When Should the Stone Patient Be Evaluated?: Limited Evaluation of Single Stone Formers

Symposium on Renal Disease: Controversies

When Should the Stone Patient Be Evaluated? Limited Evaluation of Single Stone Formers

Stephen B. Erickson, M.D.*

Before one can discuss when renal stone formers should be evaluated, one must first answer the question if they should be evaluated at all. Ultimately, an evaluation of the stone former must give information regarding cause, treatment, or prognosis to the clinician and patient; otherwise, there is no practical reason to obtain such an evaluation. In the not-toodistant past when etiologic aspects and preventive management of renal stones were poorly understood, evaluation was often and appropriately limited to a determination by intravenous pyelogram of the location, number, and size of the calculi and the degree of urinary tract obstruction. This simple preoperative evaluation of nearly all stone formers is still recommended today. Additionally, however, we have come to understand that urinary calculus formation is a "final common pathway" of numerous disorders (Table 1). Furthermore, we now understand that selective therapy for some of these disorders is efficacious in either dissolving the stones3, 5, 15 or preventing accumulation of new stone material,2, 17, 20 Thus, we can now argue cogently that evaluation of certain stone formers may reveal previously unsuspected disease processes; may guide us to selective, efficacious therapy; and, in so doing, may improve the patient's prognosis. Still moot, however, is this question: Which patients are likely to benefit from such an investigative approach? This article suggests practical guidelines for evaluation of the stone former. These guidelines should be individualized to each patient. Many clinical studies remain to be done to substantiate the validity of these recommendations. VARIABLES IN THE SELECTION OF PATIENTS FOR EVALUATION The prospect of finding information that will be of practical benefit to the clinician may increase or decrease according to whether certain factors are present. A discussion of some of these variables is in order. *Consultant, Division of Nephrology and Internal Medicine, Mayo Clinic and Mayo Foundation; Assistant Professor of Medicine, Mayo Medical School, Rochester, Minnesota

Medical Clinics of North America-Vo!' 68, No. 2, March 1984

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Table 1.

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Some Potential Causes of Urinary Stones

H ypercalcemias Primary hyperparathyroidism Sarcoidosis Multiple myleoma Bone metastases Milk-alkali syndrome Vitamin A or D toxicity Immobilization Cushing's syndrome Hyperthyroidism

Hypercalciurias Idiopathic absorptive hypercalciuria, types I and 11 Idiopathic renal leak hypercalciuria Distal renal tubular acidosis Response to acetazolamide Paget's disease of bone Exogenous steroids

H yperuricosurias Idiopathic hyperuricosuria Purine gluttony Rapid cell lysis Response to uricosuric agents (probenecid, sulfinpyrazone, high-dose aspirin) Inherited enzyme abnormalities

H yperoxalurias Primary (hereditary) hyperoxaluria, types I and 11 Pyridoxine deficiency Enteric hyperoxaluria Vitamin C abuse Ethylene glycol toxicity Oxalate gluttony

Cystinurias Types I, 11, and III

U rea-splitting urinary infections Proteus Providencia Klebsiella Enterobacter Staphylococcus Pseudomonas Serratia

Anatomic abnormalities Medullary sponge kidney Horseshoe kidney Calyceal diverticulum Obstruction of ureteropelvic junction

Miscellaneous Xanthinuria Triamterene-induced 2,8- Dihydroxyadenine

Single Stone Versus Recurrent Stone Formers A single stone former is usually defined as a person who has had only one stone in his or her lifetime. 18 All other stone patients are considered recurrent stone formers even though they may have several stones simultaneously or may have passages of stones separated by decades. In single stone formers, underlying causes have nearly the same prevalence as in recurrent stone formers, and on this basis alone a rather extensive evaluation has been recommended. 18 This approach is cost-effective only when the information gained can be used to the patient's benefit. We have preliminary clinical evidence that a large percentage of stone formers who have idiopathic calcium stone disease (idiopathic hypercalciuria, idiopathic hyperuricosuria, idiopathic hyperuricosuric-hypercalciuric nephrolithiasis, and no metabolic abnormality) and, perhaps, even those whose stones formed as a result of other causes may cease to form stones when they are placed on a conservative program designed to eliminate dietary excesses and to increase urine volume. ll Failure to increase urine volume while receiving treatment puts a stone former at increased risk for recurrence. 29 Limited in vitro and in vivo evidence also supports the ther-

