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Therapeutic approach to pancreatic extract-induced hyperuricosuria in cystic fibrosis
February 1977
302
The Journal o f P E D I A T R I C S
Therapeutic approach to pancreatic extract-induced hyperuricosuria in cystic fibrosis The relationship between the dosage of pancreatic extract and the excretion of uric acid was investigated in 29 patients with cystic .fiblvsis and exocrine pancreatic insufficiency. Urinary excretion of uric acid was normal in patients receiving small doses of pancreatic extracts and abnormally high in those receiving large amounts. In the latter group, normouricosttria was achieved by reducing the dose o/' pancreatic extract. Normal stool patterns and adequate weight gains were preserved by a diet modilication that was well accepted by the patients. To eliminate the potential renal consequences of hvperurieosuria, it seems appropriate to control the need for increasing amounts of pancreatic enzymes by limiting the dietary intake of fitt and maintaining a positive calorie and nitrogen balance with high intake of protein and carbohydrates and supplementation with medium-chain trig!vcerides.
Sanda Nousia-Arvanitakis, M.D.,* F. Bruder Stapleton, M.D., Michael A. Linshaw, M.D., and J a m e s Kennedy, M.D., K a n s a s City, Kan.
ALTHOUGH EXOCRINE pancreatic insufficiency in
cystic fibrosis has been treated with pancreatic enzyme replacement for over three decades, a standard dosage for pancreatic extracts has not been established.' Adequate replacement has been determined by stool and weight patterns.'-' Frequently, strenuous efforts to achieve completely normal stool patterns lead to large dosages of pancreatic extracts, although fat absorption rarely returns to normal." Hyperuricosuria has recently been shown to be a complication of high doses of purine-rich pancreatic extracts in patients with CF. ' Such hyperuricosuria might lead to the development of renal complications such as intratubular precipitation of uric acid and crystal nephropathy? The present study was undertaken to determine whether dietary manipulation in patients with CF might allow reduction of pancreatic extract dosage to levels sufficient to eliminate hyperuricosuria without interfering
From the Departments of Pediatrics and Medicine, University of Kansas Medical Center, and the Medical Services. Veteran's Administration Hospital *Reprint address: Department of Pediatric,v, Univervit.v of Kansas Medical Center, 39th Street at Rainbow Blvd.. Kansas City, K S 66103.
VoL 90, No. 2, pp. 302-305
with adequate weight gain, stool pattern, or the physical well being of the patients.
PATIENTS AND METHODS Twenty-nine patients attending the CF clinic at the University of Kansas Medical Center were selected at random. The diagnosis of CF was confirmed by sweat chloride levels _> 60 mEq/l as determined by' pilocarpine iontophoresis and quantitative analysis for sweat electroAbbreviations used CF: cystic fibrosis LCT: long-chain triglycerides MCT: medium-chain triglycerides KUMC: University of Kansas Medical Center lytes. All the patients were on unrestricted diets and were receiving pancrelipase (Cotazym. Organon, Inc.) or pancreatin (Viokase. VioBin Corp.). as well as approved doses of vitamins. None of the patients was given any drugs known to interfere with uric acid metabolism. Their CF symptoms were under control and their prognostic scores ranged from 48 to 97 points." On the basis of the dosage of pancreatic extract, the patients were divided into two groups. Group 1 consisted of 17 patients whose doses of pancreatic extract ranged from 6.5 to 35 gm daily.
Volume 90 Number 2
tlyperuricosuria in cystic fibrosis
700
Table I. Relationship between the dosage of pancreatic extract and the urinary excretion of uric acid in 16 patients with cystic fibrosis
High dosage Dosage* Patient No.
(units /day)
1 2 3 4 5 6 7 8 9 I0 II 12 13 14 15 16
50 30 60 36 18 18 36 34 35 98 40 30 46 46 38 18
Uric acid (mg/ 24 hr) 478 580 785 966 428 745 541 719 655 485 784 439 832 495 362 221 595 • 199t
Dosage (units /dqv) 9 10 10
10 10 4 9 18 6 10 18
10 12 12 12 5
Urie acid (mg/ 24 hr) 259 267 418 437 290 462 297 376 268 368 574 255 632 278 316 226 358 • l19t
*Cotazym (364 mg capsules) or Viokase (344 mg tablets). "~Mean _+ SD.
