Renal Stones in Wilson’s Disease
DAVID
0. WIEBERS.
M.D.
DAVID
M. WILSON,
M.D.
RICHARD
A. McLEOD,
NORMAN
P. GOLDSTEIN,
M.D. M.D.
Rochester, A4innesoto
From the Mayo Clinic and Mayo Foundation. Rochester, Minnesota. Requests for reprints should be addressed to Dr. D. 0. Wiebcrs. Section of Publications, Mayo Clinic. Rochester, Minnesota 55901. Manuscript accepted March 5. 1979.
Fifty-four patients with Wilson’s disease were studied with regard to renal stones. Seven of the 45 patients (16 per cent) who underwent roentgenographic procedures of the urinary tract had unequivocal evidence of renal stones. In four of the seven patients with Wilson’s disease who had renal stones, the stones were discovered at the time or before the diagnosis of Wilson’s disease was made. Of the several possible factors that may predispose patients with Wilson’s disease to renal stone formation, the renal tubular acidosis pattern of abnormality in acid-base excretion is probably the most significant. In general, patients with renal stones and unexplained neurologic, bony or hepatic abnormalities should be screened for Wilson’s disease by slit-lamp examination, determination of serum copper and ceruloplasmin concentrations, and urinary excretion of copper, particularly if they have relatively alkaline urine. A wide variety of renal abnormalities have been described in Wilson’s disease, including decreased renal plasma flow, decreased glomerular filtration rate and renal tubular abnormalities. The last-named may be divided into primarily proximal renal tubular dysfunction (aminoaciduria [l], hyperphosphaturia [z], hypercalciuria [3] and glucosuria [4]); primarily distal renal tubular dysfunction (potassium wasting and concentrating defects [5]); and combinations of proximal and distal renal tubular dysfunction [defective excretion of uric acid [6,7] and acid-base [8]). More specifically, the abnormalities of acid-base excretion most often represent a gradient defect for hydrogen ion excretion with a subnormal urinary acidifying capacity (distal renal tubular acidosis pattern]. Infrequently, patients with bicarbonate wastage and a low tubular maximum for bicarbonate (Tm HC@) have been described (proximal renal tubular acidosis pattern [8]). Regarding uric acid excretion, evidence for both tubular reabsorptivc and secretor! defects has been presented [5-7,9]. One aspect of renal dysfunction which has not previously been studied in Wilson’s disease is renal stones. In general, renal stones arc found in approximately 1 per cent of autopsies in the IJnited States. Studies regarding their prevalence have been scarce and difficult to assess. The data from one study conducted in this country by Resnick et al. [lo] suggest that the prevalence of renal stones is approximate11 5 per cent in the general population. The pathogenesis of renal stones is multifactorial and complex and can be partially categorized as follows: (11 excessive excretion of stone-forming constituents into the urine, including calcium, uric acid, oxalate, cystine and xanthine; (2) local causes, including urinary stasis, infections within the urinary tract, foreign bodies and epitaxy [ll] (the oriented growth of one crystal on
August 1979
The American Journal of Medicine
Volume 67
249
RENAL STONES IN WILSON’S DISEASE-WIEBERS
TABLE I
ET AL.
Data on Seven Patients With Wilson’s Disease Who Had Renal Stones
Ageal Ageal Diagnosis Diagnosis of Wilson’s Disease (yr)
of Renal Stones
Period Followed (yr)
Renal Slone Surgery
Renal Slone Passage
18
Yes
Yes(B)
50 32% 19 39
Og 17 3 7
No No Yes No
No Yes Yes No
10160 41585 7167 6/5811
10% 32%
6 1
No Yes(2)
No No
3168 31737
Case No.
Sex
1
M
40
32
2 3 4 5
M M M F
45 32% 78% 17
6 7
M M
10% 37%
(yr)
C = low-calcium diet; E = calcium disodium EDTA; F = increased + Received BAL from February 1956 through September 1958. t Patient died six months after renal stones were found. 5 Received BAL July 1957 through April 1958. 11 Received BAL 1951 thrpugh 1953. ( Medication taken sporadically. l
another of near geometric fit]; (3) other physiologic alterations of the urine, including urine pH and the absence of inhibitory substances such as pyrophosphate, citrate, magnesium, peptides and amino a’cids; and [4) idiopathic. In this study, 54 patients with Wjlson’s disease, including seven patients with renal stones, were evaluated in terms of the aforementioned possible etiologic factors. The relationship of these factors to the high incidence of renal stones in these patients with Wilson’s disease is discussed. METHODS Fifty-four patients with an unequivocal diagnosis of Wilson’s disease were evaluated at the Mayo Clinic from 1952 through 1977. Each patient underwent initial comprehensive neurologic, ophthalmologic and general medical examinations, with serial folloti-up examinations in most cases. Forty-five of the 54 patients underwent at least one plain roentgenographic examination of the kidneys, ureters and bladder, or excretory urography, as part of their evaluation; many of these patients had serial follow-up roentgenographic examinations of the urinary tract. particularly if they had renal stones or other symptoms or signs related to the urinary tract. Renal excretion of urate was st?died in 13 patients with Wilson’s disease (six with and seven without renal stones) and in 10 control subjects by a method described previously [7]. Acid-base excretion was studied in 15 patients with Wilson’s disease [five with and 10 without renal stones) and eight control subjects. also by methods described previously [8]. A Phoenix amino acid analyzer was used to quantitate urinary excretion of amino acids while patients temporarily discontinued taking D-penicillamine. Correlation with renal stone formation was facilitated by evaluating a number of other specific laboratory indices before any therapy for Wilson’s disease, at the time of initial discovery
250
August 1979
The American Journal of Medicine
o-Penicillamine Therapy Begun g/58+
fluid intake
Specific Renal Stone Therapy’ 1 l/55 C,E,F 3169 P
(>2,000
7% C,F 8167 C,F 3171 C,F 3f68 C,F 5177 C,F,P
Increased Metabolic Stone Activity
Decreased tdelabolic Stone Activity
8148, 5151, 11155, 8160, lOf65, 10167, 8169
10168
lo;&, 9170 2168, 10168 3169, 3171, l/73
6/f%’ ;;;4,
l/75
6172 3/68:2/77, 5177
ml/day); p = Polycitra.
of renal stones and at subsequent intervals when there was evidence of metabolic stone activity.* Specifically, the serum indices studied included creatinine, urea, sodium, potassium, chloride, bicarbonate, calcium, phosphorus, uric acid, copper, ceruloplasmin and arterial blood gases. Urinary indices included urinalysis, pH, daily urine volume, creatinine, calcium, phosphorus, uric acid, oxalate, copper, zinc, amino acids, ,ammonia, total nitrogen content, creatinine clearance, inulin clearance and urea clearance.
