Q. A 26-year-old man comes to see you having had his second episode of renal colic. He has passed his stone and presents it to you. He is presently symptom free. There is no family history of renal stones. What might the stone be made of?
A. The majority of stones have more than one constituent, but the major constituents of stones with their relative percentages are as follows:
|
Calcium oxalate |
70%-80% |
|
Struvite (magnesium ammonium phosphate) |
10% |
|
Uric acid |
8%-10% |
|
Cystine |
1%-2% |
|
Calcium phosphate |
1% |
Q. What are the two different forms of calcium oxalate stone, and how are such stones thought to form?
A. Calcium oxalate stones occur in two different forms: calcium oxalate monohydrate (whewellite) and calcium oxalate dihydrate (weddellite). The former are much harder to break than the latter.
Calcium oxalate stones are thought to develop as a result of a number of factors. There is an imbalance between promoters of stone formation, which are increased, and inhibitors of stone formation, which are decreased. Thus a decreased urinary volume, decreased urinary pH, and decreased urinary citrate, magnesium and glycosaminoglycans, with increased urinary uric acid, oxalate and calcium are all risk factors for urinary supersaturation with calcium oxalate. The more supersaturated the urine is, the higher the risk of stone formation. If the saturation is below the solubility product, then a stone will not form. Once it goes above this, however, crystal growth will occur, and crystals will aggregate, but de novo nucleation is very slow. An increase in inhibitors in the urine at this level may prevent stone formation. However, as the saturation of calcium oxalate in the urine increases above the formation product, nucleation can occur and inhibitors are not effective.
Q. What investigations does this man need?
A. ttere is debate as to how stone formers should be evaluated metabolically. One way to approach this is to determine the patient’s risk of developing a further stone, so that resources are directed to where they are likely to have the most benefit.
Thus, first-time stone formers who are at lower risk of developing a further stone can undergo an abbreviated workup, whereas higher-risk patients should have a more thorough workup.
tThe following are risk factors for recurrent stone formation, which necessitate a thorough metabolic workup:
Children
White patients with a positive family history
Black patients
Patients with chronic diarrhoea or malabsorptive states
History of gout
Osteoporosis
Nephrocalcinosis
Recurrent UTIs
Pathologic skeletal fractures
Patients with stones composed of uric acid, cystine or struvite
An abbreviated workup consists of
Bloods - U and Es (renal function, hypokalaemia in distal renal tubular acidosis), urate (hyperuricaemia in patients with uric acid stones), serum calcium and serum phosphate (hypercalcaemia and hypophosphataemia in patients with hyperparathyroidism)
Urine - MSU (C and S and microscopy of the sediment to look for crystals), spot cystine, urine pH (high in infection stones, <5.5 in patients with uric acid stones)
Stone - Analysis of the stone
An extensive workup consists of the previous list plus the following:
24-hour urine collections - the standard in the United Kingdom is for patients to provide two 24-hour urine collections, one in a bottle with hydrochloric acid (looking for 24-hour calcium, oxalate, phosphate, citrate and magnesium) and one plain bottle (looking for 24-hour uric acid and electrolytes and pH). Also measured is 24-hour urine volume.
A dietary diary is useful to help address with patients changes which need to be made. Furthermore, some urologists would advocate the collection of a 24-hour urine after 3 days on a standardised diet. This allows comparison of the results with a patient’s normal diet, to see which abnormalities are attributable to the diet. The standardised diet consists of avoidance of meats, sodium restriction, oxalate restriction and moderate calcium restriction.
Q. How do you tell your patients to perform a 24-hour urine collection?
A. It is important to get a complete 24-hour collection of urine, and to ensure that patients understand how to perform a 24-hour collection. Many will not really understand what you tell them in the clinic, and thus it is imperative to give them some writhen information to take home with them to read.
On the day that patients decide they are going to do their collection, they should wake up in the morning as usual. They should then void into the toilet and note the time (i.e. discard first void on the day of starting the collection). Every time they pass urine for the next 24 hours, including the first void of the following day (which should be at the same time as the void into the toilet at the start of the collection) should be collected in the bucket/collection bottle. The urine should then be kept in a cool place until it is analysed, ideally as soon as possible after the collection is complete.
Q. What is different about the metabolic management of patients with uric acid stones?
A. Uric acid stones are only formed in acid urine. Diet may be especially important in patients with uric acid stones, as a diet rich in purines and proteins with a high consumption of alcohol increases uric acid excretion and lowers urinary pH. Over 20% of patients who have gout will get uric acid stones, due to hyperuricosuria.