Group 2 consisted of 12 patients whose doses ranged from 1.5 to 3.5 gm daily. Urinary uric acid and creatinine excretions were determined on carefully timed 24-hour urine samples collected at home. Serum was obtained during the timed urine collection for determinations of uric acid and creatinine values. Fresh samples of urine were obtained for analysis. Sixteen patients from Group 1 agreed to be evaluated further. Steatorrhea, as defined by fecal fat excretion _> 5 gm/day, had been present before starting pancreatic enzyme replacement. Exocrine pancreatic insufficiency was confirmed by the absence or marked decrease of tipase ( < 300 IU/kg) and tryptic activities ( < 300 #g/kg) in the duodenal fluid. Pancreatic enzyme replacement was reduced to 25% of the initial dose. Concomitantly, each patient was placed on a low-fat diet that included 30 to 40 gm of long-chain triglycerides supplemented with 10 to 20 gm of medium-chain triglycerides daily. The intake of fat represented 15% of the total daily intake of nutrients. A high intake of protein (6 gm/kg) and carbohydrates (20 gm/kg) represented 20 and 65% of the total daily intake, respectively. The diet provided 125 kcal/kg daily. Three months later, determination of the urinary excretion of uric acid was repeated.
()= NUMBER OF PTs H = HIGH DOSE L = LOW DOSE
600
Low dosage
iiiil
:':':':-fir '.'.'.'4
5OO (D
~ 400
o
P
...-...-.... ......-...
,..t ,..t
............4 .'.'.-.'/." ......-..., ............
' ' t ,.. t , . . t
' , . ' . . . '.'.'.'.',', 9...'.'.', 9.'.'.'.',L 9.'.'.'.'.L '.','.','., 9.'.'.'.'.',
: : : : : : :
MEAN+SEM
,.......,...,t ..,.........4 ..,.........4 ...-.-.-.,,....t ...-....,.....t
~J rr
z
303
E 500
E"
:i:i:i(17):i:i:t ::::::::H:r
...-.-.....9 -. t .....--... - . t , . . . . . . . . . . t ......... 9 9 9 9 t .-.-..-,.., . . t
:D
200
- . . - . - . . '.'.-..'.-
9/ . . . - . -
: :
ii iii!r ,,,
9 ........-.-,,
".'.'....','.'.L 9 .,...-..., 9 .. 9 9 -.-...... 9 .,......,.....-.-.-...... ,....... - - ......,....,... 9 .......-...-,. 9 ,.......,....,..-
.., 9
9
- - i ",L'.'.'.'.'.'.'."
I00
i>>ii'i'i'i'i'i'~ ..... . . . . . . . . . - - - t . . . . . . . . . . . - t .-...,....,....t . - . , . . . . . . . . . . t -
0
-.-.,....
........- 9 - 9 1 .-.-.., .... , . t . . . . . . . . . . i
PANCREATIC E X T R A C T
9 ......,......... 9 .............,.., 9 ..,.....,....,.,
9 ...
9 ...,......
9 .. ,.....-........ 9 ..-.. 9 -,-......
DOSAGE
Fig. 1. Comparison of the urinary uric acid excretion of patients receiving large amounts to that of patients on small doses of pancreatic extracs.
Uric acid determinations were carried out using an automated spectrophotometric uricase method? Hyperuricosuria was defined by the following normal values: (1) adult levels after correcting body surface in our patients to 1.73 m-' ( < 600 mg/24 hours) ~ and (2) levels of normal children (7.7 to 17.7 mg/kg/24 hours)Y Adequacy of pancreatic enzyme replacement was determined by stool pattern and weight changes for a period of six months following the dietary manipulation and the reduction in the dose of enzyme. Statistical analysis was carried out by Student's t test. Since one patient was symptomatic with dysuria and uric acid crystalluriaJ we looked for evidence of interstitial nephropathy in the hospital records of 22 patients with CF who died at the University of Kansas Medical Center during the period 1965 to 1975. RESULTS Of the 29 patients studied, Group l (17 patients) who received >_ 6.5 gm of pancreatic extract daily had significantly higher urinary uric acid excretion than members of Group 2 (12 patients) on daily dosages _< 3.5 gm (Fig. 1). Sixteen patients from Group 1 had hyperuricosuria. Eleven patients from Group 2 had normal urinary uric
304
Nousia-A rvanitakis et al.