RESULTS Seven of the 45 patients (16 per cent) who underwent renal studies with plain films or excretory urograms had unequivocal roentgenographic evidence of renal stones (in two others it was equivocal]. Of the four symptomatic patients, ali had renal colic, one had recurrent frank hematuria, and one had recurrent passage of gravel. In addition, three of the seven patients underwent nephrolithotomy (Table I), and three patients spontaneously passed stones, including one patient (Case 1) who did so on three separate occasions over 19 years. At the time of diagnosis of Wilson’s disease, all of the patients.with renal stones had neurologic involvement, six of the seven had roentgenographic evidence of bony abnormalities, and six of the seven had overt clinical or laboratory evidence of hepatic dysfunction. Two of the seven patients (Cases 1 and 7) had symptomatic renal stones before the diagnosis of Wilson’s disease was made (eight and five years before, respectively], and in two others [Cases 3 and 6) renal stones were discovered at th’e time of diagnosis. * Metabolic stone activity is defined as roentgenographic evidence of stone growth or new stone formation or passage of gravel in the absence of infection or obstruction.
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RENAL
Of the five patients with stones who were followed serially at the Mayo Clinic, four had evidence of continued metabolic stone activity while receiving D-penicillamine and the stone therapy outlined in Table I. In three of these patients, stones eventually stopped growing; in two, totally negative plain roentgenographic studies of the kidneys, ureters and bladder were attained. Specific attention was given to periods of increased and decreased stone activity in an attempt to establish any consistent correlation with one or more of the specific laboratory indices outlined, but none was found. Hypercalciuria was noted in three of seven patients with stones, and three demonstrated normal urinary excretion of calcium while they were receiving D-penicillamine therapy. In each of these increased renal stone growth was documented with normal 24hour urinary excretion of calcium. The urinary excretion of calcium was not studied in the seventh patient. Five patients with stones followed serially had hypouricemia before D-penicillamine therapy, and in four of the five, serum levels of uric acid reverted to normal after seven months, four years, 13 years and 15 years. In the fifth patient, the concentration of serum uric acid increased slightly, from 2.1to 3.6mg/dl, over four years. Two other patients with stones were not followed serially. Data on plasma uric acid levels and the urinary excretion of uric acid are presented in Table II. Twenty-four hour urinary excretion of uric acid was increased in only one of five patients, but uric acid clearance relative to the inulin clearance was clearly increased in four of six patients and was borderline in the remaining two. Data on excretion of bicarbonate and ammonium loading are presented in Table III. Failure to acidify the urine to a pH of 5.2 or lower was noted in four of five patients with stones and in seven of 10 patients without stones. According to the criteria of Wrong and Davis [E] this suggests renal tubular acidosis. Only one of the six patients with stones (Case 1)consistently showed an arterial blood pH of less than 7.35, and his pH was never lower than 7.29. Tubular maximum for excretion of bicarbonate (Tm HCOs) was normal in three of four paTABLE III
STONES
TABLE II
IN WILSON’S
DISEASE-WIEHERS
ET AL.
Uric Acid Excretion in Patients With Wilson’s Disease and in Control Subjects
PlasmaUric
Cl”’ (mUmin/ 1.73 mZ)
Acid (mg/dl)
UrineUric Acid (mg/24 hr)
Cwar.+ Cl”
Patients Wtth Wilson’s Disease With Renal Stones (n = 7) 4.41 f 1.33 85.3 f 50.1 0.26 f 0.13 597 f 141 Patients With Wilson’s Disease Without Renal Stones (n = 7) 4.83 f 0.61 98.3 f 20.8 0.16 f 0.058 706 f 224
5.33 f 0.85
Control Subjects (n = 10) 109.0 f 6.9 0.098 f 0.034
(250-750)+
NOTE: All values are the mean f standard deviation. C,” = inulin clearance. +c wate/Cln = ratio of urate clearance to inulin clearance. + Accepted normal value for urinary uric acid excretion in adults. l
tients with stones and in nine of 10 patients without stones. Renal bicarbonate threshold (the lowest serum bicarbonate level at which 1 peq/min of bicarbonate is excreted in the urine] was significantly lower in patients with Wilson’s disease with and without stones than in control subjects. At constant plasma bicarbonate levels (between 23.6 and 26.3 meq/liter), urinary excretion of bicarbonate and per cent of the filtered load excreted were significantly higher in patients with Wilson’s disease than in control subjects and highest in patients with Wilson’s disease who had stones. However, the wide range of values in the patients with Wilson disease with stones makes this last distinction of questionable significance. A summary of the lowest random urine pH values is presented in Table IV. The mean value for the control group was significantly lower than the values for the patients with Wilson’s disease with and without stones. The difference between those with stones and those without stones was not statistically significant. Data on the urinary excretion of amino acids were obtained in three of the seven patients with Wilson’s disease who had renal stones and in 23 who did not have stones. Total excretion of amino acids was increased in all three of the patients with stones and in 15 of the 23 patients without stones. The pattern of aminoaciduria,
Acid-Base Excretion Data in Patients With Wilson’s Disease and in Control Subjects
UrinarypH After Ammonium Chloride
Tm HCOs’ (msq1100ml GFR+)
RenalHCOs Threshold (meq/liter)
UrinaryHCOs (meqlmin)
At ConstantPlasmapH % filtered load
GFR+ (mUmin)
Patients With Wilson’s Disease With Renal Stones (n = 7) 6.35 f 0.84
2.73 f 0.57
5.65 f 0.61
Patients With Wilson’s Disease Without Renal Stones (n = 10) 2.70 f 0.23 21.7 f 2.55 37.6 f 54.3
2.96 f 0.24
21.7 f
1.58
28.3 f 33.56
Control Subjects (n = 10) 24.5 f 2.25 7.15 f 3.04
14.9 f 25.7
80 f 32.5
1.83 f 2.96
90.8 f 21.3
0.263 f 0.100. -_
107.3 f 9.0
NOTE: All values are the mean f standard deviation. * Tm HC03 = tubular maximum for bicarbonate; + GFR = glomerular filtration rate.
August 1979
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RENAL STONES
TABLE IV
IN WILSON’S
Random UrinepH
ET AL.
