so the role of other factors in stone formation must be crucial. However, before discussion of inhibitory and promoting substances, other important factors need to be stressed. First, uric acid can precipitate in persistently acid urine, even in the absence of hyperuricaemia or hyperuricosuria. Second, uric acid can cause formation of calcium oxalate stones without being incorporated into the crystals. This catalyst-like ability is known as salting out, and is enhanced in acid urine.9 Finally, urinary pH has an essential role in many other inhibitor or promoter reactions. Lithogenic risk factors include stone promoters and inhibitors (panel 1). Effects of inhibitors on stone formation have been most studied in calcium oxalate stones. Most inhibitors are anionic and seem to exert their effects by binding to the calcium oxalate surface, although the specific structural mechanisms of this process are not known.10 The many proteins found in stones could cause, be the result of, or have no role in their formation. Nephrocalcin is an acidic protein of renal tubular origin, and in some people who form stones this protein lacks the aminoacid, ␥-carboxyglutamic acid, which reduces 651
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Panel 1: Urinary stone promoters and inhibitors6,10 Promoters ● ● ● ● ● ● ● ● ●
Calcium Sodium Oxalate Urate Cystine Low urine pH Tamm-Horsfall protein Low urine flow Bacterial products
Inhibitors Inorganic ● Magnesium ● Pyrophosphate ● Citrate Organic ● Nephrocalcin ● Tamm-Horsfall protein ● Urinary prothrombin fragment 1 ● Protease inhibitor: inter-␣-inhibitor ● Glycosaminoglycans ● High urine flow
its ability to inhibit nucleation. Additionally, nephrocalcin inhibits calcium oxalate aggregation, which some believe is a crucial step in initiation of stone formation.11 Nephrocalcin might also affect calcium phosphate crystallisation. Tamm-Horsfall protein (THP) is the most abundant protein in human urine, and is synthesised and secreted by epithelial cells of the thick ascending limb of the loop of Henle and early distal convoluted tubule. THP remains at crystal surfaces, and thus mainly affects aggregation of preformed crystals. Controversy still exists about whether this protein is a promoter or inhibitor of crystallisation.12,13 Glauser and colleagues14 measured THP in 24 h urine samples from people who formed stones and from healthy individuals. They showed that a rise in THP excretion correlated with increasing urinary calcium and oxalate excretion in healthy people but not in those who formed stones. This result could indicate that THP has an inhibitory role that prevents lithogenesis. Of considerable interest is the role of proteins that are incorporated in substantial amounts in renal stones, and their effects on stone formation. One such protein, crystal matrix protein or prothrombin fragment 1, is a peptide generated from sequential cleavage of prothrombin by factor Xa and thrombin. This peptide is present in epithelial cells of the thick ascending limb of the loop of Henle and the distal convoluted tubule in greater quantities in people who form stones than in healthy individuals.15 The peptide inhibits calcium oxalate crystal aggregation and growth in rats,16 and might be excreted by the kidney to protect against stone formation, but further research is required to show that this process occurs in people. The peptide chain of inter-␣-inhibitor has been isolated from urine, and has been reported to inhibit calcium oxalate crystallisation.17 Although research on this protein continues, Dean and colleagues18 concluded that inter-␣-inhibitor does not have a substantial inhibitory role in crystallisation, which emphasises the point that some proteins associated with stones could
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have no active involvement in their formation. Lastly, glycosaminoglycans, or urinary polyanions, are potent inhibitors of growth of calcium oxalate in urine, and block adhesion of uric acid crystals.19,20
Different stone types Calcium stones Most stones contain calcium combined with oxalate, phosphate, or occasionally uric acid. All calcium stones are radio-opaque, and calcium oxalate and calcium phosphate stones are black, grey, or white and small (⬍1 cm in diameter), dense, and sharply circumscribed on radiographs. Different conditions contribute to calcium stones. Hypercalciuria (defined as ⬎0·1 mmol/kg bodyweight of patient per day, calculated for ideal bodyweight) can be idiopathic or result from any disorder that induces even mild hypercalcaemia. Such disorders include: (1) primary hyperparathyroidism, which results from an adenoma in 85% of cases, and is associated with mild to moderate hypercalcaemia. People who form stones and have hypercalcaemia are almost certain to have this parathyroid problem. Hypercalciuria is a result of excess parathyroid hormone, which causes overproduction of 1,25–dihydroxyvitamin D in the kidney; both factors promote bone resorption, increasing the filtered load of calcium and hence calciuria. (2) Other disorders that induce hypercalcaemia can also result in hypercalciuria: malignancies, granulomatous diseases, sarcoidosis, thyrotoxicosis, and immobilisation. (3) Idiopathic hypercalciuria is a familial