acid excretion, Aside from one child in Group 1 who had uric acid crystals in his urine, urinalyses were normal in the remaining children. Creatinine clearances were normal in members of the two groups. At the time of re-evaluation (three months later), the 16 hyperuricosuric patients of Group 1 had been receiving the modified diet and doses of pancreatic extract comparable to those of Group 2. Urinary excretion of uric acid had decreased markedly in 15 patients (p < 0.001), was normal in 12 (Table I), and was comparable to that of patients in Group 2. Creatinine clearances did not change. None of the patients developed fatty diarrhea or lost weight during a six-month observation period. The stool pattern improved in 14 and remained stable in two of the 16 patients. The weight of 12 patients remained on the initial centile curve, four patients moved to the next higher, and no patient declined to a lower centile curve. Reviewing the hospital records of patients with CF who died at KUMC during the past decade revealed that five of 22 patients had been receiving > 6.5 gm of pancreatic extracts daily. In two of the five patients, clear evidence of interstitial renal fibrosis was detected at postmortem. Nonspecific renal tubular changes were described in the other three patients. The kidneys were normal in 17 patients who had been on < 3.5 gm of pancreatic extract daily. DISCUSSION
Renal excretion of uric acid in man is regulated by glomerular filtration, tubular reabsorption, and tubular secretion. 1~ " Patients with CF as a group have normal glomerular filtrationY-' Hyperuricosuria in these patients appears to be directly related to the ingestion of pancreatic extracts, known to be rich in readily absorbable uric acid precursors. + Renal complications of hyperuricosuria have not been reported in CF. It is possible that episodes of uric acid crystalluria may be subclinical as well as brief and, therefore, may have been overlooked Our finding of interstitial renal fibrosis in autopsy specimens of two patients receiving large amounts of pancreatic extract may have been related to one or more episodes of crystal deposition within the kidney leading to permanent changes. This speculation is supported by recent animal experiments,':" +4 which have shown that intratubular crystal deposits can cause intraluminal obstruction and breakdown of the integrity of the basement membrane allowing passage of crystals into the interstitium. The consequent interstitial inflammation may persist long after the crystals are no longer demonstrable and lead to progressive fibrosis. Factors affecting uric acid sohrbi{ity
The Journal of Pediatrics February 1977
in patients with CF have been discussed previously.' Specifically, water clearance studies suggest that soditun delivery past the proximal tubule is decreased. A lower sodium content might protect these patients from intratubular uric acid precipitation and might in part explain the low incidence of renal complications. Alternatively, the clinical expression of slowly progressive crystal nephropathy may be prevented by limited life span. To eliminate the potential renal consequences of hyperuricosuria, it seems appropriate to control the need for increasing amounts of pancreatic enzymes by moderately limiting intake of LCT and supplementing the diet with MCT. This would minimize offensive stools, rectal prolapse, and abdominal discomfort: it would also improve well being and social acceptability.':' A high intake of protein and carbohydrates along with the MCT as a concentrated source of calories would provide an adequate caloric supply, even in the face of minor degrees of steatorrhea or azotorrhea, Perhaps the current management of exocrine pancreatic insufficiency in CF needs revision. Rather than accomplish a completely normal stool pattern, the goals of pancreatic enzyme replacement should be to reduce the troubles associated with fatty diarrhea, restore body weight, and promote a sense of wetl being. The authors are indebted to Dr. F. E. Cuppage for reviewing autopsy material and Mrs. Susan LeClaire for secretarial assistance. REFERENCES 1.
2.
3.
4.
5. 6.
7.
8.
