Nephrology: 1. Investigation and treatment of recurrent kidney stones
A 60-year-old man is discharged from hospital after his second bout of renal colic in 2 years. Both times, he passed a stone without any need for surgical intervention. There is no other relevant history. The stones were analyzed biochemically and found to be composed of pure calcium oxalate. Imaging studies do not suggest the presence of residual calculi in the renal tract. The patient is, understandably, reluctant to pass any more kidney stones. The results of relevant laboratory investigations are as follows: serum biochemistry normal, urine volume 1.75 L over 24 hours, urinary calcium excretion 2.9 mmol/day, urinary phosphate excretion 24 mmol/day, urinary uric acid excretion 5.5 mmol/day, urinary oxalate excretion 270 μmol/day and urinary citrate excretion 0.6 mmol/day. The patient asks you what the probable cause is of his recurrent nephrolithiasis. What medication could be prescribed to help him and what side effects could he anticipate? What other measures could the patient take to reduce his risk of stone recurrence?
A 55-year-old woman with recurrent uric acid stones has begun treatment with potassium citrate, 60 mEq/day, in divided doses and allopurinol, 300 mg/day. She finds the potassium citrate unpalatable but, on your advice, agrees to continue the medication. She comes to your office 10 days after starting the medications describing general malaise, weakness, mild dysphagia and nausea. She has a generalized rash and some oral ulcers. What are the side effects of the prescribed medication? What is your diagnosis? What measures would you recommend?
Kidney stones are rarely, if ever, fatal. The main impact of nephrolithiasis is felt by young, otherwise healthy adults in the form of acute renal colic, causing symptoms of pain, nausea, vomiting and hematuria. The estimated cost of this condition in the United States for 1993 was US$1.83 billion.1 The lifetime risk of passing a kidney stone is about 8%–10% among North American males, and the peak age of incidence is 30 years. The rate of kidney stone formation in women is about half that in men, with 2 peaks, the first among women aged 35 years and the second among those aged 55 years.2 Among patients who have passed one kidney stone, the lifetime recurrence rate is 60%–80%.2 There is significant geographic and seasonal variation in rates of stone formation. The reasons for this variation are not entirely clear, but they may relate to climate and the mineral content of drinking water. The frequency of kidney stones (notably calcium oxalate stones) has increased with improved standards of living.
Medical interventions for kidney stones can be classified as general or specific. General measures, which are advisable for all patients, include increasing fluid intake to produce a urine volume of 2–3 L/day. Data on the benefits of dietary interventions are less conclusive,6,12 and well-conducted, prospective studies are lacking. Good advice is to reduce the intake of animal protein and sodium, because reduction in the renal excretion of sodium will also reduce renal calcium excretion and thus render the urine less lithogenic. As described earlier, patients should moderate their calcium intake to 1 g/day.
These general measures should be instituted in all patients with recurrent stone formation to take advantage of the well-recognized phenomenon of the “stone clinic effect,” which, it has been suggested, can reduce the 5-year stone recurrence rate by 60%.13 Specific interventions depend on stone type and identifiable factors in the urine that may increase lithogenicity, as outlined here.
Calcium oxalate stones
A recently published meta-analysis of randomized trials on preventing the recurrence of calcium oxalate stones suggested that the greatest benefit from pharmacologic intervention is associated with thiazide diuretics.14 Five trials involving thiazide diuretics and a single trial with the closely related drug indapamide suggested a risk reduction for developing new stones of 21.3% (95% confidence interval –29.2% to –13.4%) in the patients receiving medication. The combination of hydrochlorothiazide, 25–50 mg, with amiloride, 5 mg, to prevent potassium wasting was appropriate. Benefits were seen only after 3 years of treatment, so therapy should not be abandoned if stones recur early. Less benefit was conferred by citrate-containing alkalinizing compounds and allopurinol. However, oral potassium citrate, 30–80 mEq daily, is indicated for patients in whom hypocitraturia has been detected.
A randomized, placebo-controlled study showed a benefit of allopurinol, 100 mg 3 times daily, in people with hyperuricosuria and formation of calcium oxalate stones.15 In addition to a requirement for both hyperuricosuria and normocalciuria, patients who were selected for the study had formed 2 or more calculi in the 5 years before the study and at least one calculus in the previous 2 years. The rate of new stone events (defined as a composite of stone passage and the appearance of a new stone, or enlargement of an existing stone on abdominal radiography) was much higher among the 31 patients receiving placebo than among the 29 receiving allopurinol (0.26 v. 0.12 per patient year, p < 0.02).
