Clinical and Laboratory Approaches for Evaluation of Nephrolithiasis

0022-5347 /89/1413-0770$2.00/0 Vol. 141, March Printed in U.S.A.

THE JOURNAL OF UROLOGY

Copyright © 1989 by The Williams & Wilkins Co.

CLINICAL AND LABORATORY APPROACHES FOR EVALUATION OF NEPHROLITHIASIS DAVID M. WILSON From the Mayo Clinic and Mayo Foundation, Rochester, Minnesota

ABSTRACT

A medical history and laboratory investigation of patients with recurrent stones serve as the cornerstone for preventive and therapeutic treatment. Identifiable risk factors can be discovered in 90 per cent of the patients. More sophisticated analyses of urinary supersaturation can be helpful in resistant cases. (J. Ural., part 2, 141: 770-774, 1989) Presentation of the patient determines the evaluation, as well as the initial therapy of the patient with renal lithiasis. Obstruction, pain, associated infection and gross hematuria may warrant surgical management. A medical evaluation for all stone patients is necessary to determine long-term management and is the subject of this presentation. The extent of the diagnostic evaluation is stratified according to whether the stone episode is the first or a recurrent episode. The metabolic evaluation as to the cause of stone often is inappropriate at the acute obstructive phenomenon, since the usual metabolic parameters may be upset at this point and misleading data obtained. Our policy is to delay the more extensive metabolic evaluation for 4 to 6 weeks after an acute stone episode until physiological data have returned to normal.

to 2,000 ml./24 hours. Those who remained metabolically active had not increased the fluid output (fig. 2). Of the first-time stone formers 73 per cent remained inactive on followup, whereas only 56 per cent of recurrent stone formers remained inactive on this program. There was no increase in the likelihood of recurrence in those with increased calcium excretion or decreased citrate excretion, although there was a higher recurrence rate in those with increased uric acid excretion. Fluid and dietary recommendations alone constitute adequate therapy in the majority of patients. We, therefore, avoid drug therapy unless adequate fluid and dietary measures are shown to be ineffective.

INITIAL MEDICAL EVALUATION FOR CALCIUM STONE FORMERS

Patients who remain metabolically active warrant further evaluation concerning the stress factors that promote stone formation to determine further treatment, although patients may be encouraged to improve the conservative program alone, if it is clear that the fluid and/or dietary factors have been markedly suboptimal. The factors promoting supersaturation of the urine and stone formation depend on the type of stone involved. Figure 3 shows the types of stones normally seen in a general stone practice. Note that 60 per cent of the stones are composed of calcium oxalate, while 20 per cent are calcium phosphate (hydroxyapatite) or calcium oxalate/calcium phosphate, 10 per cent of the stones are infected (magnesium ammonium phosphate) and 10 per cent are uric acid. The remaining 1 to 2 per cent are composed of cystine, sodium urate, 8-hydroxyquinolone, triamterene or other unusual constituents. A good stone analysis, such as with x-ray diffraction or infrared analysis, helps to determine pathogenesis and suggests treatment strategies. A problem with the current lithotripsy procedures is that stone fragments often are not available for analysis. In addition, fragments may be small enough that the analysis is not representative of the types of stones actually removed. Many types of stones have a characteristic x-ray appearance. Examples include cystine stones (rounded and mildly opaque), struvite (branching and take the form of the calices), uric acid (radiolucent) and oxalate (may have the typical Jack Stone or hair-on-end appearance). Thus, the abdominal film or IVP often will help in the initial interpretation of the types of stones and will help to dictate which additional studies will be helpful. Further evaluation of the active calcium stone-forming patient is done with the assumption that the identification of particular stress factors in an individual will lead to a more rational and ultimately effective medical treatment approach. Clinical and laboratory studies are done to identify specific illnesses that are associated with stone disease and ultimately specific risk factors that promote stone formation, including