9+
Littman A, and Hanscon DH: Pancreatic extracts. N Engl J Med 281:201, 1969. SchwachmanH. and Khaw K: Cystic fibrosis, in Shirkey HC, editor: Pediatric therapy, St. Louis, 1975. The CV Mosby Company, p 651. HarrisR, Norman AP, and Payne WW: Effect of pancreatic therapy on fat absorption and nitrogen retention in children with fibrocystic disease of the pancreas, Arch Dis Child 30:424. 1955. Stapleton FB, Kennedy J, Nousia-Arvanitakis S. and Linshaw MA: Hyperuricosuria due to high dose pancreatic extract therapy in cystic fibrosis. N Engl J Med 295:246, 1976. Emmerson B. and Row PG: An evolution of the pathogenesis of the gouty kidney, Kidney lnt 8:65, 1975. TaussigLM. Kattwinkel J, Friedwald WT. and di Sant'Agnese PA: A new prognostic score and clinical evaluation system for cystic fibrosis, J PEDIATR82:380, 1973. Henry RJ: Clinical chemistry+ principles and techniques. New York+ 1964. Hoeber Medical Division. Harper & Row. Publishers, p 283. Seegmiller JE: Serum uric acid, in Cohen AS, editor: Laboratory diagnostic procedures in the rheumatic diseases. Boston, 1967, Little Brown & Company. p 216. Michener WM: Hyperuricemia and mental retardation. Am J Dis Child 113:195, 1967.
Volume 90 Number 2
10. Gutman AB, and Yu TF: A three-component system for regulation of renal excretion of uric acid in man. Trans Assoc Am Physicians 74:353. 1961. 11. Holmes EW, Kelley WN. and Wyngaarden JB: The kidney and uric acid excretion in man. Kidney lnt 2:115, 1972. 12. Robson AM. Tateishi S, Ingelfinger J, Strominger DB. and Klahr S: Renal function in patients with cystic fibrosis, J PED1ATR79:42, 1971,
H)'peruricosuria in cystic fibrosis
13.
305
Farebrother DA. Hatfield P. Simmonds HA et al: Experimental crystal nephropathy, Clin Nephrol 4:243. 1975. 14. Spencer HW, Yarger WE, and Robinson RR: Alterations of renal function during dietary-induced hyperuricemia in the rat. Kidney Int 9:489, 1976. 15. Gracey M, Burke V, and Anderson CM: Medium chain triglycerides in paediatric practice. Arch Dis Child 45:445, 1970.
302
The Journal o f P E D I A T R I C S
Therapeutic approach to pancreatic extract-induced hyperuricosuria in cystic fibrosis The relationship between the dosage of pancreatic extract and the excretion of uric acid was investigated in 29 patients with cystic .fiblvsis and exocrine pancreatic insufficiency. Urinary excretion of uric acid was normal in patients receiving small doses of pancreatic extracts and abnormally high in those receiving large amounts. In the latter group, normouricosttria was achieved by reducing the dose o/' pancreatic extract. Normal stool patterns and adequate weight gains were preserved by a diet modilication that was well accepted by the patients. To eliminate the potential renal consequences of hvperurieosuria, it seems appropriate to control the need for increasing amounts of pancreatic enzymes by limiting the dietary intake of fitt and maintaining a positive calorie and nitrogen balance with high intake of protein and carbohydrates and supplementation with medium-chain trig!vcerides.
Sanda Nousia-Arvanitakis, M.D.,* F. Bruder Stapleton, M.D., Michael A. Linshaw, M.D., and J a m e s Kennedy, M.D., K a n s a s City, Kan.
ALTHOUGH EXOCRINE pancreatic insufficiency in
cystic fibrosis has been treated with pancreatic enzyme replacement for over three decades, a standard dosage for pancreatic extracts has not been established.' Adequate replacement has been determined by stool and weight patterns.'-' Frequently, strenuous efforts to achieve completely normal stool patterns lead to large dosages of pancreatic extracts, although fat absorption rarely returns to normal." Hyperuricosuria has recently been shown to be a complication of high doses of purine-rich pancreatic extracts in patients with CF. ' Such hyperuricosuria might lead to the development of renal complications such as intratubular precipitation of uric acid and crystal nephropathy? The present study was undertaken to determine whether dietary manipulation in patients with CF might allow reduction of pancreatic extract dosage to levels sufficient to eliminate hyperuricosuria without interfering
From the Departments of Pediatrics and Medicine, University of Kansas Medical Center, and the Medical Services. Veteran's Administration Hospital *Reprint address: Department of Pediatric,v, Univervit.v of Kansas Medical Center, 39th Street at Rainbow Blvd.. Kansas City, K S 66103.
