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Recurrent Urinary Calculi Associated with Toluene Sniffing
0022-5347 /80/1231-0089$02.00/0 Vol. 123, January Printed in U.S.A.
THE JOURNAL OF UROLOGY
Copyright© 1980 by The Williams & Wilkins Co.
Case Reports RECURRENT URINARY CALCULI ASSOCIATED WITH TOLUENE SNIFFING R. MICHAEL KROEGER, ROBERT J. MOORE, THEODORE H. LEHMAN, JERRY D. GIESY AND C. EDWARD SKEETERS From the Division of Urology, University of Oregon Health Sciences Center and Emanuel Hospital, Portland, Oregon
ABSTRACT
A young man who presented initially with a ureteral stone was found to have toluene-induced renal tubular acidosis. Persistent toluene sniffing resulted in recurrent calculi and life-threatening hypokalemic paralysis. The pathophysiology, classification and treatment of renal tubular acidosis are discussed. Toluene (methylbenzene) is an aromatic hydrocarbon used extensively as an industrial solvent. Although it has not been an important factor in occupational illness 1 deliberate inhalation produces high levels of exposure and this practice has been associated with hepatomegaly, eosinophilia, abnormal urinary sediment, a wide range of neurologic abnormalities and sudden death. 2 • 3 Recently, Taher and associates found renal tubular acidosis in 2 patients who sniffed toluene. 4 Herein we report on an additional patient with toluene-induced renal tubular acidosis who presented with recurrent urinary calculi. To the best of our knowledge urolithiasis secondary to solvent inhalation has not been reported previously.
sisted with his habit and in September he was hospitalized with a history of vomiting, mild left lower quadrant pain and weakness in the lower extremities. He had been unable to walk for the previous 24 hours. Physical examination confirmed the presence of paraparesis with normal upper extremity strength. Laboratory data revealed a serum potassium of 1.5 mEq./1., chloride 109 mEq./1. and bicarbonate 14.6 mEq./1. Arterial blood gases on room air were pH 7.34, oxygen pressure 115 mm. Hg and carbon dioxide pressure 20 mm. Hg. The patient was admitted to the intensive care unit and potassium chloride was administered, resulting in rapid improvement in muscular strength. Serum potassium 3 days later was 4.6 mEq./1., chloride 105 mEq./1. and bicarbonate 28 mEq./1., although no bicarbonate had been administered. This was presumably owing to the reversibility of toluene-induced renal tubular acidosis upon withdrawal of the drug. When the patient was stable an IVP showed another left ureteral stone that was removed in N ovember, representing the fourth stone operation in 15 months.
CASE REPORT
J. H., a 23-year-old white man, began sniffing toluene on a regular basis when he was 18 years old. In July 1977 he presented with left flank pain and hematuria. An excretory urogram (IVP) showed a calculus within a left ureterocele, which was removed by transurethral meatotomy. In November a right pyelolithotomy was done and in August 1978 an obstructing stone was removed from the upper left ureter, with concomitant renal biopsy. Crystallographic analysis of this calculus revealed 70 per cent calcium phosphate, 15 per cent calcium oxalate and 15 per cent calcium carbonate. Histologic changes in the kidney were limited to variation in glomerular basement membrane thickness with some instances of fine splitting of the membrane on electron microscopy. Immunofluorescence studies for IgG, IgM, IgA, complement, fibrin and fibrinogen were negative. Admission serum chloride levels during this period of active stone formation ranged from 109 to 114 mEq./1., with serum bicarbonate levels of 13 to 23 mEq./1. The finding ofhyperchloremic acidosis in a stone former immediately suggests renal tubular acidosis. Further evaluation revealed a urine pH of 5.82 with a simultaneous arterial pH of 7.36. Bicarbonate loading studies revealed a normal tubular capacity for reabsorption of bicarbonate and the diagnosis was distal (classic, type I) renal tubular acidosis. Testing of family members ruled out a familial disorder. It was concluded that solvent sniffing was responsible for the urinary acidification defect and, thus, the recurrent stone formation. Despite our fmdings and recommendations the patient per-
DISCUSSION
Toluene inhalation can produce effects similar to that of diethyl ether anesthesia, with an initial excitatory phase followed by central nervous system depression. 5 The typical solvent sniffer is a boy between 13 and 15 years old from a family of middle or low income. Although tolerance and psychological dependence do occur there is no good evidence for true physical addiction. Most youngsters stop sniffmg as they grow older, making toluene habituation relatively rare among adults. Renal tubular acidosis represents an important clinical form of toluene toxicity, particularly in the habitual user. Although this complication has been described only recently earlier studies of solvent inhalation did not include determinations of serum electrolytes or urine pH. The mechanism of toluene renal toxicity is unknown. All patients reported to date have had distal renal tubular acidosis, which has been reversible upon withdrawal of the toxin. Renal tubular acidosis is actually a group of disorders with the common denominator of impaired hydrogen ion secretion in the renal tubule. The metabolic consequences of this defect depend on which portion of the tubule is affected. The proximal tubule is the primary site for bicarbonate reabsorption, reclaiming 85 per cent of the filtered bicarbonate in a process that is intimately linked to hydrogen ion secretion (table 1). Impaired hydrogen ion transport at this level effec-
Accepted for publication April 20, 1979.
