The simple investigation and medical treatment of renal calculi

Summary
The formation of urinary stones is relatively common. They may contain uric acid, struvite or cystine, but they are most frequently formed from calcium oxalate. Patients who have stones which result in symptoms should have urine microscopy, renal function tests and imaging of the urinary tract. Although surgical treatment may be required, the role of diet and increased fluid intake should not be overlooked. Up to half the patients will develop recurrent stones.

Introduction
As many as one in 10 men and one in 20 women will experience an episode of renal colic. Considerable debate still exists as to the most appropriate manner of investigating and treating stone sufferers, particularly those who have calcium oxalate stones.

The treatment of urinary stone disease has undergone dramatic change over the last two decades. However, the changes have been largely limited to the procedures rather than non-interventional management. The factors that influence both the need for and the nature of treatment in the acute phase have been established for decades. They are:

• size of the stone
• composition of the stone
• degree of obstruction
• overall renal function
• infection
• severity and frequency of the pain

While the sudden onset of severe renal colic usually leads to the diagnosis of a renal stone, it is important to realise that, in spite of what is usually a dramatic event for the patient, the majority of stones are small and will pass spontaneously. This means that most patients will not need hospitalisation or surgical intervention and can usually be managed without referral to hospital, provided adequate pain relief can be supplied.

Clinical assessment
The assessment of a patient with a clinical diagnosis of renal calculi requires a few simple steps. Firstly, is there a past history of stones? This is important as the recurrent stone-former will require a different pattern of evaluation from the patient presenting with their first stone. For example, recurrent stones in a young patient may suggest cystinuria. Other pieces of information that need to be elicited are occupation (possible cause of dehydration), nature of the diet, fluid intake and other medical conditions such as recurrent urinary infections, gout, sarcoidosis and bowel surgery e.g. early forms of bypass surgery for obesity. A family history of gout or renal calculi would also influence the decision to investigate.

Investigations
The first 3 key investigations are urine microscopy and culture, assessment of renal function and imaging of the urinary tract. This series of investigations should reveal the position, size and nature of the stone and, to a large extent, exclude structural or infective factors as possible causative agents in the majority of patients presenting with their first episode of renal colic.

Microscopy
Urine microscopy is essential in the acute phase, as the combination of infection and obstruction in the renal tract can rapidly result in septicaemia and permanent impairment of renal function. Infection may also point to a possible aetiological factor as urea-splitting organisms such as Proteus are frequently associated with the formation of struvite calculi. Microscopic haematuria occurs in most patients with urinary stones.

Renal function
Measuring renal function is important to ensure that overall function is not compromised and sufficient function exists for an intravenous urogram to outline the upper urinary tracts adequately. Hypercalcaemia and hyperuricaemia may suggest the composition of the stones.

Imaging
An intravenous urogram is the best means of identifying a stone, particularly in the ureter, and provides information about the degree and site of obstruction. It also has the ability to show structural abnormalities which are important in the evaluation of a patient with renal colic.

Diagnostic ultrasound is an alternative and, particularly in conjunction with an abdominal X-ray, may be the preferred method of assessing patients with recurrent stones. It is also used when irradiation is contraindicated as in pregnancy. Ultrasound is also valuable in the assessment of patients with radiolucent stones, particularly where the nature of the radiolucent filling defect seen on an intravenous urogram is uncertain.

Fewer than 5% of patients will require more complex investigations such as a retrograde pyelogram or a CT scan.

Stone analysis
Analysis of the stone, whenever possible, will help in the further management. However, if this is not possible, the chemical nature of the stone can usually be inferred from the radiological findings. The stone types most commonly encountered are calcium oxalate (>80%), with urate stones being the next most common, followed by struvite and the rare cystine stone.

Uric acid stones
Uric acid stones can occur in patients with normal serum and urinary levels of uric acid. However, not surprisingly, there is a strong association between gout and stone formation. About half of the patients with uric acid stones will either have been diagnosed as having gout or be shown to have gout during the investigation of their stones. Other causes of uric acid stones are myeloproliferative disorders and chemotherapy.

The majority of uric acid stones can be treated medically. Treatment involves a high fluid intake to maintain an output of at least 2 L of urine a day and the adjustment of the urinary pH to 6.5-7.0. This can usually be achieved by an oral dose of 1 g sodium bicarbonate 3-4 times a day. This dose may need to be varied and so it is important to ensure that patients monitor their urine pH with test strips and adjust the dose of bicarbonate accordingly. If increased hydration and adjustment of pH do not achieve dissolution or prevent recurrence, the latter usually due to patient non-compliance, then uric acid excretion can be reduced by commencing allopurinol in a dose of 200-400 mg per day. This regimen should prevent most recurrences.