VoL 90, No. 2, pp. 302-305
with adequate weight gain, stool pattern, or the physical well being of the patients.
PATIENTS AND METHODS Twenty-nine patients attending the CF clinic at the University of Kansas Medical Center were selected at random. The diagnosis of CF was confirmed by sweat chloride levels _> 60 mEq/l as determined by' pilocarpine iontophoresis and quantitative analysis for sweat electroAbbreviations used CF: cystic fibrosis LCT: long-chain triglycerides MCT: medium-chain triglycerides KUMC: University of Kansas Medical Center lytes. All the patients were on unrestricted diets and were receiving pancrelipase (Cotazym. Organon, Inc.) or pancreatin (Viokase. VioBin Corp.). as well as approved doses of vitamins. None of the patients was given any drugs known to interfere with uric acid metabolism. Their CF symptoms were under control and their prognostic scores ranged from 48 to 97 points." On the basis of the dosage of pancreatic extract, the patients were divided into two groups. Group 1 consisted of 17 patients whose doses of pancreatic extract ranged from 6.5 to 35 gm daily.
Volume 90 Number 2
tlyperuricosuria in cystic fibrosis
700
Table I. Relationship between the dosage of pancreatic extract and the urinary excretion of uric acid in 16 patients with cystic fibrosis
High dosage Dosage* Patient No.
(units /day)
1 2 3 4 5 6 7 8 9 I0 II 12 13 14 15 16
50 30 60 36 18 18 36 34 35 98 40 30 46 46 38 18
Uric acid (mg/ 24 hr) 478 580 785 966 428 745 541 719 655 485 784 439 832 495 362 221 595 • 199t
Dosage (units /dqv) 9 10 10
10 10 4 9 18 6 10 18
10 12 12 12 5
Urie acid (mg/ 24 hr) 259 267 418 437 290 462 297 376 268 368 574 255 632 278 316 226 358 • l19t
*Cotazym (364 mg capsules) or Viokase (344 mg tablets). "~Mean _+ SD.
Group 2 consisted of 12 patients whose doses ranged from 1.5 to 3.5 gm daily. Urinary uric acid and creatinine excretions were determined on carefully timed 24-hour urine samples collected at home. Serum was obtained during the timed urine collection for determinations of uric acid and creatinine values. Fresh samples of urine were obtained for analysis. Sixteen patients from Group 1 agreed to be evaluated further. Steatorrhea, as defined by fecal fat excretion _> 5 gm/day, had been present before starting pancreatic enzyme replacement. Exocrine pancreatic insufficiency was confirmed by the absence or marked decrease of tipase ( < 300 IU/kg) and tryptic activities ( < 300 #g/kg) in the duodenal fluid. Pancreatic enzyme replacement was reduced to 25% of the initial dose. Concomitantly, each patient was placed on a low-fat diet that included 30 to 40 gm of long-chain triglycerides supplemented with 10 to 20 gm of medium-chain triglycerides daily. The intake of fat represented 15% of the total daily intake of nutrients. A high intake of protein (6 gm/kg) and carbohydrates (20 gm/kg) represented 20 and 65% of the total daily intake, respectively. The diet provided 125 kcal/kg daily. Three months later, determination of the urinary excretion of uric acid was repeated.
()= NUMBER OF PTs H = HIGH DOSE L = LOW DOSE
600
Low dosage
iiiil
:':':':-fir '.'.'.'4
5OO (D
~ 400
o
P
...-...-.... ......-...
,..t ,..t
............4 .'.'.-.'/." ......-..., ............