The initial evaluation for most first-time stone patients includes urinalysis, Gram stain and blood profile, including analysis of calcium, phosphorus, uric acid and creatinine. An excretory urogram (IVP) should include tomographic cuts before and after injection of contrast medium. The charges for this evaluation range from $227 to $269, depending on whether urine cultures are indicated. At this point patients usually are advised to improve fluid intake and avoid excesses with respect to calcium, oxalate and purines in the diet. They are advised to have followup x-rays at 6 to 12-month intervals to determine whether these changes will be sufficient to prevent further stone growth. If it is clear that the patient has had more than 1 stone or he is metabolically active further evaluation is indicated. Metabolically active stones are those that form within the last year, grow on x-ray within the last year or result in the passage of documented gravel.' Otherwise, they are considered to be metabolically inactive. Many stones are metabolically indeterminant when first seen, since previous information is not available. Patients with metabolically inactive or indeterminant stones do not necessarily need any change in the medical therapy, even if they are surgically active. Patients who are metabolically inactive are advised to follow a prudent therapeutic program and have a periodic evaluation of the stone disease as outlined previously. Patients who are metabolically indeterminant also are treated with a prudent diet and fluid program depending upon the clinical situation. A followup analysis of 100 patients with noninfected calcium stones and nonobstructed kidney stones with indeterminant activity treated in this manner revealed that 58.3 per cent remained metabolically inactive during a 5-year period (fig. 1). 2 Of the patients 35 to 40 per cent had continued stone growth but only 1 had a stone requiring surgical removal during followup. Patients who remained metabolically inactive on this program were shown to have increased urine volume from 1,500 770

DIAGNOSTIC EVALUATION FOR PERSISTENT CALCIUM STONE FORMERS

771

CLINICAL AND LABORATORY APPROACHES FOR EVALUATION OF NEPHROLITHIASIS

Metabolically inactive

(63)

58.3%

41.7%

Metabolically active

(45)

FIG. 1. Metabolic activity at followup in 108 patients initially categorized as metabolically indeterminant.

2,000

Urine volume, ml

-

Metabolic activity

1,000

No metabolic activity 0

Follow-up

Initial

CJ

FIG. 2. Fluid output of 24-hour urine sample initially and at followup in patients with idiopathic renal lithiasis.

Calcium oxalate 58.8% Misc 0.8% Cystine 0.7% Mixed calcium oxalate Calcium phosphate 11.4% - - - ~ , Calcium phosphate 8.9% -----~

FIG. 3. Composition of 1,000 stones from renal stone clinic at Mayo Clinic.

fluid intake, climate, geographic location, occupation, immobilization, diet, medication and other factors. The metabolic evaluation for active stone formers includes a 24-hour urine collection for calcium, phosphorous, oxalate, uric acid, citrate, sodium, creatinine, volume and often magnesium while on the usual diet (table 1). An increase in the factors promoting supersaturation or a decrease in those that decrease supersaturation, such as citrate, volume or magnesium may be identified in this way. Virtually all of these metabolites are diet-dependent and many patients have already altered the diet by the time they present to the physician. It may be difficult to interpret whether the diet-dependent factors are truly abnormal or the diet has been altered. Analysis of diets from 100 stone formers revealed that the intake of calcium was decreased by 50 per cent, magnesium by 25 per cent, potassium by 20 per cent and phosphate by 20 per cent compared to a group of normals." A diet history helps to interpret these values. Alternatively, specific stress diets can be used to evaluate urinary chemistry studies. Further historical evaluation of potential stress factors is done, including immobilization, medications and/or abnormal fluid losses from occupation or clinical conditions. This type of evaluation of 100 patients with idiopathic calcium stone disease showed that only 10 per cent of the cases