Struvite stones
Struvite stones consist of magnesium ammonium phosphate and occur twice as commonly in women as in men. The stones are frequently associated with infection, although it is still unclear whether it is the stone that causes the infection or vice versa. The organisms associated with these stones produce urease which splits urea. This raises urinary pH and causes precipitation. The organisms commonly involved are Proteus, Pseudomonas and Klebsiella, but others, such as Staphylococcus, are occasionally responsible.

Surgical removal of the stone, either by extracorporeal shock wave lithotripsy, percutaneous techniques or open surgery, is usually required, but successful dissolution of struvite has been reported. The agent most commonly used is hemiacidrin which is a solution that contains magnesium hydroxycarbonate, magnesium acid citrate, citric acid, anhydrous D gluconic acid and calcium carbonate. It is given directly into the kidney by ureteric catheter or percutaneous nephrostomy. Hemiacidrin can cause pain, fever and hypermagnesaemia and deterioration in renal function. These complications are enhanced by inter current infection, so it is imperative that the urine has been sterilised with appropriate antibiotics before starting treatment. If the risk of recurrence is to be minimised, complete removal of the stone should be attempted and a high fluid intake should be maintained. A sterile urine is vital, but can be difficult to achieve and may require prolonged courses of antibiotics.

Urease inhibitors, such as acetohydroxamic acid or hydroxyurea, have been used to prevent the alkalisation of the urine and the precipitation of struvite. Neither agent has been used in long-term randomised trials so it is difficult to assess their efficacies in preventing recurrences.

Agents that alter the urinary pH may have a role in the treatment of struvite stones. The problem is that often the kidneys are badly damaged and so it is very difficult to acidify the urine.

Cystine stones
Cystine stones account for only 1% of stones and deserve mention largely because the correct diagnosis is often delayed. Many patients are subjected to frequent surgical procedures before appropriate preventive measures are initiated. The family history is important as this condition is due to an inherent error in metabolism, which is characterised by increased excretion of the amino acids, cystine, ornithine, arginine and lysine. The stones are composed of cystine as it is much less soluble in the urine than the other amino acids. If a patient presents with a family history of stones, usually at an early age, and has not responded to common forms of treatment, cystine stones should be suspected. The diagnosis can be confirmed by either rapid screening using the nitroprusside test or a high 24-hour cystine excretion or stone analysis.

As with uric acid stones, the key to successful prevention is adequate hydration (the patient needs to produce more than 3 L of urine per 24 hours, which usually means drinking at least two glasses of water at night) and alkalisation of the urine with large amounts of bicarbonate. Most patients find it difficult to maintain this regimen long-term and there is a high recurrence rate.

Cystine-binding drugs have also been used and penicillamine, starting at 150 mg 3 times a day, may be beneficial. However, this drug has a wide range of adverse effects, particularly at high doses, including nausea, rashes, agranulocytosis, proteinuria and iron depletion, which to date have seriously limited its usefulness. The drug alpha-mercaptopropionylglycine has also been used. This has fewer adverse effects than penicillamine, but has not been extensively studied.

Calcium-containing stones
Two major problems exist with regard to these stones. Firstly, there is no agreement as to what constitutes an appropriate evaluation of a patient presenting with their first stone. Secondly, a variety of preventive treatments have been used, but there are very few appropriately controlled trials.

The investigation of a patient with a calcium oxalate stone
There has been some enthusiasm for the detailed metabolic evaluation of patients presenting with their first stone. This enthusiasm seems to have waned and most clinicians would now only undertake detailed evaluation after the second or even third episode. Whether or not it is worth measuring the urine chemistry after the first stone is debatable.

The substances most commonly quantified are calcium, uric acid, oxalate, phosphorus, citrate and creatinine. While abnormalities will undoubtedly be detected, their significance is at best uncertain. For example, there is no agreement on the upper limit of calcium excretion for normal men. It can vary by 100% from one geographic location to another, without a greater stone incidence.¹ Similarly, there is considerable variation in the day-to-day excretion of most of the substances when measured in men on a free diet, which is analogous to the clinical situation. Between 3 and 6 consecutive 24-hour urine collections would be necessary to assess a patient adequately under these circumstances. Data from a single 24-hour urine collection from a patient on a free diet are not an adequate or appropriate base for long-term management strategies.

If detailed metabolic studies are to be undertaken, then evaluation protocols should be used² e.g. this may entail the collection of two 24-hour urine specimens with a patient on a normal diet. The parameters measured are volume, pH, calcium, phosphate, urate, oxalate, creatinine and citrate. The patient then starts on a calcium- and sodium-restricted diet for one week (400 g calcium and 100 mg sodium a day) and then a further 24-hour specimen is collected and analysed for the same parameters. Blood tests for calcium, phosphorus, uric acid and creatinine are taken while the patient is on the free and the restricted diet. The protocol is also extended to exclude renal tubular acidosis by means of the ammonium chloride loading test and to determine whether the elevated calcium levels are due to disturbances of absorption from the gut or due to altered renal handling.