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apeutic efficacy of a large fluid intake in reducing urinary supersaturation in stone-forming patients whose calcium stones formed as a result of other causes. 21 Thus, for the single stone former and even for the recurrent stone former who has not had a trial of fluid-diet therapy, we recommend only a limited, low-cost evaluation (which will be described below) to detect any abnormalities unlikely to respond to "conservative" therapy. Only recurrent stone formers who have formed stones while adhering to a fluiddiet program should be evaluated by a more extensive protocol (see below). Metabolically Inactive or Indeterminate Versus Metabolically Active Stone Formers Metabolic stone activity is a clinically useful concept and has been defined as radiologic evidence of new stone formation or old stone growth or documentation of gravel passage within the past year. 2s ·Metabolic inactivity refers to stone disease that does not fulfill any of these criteria, and indeterminate activity refers to the common situation in which data do not exist from which to make a determination. Experienced clinicians are well aware of the vagaries of stone disease. Periods of frequent passage or formation may be interspersed with times of dormancy. This concept is easily understood in the light of studies that suggest that stones may form only during periods of dietary excesses 6, 13 or in response to certain drugs such as acetazolamide, 26 vitamin D,26 or chemotherapeutic agents. 27 There appears to be little justification for evaluation of a stone former who currently may not be forming stones. Cautions regarding diet, fluid, and drugs, coupled with serial follow-up roentgenograms (see below), should be adequate. Only metabolically active stone formers should be considered for extensive evaluation. Elderly Versus Young Stone Formers In our local population, 60 per cent of the men and 75 per cent of the women remain free of stone recurrence 10, years after their initial episode. 12 Assuming that this overall recurrence rate remains true in the elderly population, we must recognize that an extensive investigation of elderly stone formers may not be justified because many patients older than 70 years of age will not live long enough to form a second stone, even without treatment. The same reasoning holds true for patients who have a rather limited life expectancy. Conversely, young stone formers have a strong likelihood of forming additional stones during their lifetime and would be more likely to benefit from careful evaluation. Calcium Urolithiasis Versus Stones of Other Composition Although, as previously mentioned, information exists to show that calcium stone formers whose stones result from several causes can often be controlled with a diet-fluid regimen, such data do not exist for stone formers who have stones of other types. Struvite stones are usually removed surgically.7 Cystine stones often are not controlled by fluid alone and require the use of alkali, penicillamine, or both. 3 Although we have found that some stone formers with uric acid stones respond to fluid ther-

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apy, others require alkalization, allopurinol, or both.l5 For these reasons, analysis of a patient's first stone is indicated, and when noncalcium urolithiasis occurs, additional diagnostic testing and institution of selective treatment are often required. Urolithiasis Versus Nephrocalcinosis Not only does the composition of a urinary stone indicate the type of evaluation required but so does its location. It has long been thought that renal stones originate at the papillary tips24 or near the calyceal fornices l and then may move into the renal pelvis, ureter, or bladder. As previously noted, a high percentage of these stones will be assigned to an idiopathic group, even with extensive evaluation. A much rarer sort of calculi formation is called "nephrocalcinosis." Nephrocalcinosis is defined as diffuse, bilateral cortical calcifications visible by roentgenograms. 16 Although not actually present in the renal collecting system, these parenchymal calculi can occasionally erode into the renal tubules and pass into the collecting system, where they can become symptomatic. Although some cases of nephrocalcinosis are idiopathic, there is a high percentage of cases in which primary hyperparathyroidism, distal renal tubular acidosis, or an uncommon cause of hypercalcemia is found. 23 Thus, nephrocalcinosis, when detected, requires a careful metabolic evaluation because of the high prevalence of associated systemic diseases that affect calcium metabolism. Hypercalcemia Versus Normocalcemia If hypercalcemia is discovered during a limited metabolic evaluation of a stone former, this is an important clue that systemic illness is present. Seldom is hypercalcemia idiopathic. Table 2 lists a differential diagnosis of hypercalcemia.l 4 Perusal of this table reveals many disorders that require selective treatment. In addition, treatment of the systemic disorder may inactivate the metabolic cause of the stone formation and thus make the search for hypercalcemia doubly rewarding. Potential Stone Formers Consideration must also be given to the evaluation of potential stone formers, those patients who may not have formed a stone but are at increased risk of doing so. Siblings of patients who have primary hyperoxalurialO or cystinuria3have a one-in-four chance of inheriting these autosomal recessive conditions in which stones often form. These siblings should be evaluated for their potential disorder because detection would, at a minimum, commit them to a high-fluid regimen and close follow-up examinations. Patients with suspected primary hyperparathyroidism should have a Table 2.

Causes of Hypercalcemia

Primary hyperparathyroidism Sarcoidosis (and other granulomatous diseases) Vitamin A or D toxicity Immobilization Malignant lesions

Milk-alkali syndrome Hyperthyroidism Acromegaly Pheochromocytoma Diuretics Lithium