Random Urine pH Data Patients With Wilson’s Disease
Lowest
DISEASE-WIEBERS
WithRenalStones (N = 7)
Patients With Wilson’s Disease
WithoutStones (N = 22)
6.37 5.5-7.4
Mean Range
6.54 5.6-7.5
Control Subjects (N = 20) 5.69 5.2-6.7
when studied in terms of 13 individual amino acids, was one of diffuse increases varying from patient to patient such that no specific amino acid abnormalities were characteristic of the group. Two of the seven patients had spontaneously passed stone material recovered for analysis. In both the material consisted of a combination of calcium phosphate (major constituent) and calcium carbonate. Significant microscopic hematuria was found in 24 of the 54 patients with Wilson’s disease (44 per cent), including 19 of 47 patients with Wilson’s disease who did not have stones (40 per cent) and five of seven patients with Wilson’s disease who had stones (71 per cent). Gallstones were discovered in two of the seven patients with Wilson’s disease who had stones-10 years after the onset of D-penicillamine therapy in one case (Case 5) and at the time of diagnosis of Wilson’s disease in the other (Case 7). CASE STUDY Case 7. A 41 year old oriental man underwent
a cholecystectomy in 1973 for a nonfunctioning gallbladder. A liver biopsy performed at the time disclosed early posthepatitic cirrhosis, which, along with low serum levels of ceruloplasmin and copper, led to the diagnosis
of Wilson’s disease.
He was
Figure 1. Tomogram of patient (Case 7) showing two stones in lower pole of left kidney. Excretory urogram demonstrated that these stones were within collecting system.
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Journal of Medicine
started on a regimen of D-penicillamine and potassium sulfide, which he used only sporadically. Before thetime of this diagnosis, he had been asymptomatic except for two episodes of right renal colic and frank hematuria, which had resulted in a right nephrolithotomy five years previously. Subsequently, he continued to have episodes of frank hematuria without renal colic. In September 1976, mild incoordination in both upper and lower limbs was first noticed, and an excretory urogram showed at least two stones in the left kidney. Another episode of renal colic in February 1977, with hematuria and increased urgency, resulted in the diagnosis and surgical removal of a stone in the left ureter. Subsequently, the patient noted worsening of incoordination in all four extremities, with tremor in the upper limbs, slowness of speech and difficulty with balance: this led to his referral to the Mayo Clinic in May 1977. Physical examination revealed bilateral Kayser-Fleischer (stage 3) rings [13], confirmed by slit-lamp biomicroscopy. The liver was percussed at 7 cm below the costal margin in the right mid-clavicular line: the spleen was not enlarged. Neurologic examination showed mild dysarthria and slight masking of the facies. The patient had a slightly wide-based gait and mild incoordination of both upper and lower limbs but no tremor. He also had mild rigidity in the upper limbs but no cogwheeling. Results of laboratory studies included values for serum ceruloplasmin of 0.8 mg/dl, serum copper of 30 pg/dl and urinary excretion of copper of 112 pg/24 hours when the patient was not taking D-penicillamine; the excretion of copper increased to 801 l.rg/24 hours when the patient was on a regimen of 250 mg of D-penicillamine four times daily. A liver biopsy specimen showed regenerative nodules and areas of postnecrotic collapse, with a markedly increased hepatic concentration of copper (454 pg/g dry weight). Results of a radiocopper (64Cu) kinetic study were consistent with the diagnosis of Wilson’s disease. Regarding renal function, serum creatinine, calcium, phosphorus and uric acid were all within normal limits as were inulin clearance and 24-hour urinary excretion of calcium. The 24-hour urinary excretion of phosphorus was slightly increased (1,347 mg]. In addition, tomography showed at least two stones in the lower pole of the left kidney [Figure l), and an excretory urogram demonstrated stones within the collecting system. A pattern of distal renal tubular acidosis was established on the basis of the following criteria: (1)10hours after the patient had received 100 mg/kg of ammonium chloride, urinary pH did not decrease below 7.32 despite decreases in the serum bicarbonate from 22.4 to 16.6 meq/liter and in blood pH from 7.35 to 7.33; (2) the Tm HCOs was 3.0 meq/liter (normal for this laboratory is 2.8 to 3.2 meq/liter); (3) at a constant normal serum level of bicarbonate (25 meq/liter], the fractional excretion of bicarbonate was 3.8 per cent (increased]; and [4] at a urine pH of 7.5, the urinary Pcoz exceeded the blood Pcoz by only 3.45 mm Hg by the method described by Halperin et al. [14]. Evidence of proximal renal tubular dysfunction was also present, including a lowered tubular reabsorption of phosphorus (54 per cent), aminoaciduria and an increased fractional excretion of urate (14.4 per cent].* * Fractional excretion of urate is expressed as the percentage of the filtered load excreted during pyrazinamide administration.
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RENAL
STONES
IN WILSON’S
DISEASE--WIEHERS
ET 41..
The patient was treated with D-penicillamine, Polycitra (potassium citrate, sodium citrate and citric acid solution] and vitamin supplements. He was instructed to follow a low-copper, low-calcium diet and a fluid intake of at least 8 fluid ounces per hour. Over the ensuing 11 months the patient’s mobility and speech have improved to virtually normal, and there has been no further stone formation. COMMENTS The percentage (16 per cent) of patients with Wilson’s disease in this series who had renal stones is significantly higher than that in the general population, particularly when one considers the younger age group of patients with Wilson’s disease. Although Wilson’s disease is a relatively rare condition, it should be kept in mind in patients who have renal stones, especially when there is evidence of neurologic, hepatic or joint disease of unexplained cause. Such patients are easily screened by slit-lamp examination [u], determination of serum concentrations of copper and ceruloplasmin, and measurement of urinary excretion of copper. The need for such screening is substantiated by the observation that four of the seven patients in this group had evidence of renal stones at or before the time Wilson’s disease was diagnosed. In addition, asymptomatic renal stones may be found on either’plain roentgenograms or excretory urograms. This is exemplified by one patient (Case 5) who had no history of renal colic but in whom a plain roentgenogram of the kidneys showed stones in the lower pole of the left kidney [Figure 2). Factors that may be important in the formation of renal stones in patients with Wilson’s disease include the following: (1)Hypercalciuria, which was noted in three of seven patients with stones in our group and has previously been reported in patients with Wilson’s disease (31, may represent a renal tubular dysfunction, increased absorption of calcium from the gastrointestinal tract or a skeletal abnormality. (2) Local damage to the kidney or irritant effect of copper on glomeruli and renal tubules may account for the high percentage (44 per cent) of patients with Wilson’s disease in our series who had microscopic hematuria. (31 The role of urate crystals in the formation of calcium stones on the basis of epitaxy has been discussed by Coe and Kavalach [ll] in patients with hyperuricosuria. In our series, however, uric acid clearance rather than total uric acid excretion was consistently increased. (4) Abnormal acid-base excretion, namely, inability to acidify the urine to a pH of less than 5.2 after an acid load, was noted in 11 of 15 patients with Wilson’s disease, including four of five who had stones. The mean lowest random urinary pH was significantly higher in patients with Wilson’s disease, with and without stones, than in the control subjects. A great majority of these patients maintained normal or near-normal plasma pH, and chloride and potassium levels and, thereby remained asymptomatic. Such patients have been referred to by some investi-
August
Figure 2. Plain roentgenogram of patient (Case 5) showing large radiopaque stones in lower pole of left kidney. Repeat film two years later showed no evidence of renal calculi.