89
90
KROEGER AND ASSOCIATES
tively limits the maximum capacity of the tubule to reabsorb bicarbonate, which appears in the urine. Serum bicarbonate levels decrease until the new threshold level is reached. At this point a steady state of metabolic acidosis exists. The proximal tubule can handle the decreased filtered load of bicarbonate and the distal tubule is not flooded with bicarbonate. Distal acidification and net acid excretion are possible. However, decreased hydrogen ion secretion in the distal nephron impairs bicarbonate regeneration (table 2). Decreasing urinary ammonium and titratable acid limits net acid excretion. When net acid excretion decreases below the fixed acid production of the body (normally 1 mEq./kg. per 24 hours) progressive acidosis ensues. 6 This brief discussion of the pathophysiology of renal tubular acidosis explains many of the clinical features that form the basis for diagnosis and classification of the disease (table 3). (Other forms of renal tubular acidosis have been described but they are beyond the scope of this report.) Although the diagnosis often is suggested by routine laboratory tests incomplete forms of distal renal tubular acidosis do not present with acidosis and require acid loading studies for diagnosis. Such investigations usually are prompted by a family history of renal tubular acidosis, history of nephrolithiasis or the presence of a condition known to be associated with secondary renal tubular acidosis. Table 4 lists some conditions associated with renal tubular acidosis likely to be seen by urologists. Current concepts of stone formation in renal tubular acidosis relate to altered metabolism of calcium and citrate in systemic acidosis. Chronic acid retention titrates alkaline bone salts, leading to mobilization of calcium and hypercalciuria. Direct effects of acidosis on the renal tubule also may have a role in increasing urinary calcium. 7 Acidosis per se reduces urinary citrate, a well known inhibitor of crystallization. Alkaline urine decreases the solubility of calcium salts, particularly calcium phosphate. Since toluene-induced renal tubular acidosis is reversible, it seems likely that only regular, long-term users will have urolithiasis. This pathogenetic scheme seems valid for patients with complete renal tubular acidosis but it does not explain why patients with incomplete renal tubular acidosis (not acidotic by definition) also tend to form stones. Also unexplained is the relative rarity of urolithiasis in proximal renal tubular acidosis. Thus, it seems likely that other metabolic abnormalities contribute to calculogenesis in this disease. In this regard recent evidence has suggested that some familial types of renal tubular acidosis are actually secondary to a primary disturbance of calcium metabolism. 8 Treatment of renal tubular acidosis with sodium bicarbonate or other alkalizing medications can be expected to decrease the rate of stone formation. Alkali should be given in amounts sufficient to produce a normal serum bicarbonate. In general, patients with distal renal tubular acidosis are relatively sensitive to alkalization, while proximal renal tubular acidosis patients
TABLE
3. Clinical features of renal tubular acidosis
Serum chloride Serum bicarbonate Serum potassium Anion gap Urine pH (a.m.) Urine pH (acid load) Stones Fanconi's syndrome Bicarbonate requirement
TABLE 4.