had no urinary abnormality. Of the patients 39 per cent were hypercalciuric, 38 per cent were hyperuricosuric, 16 per cent were hyperoxaluric, 19 per cent had decreased citrates and 23 per cent had decreased inhibitors (fig. 4). As seen in these data many patients had more than 1 risk factor. An analysis of the reasons for the urinary abnormalities often is clinically rewarding. Although these constituents may be abnormal on a dietary basis there are other clinical conditions that alter each urinary analyte and for which therapeutic intervention may resolve the risk for stone disease. The further evaluation of the multiple causes for hypercalciuria, for example, is important. Hypercalciuria associated with increased gut absorption of calcium often responds to dietary restriction of calcium and does not generally lead to calcium depletion. Conversely, the hypercalciurias associated with renal wasting of calcium would be treated inappropriately by restricting calcium intake, since patients will continue to lose calcium and eventually become calcium depleted. This may be particularly important for female patients who are prone to osteoporosis. Patients with phosphate wasting leading to increased vitamin D formation and subsequent increased calcium absorption and excretion can be treated appropriately with phosphorus supplements. Phosphorus supplements can reduce calcium wasting and make an effective treatment program for this group.4 Hyperoxaluria results from several different sources, including increased production from enzyme abnormalities, vitamin B6 deficiency or vitamin C excess, abnormalities of absorption from the gut as in enteric hyperoxaluria, oxalate gluttony or secondary to increased availability in the gut as in patients with hyperabsorption of calcium or possibly other organic acids. Each of these has specific therapeutic implications in a given individual. Hypocitraturia may be a specific defect in a stone inhibitor that can be treated. Several of the multiple reasons for severe hypocitraturia are seen in table 2. Some conditions, such as hypokalemia, hypomagnesemia or malabsorption from the gastrointestinal tract require specific therapy other than alkali or citrate replacement. Hyperuricosuria can result from either metabolic or dietary causes and treatment can be tailored to the underlying pathogenetic mechanisms. Many patients have more than 1 risk factor. Of those patients with hypercalciuria at least 54 per cent had increased uric acid (fig. 4, B). Similarly, hyperoxaluria, hypocitraturia and hyperuricosuria are associated with more than 1 abnormality (fig. 4, B to E).Our initial therapeutic approach is to alter those factors that can be altered by dietary means. Subsequently, factors affected by pharmacological means are altered one at a time until it is clear that the patients have become metabolically stable. Our approach to management of metabolically active recurrent stone formers is to assess and treat the patient for diseases that promote stress factors for stone disease, such as hyperparathyroidism, renal tubular acidosis, gout and abnormalities of bowel absorption. Otherwise therapy is tailored to the stress factors themselves. For example, those patients with increased urinary calcium, unresponsive to dietary restriction, are given TABLE

1. Typical evaluation and cost for patients with recurrent stone

formation Cost 24-hr. urine* (calcium, phosphorus, oxalate, uric acid, cystine, citrate, sodium, creatinine) Acid load for renal tubular acidosis Parathyroid hormone 2-hr. fasting urinary calcium Urinary supersaturation (2-hr. fasting) Total cost * Diet dependent results

$162.80 $120.00 $86.00 $117.00 $212.00 $162-697

772

WILSON

II

Hypercalc1una (?' 7 O mmol/24 hr) O

Percent

Ca only t

50

38

7

54 11

t Citrate t

Inhibitors

A

11 11

a,v 1

Hyperuricosuria (> 5 mmol/24 hr)

~Ill 6

Percent

Uric acid t only Calciumt

t Citrate t

B 0

56 19 11 22

c,VI

D

IV Hyperoxaluna (> O625 mmol/24 hr) O

Percent

8

C 20 4 only 33 Calcium t,___ _ ___,27 Uric acid

19

Uric acidt

19

50

43

E

38

Citrate+ Hypocitraturia ( S 1.2 mmol/24 hr) Percent

t

Citrate only Calciumt

Uric acid t

50

ti-----~

5

Percent

t

Inhibitors only Calciumt

C204 t

17

C204 t Inhibitors

50

Low/inhibitors(< 40 1Us/24hr)

50

17 17 11

C204 t

44

t

44

Inhibitors

tt - - - - - - - - - - - ' 47

Inhibitors+,___ _ ___, 27

C

Citrate

t

13

FIG. 4. A, hypercalciuria associated stress factors in patients with idiopathic renal lithiasis. B, hyperuricosuria and associated abnormalities in patients with idiopathic renal lithiasis. C, hyperoxaluria and associated abnormalities in patients with idiopathic renal lithiasis. D, low inhibitors and associated abnormalities in patients with idiopathic renal lithiasis. E, hypocitraturia and associated abnormalities in patients with idiopathic renal lithiasis. Pie diagrams indicate number and per cent of entire cohort of 96 patients. C2 0 4 , oxalate.