gators
as having
incomplete
renal tubular acidosis defect is suggested in our patients by the trend of normal Tm HC03 values and filtered bicarbonate loads at normal serum bicarbonate concentrations. The propensity to the formation of renal stones in patients with distal (type I) renal tubular acidosis and incomplete renal tubular acidosis has been widely reported [15-181. Contributing factors are thought to include (1) decreased solubility of calcium phosphate in alkaline urine; (2) decreased inhibitor activity from decreased citrate excretion (usually seen under conditions of systemic acidosis) [li’]; and (3) hypercalciuria as a result of mobilization of bonv calcium, with bone acting as a buffer to stabilize systemic acidosis [15,16]. A distal renal tubular
1191. We believe that the abnormality in acid-base excretion is of particular significance in renal stone formation in Wilson’s disease. The bony abnormalities in these patients may be related to the prevention of systemic acidosis by bone buffer activity, with resultant hypercalciuria in many cases. Furthermore, the previously reported association of distal renal tubular acidosis and alkaline urine with decreased urinary solubility of calcium phosphate [16] correlates with the relatively unusual composition of calcium phosphate of both chemically analyzed stones from our patients. It should be mentioned that patterns of distal renal tubular acidosis have been observed in patients with various other forms of hepatic disease [ZO]. Since six of the seven patients with Wilson’s disease who had stones had manifested hepatic dysfunction at the time renal stones were diagnosed, the possible interrelationship of the two should be considered. The finding of diffuse aminoaciduria in all three patients with Wilson’s disease who had stones and in 15 of 23 of whose without stones seems to contradict the
1979
The American Journal of Medicine
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67
253
RENAL STONES IN WILSON’S DISEASE-WIEBERS
ET AL.
concept held by some that amino acids may protect patients from stone formation by acting as stone-inhibiting substances in the urine. On the other hand, in patients with distal renal tubular acidosis, the number with stones is very high, and our patients may be partially protected by their aminoaciduria. Treatment of the patients with Wilson’s disease who
had stones consisted of D-penicillamine, Polycitra, low-copper and low-calcium diet, increased fluid intake and vitamin supplementation. A definitive statement regarding the efficacy of such therapy with respect to the renal stones could not be made from this series because treatment was not sufficiently standardized, and a control group was not available.
REFERENCES 1. Uzman L, Denny-Brown D: Amino-aciduria in hepatolenticular degeneration IWilson’s diseasel. I Am 1 I Med Sci 215: 599.1948. 2. Bearn AG, Yu TF, Gutman AB: Renal function in Wilson’s disease. J Clin Invest 36: 1107.1957. 3. Litin RB, Randall RV, Goldstein NP, et al.: Hypercalciuria in hepatolenticular degeneration [Wilson’s disease). Am 1Med Sci 238: 614.1959. 4. Beam AG: Wilson’s disease: an inborn error of metabolism with multiple manifestations. Am J Med 22: 747,1957. 5. Leu ML, Strickland GT, Gutman RA: Renal function in Wilson’s disease: response to penicillamine therapv. . _ Am J Med Sci 260: 381.1970. _ 6. Wilson DM, Goldstein NP: Evidence for a urate reabsorptive defect in patients with Wilson’s disease. PurineMetabolism in Man: Biochemistry and Pharmacology of Uric Acid Metabolism, vol41B, (Sperling 0, De Vries-A, Wyngaarden lB, eds). New York, Plenum Press, 1974, p 729. 7. Wilson D’M, Goldstein NP: Renal urate excretion in patients with Wilson’s disease. Kidney Int 4: 381,1978. a. Wilson DM, Goldstein NP: Bicarbonate excretion in Wilson’s disease (hepatolenticular degeneration]. Mayo Clin Proc 49: 394, 1974. 9. Mahoney JP, Sandberg AA, Gubler CJ, et al.: Uric acid metabolism in hepatolenticular degeneration. Proc Sot Exp Biol Med 88: 427,1955. 10. Resnick M, Pridgen DB, Goodman HO: Genetic predisposition to formation of calcium oxalate renal calculi. N Engl J Med 278: 1313.1968. 11. Coe FL, Kavalach AG: Hypercalciuria and hyperuricosuria
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12. 13. 14.
15. 16.
17.
18. 19.
20.
in patients with calcium nephrolithiasis. N Engl J Med 291: 1344.1974. Wrong 0. Davies HEF: The excretion of acid in renal disease. Q I Med 28: 259.1959. Wiebers DO, Hollenhorst RW. Goldstein NP: The ophthalmologic manifestations of Wilson’s disease. Mavo Clin Proc 52: 409, 1977. Halnerin ML. Goldstein MB, Ha& A. et al.: Studies on the pathogenesis of Type I [distal] Fenal tubular acidosis as revealed bv the urinary PCOZtensions. 1Clin Invest 53: 669, 1974. Morris RC Jr, Sebastian A, McSherry E: Renal acidosis. Kidney Int 1: 322.1972. Buckalew VM Jr, McCurdy DK, Ludwig GD, et al.: Incomplete renal tubular acidosis: physiologic studies in three patients with a defect in lowering urine pH. Am J Med 45: 32, 1968. Gyory AZ, Edwards KDG: Renal tubular acidosis: a family with an autosomal dominant genetic defect in renal hydrogen ion transport, with proximal tubular and collecting duct dysfunction and increased metabolism of citrate and ammonia. Am J Med 45: 43,1968. Van Den Berg CJ: Urolithiasis. Textbook of Renal Pathophysiology, (Knox FG, ed), Hagerstown, Maryland, Harper & Row, 1978, p 262. Seldin DW, Wilson JD Renal tubular acidosis. The Metabolic Basis of Inherited Disease, 3rd ed, (Stanbury JB. Wyngaarden JB, Fredrickson DS, eds), New York, McGraw-Hill Book Co.. 1972, p 1548. Golding PL, Mason ASM: Renal tubular acidosis and autoimmune liver disease. Gut 12: 153.1971.