disorder affecting both sexes equally, in which urinary calcium concentration is raised despite normal concentrations of blood calcium. The primary mechanisms for such hypercalciuria can occur individually or in combination21 and include high intestinal calcium absorption (the commonest mechanism), with a normal or slightly raised serum calcium, suppressed parathyroid hormone, and increased renal filtered load; increased bone resorption; defective renal-tubular calcium reabsorption, with an inappropriately high phosphate excretion for any given calcium concentration, which might induce increased activation of 1,25–dihydroxyvitamin D; and raised phospholipid-arachidonic acid concentration in serum and erythrocytes, with raised urinary prostaglandin E2 concentrations.22 (4) Mutations in the CLCN5 chloride channel in Japanese patients resulted in low-molecular-weight proteinuria, hypercalciuria, and calcium stone formation.23 (5) Other causes of hypercalciuria are inherited syndromes of familial benign and autosomal dominant hypercalciuric hypocalcaemia. These disorders are the result of a mutation in the calcium receptor gene. The calcium receptor facilitates regulation of parathyroid hormone secretion and renal-tubular calcium reabsorption in response to changes in extracellular calcium concentrations.24 Another condition associated with renal stone formation is hyperoxaluria. Oxalate is an end-product of metabolism, is largely derived from endogenous sources, and is excreted unchanged in urine. Foods rich in oxalate—rhubarb, standard teas, nuts, beans, spinach, coffee, and chocolates—can increase concentrations in urine to 670 mol/day (normal value 440 mol/day). However, concentrations of more than 890 mol/day indicate enteric oxaluria (associated with malabsorptive small-bowel diseases), mild metabolic hyperoxaluria, or primary hyperoxaluria.
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Mild metabolic hyperoxaluria does not seem to represent a substantial fraction of hyperoxalurias, although in one study from South Africa, 20% of patients with recurrent renal stones had this disorder.3 Cytosolic enzyme perturbations are thought to result in mild hyperoxaluria and recurrent calcium oxalate stones, but the exact pathogenic mechanisms have not been identified. Pyridoxine, which is a cofactor in shunting glyoxalate to glycine and pyruvate (ie, away from oxalate), has been successfully used to treat these patients. Primary hyperoxaluria type 1 disease is caused by lack of the liver enzyme alanine:glyoxylate aminotransferase, and type 2 disease by lack of D-glycerate dehydrogenase.25 The defective genes that cause these diseases and their abnormal liver enzyme products cause excessive oxalate metabolism, which results in systemic calcium-oxalate deposition from a young age. Finally, hypocitraturia is also associated with renal lithogenesis. Citrate forms a highly soluble complex with calcium, and thus acts as an inorganic inhibitor of stone formation and interferes with surface-controlled crystallisation. Hypocitraturia could result from causes of intracellular acidosis such as renal failure, potassium deficiency, distal renal tubular acidosis, chronic diarrhoeal states, and drugs such as acetazolamide. Many patients with stones have unexplained low urinary citrate, dysfunction of the renal sodium-citrate cotransporter has been proposed as a possible mechanism.26 Uric acid stones Uric acid stones are smooth, round, yellow-orange and nearly radiographically transparent—unless mixed with calcium crystals or struvite. They are typically seen as filling defects on intravenous pyelograms, and computed tomography scanning can distinguish them from kidney tissue or blood clots. Diets high in purines, especially those containing organ meats and fish, result in hyperuricosuria, and, in combination with low urine volume and low urinary pH (as a result of impaired renal ammonia production), can exacerbate uric-acid stone formation. Uric acid salts out calcium oxalate, and can precipitate out in acid urine even in the absence of raised serum or urinary uric-acid concentrations. Furthermore, hyperuricaemic disorders including gout (about 20% of patients with gout are hyperuricosuric), myeloproliferative disorders, tumour lysis syndrome, and inborn errors of metabolism (such as Lesch-Nyhan syndrome and glucose6–phosphatase deficiency) result in an increased filtered load of uric acid and thus, hyperuricosuria.27 As with all stones, certain drugs may enhance stone formation, and in the case of uric acid stones, hyperuricosuric agents include low dose salicylates, probenecid, and thiazides. Struvite or triple phosphate stones Radiographs show struvite stones as large, gnarled, and laminated. They are associated with substantial morbidity including bleeding, obstruction, and urinarytract infection. Signs of struvite stones include urinary pH greater than 7, staghorn calculi, and urease that grows bacteria on culture (proteus, klebsiella, pseudomonas). Stones develop if urine is alkaline, has a raised concentration of ammonium, contains trivalent phosphate, and contains urease produced by bacteria. Cystine stones Cystine stones should be suspected in patients with a history of childhood stones or a strong family history.