TABLE 2.

Disorders associated with severe hypocitraturia (urinary citrate less than 100 mg.) Finding

Intestinal disorder: Small bowel disorder, 19 Ileostomy, 6 Laxative abuse, 1 Renal tubular acidosis Drugs: Carbonic anhydrase inhibitor, 8 Ammonium chloride, 2 Hypokalemia: Bartter's syndrome, 2 Thiazides, 2 Ilea! conduit Renal insufficiency (creatinine >1.4 mg./dl.) Idiopathic calcium urolithiasis Infection(? spurious)

% Pts.

26

21 10 4

3

14 16 6

thiazide diuretics (80 per cent success rate). In patients with increased urinary uric acid in addition to increased calcium (about 50 per cent of those cases) allopurinol is given if stone activity persists after thiazide therapy has failed. Allopurinol is successful in patients with an isolated increase in uric acid excretion. Low urinary citrates are treated with potassium citrate, sodium bicarbonate or other alkali therapy (80 per cent success rate). Patients with none of the abnormalities outlined previously are treated with neutral phosphate (2 gm. daily) divided into a 4 times daily dose (95 per cent success rate). 0 A small percentage (5 to 10 per cent) of patients require multiple therapies to deal with active stones. Over-all, this approach prevents further stone growth in 95 per cent of our compliant group.

EVALUATION OF REFRACTORY CALCIUM STONE-FORMING PATIENTS

Evaluation of the refractory patient necessitates further analyses of the factors involved in stone growth. These include the interaction between inhibitors of crystal aggregation and growth, supersaturation, infection and obstruction. For example, in patients with enteric hyperoxaluria not only is total oxalate excretion increased but the oxalate ion activity is increased even further. At the same time calcium ion activity is not low despite a low total calcium excretion rate. 6 Urinary phosphate, sulfate and citrate normally bind calcium and are all low in these patients resulting in an increased percentage of free calcium ions. Similarly, sodium, potassium and magnesium are also decreased. Therefore, a larger percentage of free oxalate ions are available to react with calcium, increasing calcium oxalate supersaturation. We have used the Equil computer program to assess free ion activity, ionic strengths, activity products and supersaturation by measuring the urine pH and relevant ion contents.7· 8 Since affinity constants of the major cations and anions are known one can calculate the free ion activity for calcium and oxalate, and, therefore, the various calcium oxalate, calcium hydroxyapatite, brushite and uric acid ion products. Therefore, the relative supersaturation for a given urine can be calculated. The computer program allows for modeling of urine supersaturation and can be used to predict the outcome of therapeutic maneuvers that may have opposing effects on the parameters of stone formation. For example, alkali treatment beneficially increases urinary citrate but for calcium apatite it detrimentally increases urine pH. Thiazides improve hypercalciuria but also may decrease urinary citrate. Thus, one can predict the effect

773

CLINICAL AND LABORATORY APPROACHES FOR EVALUATION OF NEPHROLITHIASIS

of therapy and assess it short-term after therapy is given, rather than merely observing for stone formation (cost $220). An example of this approach is seen in table 3. This figure shows the data on a patient with periodic paralysis who required acetazolamide therapy to prevent paralysis. Treatment was complicated by the formation of calcium-apatite kidney stones that had been persistently active for several years. Table 3 shows the supersaturation data of the urine. Note that the number for supersaturation is given as a DG number, which loosely interpreted, is the driving force for crystal precipitation and stone formation. Any number greater than O represents supersaturation. Numbers less than O are undersaturated with respect to the crystal form in question. Normal values depicted show that normal individuals are moderately supersaturated with respect to calcium oxalate and calcium phosphate but are less saturated than stone formers. This particular patient was markedly supersaturated for calcium apatite. Table 4 shows the data after this patient had been treated. Note that there has been some improvement in supersaturation for hydroxyapatite after thiazide treatment. The effect of the combination of a thiazide and alkali (potassium citrate) on supersaturation shows that supersaturation is closer to the normal range. Indeed, in this patient stones formed less clinically on this program. This technique also is particularly useful in patients with enteric hyperoxaluria in whom multiple abnormalities are present. One can assess the effects of specific pharmacological or dietary manipulations on supersaturation. A major area for development involves the role of the "unknown inhibitors", which are neglected in this computer modeling approach. As the activity and measurement of additional inhibitors become known the computer models can be readjusted. EVALUATION OF URIC STONE FORMERS