Volume 67
DAVID
0. WIEBERS.
M.D.
DAVID
M. WILSON,
M.D.
RICHARD
A. McLEOD,
NORMAN
P. GOLDSTEIN,
M.D. M.D.
Rochester, A4innesoto
From the Mayo Clinic and Mayo Foundation. Rochester, Minnesota. Requests for reprints should be addressed to Dr. D. 0. Wiebcrs. Section of Publications, Mayo Clinic. Rochester, Minnesota 55901. Manuscript accepted March 5. 1979.
Fifty-four patients with Wilson’s disease were studied with regard to renal stones. Seven of the 45 patients (16 per cent) who underwent roentgenographic procedures of the urinary tract had unequivocal evidence of renal stones. In four of the seven patients with Wilson’s disease who had renal stones, the stones were discovered at the time or before the diagnosis of Wilson’s disease was made. Of the several possible factors that may predispose patients with Wilson’s disease to renal stone formation, the renal tubular acidosis pattern of abnormality in acid-base excretion is probably the most significant. In general, patients with renal stones and unexplained neurologic, bony or hepatic abnormalities should be screened for Wilson’s disease by slit-lamp examination, determination of serum copper and ceruloplasmin concentrations, and urinary excretion of copper, particularly if they have relatively alkaline urine. A wide variety of renal abnormalities have been described in Wilson’s disease, including decreased renal plasma flow, decreased glomerular filtration rate and renal tubular abnormalities. The last-named may be divided into primarily proximal renal tubular dysfunction (aminoaciduria [l], hyperphosphaturia [z], hypercalciuria [3] and glucosuria [4]); primarily distal renal tubular dysfunction (potassium wasting and concentrating defects [5]); and combinations of proximal and distal renal tubular dysfunction [defective excretion of uric acid [6,7] and acid-base [8]). More specifically, the abnormalities of acid-base excretion most often represent a gradient defect for hydrogen ion excretion with a subnormal urinary acidifying capacity (distal renal tubular acidosis pattern]. Infrequently, patients with bicarbonate wastage and a low tubular maximum for bicarbonate (Tm HC@) have been described (proximal renal tubular acidosis pattern [8]). Regarding uric acid excretion, evidence for both tubular reabsorptivc and secretor! defects has been presented [5-7,9]. One aspect of renal dysfunction which has not previously been studied in Wilson’s disease is renal stones. In general, renal stones arc found in approximately 1 per cent of autopsies in the IJnited States. Studies regarding their prevalence have been scarce and difficult to assess. The data from one study conducted in this country by Resnick et al. [lo] suggest that the prevalence of renal stones is approximate11 5 per cent in the general population. The pathogenesis of renal stones is multifactorial and complex and can be partially categorized as follows: (11 excessive excretion of stone-forming constituents into the urine, including calcium, uric acid, oxalate, cystine and xanthine; (2) local causes, including urinary stasis, infections within the urinary tract, foreign bodies and epitaxy [ll] (the oriented growth of one crystal on
August 1979
The American Journal of Medicine
Volume 67
249
RENAL STONES IN WILSON’S DISEASE-WIEBERS
TABLE I
ET AL.
Data on Seven Patients With Wilson’s Disease Who Had Renal Stones
Ageal Ageal Diagnosis Diagnosis of Wilson’s Disease (yr)
of Renal Stones
Period Followed (yr)
Renal Slone Surgery
Renal Slone Passage
18
Yes
Yes(B)
50 32% 19 39
Og 17 3 7
No No Yes No
No Yes Yes No
10160 41585 7167 6/5811
10% 32%
6 1
No Yes(2)
No No
3168 31737
Case No.
Sex
1
M
40
32
2 3 4 5
M M M F
45 32% 78% 17
6 7
M M
10% 37%
(yr)
C = low-calcium diet; E = calcium disodium EDTA; F = increased + Received BAL from February 1956 through September 1958. t Patient died six months after renal stones were found. 5 Received BAL July 1957 through April 1958. 11 Received BAL 1951 thrpugh 1953. ( Medication taken sporadically. l
another of near geometric fit]; (3) other physiologic alterations of the urine, including urine pH and the absence of inhibitory substances such as pyrophosphate, citrate, magnesium, peptides and amino a’cids; and [4) idiopathic. In this study, 54 patients with Wjlson’s disease, including seven patients with renal stones, were evaluated in terms of the aforementioned possible etiologic factors. The relationship of these factors to the high incidence of renal stones in these patients with Wilson’s disease is discussed. METHODS Fifty-four patients with an unequivocal diagnosis of Wilson’s disease were evaluated at the Mayo Clinic from 1952 through 1977. Each patient underwent initial comprehensive neurologic, ophthalmologic and general medical examinations, with serial folloti-up examinations in most cases. Forty-five of the 54 patients underwent at least one plain roentgenographic examination of the kidneys, ureters and bladder, or excretory urography, as part of their evaluation; many of these patients had serial follow-up roentgenographic examinations of the urinary tract. particularly if they had renal stones or other symptoms or signs related to the urinary tract. Renal excretion of urate was st?died in 13 patients with Wilson’s disease (six with and seven without renal stones) and in 10 control subjects by a method described previously [7]. Acid-base excretion was studied in 15 patients with Wilson’s disease [five with and 10 without renal stones) and eight control subjects. also by methods described previously [8]. A Phoenix amino acid analyzer was used to quantitate urinary excretion of amino acids while patients temporarily discontinued taking D-penicillamine. Correlation with renal stone formation was facilitated by evaluating a number of other specific laboratory indices before any therapy for Wilson’s disease, at the time of initial discovery
250
August 1979
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o-Penicillamine Therapy Begun g/58+
fluid intake
Specific Renal Stone Therapy’ 1 l/55 C,E,F 3169 P
(>2,000
7% C,F 8167 C,F 3171 C,F 3f68 C,F 5177 C,F,P
Increased Metabolic Stone Activity
Decreased tdelabolic Stone Activity
8148, 5151, 11155, 8160, lOf65, 10167, 8169
10168
lo;&, 9170 2168, 10168 3169, 3171, l/73
6/f%’ ;;;4,
l/75
6172 3/68:2/77, 5177
ml/day); p = Polycitra.
of renal stones and at subsequent intervals when there was evidence of metabolic stone activity.* Specifically, the serum indices studied included creatinine, urea, sodium, potassium, chloride, bicarbonate, calcium, phosphorus, uric acid, copper, ceruloplasmin and arterial blood gases. Urinary indices included urinalysis, pH, daily urine volume, creatinine, calcium, phosphorus, uric acid, oxalate, copper, zinc, amino acids, ,ammonia, total nitrogen content, creatinine clearance, inulin clearance and urea clearance.