Proximal
Distal
High >15 mEq./1. Normal to low Normal Maybe <6.0 <5.3 Uncommon Common High
High <15 mEq,/1. Normal to low Normal >6.0 >5.3 Common Rare Low
Secondary renal tubular acidosis Proximal
Lowe's syndrome Amyloidosis Nephrotic syndrome Renal transplantation Medullary cystic disease
Outdated tetracycline Acetazolamide Mafenide Heavy metals
Distal Primary hyperparathyroidism Idiopathic hypercalciuria Medullary sponge kidney Pyelonephritis Obstructive uropathy
Renal transplantation Amphotericin B Lithium carbonate Toluene
require more medication. In secondary forms of renal tubular acidosis treatment of the underlying disease or removal of the toxin may ameliorate the tubular dysfunction, making bicarbonate therapy unnecessary. In these cases it is prudent to put the patient on the alkalizing agents until definite evidence for complete reversal of the defect is obtained. The acute complication of hypokalemic paralysis in our case has been reported previously. 4 Impaired sodium-hydrogen exchange in the distal nephron leads to sodium depletion, secondary hyperaldosteronism and potassium wasting. This results in the unusual combination of hypokalemia and acidosis. Proper management of these patients requires continuous monitoring of the electrocardiogram and frequent determinations of serum electrolytes while potassium chloride is being given. Administration of solutions containing bicarbonate or glucose will drive potassium into the intracellular compartment and exacerbate the hypokalemia. Therefore, no attempt is made to correct the acidosis until the serum potassium is at least 3.0 mEq./1. Respiratory insufficiency owing to ascending paralysis precipitated by bicarbonate administration in this setting has been reported. 9 A normal or elevated carbon dioxide pressure in the presence of metabolic acidosis may be an early clue to hypoventilation. While the high priority of potassium replacement deserves emphasis it also is important to indicate that rapid infusion of potassium to an acidotic patient can lead to dangerously high serum levels of potassium. Therefore, the proper approach depends on carefully titrating the patient with potassium and subsequently bicarbonate, and using the electrocardiogram and frequent determinations of serum electrolytes to monitor therapy.
1. Characteristics of bicarbonate reabsorption
85-90% proximal tubule 10-15% distal tubule 1 hydrogen ion secreted for each bicarbonate reabsorbed No net hydrogen ion excreted Carbonic anhydrase required
TABLE
TABLE
2. Characteristics of bicarbonate regeneration
Distal tubule and collecting duct 1 hydrogen ion excreted for each bicarbonate regenerated Net hydrogen ion excretion does occur Net acid excretion = urinary ammonium + titratable acid - bicarbonate Carbonic anhydrase not required
REFERENCES 1. von Oettingen, W. F., Neal, P.A. and Donahue, D. D.: Toxicity and
2. 3. 4. 5.
potential dangers of toluene; preliminary report. J.A.M.A., 118: 579, 1942. Press, E. and Done, A. K.: Solvent sniffing. Physiologic effects and community control measures for intoxication from the intentional inhalation of organic solvents. I. Pediatrics, 39: 451, 1967. Press, E. and Done, A. K.: Solvent sniffing. Physiologic effects and community control measures for intoxication from the intentional inhalation of organic solvents. II. Pediatrics, 39: 611, 1967. Taher, S. M., Anderson, R. J., McCartney, R., Popovtzer, M. M. and Schrier, R. N.: Renal tubular acidosis associated with toluene "sniffing". New Engl. J. Med., 290: 765, 1974. Wyse, D. G.: Deliberate inhalation of volatile hydrocarbons: a
RECURRENT
Ass. ,l., and G-oidhergJ
71, 1973. · Renal tubular acidosis:
and treatrnent" DJ\/1, fL
ASSOCIATED 'VVITl-I TOLUENE S~NIFFIN'G
8, Buckalew, Vo l\/1.) Jr., Purvis Nt L.; Shulman, :rvI. G. Herndon, C. 1
1
N. and Rudman, D.: Hereditary renal tubular acidosis. Tv1edicine, 53: 229, 1974.
J. D. and iieal loop
THE JOURNAL OF UROLOGY
Copyright© 1980 by The Williams & Wilkins Co.