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Panel 2: Drugs associated with renal stone formation Drugs that promote calcium stone formation: ● ● ● ● ● ●
Loop diuretics Antacids (calcium and non-calcium) Acetazolamide Glucocorticoids Theophylline Vitamins D and C
Drugs that promote uric acid stone formation: ● Thiazides ● Salicylates ● Probenecid ● Allopurinol Drugs that precipitate into stones: ● Triamterine ● Aciclovir ● Indinavir (Adapted with permission from Monk).27
They are greenish-yellow, flecked with shiny crystallites, and are moderately radio-opaque with a rounded appearance. Calcium stones are denser than vertebral bodies, whereas cystine stones are less dense. People who are homozygous for cystinuria (an autosomal recessive disorder) excrete more than 600 mg per day of insoluble cystine. More than half the stones in cystinuria are of mixed composition, and many patients have associated physiological problems such as hypercalciuria (19% of patients), hyperuricosuria (22%), and hypocitraturia (44%).28
Clinical presentation of acute stone episode When a urinary stone moves into the renal collecting system, the resulting increase in intraluminal pressure stretches nerve endings in the mucosa, and produces a severe and often colicky pain. This pain radiates downward on the anterior from the flank toward the groin, and is often accompanied by frequent urination, dysuria, oliguria, haematuria, acute nausea, and hypotension. In the acute setting, stones can obstruct the urinary tract producing serious symptoms, or obstruction can be a relatively slow and painless process resulting from slow stone growth and presenting with advanced renal parenchymal damage. Precipitants of acute stone episodes include dehydration and reduced urine output, increased protein intake, heavy physical exercise, and various drugs (panel 2).
Investigations Acute setting Documentation of stone characteristics is extremely important (type, size, and location). Although there is a risk of allergy and contrast nephropathy, intravenous pyelography remains the gold standard for such identification. Ultrasonography can indicate whether a stone is in the kidney or ureter, the degree of any obstruction, and quality of renal parenchyma. Plain abdominal radiography is useful for stones above the pelvic brim, and, with ultrasonography, is the investigation of choice in patients unable to tolerate an intravenous pyelogram (for reasons such as allergy to iodine or renal insufficiency). Medical management of a stone depends on the type of stone, and includes correction of dietary aberrations, metabolic defects, or both. Panel 3 shows recommended investigations.
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Panel 3: Investigations for a renal stone Blood ● ● ● ● ● ● ● ● ●
Full blood count Urea and electrolytes Calcium Phosphate Bicarbonate or carbon dioxide Uric acid Parathyroid hormone Alkaline phosphatase Cholesterol
Urine ● Spot pH (include an acid load test if pH >5·4) ● Specific gravity ● Culture ● 24-h analysis of urinary: volume, calcium, sodium, urate, creatinine, phosphate, citrate, and oxalate ● Polarisation microscopy (after fracture of calculi) ● Urinary calcium: creatinine ratios ● Infrared spectrometry
Classification of hypercalciurias is of limited use in management patients with calcium stones, and the calcium-loading test has become obsolete.29 Chronic setting All kidney stones should be investigated30 and assessment needs to include a thorough medical history, drugs taken, family history, lifestyle and diet, fluid intake, and a clinical examination. Investigations outlined in panel 3 should be done. Saturation with stone-forming salts can be calculated from these measurements with commercially available computer software. More than one 24 h urine sample might be needed, especially to be able to define a stone as idiopathic if all results are negative. Optimum values of 24 h urine sample constituents are shown in panel 4.