RESULTS Seven of the 45 patients (16 per cent) who underwent renal studies with plain films or excretory urograms had unequivocal roentgenographic evidence of renal stones (in two others it was equivocal]. Of the four symptomatic patients, ali had renal colic, one had recurrent frank hematuria, and one had recurrent passage of gravel. In addition, three of the seven patients underwent nephrolithotomy (Table I), and three patients spontaneously passed stones, including one patient (Case 1) who did so on three separate occasions over 19 years. At the time of diagnosis of Wilson’s disease, all of the patients.with renal stones had neurologic involvement, six of the seven had roentgenographic evidence of bony abnormalities, and six of the seven had overt clinical or laboratory evidence of hepatic dysfunction. Two of the seven patients (Cases 1 and 7) had symptomatic renal stones before the diagnosis of Wilson’s disease was made (eight and five years before, respectively], and in two others [Cases 3 and 6) renal stones were discovered at th’e time of diagnosis. * Metabolic stone activity is defined as roentgenographic evidence of stone growth or new stone formation or passage of gravel in the absence of infection or obstruction.
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Of the five patients with stones who were followed serially at the Mayo Clinic, four had evidence of continued metabolic stone activity while receiving D-penicillamine and the stone therapy outlined in Table I. In three of these patients, stones eventually stopped growing; in two, totally negative plain roentgenographic studies of the kidneys, ureters and bladder were attained. Specific attention was given to periods of increased and decreased stone activity in an attempt to establish any consistent correlation with one or more of the specific laboratory indices outlined, but none was found. Hypercalciuria was noted in three of seven patients with stones, and three demonstrated normal urinary excretion of calcium while they were receiving D-penicillamine therapy. In each of these increased renal stone growth was documented with normal 24hour urinary excretion of calcium. The urinary excretion of calcium was not studied in the seventh patient. Five patients with stones followed serially had hypouricemia before D-penicillamine therapy, and in four of the five, serum levels of uric acid reverted to normal after seven months, four years, 13 years and 15 years. In the fifth patient, the concentration of serum uric acid increased slightly, from 2.1to 3.6mg/dl, over four years. Two other patients with stones were not followed serially. Data on plasma uric acid levels and the urinary excretion of uric acid are presented in Table II. Twenty-four hour urinary excretion of uric acid was increased in only one of five patients, but uric acid clearance relative to the inulin clearance was clearly increased in four of six patients and was borderline in the remaining two. Data on excretion of bicarbonate and ammonium loading are presented in Table III. Failure to acidify the urine to a pH of 5.2 or lower was noted in four of five patients with stones and in seven of 10 patients without stones. According to the criteria of Wrong and Davis [E] this suggests renal tubular acidosis. Only one of the six patients with stones (Case 1)consistently showed an arterial blood pH of less than 7.35, and his pH was never lower than 7.29. Tubular maximum for excretion of bicarbonate (Tm HCOs) was normal in three of four paTABLE III
STONES
TABLE II
IN WILSON’S
DISEASE-WIEHERS
ET AL.
Uric Acid Excretion in Patients With Wilson’s Disease and in Control Subjects
PlasmaUric
Cl”’ (mUmin/ 1.73 mZ)
Acid (mg/dl)
UrineUric Acid (mg/24 hr)
Cwar.+ Cl”
Patients Wtth Wilson’s Disease With Renal Stones (n = 7) 4.41 f 1.33 85.3 f 50.1 0.26 f 0.13 597 f 141 Patients With Wilson’s Disease Without Renal Stones (n = 7) 4.83 f 0.61 98.3 f 20.8 0.16 f 0.058 706 f 224
5.33 f 0.85
Control Subjects (n = 10) 109.0 f 6.9 0.098 f 0.034
(250-750)+
NOTE: All values are the mean f standard deviation. C,” = inulin clearance. +c wate/Cln = ratio of urate clearance to inulin clearance. + Accepted normal value for urinary uric acid excretion in adults. l
tients with stones and in nine of 10 patients without stones. Renal bicarbonate threshold (the lowest serum bicarbonate level at which 1 peq/min of bicarbonate is excreted in the urine] was significantly lower in patients with Wilson’s disease with and without stones than in control subjects. At constant plasma bicarbonate levels (between 23.6 and 26.3 meq/liter), urinary excretion of bicarbonate and per cent of the filtered load excreted were significantly higher in patients with Wilson’s disease than in control subjects and highest in patients with Wilson’s disease who had stones. However, the wide range of values in the patients with Wilson disease with stones makes this last distinction of questionable significance. A summary of the lowest random urine pH values is presented in Table IV. The mean value for the control group was significantly lower than the values for the patients with Wilson’s disease with and without stones. The difference between those with stones and those without stones was not statistically significant. Data on the urinary excretion of amino acids were obtained in three of the seven patients with Wilson’s disease who had renal stones and in 23 who did not have stones. Total excretion of amino acids was increased in all three of the patients with stones and in 15 of the 23 patients without stones. The pattern of aminoaciduria,
Acid-Base Excretion Data in Patients With Wilson’s Disease and in Control Subjects
UrinarypH After Ammonium Chloride
Tm HCOs’ (msq1100ml GFR+)
RenalHCOs Threshold (meq/liter)
UrinaryHCOs (meqlmin)
At ConstantPlasmapH % filtered load
GFR+ (mUmin)
Patients With Wilson’s Disease With Renal Stones (n = 7) 6.35 f 0.84
2.73 f 0.57
5.65 f 0.61
Patients With Wilson’s Disease Without Renal Stones (n = 10) 2.70 f 0.23 21.7 f 2.55 37.6 f 54.3
2.96 f 0.24
21.7 f
1.58
28.3 f 33.56
Control Subjects (n = 10) 24.5 f 2.25 7.15 f 3.04
14.9 f 25.7
80 f 32.5
1.83 f 2.96
90.8 f 21.3
0.263 f 0.100. -_
107.3 f 9.0
NOTE: All values are the mean f standard deviation. * Tm HC03 = tubular maximum for bicarbonate; + GFR = glomerular filtration rate.
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TABLE IV
IN WILSON’S
Random UrinepH
ET AL.