Case Reports RECURRENT URINARY CALCULI ASSOCIATED WITH TOLUENE SNIFFING R. MICHAEL KROEGER, ROBERT J. MOORE, THEODORE H. LEHMAN, JERRY D. GIESY AND C. EDWARD SKEETERS From the Division of Urology, University of Oregon Health Sciences Center and Emanuel Hospital, Portland, Oregon
ABSTRACT
A young man who presented initially with a ureteral stone was found to have toluene-induced renal tubular acidosis. Persistent toluene sniffing resulted in recurrent calculi and life-threatening hypokalemic paralysis. The pathophysiology, classification and treatment of renal tubular acidosis are discussed. Toluene (methylbenzene) is an aromatic hydrocarbon used extensively as an industrial solvent. Although it has not been an important factor in occupational illness 1 deliberate inhalation produces high levels of exposure and this practice has been associated with hepatomegaly, eosinophilia, abnormal urinary sediment, a wide range of neurologic abnormalities and sudden death. 2 • 3 Recently, Taher and associates found renal tubular acidosis in 2 patients who sniffed toluene. 4 Herein we report on an additional patient with toluene-induced renal tubular acidosis who presented with recurrent urinary calculi. To the best of our knowledge urolithiasis secondary to solvent inhalation has not been reported previously.
sisted with his habit and in September he was hospitalized with a history of vomiting, mild left lower quadrant pain and weakness in the lower extremities. He had been unable to walk for the previous 24 hours. Physical examination confirmed the presence of paraparesis with normal upper extremity strength. Laboratory data revealed a serum potassium of 1.5 mEq./1., chloride 109 mEq./1. and bicarbonate 14.6 mEq./1. Arterial blood gases on room air were pH 7.34, oxygen pressure 115 mm. Hg and carbon dioxide pressure 20 mm. Hg. The patient was admitted to the intensive care unit and potassium chloride was administered, resulting in rapid improvement in muscular strength. Serum potassium 3 days later was 4.6 mEq./1., chloride 105 mEq./1. and bicarbonate 28 mEq./1., although no bicarbonate had been administered. This was presumably owing to the reversibility of toluene-induced renal tubular acidosis upon withdrawal of the drug. When the patient was stable an IVP showed another left ureteral stone that was removed in N ovember, representing the fourth stone operation in 15 months.
CASE REPORT
J. H., a 23-year-old white man, began sniffing toluene on a regular basis when he was 18 years old. In July 1977 he presented with left flank pain and hematuria. An excretory urogram (IVP) showed a calculus within a left ureterocele, which was removed by transurethral meatotomy. In November a right pyelolithotomy was done and in August 1978 an obstructing stone was removed from the upper left ureter, with concomitant renal biopsy. Crystallographic analysis of this calculus revealed 70 per cent calcium phosphate, 15 per cent calcium oxalate and 15 per cent calcium carbonate. Histologic changes in the kidney were limited to variation in glomerular basement membrane thickness with some instances of fine splitting of the membrane on electron microscopy. Immunofluorescence studies for IgG, IgM, IgA, complement, fibrin and fibrinogen were negative. Admission serum chloride levels during this period of active stone formation ranged from 109 to 114 mEq./1., with serum bicarbonate levels of 13 to 23 mEq./1. The finding ofhyperchloremic acidosis in a stone former immediately suggests renal tubular acidosis. Further evaluation revealed a urine pH of 5.82 with a simultaneous arterial pH of 7.36. Bicarbonate loading studies revealed a normal tubular capacity for reabsorption of bicarbonate and the diagnosis was distal (classic, type I) renal tubular acidosis. Testing of family members ruled out a familial disorder. It was concluded that solvent sniffing was responsible for the urinary acidification defect and, thus, the recurrent stone formation. Despite our fmdings and recommendations the patient per-
DISCUSSION
Toluene inhalation can produce effects similar to that of diethyl ether anesthesia, with an initial excitatory phase followed by central nervous system depression. 5 The typical solvent sniffer is a boy between 13 and 15 years old from a family of middle or low income. Although tolerance and psychological dependence do occur there is no good evidence for true physical addiction. Most youngsters stop sniffmg as they grow older, making toluene habituation relatively rare among adults. Renal tubular acidosis represents an important clinical form of toluene toxicity, particularly in the habitual user. Although this complication has been described only recently earlier studies of solvent inhalation did not include determinations of serum electrolytes or urine pH. The mechanism of toluene renal toxicity is unknown. All patients reported to date have had distal renal tubular acidosis, which has been reversible upon withdrawal of the toxin. Renal tubular acidosis is actually a group of disorders with the common denominator of impaired hydrogen ion secretion in the renal tubule. The metabolic consequences of this defect depend on which portion of the tubule is affected. The proximal tubule is the primary site for bicarbonate reabsorption, reclaiming 85 per cent of the filtered bicarbonate in a process that is intimately linked to hydrogen ion secretion (table 1). Impaired hydrogen ion transport at this level effec-
Accepted for publication April 20, 1979.