At the end of this process, the patient can be categorised as having an abnormally high excretion of calcium, oxalate or urate, or a combination of all three. Patients with renal tubular acidosis will also be identified.

Evaluation protocols of this type do not assess the inhibitory activity of the urinary macromolecules. This may be an important deficiency as experimentally these substances have a very significant role in the prevention of both the growth and aggregation of calcium oxalate crystals, and thus may have an important bearing on stone formation. It is also important to stress that there are considerable geographic differences in the urine chemistry. The upper limits of calcium, urate and oxalate excretion in non-stone formers drawn from the same population must be used and not reference ranges from studies based on different populations.

Treatment of calcium oxalate stones

Fluid and diet
Both fluid intake and diet influence the formation of stones. One would certainly expect a high fluid intake to be beneficial. Increasing the volume should be effective by diluting calcium and oxalate. However, there are no studies that have unequivocally shown that increasing urinary output reduces stone recurrence. The difficulty is knowing what the patient's output was before the development of the first stone as the patient is invariably told to drink more fluid and hence their behaviour has already been modified by the time they enter any trials. Perhaps of more relevance however, is what the ideal volume of urine passed in a 24-hour period should be. A variety of studies suggest that all stone-formers should aim to pass at least 1.5 L of urine per 24 hours. A simple guide for the patient is to aim to keep the urine as colourless as possible; as a rule, the darker the urine, the more concentrated, hence the greater likelihood of crystal formation and subsequent stones.

The other long-standing advice given to these individuals has been to reduce their calcium intake. However, doubt has been cast on the usefulness of this advice by two recent studies. A high calcium diet has been advocated for stone-formers with mild hyperoxaluria.³ The rationale is that calcium binds the free oxalate in the intestine and prevents its absorption and subsequent excretion in the urine. The other study, a large prospective epidemiologic study⁴ involving more than 45 000 men, showed that men who maintained a high dietary intake of calcium had a lower incidence of stones than those with a reduced intake. While this phenomenon requires further study, encouraging stone-formers to reduce their calcium intake may not be sound advice! Also, the strategy of encouraging stone-formers to eat more foods rich in fibre content and hence phytic acid with the aim of binding calcium in the gut may have to be revisited, as this may make the ingested calcium less available to bind oxalate.

The other obvious strategy is to keep the diet low in oxalate. However, it is often difficult to identify oxalate in the diet. If fluids and diet are not successful, then most therapies have focused on reducing urinary calcium excretion. In theory, it would be preferable to lower the oxalate, but experience is limited to pyridoxine.

Thiazide diuretics
The most commonly used agents to reduce calcium excretion have been the thiazide group of diuretics. These drugs increase the reabsorption of calcium in the kidney tubules. The doses may be higher than those given for hypertension, and hydrochlorothiazide 50 mg a day is commonly used. Thiazides are effective in reducing the frequency of stone episodes in trials and they have been found to be equally effective irrespective of the level of urinary calcium.

Citrate
Citrate, because of its ability to form complexes with calcium in the urine, has been used orally in doses of 30 mL/Eq per day in an attempt to prevent recurrence. Although some studies show a beneficial effect, a recent controlled study found no benefit.

Allopurinol
There is an association between a high urinary urate excretion and the incidence of calcium oxalate stones. While the mechanism for this process is still debated, a number of clinical trials have shown that allopurinol can reduce the incidence of stones.

Sodium intake
Increasing dietary sodium increases the excretion of calcium. Patients with high calcium excretion are more sensitive to changes in sodium and so a small increase in the dietary sodium produces a higher than anticipated increase in calcium excretion. Limiting dietary sodium may be another way of effectively lowering calcium excretion and therefore preventing recurrence; however, this has not been subjected to any detailed trials.

Cellulose phosphate and orthophosphate
Cellulose phosphate and orthophosphate have also been used sporadically to prevent calcium stones, but, because of the adverse effects and often poor patient compliance, they have not achieved wide acceptance.

Conclusion
The advice of Hippocrates to drink more water is as valid and useful today as it was centuries ago. Equally, enthusiasm for detailed investigations must be tempered by the somewhat limited range of therapies available and the fact that, at worst, only 50% of stone sufferers will develop another stone. It is also important before starting any of these therapies to recognise that they may not have been subjected to adequate long-term randomised controlled trials. The patient may be placed on an agent with significant adverse effects without any proven benefit. Therefore, there seems little place for long-term therapy in any patient other than those with frequent recurrences i.e. at least one new stone episode a year.