Random Urine pH Data Patients With Wilson’s Disease
Lowest
DISEASE-WIEBERS
WithRenalStones (N = 7)
Patients With Wilson’s Disease
WithoutStones (N = 22)
6.37 5.5-7.4
Mean Range
6.54 5.6-7.5
Control Subjects (N = 20) 5.69 5.2-6.7
when studied in terms of 13 individual amino acids, was one of diffuse increases varying from patient to patient such that no specific amino acid abnormalities were characteristic of the group. Two of the seven patients had spontaneously passed stone material recovered for analysis. In both the material consisted of a combination of calcium phosphate (major constituent) and calcium carbonate. Significant microscopic hematuria was found in 24 of the 54 patients with Wilson’s disease (44 per cent), including 19 of 47 patients with Wilson’s disease who did not have stones (40 per cent) and five of seven patients with Wilson’s disease who had stones (71 per cent). Gallstones were discovered in two of the seven patients with Wilson’s disease who had stones-10 years after the onset of D-penicillamine therapy in one case (Case 5) and at the time of diagnosis of Wilson’s disease in the other (Case 7). CASE STUDY Case 7. A 41 year old oriental man underwent
a cholecystectomy in 1973 for a nonfunctioning gallbladder. A liver biopsy performed at the time disclosed early posthepatitic cirrhosis, which, along with low serum levels of ceruloplasmin and copper, led to the diagnosis
of Wilson’s disease.
He was
Figure 1. Tomogram of patient (Case 7) showing two stones in lower pole of left kidney. Excretory urogram demonstrated that these stones were within collecting system.
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started on a regimen of D-penicillamine and potassium sulfide, which he used only sporadically. Before thetime of this diagnosis, he had been asymptomatic except for two episodes of right renal colic and frank hematuria, which had resulted in a right nephrolithotomy five years previously. Subsequently, he continued to have episodes of frank hematuria without renal colic. In September 1976, mild incoordination in both upper and lower limbs was first noticed, and an excretory urogram showed at least two stones in the left kidney. Another episode of renal colic in February 1977, with hematuria and increased urgency, resulted in the diagnosis and surgical removal of a stone in the left ureter. Subsequently, the patient noted worsening of incoordination in all four extremities, with tremor in the upper limbs, slowness of speech and difficulty with balance: this led to his referral to the Mayo Clinic in May 1977. Physical examination revealed bilateral Kayser-Fleischer (stage 3) rings [13], confirmed by slit-lamp biomicroscopy. The liver was percussed at 7 cm below the costal margin in the right mid-clavicular line: the spleen was not enlarged. Neurologic examination showed mild dysarthria and slight masking of the facies. The patient had a slightly wide-based gait and mild incoordination of both upper and lower limbs but no tremor. He also had mild rigidity in the upper limbs but no cogwheeling. Results of laboratory studies included values for serum ceruloplasmin of 0.8 mg/dl, serum copper of 30 pg/dl and urinary excretion of copper of 112 pg/24 hours when the patient was not taking D-penicillamine; the excretion of copper increased to 801 l.rg/24 hours when the patient was on a regimen of 250 mg of D-penicillamine four times daily. A liver biopsy specimen showed regenerative nodules and areas of postnecrotic collapse, with a markedly increased hepatic concentration of copper (454 pg/g dry weight). Results of a radiocopper (64Cu) kinetic study were consistent with the diagnosis of Wilson’s disease. Regarding renal function, serum creatinine, calcium, phosphorus and uric acid were all within normal limits as were inulin clearance and 24-hour urinary excretion of calcium. The 24-hour urinary excretion of phosphorus was slightly increased (1,347 mg]. In addition, tomography showed at least two stones in the lower pole of the left kidney [Figure l), and an excretory urogram demonstrated stones within the collecting system. A pattern of distal renal tubular acidosis was established on the basis of the following criteria: (1)10hours after the patient had received 100 mg/kg of ammonium chloride, urinary pH did not decrease below 7.32 despite decreases in the serum bicarbonate from 22.4 to 16.6 meq/liter and in blood pH from 7.35 to 7.33; (2) the Tm HCOs was 3.0 meq/liter (normal for this laboratory is 2.8 to 3.2 meq/liter); (3) at a constant normal serum level of bicarbonate (25 meq/liter], the fractional excretion of bicarbonate was 3.8 per cent (increased]; and [4] at a urine pH of 7.5, the urinary Pcoz exceeded the blood Pcoz by only 3.45 mm Hg by the method described by Halperin et al. [14]. Evidence of proximal renal tubular dysfunction was also present, including a lowered tubular reabsorption of phosphorus (54 per cent), aminoaciduria and an increased fractional excretion of urate (14.4 per cent].* * Fractional excretion of urate is expressed as the percentage of the filtered load excreted during pyrazinamide administration.
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STONES
IN WILSON’S
DISEASE--WIEHERS
ET 41..
The patient was treated with D-penicillamine, Polycitra (potassium citrate, sodium citrate and citric acid solution] and vitamin supplements. He was instructed to follow a low-copper, low-calcium diet and a fluid intake of at least 8 fluid ounces per hour. Over the ensuing 11 months the patient’s mobility and speech have improved to virtually normal, and there has been no further stone formation. COMMENTS The percentage (16 per cent) of patients with Wilson’s disease in this series who had renal stones is significantly higher than that in the general population, particularly when one considers the younger age group of patients with Wilson’s disease. Although Wilson’s disease is a relatively rare condition, it should be kept in mind in patients who have renal stones, especially when there is evidence of neurologic, hepatic or joint disease of unexplained cause. Such patients are easily screened by slit-lamp examination [u], determination of serum concentrations of copper and ceruloplasmin, and measurement of urinary excretion of copper. The need for such screening is substantiated by the observation that four of the seven patients in this group had evidence of renal stones at or before the time Wilson’s disease was diagnosed. In addition, asymptomatic renal stones may be found on either’plain roentgenograms or excretory urograms. This is exemplified by one patient (Case 5) who had no history of renal colic but in whom a plain roentgenogram of the kidneys showed stones in the lower pole of the left kidney [Figure 2). Factors that may be important in the formation of renal stones in patients with Wilson’s disease include the following: (1)Hypercalciuria, which was noted in three of seven patients with stones in our group and has previously been reported in patients with Wilson’s disease (31, may represent a renal tubular dysfunction, increased absorption of calcium from the gastrointestinal tract or a skeletal abnormality. (2) Local damage to the kidney or irritant effect of copper on glomeruli and renal tubules may account for the high percentage (44 per cent) of patients with Wilson’s disease in our series who had microscopic hematuria. (31 The role of urate crystals in the formation of calcium stones on the basis of epitaxy has been discussed by Coe and Kavalach [ll] in patients with hyperuricosuria. In our series, however, uric acid clearance rather than total uric acid excretion was consistently increased. (4) Abnormal acid-base excretion, namely, inability to acidify the urine to a pH of less than 5.2 after an acid load, was noted in 11 of 15 patients with Wilson’s disease, including four of five who had stones. The mean lowest random urinary pH was significantly higher in patients with Wilson’s disease, with and without stones, than in the control subjects. A great majority of these patients maintained normal or near-normal plasma pH, and chloride and potassium levels and, thereby remained asymptomatic. Such patients have been referred to by some investi-
August
Figure 2. Plain roentgenogram of patient (Case 5) showing large radiopaque stones in lower pole of left kidney. Repeat film two years later showed no evidence of renal calculi.