' ' t ,.. t , . . t
' , . ' . . . '.'.'.'.',', 9...'.'.', 9.'.'.'.',L 9.'.'.'.'.L '.','.','., 9.'.'.'.'.',
: : : : : : :
MEAN+SEM
,.......,...,t ..,.........4 ..,.........4 ...-.-.-.,,....t ...-....,.....t
~J rr
z
303
E 500
E"
:i:i:i(17):i:i:t ::::::::H:r
...-.-.....9 -. t .....--... - . t , . . . . . . . . . . t ......... 9 9 9 9 t .-.-..-,.., . . t
:D
200
- . . - . - . . '.'.-..'.-
9/ . . . - . -
: :
ii iii!r ,,,
9 ........-.-,,
".'.'....','.'.L 9 .,...-..., 9 .. 9 9 -.-...... 9 .,......,.....-.-.-...... ,....... - - ......,....,... 9 .......-...-,. 9 ,.......,....,..-
.., 9
9
- - i ",L'.'.'.'.'.'.'."
I00
i>>ii'i'i'i'i'i'~ ..... . . . . . . . . . - - - t . . . . . . . . . . . - t .-...,....,....t . - . , . . . . . . . . . . t -
0
-.-.,....
........- 9 - 9 1 .-.-.., .... , . t . . . . . . . . . . i
PANCREATIC E X T R A C T
9 ......,......... 9 .............,.., 9 ..,.....,....,.,
9 ...
9 ...,......
9 .. ,.....-........ 9 ..-.. 9 -,-......
DOSAGE
Fig. 1. Comparison of the urinary uric acid excretion of patients receiving large amounts to that of patients on small doses of pancreatic extracs.
Uric acid determinations were carried out using an automated spectrophotometric uricase method? Hyperuricosuria was defined by the following normal values: (1) adult levels after correcting body surface in our patients to 1.73 m-' ( < 600 mg/24 hours) ~ and (2) levels of normal children (7.7 to 17.7 mg/kg/24 hours)Y Adequacy of pancreatic enzyme replacement was determined by stool pattern and weight changes for a period of six months following the dietary manipulation and the reduction in the dose of enzyme. Statistical analysis was carried out by Student's t test. Since one patient was symptomatic with dysuria and uric acid crystalluriaJ we looked for evidence of interstitial nephropathy in the hospital records of 22 patients with CF who died at the University of Kansas Medical Center during the period 1965 to 1975. RESULTS Of the 29 patients studied, Group l (17 patients) who received >_ 6.5 gm of pancreatic extract daily had significantly higher urinary uric acid excretion than members of Group 2 (12 patients) on daily dosages _< 3.5 gm (Fig. 1). Sixteen patients from Group 1 had hyperuricosuria. Eleven patients from Group 2 had normal urinary uric
304
Nousia-A rvanitakis et al.
acid excretion, Aside from one child in Group 1 who had uric acid crystals in his urine, urinalyses were normal in the remaining children. Creatinine clearances were normal in members of the two groups. At the time of re-evaluation (three months later), the 16 hyperuricosuric patients of Group 1 had been receiving the modified diet and doses of pancreatic extract comparable to those of Group 2. Urinary excretion of uric acid had decreased markedly in 15 patients (p < 0.001), was normal in 12 (Table I), and was comparable to that of patients in Group 2. Creatinine clearances did not change. None of the patients developed fatty diarrhea or lost weight during a six-month observation period. The stool pattern improved in 14 and remained stable in two of the 16 patients. The weight of 12 patients remained on the initial centile curve, four patients moved to the next higher, and no patient declined to a lower centile curve. Reviewing the hospital records of patients with CF who died at KUMC during the past decade revealed that five of 22 patients had been receiving > 6.5 gm of pancreatic extracts daily. In two of the five patients, clear evidence of interstitial renal fibrosis was detected at postmortem. Nonspecific renal tubular changes were described in the other three patients. The kidneys were normal in 17 patients who had been on < 3.5 gm of pancreatic extract daily. DISCUSSION