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radiologic examination for renal stones, which occur in approximately 4 to 51 per cent of this population. 9 Discovery of stones would indicate the need for surgical exploration of the neck; otherwise, uncomplicated primary hyperparathyroidism may be followed medically.22 Patients with renal tubular acidosis should also have a roentgenographic examination for renal calculi, given the 48 per cent prevalence of stones and the specific treatment available. 8 Relapsing urinary tract infections may indicate the presence of infection stones. A diligent search should be made for infection stones because the infection cannot be cured while stones are present. 7 Patients with severe regional enteritis or those who have small bowel bypass procedures for obesity should be carefully watched for the development of calcium oxalate nephrolithiasis. If such patients have enteric hyperoxaluria, they may be among the most "malignant" of stone formers, yet they may respond to medical therapy or bypass reversal. 28 Although a family history of stone formation may often be elicited from patients with idiopathic calcium urolithiasis, 26 the likelihood of finding a stone in any asymptomatic family member is not strong enough to warrant medical investigation. EVALUATION OF THE STONE FORMER Outpatient evaluation of stone formers for metabolic causes is both feasible and preferable. Other investigators agree. 4, 19 Although the composition of the patient's diet cannot be carefully controlled during an evaluation on an outpatient basis, it is preferable for the metabolic evaluation to take place while the patient's usual food and fluid intake is continued. It is on this program that the patient formed stones. We certainly agree that there is a place for in-hospital evaluation on a metabolic ward. However, the clinician should understand that the common practice of collecting in-hospital urinary specimens, often while the patient is eating little and receiving intravenous fluids, does not approximate the conditions of either a metabolic ward or the patient's home environment. Thus, test results obtained during episodes of renal colic or immediately after operation only confuse the issue. Additionally, in-hospital 24-hour urine collections, which have to be supervised by a minimum of three separate nursing shifts, are often inaccurate. Limited Metabolic Stone Evaluation As discussed above, there may be specific instances in which only a limited metabolic evaluation is indicated. Table 3 lists a few tests that are Table 3.

A Limited Metabolic Stone Evaluation

History (including history of stones in family members) Stone analysis Serum calcium concentration Urine culture or Gram's stain Kidney-ureter-bladder roentgenogram with or without intravenous pyelogram

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sufficient for the metabolic evaluation of many stone formers. The purpose of these limited evaluations is to look for specific abnormalities that would indicate a need for additional diagnostic testing or specific treatment. The history provides important information for the evaluation, such as age, gender, geographic location, previous stone passages and chemical analyses, diet and fluid habits, attempted medical treatment, previous surgery, associated illnesses, and a family history of metabolic disorders. A stone analysis separates the stone former whose calcium stone is often idiopathic from those with other types of stones who may require additional investigation, as noted above. The serum calcium determination identifies hypercalcemia, and urine culture (or Gram's stain) points to the possibility of infection (struvite) stones. Radiographic studies document the number, size, location, and opacity of stones, which is necessary information for comparison of follow-up roentgenograms. Important anatomic abnormalities may also be discovered. Extensive Metabolic Stone Evaluation In contrast is a thorough metabolic stone evaluation, for which an incomplete listing is given in Table 4. Discussion of the rationale behind these tests is beyond the scope of this article, as is discussion of general and selective treatment. It can readily be seen, however, that considerable time and expense may be involved in completing such an extensive evaluation. Of course, not every test is appropriate even for the most active and refractory stone former. Considerable clinical judgment and skill must be exercised in selecting the proper methods of investigation. Follow-Up Examinations Perhaps as important as the initial metabolic investigation are subsequent follow-up observations. Again, the evaluation indicated will vary from patient to patient but should include, at a minimum, a historical evaluation of compliance with diet, fluids, and drugs, if any, and a history of interim stone or gravel passage. A radiologic examination to search for' the presence of new stone material (metabolic activity) is especially important Table 4.

A More Thorough Metabolic Stone Evaluation

History and physical examination Stone analysis Kidney-ureter-bladder roentgenograms, intravenous pyelogram with preinjection and postinjection tomograms Urinalysis, urine culture 24-hour urine collection for calcium, oxalate, urate, creatinine, cystine, volume, citrate, phosphate, sodium, magnesium, supersaturation, inhibitors of crystallization Serum calcium (3 times), phosphate, uric acid, creatinine, thyroxine, corticosteroids, protein electrophoresis, alkaline phosphatase Urinary calcium during fast and load Urinary ammonium chloride acidification Quantitative stool fat Gastrointestinal barium roentgenograms Chest roentgenogram, blood angiotensin converting enzyme Immunoreactive parathyroid hormone, urinary cyclic adenosine monophosphate

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because such material, if detected, would indicate failure of the current treatment program and often point to a need for additional diagnostic evaluation and other modalities of treatment. The frequency of follow-up examinations must be individualized to each patient, but examinations should initially be done every 3 to 12 months. Longer intervals may elapse between follow-up visits if the stone disease remains metabolically inactive.

SUMMARY Kidney stone formation is a preventable condition representing a "final common pathway" of diverse metabolic and anatomic disorders. A difficult clinical decision is that of when and how extensively to evaluate the stone-forming patient. We recommend only a limited metabolic evaluation for the first-time stone former, the stone former with recurrent but never treated stones, the stone former who is metabolically inactive or indeterminate, and the elderly stone former. These patients often form no new stones when placed on a careful program of diet and fluid therapy. A more thorough evaluation is indicated for patients whose stone disease is metabolically active despite dietary and fluid treatment; those with struvite, urate, or cystine calculi; those with hypercalcemia, relapsing urinary infections, nephrocalcinosis, or short bowel syndromes; and those with a family history of primary hyperoxaluria or cystinuria. Almost all patients require close medical follow-up in order to assess the need for additional investigation and treatment. ACKNOWLEDGMENT

The author wishes to thank Drs. L. H. Smith and C. J. Van Den Berg for their helpful comments during the preparation of this manuscript.

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Division of Nephrology and Internal Medicine Mayo Clinic and Mayo Foundation Rochester, Minnesota 55905