gators
as having
incomplete
renal tubular acidosis defect is suggested in our patients by the trend of normal Tm HC03 values and filtered bicarbonate loads at normal serum bicarbonate concentrations. The propensity to the formation of renal stones in patients with distal (type I) renal tubular acidosis and incomplete renal tubular acidosis has been widely reported [15-181. Contributing factors are thought to include (1) decreased solubility of calcium phosphate in alkaline urine; (2) decreased inhibitor activity from decreased citrate excretion (usually seen under conditions of systemic acidosis) [li’]; and (3) hypercalciuria as a result of mobilization of bonv calcium, with bone acting as a buffer to stabilize systemic acidosis [15,16]. A distal renal tubular
1191. We believe that the abnormality in acid-base excretion is of particular significance in renal stone formation in Wilson’s disease. The bony abnormalities in these patients may be related to the prevention of systemic acidosis by bone buffer activity, with resultant hypercalciuria in many cases. Furthermore, the previously reported association of distal renal tubular acidosis and alkaline urine with decreased urinary solubility of calcium phosphate [16] correlates with the relatively unusual composition of calcium phosphate of both chemically analyzed stones from our patients. It should be mentioned that patterns of distal renal tubular acidosis have been observed in patients with various other forms of hepatic disease [ZO]. Since six of the seven patients with Wilson’s disease who had stones had manifested hepatic dysfunction at the time renal stones were diagnosed, the possible interrelationship of the two should be considered. The finding of diffuse aminoaciduria in all three patients with Wilson’s disease who had stones and in 15 of 23 of whose without stones seems to contradict the
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RENAL STONES IN WILSON’S DISEASE-WIEBERS
ET AL.
concept held by some that amino acids may protect patients from stone formation by acting as stone-inhibiting substances in the urine. On the other hand, in patients with distal renal tubular acidosis, the number with stones is very high, and our patients may be partially protected by their aminoaciduria. Treatment of the patients with Wilson’s disease who
had stones consisted of D-penicillamine, Polycitra, low-copper and low-calcium diet, increased fluid intake and vitamin supplementation. A definitive statement regarding the efficacy of such therapy with respect to the renal stones could not be made from this series because treatment was not sufficiently standardized, and a control group was not available.
REFERENCES 1. Uzman L, Denny-Brown D: Amino-aciduria in hepatolenticular degeneration IWilson’s diseasel. I Am 1 I Med Sci 215: 599.1948. 2. Bearn AG, Yu TF, Gutman AB: Renal function in Wilson’s disease. J Clin Invest 36: 1107.1957. 3. Litin RB, Randall RV, Goldstein NP, et al.: Hypercalciuria in hepatolenticular degeneration [Wilson’s disease). Am 1Med Sci 238: 614.1959. 4. Beam AG: Wilson’s disease: an inborn error of metabolism with multiple manifestations. Am J Med 22: 747,1957. 5. Leu ML, Strickland GT, Gutman RA: Renal function in Wilson’s disease: response to penicillamine therapv. . _ Am J Med Sci 260: 381.1970. _ 6. Wilson DM, Goldstein NP: Evidence for a urate reabsorptive defect in patients with Wilson’s disease. PurineMetabolism in Man: Biochemistry and Pharmacology of Uric Acid Metabolism, vol41B, (Sperling 0, De Vries-A, Wyngaarden lB, eds). New York, Plenum Press, 1974, p 729. 7. Wilson D’M, Goldstein NP: Renal urate excretion in patients with Wilson’s disease. Kidney Int 4: 381,1978. a. Wilson DM, Goldstein NP: Bicarbonate excretion in Wilson’s disease (hepatolenticular degeneration]. Mayo Clin Proc 49: 394, 1974. 9. Mahoney JP, Sandberg AA, Gubler CJ, et al.: Uric acid metabolism in hepatolenticular degeneration. Proc Sot Exp Biol Med 88: 427,1955. 10. Resnick M, Pridgen DB, Goodman HO: Genetic predisposition to formation of calcium oxalate renal calculi. N Engl J Med 278: 1313.1968. 11. Coe FL, Kavalach AG: Hypercalciuria and hyperuricosuria
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12. 13. 14.
15. 16.
17.
18. 19.
20.
in patients with calcium nephrolithiasis. N Engl J Med 291: 1344.1974. Wrong 0. Davies HEF: The excretion of acid in renal disease. Q I Med 28: 259.1959. Wiebers DO, Hollenhorst RW. Goldstein NP: The ophthalmologic manifestations of Wilson’s disease. Mavo Clin Proc 52: 409, 1977. Halnerin ML. Goldstein MB, Ha& A. et al.: Studies on the pathogenesis of Type I [distal] Fenal tubular acidosis as revealed bv the urinary PCOZtensions. 1Clin Invest 53: 669, 1974. Morris RC Jr, Sebastian A, McSherry E: Renal acidosis. Kidney Int 1: 322.1972. Buckalew VM Jr, McCurdy DK, Ludwig GD, et al.: Incomplete renal tubular acidosis: physiologic studies in three patients with a defect in lowering urine pH. Am J Med 45: 32, 1968. Gyory AZ, Edwards KDG: Renal tubular acidosis: a family with an autosomal dominant genetic defect in renal hydrogen ion transport, with proximal tubular and collecting duct dysfunction and increased metabolism of citrate and ammonia. Am J Med 45: 43,1968. Van Den Berg CJ: Urolithiasis. Textbook of Renal Pathophysiology, (Knox FG, ed), Hagerstown, Maryland, Harper & Row, 1978, p 262. Seldin DW, Wilson JD Renal tubular acidosis. The Metabolic Basis of Inherited Disease, 3rd ed, (Stanbury JB. Wyngaarden JB, Fredrickson DS, eds), New York, McGraw-Hill Book Co.. 1972, p 1548. Golding PL, Mason ASM: Renal tubular acidosis and autoimmune liver disease. Gut 12: 153.1971.
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