Management of acute stones Pain relief Renal colic is one of the most intense forms of pain and requires prompt symptomatic treatment. Non-steroidal anti-inflammatory drugs given orally or intravenously have good analgesic properties,31 although they also have serious gastrointestinal and renal side-effects. Renal side-effects are especially important in dehydrated patients and those at risk of allergy to these drugs.
Panel 4: Optimum values of 24 h urine sample constituents ● Volume ● pH ● Calcium ● ● ● ● ●
Oxalate Uric acid Citrate Sodium Phosphate
>2–2·5 L >5·5 and <7·0 (a spot urine specimen will suffice) <0·1 mmol/kg, or <7·5 mmol in men, <6·3 mmol in women 180–350 mol 1·5–4·4 mmol 2·4–5·1 mmol <200 mmol <35·2 mmol
To ensure adequacy of collection, urine creatinine should be: 7·1–15·9 mmol in men 5·2–14·1 mmol in women (Adapted with permission from Monk).27
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Cyclo-oxygenase-II inhibitors have been developed to reduce gastrointestinal effects, but they also inhibit renal vasoactive substances and are contraindicated in patients with renal insufficiency.32 Paracetamol given every 4 h is well tolerated, but pain relief is often inadequate with this agent alone. Narcotic analgesics including morphine (given intramuscularly or intravenously) and pethidine offer excellent pain relief and are the drugs of choice for acute renal colic. However, they are sedative and have the risk of dependence if used for a long time. Their emetogenic side-effects can be counteracted with antihistamines such as hydroxyzine, which has additive analgesic properties in combination with narcotic agents. Codeine is physiologically related to morphine, and, when combined with paracetamol or aspirin, is effective for moderate pain. Dextropropoxyphene combined with paracetamol has been used in the acute setting, and offers fair pain relief if other opiates are contraindicated. Fluids An increase in diuresis will help patients to pass stones, and stone and urinary supersaturation can be reduced by judicious fluid management. Patients should drink 2–3 L of water daily, or be given water by intravenous infusion if nauseous. However, an increase in diuresis can worsen pain, hydronephrosis, and ureteral function, in which case ureteral stenting might be necessary. General therapies A regular catharsis should be encouraged, and although uncommon in the acute setting, urinary-tract infection should be investigated and treated if found. Education of patients about maintenance of adequate hydration, and avoidance of precipitating drugs and foods should begin as soon as possible after an acute event.
Management of chronic stones General measures Non-pharmacological interventions reduce 5 year rate of stone recurrence by up to 60%33 in people who adhere to a sensible diet. Patients should be encouraged to increase their basic intake of water to at least 2 L daily, and especially so during heavy exercise, pyrexial episodes, and when travelling long distances. Maximum urine output should be encouraged in patients with renal insufficiency, with careful monitoring of volume status and weight gain. A non-animal low protein diet (0·8–1·0 g/kg per day) prevents the mild acidosis induced by animal protein breakdown, and improves calcium homoeostasis. Severe protein restriction results in malnutrition and muscle breakdown and should be discouraged.34 Measurement of urea and, if possible, inorganic sulphate excretion are easy ways to assess total and animal protein intakes. Calcium binds oxalate in the gut, thus people who form stones and are on a high calcium diet paradoxically have a lower occurence of stone formation than those not on such a diet. Dietary calcium should be limited to about 1 g/day in patients who remain hypercalciuric despite pharmacological treatment. An increased tubular sodium load results in reduced tubular reabsorption of calcium, therefore a low sodium diet (2–3 g/day) is recommended for hypercalciuric patients. Specific therapies These therapies are designed for metabolically active stone disease.
