Pediatric Nephrology
Pediatr Nephrol (1990) 4:166-168 9 IPNA 1990
Brief report Serum interleukin-2 levels in a patient with focal segmental glomerulosclerosis Relationship to clinical course and cyclosporin A therapy Stanley C. Jordan, Uwe Querfeld, Mieko Toyoda, and John Prehn Pediatric Renal Immunology Laboratory, Ahmanson, Pediatric Center, Cedars-Sinai Medical Center, Los Angeles, California, USA Received December 29, 1988; accepted June 1, 1989
Abstract. We describe a patient with steroid-resistant focal segmental glomerulosclerosis (FSGS) whose serum interleukin-2 (IL-2) levels were markedly elevated in association with disease activity. With cyclosporin A (CsA) treatment, the patient entered remission and serum IL-2 fell to undetectable levels. After cessation of CsA, the patient relapsed and the serum IL-2 levels were elevated again. Reinstitution of CsA therapy was followed by a partial remission and disappearance of detectable serum IL-2 levels. Key words: Interleukin-2 -
Focal segmental glomerulosclerosis - Cyclosporin A
Introduction Dysfunctional T-cell activation is thought to be important in the genesis of both focal segmental glomerulosclerosis (FSGS) and minimal change nephrotic syndrome (MCNS) [1-6]. Corticosteroids and cytotoxic drugs readily induce remissions of proteinuria in MCNS, although only 10%-20% of patients with FSGS respond [6]. The pathogenesis of both conditions remains unclear, but the nephrotic range proteinuria may result from a loss of anionic charge on the glomerular basement membrane [1] mediated by abnormal lymphokine(s) produced by activated lymphocytes. Schnaper and Aunne [5] recently identified a lymphokine in MCNS patients, designated sol-
Offprint requests to: S. C. Jordan, Cedars-Sinai Medical Center, 8700 Beverly Boulevard, Los Angeles, CA 90048, USA
uble immune response suppressor factor (SIRS). It was present in all steroid-responsive MCNS patients tested, but was no longer detectable after steroid-induced remissions. Neither the mechanism(s) responsible for dysfunctional T-cell activation in MCNS or FSGS, nor how lymphokines may mediate these disorders [1-6], however, have been delineated by these previous studies. Cyclosporin A (CsA) is a potent immunosuppressive agent which modifies T-cell functions [8, 9], inhibiting mitogen- and antigen-induced T-cell proliferation, IL-2 production and gamma interferon production [8-10]. It may be effective in treating steroid-resistant MCNS and FSGS [1-3, 6] although the mechanism is unknown. IL-2 is a lymphokine required for the initiation and maintenance of many normal T- and B-cell functions. IL-2 infusions have been given to humans with malignancies, and have been associated with edema formation, salt retention and hypoalbuminemia [11]; however, there have been no reports of IL-2 infusions causing albuminuria. In this report, we describe a patient with steroid-resistant FSGS whose serum IL-2 levels were elevated during two periods of disease activity and fell during remissions following treatment with CsA.
Case report A 14-month-old Hispanic male was admitted to CSMC with generalized edema, ascites, hypertension, and proteinuria. The child's past medical history was significant for recurrent urinary tract infections, otitis media, and failure to thrive. There was no evidence of infection at the time of presentation. The patient's height, weight, and head circumference were all below the 5th percentile for age. Pertinent initial laboratory values showed: serum albumin of 1.0 g/dl, urine protein of 20 g/day, normal C3, C4, CH 50, ASO and antinuclear anti-
167 body titers. The patient was treated with a salt-restricted diet, salt-poor albumin (25%) infusions, methylprednisolone (2 mg/ kg per day) and intravenous gamma globulin for a serum IgG level below 100 mg/dl. The patient did not respond to this treatment and remained hospitalized for approximately 1 month. At that time a renal biopsy was performed and revealed FSGS. Subsequently steroid dosage was tapered and therapy with CsA (3.5 mg/kg twice daily) initiated. Within 10 days of initiation of CsA therapy, the patient improved and remission occurred after 2.5 weeks of CsA therapy. CsA therapy was continued for 2 months and the patient was tapered off the drug (duration of therapy: 15 weeks). Two weeks after discontinuation of CsA therapy, the patient relapsed. He was treated initially with methylprednisolone (2 mg/kg per day) for 3 weeks, but failed to respond. Steroid therapy was again tapered and CsA was initiated at a dose of 5 mg/kg per day. Proteinuria decreased gradually over the next month. The patient is currently free of edema with 1 + proteinuria and no hypertension.