Uric acid stones are difficult to identify on plain x-rays and often require an IVP that shows a lucent filling defect. Recent development of ultrasonic techniques has made the differential evaluation of a lucent defect on the IVP easier. Ultrasound clearly differentiates tissue masses from stone material. The principles governing uric acid stone formation are different from other stones. 9 As with other stones, however, the assessment of factors that promote supersaturation for uric acid crystals is pertinent to the evaluation of patients with uric acid stones. In these patients the solubility of uric acid is increased at higher urine pHs as well as with increased urine volume. Some patients have increased uric acid production rates and

TABLE

3. Supersaturation data in norma/,S and a patient receiving

acetazolamide Pt. on Acetazolamide Treatment

Calcium oxalate Brushite Hydroxyapatite Uric acid Sodium urate Potassium urate

Supersaturation

DG

Normal DG Values

3.2 1.6

1.5 0.6 6.6 -5.6 0.08 -235

1.8 ± 0.2 0.9 ± 0.2 3.1 ± 0.3

9.5 X 109 0.1 1.1

0.2

Interpretive values-supersaturation greater than 0, saturation O and undersaturation less than 0.

TABLE

some may have decreased renal ammonia production resulting in lowered urinary pHs. Dissolution of uric acid stones usually requires a reduction in uric acid excretion. Our data show that 80 per cent of the uric acid stones can be dissolved. 10 The major reason for failure to dissolve these stones is the inclusion of calcium crystals in the uric acid stones. Once the stones are dissolved or removed our practice has been to treat with allopurinol only if alkali alone is insufficient. EVALUATION OF CYSTINE STONE FORMERS

The approach to patients with cystinuria starts with the identification of cystine stones. Often cystine stones are difficult to suspect unless the stone is available for analysis. However, it can be suggested by the x -ray appearance of the stones, urinalysis showing cystine crystals, qualitative analysis of the urine (by high voltage electrophoresis) or quantitative 24-hour urine study for cystine. Management of these patients is related to the amount of cystine in the urine. Patients with less than 1,000 mg. cystine excretion per day often can be managed with aggressive alkali therapy sufficient to keep the urine pH in the 7.5 range, especially at night. Patients with more than 1,000 mg. cystine per day require some form of therapy to reduce cystine excretion. This can be done with d-penicillamine (and pyridoxine) in doses starting at 500 mg., increasing to 2 gm. if necessary, to bring the cystine excretion rates to 400 mg. per day or less. Other forms of therapy, such as glutamine, have been believed to be helpful to some patients. Captopril recently has been reported to reduce cystine excretion in some patients. Careful attention to the details of management is necessary for prevention of stones in these patients. This includes nighttime alkali, administration of the d-penicillamine on an empty stomach and attention to not only the amount but the distribution of fluids. Our initial data suggest that if the patient is free of stone when therapy is started, alkali alone will prevent stones in about 45 per cent of the patients. If stones are present alkali therapy is successful in only about 20 per cent. By using fluids, alkali and d-penicillamine we have been able to prevent further stones in about 70 per cent of our patients. 11 EVALUATION OF PATIENTS WITH INFECTED STONES

Our approach to patients with infected stones revolves around 4 principles: 1) the underlying metabolic stone disease, 2) the management of the infection, which includes identification and treatment of the offending organism, 3) the surgical removal of infected stones and correction of drainage problems, and 4) the long-term suppression of bacterial growth. Studies at our stone clinic revealed that 62 per cent of the patients with infected stones have metabolic abnormalities similar to those that produce metabolic stone disease. An additional 14 per cent of those patients will have structural abnormalities promoting stone disease. Management of these patients requires careful cooperation between the surgeon and internist in that if the infected stone material is retained 85 per cent of those patients will have recurrent infected stone growth. If the stone material can be removed 50 per cent of those patients will remain free of stones and infection, 25 per cent will continue to have problems with urinary tract infection and about 15 per cent will have recurrent metabolic stone disease. 12 Suppression of