There is no strong evidence to support the use of measures to reduce urinary oxalate, such as oral calcium supplementation and administration of cholestyramine.
Uric acid stones
Uric acid is soluble in alkaline urine. Thus, management of uric acid stones generally involves alkalinization of the urine. The target range for urine pH should be 6.0–6.5 for therapy, because formation of another type of stone, calcium phosphate, may be induced by urinary pH above 7. Urine can be alkalinized with either oral potassium citrate or sodium bicarbonate. The former has the advantage of avoiding a sodium load, which may lead to hypercalciuria, and has been shown to reduce significantly the recurrence of uric acid stones when given at doses of 30–80 mEq/day,16 but it should be used cautiously in combination with potassium-sparing diuretics because of concerns about hyperkalemia.
Struvite stones form in infected urine and are frequently large enough to fill the entire pelvicalyceal system; in this situation, they are known as staghorn calculi. In rare cases, staghorn calculi are composed purely of cystine or calcium oxalate monohydrate. Because of their size and the presence of infection, a combined surgical and medical approach, including increased fluid intake and the use of antibiotics, is required. The American Urological Association has published clinical practice guidelines for the management of staghorn calculi.17 It recommends extracorporeal shock wave lithotripsy (ESWL) combined with percutaneous stone removal. Removal of all stone fragments and antibiotic therapy to sterilize the urine are required to prevent recurrence.
Despite the rarity of cystine stones (1%–2% in adults, 6%–8% in children), they deserve special mention. Cystinuria is an inborn error of metabolism characterized by defective tubular and intestinal transport of cystine, ornithine, lysine and arginine. Although large amounts of all of these amino acids appear in the urine, only the cystine precipitates at physiologic pH. A high fluid intake throughout each 24-hour period decreases the rate of recurrence. Sodium restriction (to 80–100 mmol/day) significantly reduces cystine excretion.18 Other therapies for cystine stones include drugs such as penicillamine, tiopronin and captopril.19 These medications increase the solubility of cystine by cleaving the disulfide bond of the amino acid.
There have been major advances in the surgical management of renal and ureteric calculi over the past 15 years. Renal calculi that are increasing in size or causing symptoms or obstruction should be dealt with by one of the techniques that result in complete clearance of the stone and any fragments.
First described by Chaussy in 1982,20 ESWL is now the primary surgical modality for most renal calculi, although the clearance rate for all stone fragments is not as high as originally reported. Plain radiography indicates stone-free status in approximately 34% of patients, but nephrotomography indicates this degree of success in only 17%.21 The success of ESWL varies with the composition, location and size of the stone, the type of generator used and the “targetability” of the stone. Close follow-up to ensure passage and removal of all stone fragments is required. The rate of recurrence after ESWL varies according to stone type but is as high as 20% in patients with infected stones. If stone fragments are retained, regrowth rates are about 33% at 3.6 years.21
For most ESWL procedures conducted with modern equipment, anesthesia is not required, and patients are treated in the outpatient setting with light sedation. During the treatment, the patient receives about 2000 shocks from an ellipsoid generator; this lasts about 30 minutes depending on the size of the stone and the number of shocks that have to be delivered. This is associated with some discomfort, hematuria and the passage of multiple small stone fragments.
A number of other minimally invasive ureteroscopic and percutaneous surgical procedures are available. The combination of these with ESWL for large and staghorn calculi has given rise to the term “sandwich therapy.”22 This combined therapy entails percutaneous fragmentation and removal of as much stone as possible, followed by ESWL to those areas that could not be reached initially. Fewer percutaneous passes are required, and the risk of bleeding and infection is lessened. Second-look percutaneous nephrostomy passing through previously created tracts can be performed to remove stone fragments that are not passed after ESWL. Follow-up surveillance and antibiotic therapy, where appropriate, form an integral part of this therapy.
Newer techniques involving retrograde approaches to ureteral and renal calculi use miniature flexible and semi-rigid ureteroscopes, which permit access to the entire ureter and collecting system. There are few stones that cannot be managed by minimally invasive techniques. Open stone removal is necessary only for patients with anatomic anomalies and those for whom the newer modalities have failed.
Morton, A R et. al. Nephrology: 1. Investigation and treatment of recurrent kidney stones. PMC. January 2002