89
90
KROEGER AND ASSOCIATES
tively limits the maximum capacity of the tubule to reabsorb bicarbonate, which appears in the urine. Serum bicarbonate levels decrease until the new threshold level is reached. At this point a steady state of metabolic acidosis exists. The proximal tubule can handle the decreased filtered load of bicarbonate and the distal tubule is not flooded with bicarbonate. Distal acidification and net acid excretion are possible. However, decreased hydrogen ion secretion in the distal nephron impairs bicarbonate regeneration (table 2). Decreasing urinary ammonium and titratable acid limits net acid excretion. When net acid excretion decreases below the fixed acid production of the body (normally 1 mEq./kg. per 24 hours) progressive acidosis ensues. 6 This brief discussion of the pathophysiology of renal tubular acidosis explains many of the clinical features that form the basis for diagnosis and classification of the disease (table 3). (Other forms of renal tubular acidosis have been described but they are beyond the scope of this report.) Although the diagnosis often is suggested by routine laboratory tests incomplete forms of distal renal tubular acidosis do not present with acidosis and require acid loading studies for diagnosis. Such investigations usually are prompted by a family history of renal tubular acidosis, history of nephrolithiasis or the presence of a condition known to be associated with secondary renal tubular acidosis. Table 4 lists some conditions associated with renal tubular acidosis likely to be seen by urologists. Current concepts of stone formation in renal tubular acidosis relate to altered metabolism of calcium and citrate in systemic acidosis. Chronic acid retention titrates alkaline bone salts, leading to mobilization of calcium and hypercalciuria. Direct effects of acidosis on the renal tubule also may have a role in increasing urinary calcium. 7 Acidosis per se reduces urinary citrate, a well known inhibitor of crystallization. Alkaline urine decreases the solubility of calcium salts, particularly calcium phosphate. Since toluene-induced renal tubular acidosis is reversible, it seems likely that only regular, long-term users will have urolithiasis. This pathogenetic scheme seems valid for patients with complete renal tubular acidosis but it does not explain why patients with incomplete renal tubular acidosis (not acidotic by definition) also tend to form stones. Also unexplained is the relative rarity of urolithiasis in proximal renal tubular acidosis. Thus, it seems likely that other metabolic abnormalities contribute to calculogenesis in this disease. In this regard recent evidence has suggested that some familial types of renal tubular acidosis are actually secondary to a primary disturbance of calcium metabolism. 8 Treatment of renal tubular acidosis with sodium bicarbonate or other alkalizing medications can be expected to decrease the rate of stone formation. Alkali should be given in amounts sufficient to produce a normal serum bicarbonate. In general, patients with distal renal tubular acidosis are relatively sensitive to alkalization, while proximal renal tubular acidosis patients
TABLE
3. Clinical features of renal tubular acidosis
Serum chloride Serum bicarbonate Serum potassium Anion gap Urine pH (a.m.) Urine pH (acid load) Stones Fanconi's syndrome Bicarbonate requirement
TABLE 4.