patients with After general
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measures have been instituted, further treatment is based on stone composition and abnormalities noted from the 24 h urine sample analyses. Calcium stones—hypercalciuria Thiazide diuretics such as hydrochlorothiazide (at doses of 25–50 mg/day) increase distal tubular reabsorption and reduce intestinal calcium reabsorption. Indapamide (2·5–5·0 mg/day) has been shown to be best for treatment of recurrent stones associated with idiopathic hypercalciuria. This agent has fewer untoward metabolic effects than other thiazides if used in high doses.35 Addition of potassium citrate maintains potassium concentration at the ideal of 3·5–4·0 mmol/L and this, together with citrate, improves citrate excretion in the tubules thereby reducing crystal agglomeration.36 Persistent hypercalciuria can respond to potassium-sparing diuretics, calcium restriction (800–1000 mg/day), and reassessment of compliance. Phosphate rarely needs to be replaced even in patients with phosphate-losing tubular defect. In patients with intractable stone recurrence and idiopathic hypercalciuria, Coe and colleagues37 recommend a calcium-binding resin (sodium cellulose phosphate) with a thiazide diuretic, although no controlled clinical studies in support of such treatment have been done. Use of ethyl icosapentate (a polyunsaturated fatty acid) has yielded disappointing results with regard to urinary calcium and oxalate excretion, although calciuria was reduced in some patients and further research is advocated.38 Calcium stones—hyperoxaluria First principles of treatment include increased fluid intake and urinary alkalinisation, treatment of the underlying cause of disease, dietary restriction of foods high in oxalate, and an increase in dietary calcium. Calcium carbonate (500–650 mg tablets, two or three to be taken with every meal) binds dietary oxalate, and potassium citrate (450 mg capsules taken two to three times per day) in combination with magnesium gluconate (0·5–1·0 g/day) is a useful adjunct.39 Mild metabolic hyperoxaluria can be treated with pyridoxine, but not very successfully. Primary hyperoxaluria can be cured only by liver transplantation, although pyridoxine supplementation may reduce endogenous oxalate production. Calcium stones—hypocitraturia Because citrate forms a soluble complex with calcium, citrate is an effective treatment for most calcium stones, irrespective of their cause. Urinary citrate concentrations should be maintained above 2·4–5·1 mmol/day, and an initial dose of 450 mg of potassium citrate two to three times daily might have to be increased to achieve this level. Potassium citrate must be used rather than sodium bicarbonate, because sodium bicabonate increases delivery of sodium to the renal tubules, which results in an increase in urinary calcium.
Calcium stones—hyperuricosuria Recommended therapies are increased fluid intake, treatment of the underlying cause of disease, and a low purine diet with the addition of allopurinol if other measures fail. Uric acid stones Recommended therapies include adequate fluid intake, a low purine diet, and urinary alkalinisation (pH 6·5) with potassium citrate. Such measures should pre-empt use of allopurinol and acetazolamide for urinary uric acid secretion and alkaline pH maintenance. Acetazolamide should not be used in the long term. Struvite stones Because urease-producing bacteria are often embedded in these stones, antibiotics can be ineffective in eradication of the offending pathogen. Early urological intervention is warranted in patients with these stones, as is use of culture-specific antibiotics around the time of operation. Furthermore, once the patient is stone free, Wong and colleagues41 recommend continuation of antibiotics until cultures remain negative for at least 3 months. As an adjunct, oral phosphate binders reduce phosphate content of these stones. Cystine stones Treatment for these stones is aimed at improvement of solubility of cystine in urine, by increase of fluid intake to more than 4 L/day and alkalisation of urinary pH to more than 7·4 with potassium citrate. Treatment also includes restriction of dietary sodium, and occasionally, d-penicillamine can be used as a chelating agent— although occasionally side-effects (agranulocytosis and thrombocytopenia) limit its clinical use.42 Because cystine stones do not disperse well with extracorporeal shock-wave lithotripsy, formal urological procedures might be necessary to remove these stones. Urological intervention43 Advances in urological techniques have drastically altered management of patients with symptomatic stones that require treatment. Most symptomatic upper urinary-tract stones are small, occur in normal kidneys, and pass spontaneously if less than 5 mm in diameter. Up to 85% of stones smaller than 2 cm in diameter that need to be removed are best treated with extracorporeal shock-wave lithotripsy. An endoluminal approach with ureteroscopy or percutaneous nephrolithotomy is best suited for large or complex stones, stones associated with urinary tract abnormalities, those in the lower ureter, or ones that do not fragment after extracorporeal shock-wave lithotripsy. Fortunately, formal surgical lithotomy has been relegated to anecdotal status. We thank Maria Martins for her assistance, advice, and encouragement with the preparation of this manuscript.
References 1
Calcium stones—renal tubular acidosis These patients have a mild metabolic acidosis that results in increased renal tubular reabsorption, metabolism of citrate, and hypercalciuria.40 In patients with type 1 renal tubular acidosis (distal), raised urinary pH promotes calcium phosphate precipitation, and high doses of potassium might be necessary to prevent stone formation.
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