4. Supersaturation values (DG) in a patient on acetazolamide and different treatment programs Hydroxyapatite DG Values Acetazolamide

Hydroxyapatite supersaturation Hydroxyapatite "DG"

9.5

X

6.6

109

Acetazolamide +HCT 5.5

X

5.1

107

Acetazolamide + Potassium Citrate 1.1

X

4.0

106

Acetazolamide +HCT+ Potassium Citrate 7.7

X

2.6

103

774

WILSON

the urease in the urea-splitting bacteria may prevent stone growth when surgery is unsuccessful or inadvisable. CONCLUSION

The long-term management of renal lithiasis would appear to be a cooperative venture between surgical and metabolic avenues. Rational management of stone disease requires and takes advantage of the increasing understanding of the multiple pathophysiological mechanisms that underlie new stone formation as well as the technological advances for the removal of stones. REFERENCES 1. Smith, L. H.: Medical evaluation of urolithiasis: etiologic aspects

and diagnostic evaluation. Urol. Clin. N. Amer., 1: 241, 1974. 2. Hosking, D. H., Erickson, S. B., Van Den Berg, C. J., Wilson, D. M. and Smith, L. H.: The stone clinic effect in patients with idiopathic calcium urolithiasis. J. Urol., 130: 1115, 1983. 3. Smith, L. H., Werness, P. G. and Wilson, D. M.: Metabolic and clinical disturbances in patients with calcium urolithiasis. Scand. J. Urol. Nephrol., suppl., 53: 213, 1980. 4. Van Den Berg, C. J., Kumar, R., Wilson, D. M., Heath, H., III and Smith, L. H.: Orthophosphate therapy decreases urinary calcium excretion and serum 1,25-dihydroxyvitamin D concentrations in

idiopathic hypercalciuria. J. Clin. Endocr. Metab., 51: 998, 1980. 5. Smith, L. H., Wilson, D. M., Van Den Berg, C. J. and Meyer, J. L.: Orthophosphate therapy in calcium urolithiasis. Proceedings of the American Society of Nephrology, p. 25, 1976. 6. Wilson, D. M.: Gastrointestinal disorders and urolithiasis. In: Stone Disease: Diagnosis and Management. Edited by S. N. Rous. Orlando: Grune & Stratton, Inc., chapt. 14, pp. 147-159, 1987. 7. Meyer, J. L. and Smith. L. H.: Growth of calcium oxalate crystals. I. A model for urinary stone growth. Invest. Urol., 13: 31, 1976. 8. Meyer, J. L. and Smith, L. H.: Growth of calcium oxalate crystals. II. Inhibition by natural urinary crystal growth inhibitors. Invest. Urol., 13: 36, 1976. 9. Wilson, D. M.: Uric acid lithiasis. In: Stone Disease: Diagnosis and Management. Edited by S. N. Rous. Orlando: Grune & Stratton, Inc., chapt. 10, pp. 109-123, 1987. 10. Erickson, S. B., Smith, L. H. and Wilson, D. M.: Dissolution of uric acid stones. VI International Symposium on Urolithiasis and Related Clinical Research. Vancouver, Canada, in press. 11. Dahlberg, P. J., van den Berg, C. J., Kurtz, S. B., Wilson, D. M. and Smith, L. H.: Clinical features and management of cystinuria. Mayo Clin. Proc., 52: 533, 1977. 12. Segura, J. W., Erickson, S. B., Wilson, D. M., Van Den Berg, C. J. and Smith. L. H.: Infected renal lithiasis: results of long-term surgical and medical management. In: Urolithiasis: Clinical and Basic Research. Edited by L. H. Smith, W. G. Robertson and B. Finlayson. New York: Plenum Press, pp. 195-218, 1981.