Proximal
Distal
High >15 mEq./1. Normal to low Normal Maybe <6.0 <5.3 Uncommon Common High
High <15 mEq,/1. Normal to low Normal >6.0 >5.3 Common Rare Low
Secondary renal tubular acidosis Proximal
Lowe's syndrome Amyloidosis Nephrotic syndrome Renal transplantation Medullary cystic disease
Outdated tetracycline Acetazolamide Mafenide Heavy metals
Distal Primary hyperparathyroidism Idiopathic hypercalciuria Medullary sponge kidney Pyelonephritis Obstructive uropathy
Renal transplantation Amphotericin B Lithium carbonate Toluene
require more medication. In secondary forms of renal tubular acidosis treatment of the underlying disease or removal of the toxin may ameliorate the tubular dysfunction, making bicarbonate therapy unnecessary. In these cases it is prudent to put the patient on the alkalizing agents until definite evidence for complete reversal of the defect is obtained. The acute complication of hypokalemic paralysis in our case has been reported previously. 4 Impaired sodium-hydrogen exchange in the distal nephron leads to sodium depletion, secondary hyperaldosteronism and potassium wasting. This results in the unusual combination of hypokalemia and acidosis. Proper management of these patients requires continuous monitoring of the electrocardiogram and frequent determinations of serum electrolytes while potassium chloride is being given. Administration of solutions containing bicarbonate or glucose will drive potassium into the intracellular compartment and exacerbate the hypokalemia. Therefore, no attempt is made to correct the acidosis until the serum potassium is at least 3.0 mEq./1. Respiratory insufficiency owing to ascending paralysis precipitated by bicarbonate administration in this setting has been reported. 9 A normal or elevated carbon dioxide pressure in the presence of metabolic acidosis may be an early clue to hypoventilation. While the high priority of potassium replacement deserves emphasis it also is important to indicate that rapid infusion of potassium to an acidotic patient can lead to dangerously high serum levels of potassium. Therefore, the proper approach depends on carefully titrating the patient with potassium and subsequently bicarbonate, and using the electrocardiogram and frequent determinations of serum electrolytes to monitor therapy.
1. Characteristics of bicarbonate reabsorption
85-90% proximal tubule 10-15% distal tubule 1 hydrogen ion secreted for each bicarbonate reabsorbed No net hydrogen ion excreted Carbonic anhydrase required
TABLE
TABLE
2. Characteristics of bicarbonate regeneration
Distal tubule and collecting duct 1 hydrogen ion excreted for each bicarbonate regenerated Net hydrogen ion excretion does occur Net acid excretion = urinary ammonium + titratable acid - bicarbonate Carbonic anhydrase not required
REFERENCES 1. von Oettingen, W. F., Neal, P.A. and Donahue, D. D.: Toxicity and
2. 3. 4. 5.
potential dangers of toluene; preliminary report. J.A.M.A., 118: 579, 1942. Press, E. and Done, A. K.: Solvent sniffing. Physiologic effects and community control measures for intoxication from the intentional inhalation of organic solvents. I. Pediatrics, 39: 451, 1967. Press, E. and Done, A. K.: Solvent sniffing. Physiologic effects and community control measures for intoxication from the intentional inhalation of organic solvents. II. Pediatrics, 39: 611, 1967. Taher, S. M., Anderson, R. J., McCartney, R., Popovtzer, M. M. and Schrier, R. N.: Renal tubular acidosis associated with toluene "sniffing". New Engl. J. Med., 290: 765, 1974. Wyse, D. G.: Deliberate inhalation of volatile hydrocarbons: a
RECURRENT
Ass. ,l., and G-oidhergJ
71, 1973. · Renal tubular acidosis:
and treatrnent" DJ\/1, fL
ASSOCIATED 'VVITl-I TOLUENE S~NIFFIN'G
8, Buckalew, Vo l\/1.) Jr., Purvis Nt L.; Shulman, :rvI. G. Herndon, C. 1
1
N. and Rudman, D.: Hereditary renal tubular acidosis. Tv1edicine, 53: 229, 1974.
J. D. and iieal loop