Uric acid stones are the only stones that can be dissolved by medical agents. This can be successful in the majority of patients. Oral chemolysis is carried out by alkalinising the urine, preferably using potassium citrate. The dosage of agent should be determined by the pH response in the urine. In patients who have high uric acid excretion, hyperuricosuria, prescription of allopurinol should be considered. Finally, as with all stone formers, diuresis should be promoted by increasing fluid intake.
Q. Tell me what you know about cystinuria.
A. Cystine stones are caused by an autosomally recessive inherited inborn error of metabolism, such that the proximal tubular reabsorption of the dibasic amino acids Cystine, Ornithine, Lysine and Arginine (COLA) is decreased. However, cystine is the only poorly soluble amino acid out of these, and thus these patients form only cystine stones.
Cystine stones account for about 1% of adult renal tract stones. The peak incidence of stone formation is in the second to third decades of life, but these patients get recurrent stones, which typically have a ground glass appearance. The crystals are hexagonal.
Diagnosis is made based on stone examination, microscopy of urinary sediment or measurement of urinary cystine levels. The cyanide-nitroprusside test (Brand’s test) is a spot test to detect cystinuria, but in patients with a suspected diagnosis a 24-hour collection is performed, which will determine if the patient is homozygous or heterozygous.
Medical care of these patients consists of advice to drink copious amount of fluid, aiming for 4 or more litres of fluid intake a day. Alkalinisation of the urine to a high pH increases solubility of cystine, and further medical treatment includes the use of complexing agents to bind with cystine forming soluble compounds. Such agents include D-penicillamine and a-mercaptopropionylglycine (Thiola). Finally captopril can be used. Captopril is a first- generation angiotensin-converting enzyme (ACE) inhibitor and has been shown to form a complex with cystine that is 200 times more soluble.
Surgical care of these patients is similar to that of patients with other types of stone, except that it should be noted that cystine stones are more resistant to ESWL than many other stone types.
Q. How does Brand’s test work? What levels of cystine in the urine would indicate that the patient was a homozygote?
A. Cyanide-nitroprusside test: ttis is a rapid, simple and qualitative determination of cystine concentration. Cyanide converts cystine to cysteine. Nitroprusside then binds, causing a purple hue in 2-10 minutes. The test detects cystine levels of higher than 75 mg/L. Falsepositive test results occur in some individuals with homocystinuria or acetonuria and in people taking sulfa drugs, ampicillin, or N-acetylcysteine. The normal excretion rate is 40-80 mg/day. Heterozygotes excrete 200-400 mg/day. Homozygotes usually excrete >600 mg/day.
Q. What are the principles of treatment of patients with cystine stones?
A. The main considerations are that these patients are young, will tend to have recurrent stone episodes and hence may require multiple interventions. As such prevention is vitally important, bearing in mind the significant risk of poor compliance.
Diet
As cystine is produced from the essential amino acid methionine, attempts are made to reduce foods high in methionine, such as red meat, fish and poultry.
High fluid input
Ideally >3-4 L/day, as it is known that 250 mg cystine will dissolve in 1 L of fluid.
Alkalinisation
Using potassium citrate, sodium bicarbonate (NaHCO3) or in some cases acetazolamide, which is a carbonic anhydrase inhibitor and thus increases HCO3 excretion.
Oral chelators
These drugs combine with cystine to form a soluble complex thus preventing stone formation and possibly even dissolving existing cystine stones, and include D-penicillamine, a-mercaptopropionylglycine and captopril.
Q. How would you make a clinical diagnosis of renal tubular acidosis (RTA)?
A. Patients with RTA are unable to acidify their urine, and thus the pH of the urine never goes below 5.8. Confirmation of the diagnosis requires ammonium chloride loading test.
In addition there is a decrease in blood pH, lowered plasma bicarbonate and raised serum chloride. Urinary calcium and phosphate levels are raised.
Q. Why do you get these findings with RTA?
A. RTA results from a disturbed secretion of H+ ions in the renal tubules, with too few H+ ions available for adequate bicarbonate reabsorption in exchange for acid ions. Instead, chloride ions are reabsorbed and a hyperchloremic metabolic acidosis develops which in turn leads to resorption of apatite from bone and thus increased serum calcium. Hypercalcuria follows, with recurrent stone formation and often nephrocalcinosis. Only distal RTA is of importance in stone formers.
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