Renal excretion of uric acid in man is regulated by glomerular filtration, tubular reabsorption, and tubular secretion. 1~ " Patients with CF as a group have normal glomerular filtrationY-' Hyperuricosuria in these patients appears to be directly related to the ingestion of pancreatic extracts, known to be rich in readily absorbable uric acid precursors. + Renal complications of hyperuricosuria have not been reported in CF. It is possible that episodes of uric acid crystalluria may be subclinical as well as brief and, therefore, may have been overlooked Our finding of interstitial renal fibrosis in autopsy specimens of two patients receiving large amounts of pancreatic extract may have been related to one or more episodes of crystal deposition within the kidney leading to permanent changes. This speculation is supported by recent animal experiments,':" +4 which have shown that intratubular crystal deposits can cause intraluminal obstruction and breakdown of the integrity of the basement membrane allowing passage of crystals into the interstitium. The consequent interstitial inflammation may persist long after the crystals are no longer demonstrable and lead to progressive fibrosis. Factors affecting uric acid sohrbi{ity
The Journal of Pediatrics February 1977
in patients with CF have been discussed previously.' Specifically, water clearance studies suggest that soditun delivery past the proximal tubule is decreased. A lower sodium content might protect these patients from intratubular uric acid precipitation and might in part explain the low incidence of renal complications. Alternatively, the clinical expression of slowly progressive crystal nephropathy may be prevented by limited life span. To eliminate the potential renal consequences of hyperuricosuria, it seems appropriate to control the need for increasing amounts of pancreatic enzymes by moderately limiting intake of LCT and supplementing the diet with MCT. This would minimize offensive stools, rectal prolapse, and abdominal discomfort: it would also improve well being and social acceptability.':' A high intake of protein and carbohydrates along with the MCT as a concentrated source of calories would provide an adequate caloric supply, even in the face of minor degrees of steatorrhea or azotorrhea, Perhaps the current management of exocrine pancreatic insufficiency in CF needs revision. Rather than accomplish a completely normal stool pattern, the goals of pancreatic enzyme replacement should be to reduce the troubles associated with fatty diarrhea, restore body weight, and promote a sense of wetl being. The authors are indebted to Dr. F. E. Cuppage for reviewing autopsy material and Mrs. Susan LeClaire for secretarial assistance. REFERENCES 1.
2.
3.
4.
5. 6.
7.
8.
9+
Littman A, and Hanscon DH: Pancreatic extracts. N Engl J Med 281:201, 1969. SchwachmanH. and Khaw K: Cystic fibrosis, in Shirkey HC, editor: Pediatric therapy, St. Louis, 1975. The CV Mosby Company, p 651. HarrisR, Norman AP, and Payne WW: Effect of pancreatic therapy on fat absorption and nitrogen retention in children with fibrocystic disease of the pancreas, Arch Dis Child 30:424. 1955. Stapleton FB, Kennedy J, Nousia-Arvanitakis S. and Linshaw MA: Hyperuricosuria due to high dose pancreatic extract therapy in cystic fibrosis. N Engl J Med 295:246, 1976. Emmerson B. and Row PG: An evolution of the pathogenesis of the gouty kidney, Kidney lnt 8:65, 1975. TaussigLM. Kattwinkel J, Friedwald WT. and di Sant'Agnese PA: A new prognostic score and clinical evaluation system for cystic fibrosis, J PEDIATR82:380, 1973. Henry RJ: Clinical chemistry+ principles and techniques. New York+ 1964. Hoeber Medical Division. Harper & Row. Publishers, p 283. Seegmiller JE: Serum uric acid, in Cohen AS, editor: Laboratory diagnostic procedures in the rheumatic diseases. Boston, 1967, Little Brown & Company. p 216. Michener WM: Hyperuricemia and mental retardation. Am J Dis Child 113:195, 1967.
Volume 90 Number 2
10. Gutman AB, and Yu TF: A three-component system for regulation of renal excretion of uric acid in man. Trans Assoc Am Physicians 74:353. 1961. 11. Holmes EW, Kelley WN. and Wyngaarden JB: The kidney and uric acid excretion in man. Kidney lnt 2:115, 1972. 12. Robson AM. Tateishi S, Ingelfinger J, Strominger DB. and Klahr S: Renal function in patients with cystic fibrosis, J PED1ATR79:42, 1971,
H)'peruricosuria in cystic fibrosis
13.
305
Farebrother DA. Hatfield P. Simmonds HA et al: Experimental crystal nephropathy, Clin Nephrol 4:243. 1975. 14. Spencer HW, Yarger WE, and Robinson RR: Alterations of renal function during dietary-induced hyperuricemia in the rat. Kidney Int 9:489, 1976. 15. Gracey M, Burke V, and Anderson CM: Medium chain triglycerides in paediatric practice. Arch Dis Child 45:445, 1970.