Materials and methods IL-2 assay. Weekly serum samples were obtained from the patient and normal controls, and were analyzed for IL-2 using a modified enzyme-linked immunosorbent assay (ELISA) system (Genzyme, Boston, Mass.). Results
D a t a f o r m the entire t r e a t m e n t course are s h o w n in Fig. 1. After 4 weeks o f daily p r e d n i s o l o n e thera p y (2 m g / k g per day), the patient's serum alb u m i n was 1 g / d l , a n d the serum IL-2 level was 16 u n i t s / m l ( n o r m a l : < 1 u n i t / m l ) . After the initiation o f CsA t h e r a p y a n d tapering o f the steroid dosage the patient rapidly d e v e l o p e d a clinical a n d biochemical remission. This was a c c o m p a nied by a rapid and steady weekly decrease in the serum IL-2 level t o w a r d s normal. T h e initial urine protein excretion was greater than 20 g / d a y , and did not r e s p o n d to steroid therapy. Two weeks after starting CsA therapy, the urine protein excretion was greater than 2 g / d a y and 200 m g / d a y at 4 weeks. T r e a t m e n t with CsA was c o n t i n u e d for 4
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15
3
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10
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~
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. . . . . . . . Dec Jan Feb Mar Apr May Jun Jul
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2
15 weeks. Within 3 weeks o f cessation o f CsA therapy, and 1 week prior to d e v e l o p m e n t o f a full biochemical and clinical relapse, the patient's serum IL-2 level was 20.0 u n i t s / m l . Discussion
This is the first study to d e m o n s t r a t e a b n o r m a l levels o f l y m p h o k i n e s in the serum o f patients with either M C N S or FSGS. Our study was carried out to d e t e r m i n e if elevated serum IL-2 levels might serve as a m a r k e r for dysfunctional T-cell activation in n e p h r o t i c s y n d r o m e and if levels would r e s p o n d to t r e a t m e n t with the T-cell inhibitory drug CsA. Although this r e p o r t details our experience with only o n e patient, we believe these observations are o f interest and m a y be relevant to determining which steroid-resistant patients might r e s p o n d to CsA. Serum and urine levels o f IL-2 have p r o v e n useful in diagnosing allograft rejection, a n o t h e r condition where a b n o r m a l T-cell activation occurs [12]. These investigators also showed that patients with CsA toxicity had u n d e t e c t a b l e levels o f IL-2 in their urine and serum. Tejani et al. [6] r e p o r t e d that pre-therapy IL-2 p r o d u c t i o n by p e r i p h e r a l b l o o d m o n o n u clear cells was s u p r a n o r m a l in six o f eight F S G S patients who r e s p o n d e d to CsA. Published reports o f CsA t r e a t m e n t for steroid-resistant M C N S a n d F S G S have shown variable results; however, the patients who derived the most benefit were treated within 6 m o n t h s o f diagnosis [ 1 - 4 , 6]. The relationship between T-cell activation, l y m p h o k i n e s and n e p h r o t i c s y n d r o m e is obscure, but the response o f patients with M C N S and F S G S to agents k n o w n to m o d i f y T-cell functions (steroids and CsA) suggests that this relationship is a strong one. Since IL-2 p r o d u c t i o n is essential for T-cell activation and proliferation, detection o f IL-2 in biological fluids should be a g o o d marker for T-cell activation. H o w e v e r , one must always be cautious, since c o n c o m i t a n t infection could also increase IL-2 levels. T h e patient presented here showed a g o o d correlation between s y m p t o m s o f the n e p h r o t i c s y n d r o m e , IL-2 levels, a n d response o f b o t h to CsA therapy.
~
Aug
CSA ~ 1
Time (months)
Acknowledgements. This work was supported by the Rebecca Sakai Memorial Fund, by a grant (DK-38831) from the NIDDK of the NIH and a Research Career Development Award (DK-01183)to Dr. Jordan.
Fig. 1. The relationship of serum interleukin-2 (IL-2) levels
(bars) and serum albumin (solid line) in response to cyclosporin A (CsA) therapy in a patient with steroid-resistant focal segmental glomerulosclerosis. High levels of IL-2 were observed with disease activity; levels decreased with clinical remissions of the nephrotic syndrome
References
1. Meyrier A, Simon P, Perret G, Condamin MC (1986) Remission of idiopathic nephrotic syndrome after treatment with cyclosporin A. Br Med J 292:789-792
168 2. Tejani A, Butt K, Trachtman H, Suthanthiran M, Rosenthal C, Khawar MR (1987) Cyclosporin-induced remission of relapsing nephrotic syndrome in children. J Pediatr l l l : 1056-1061 3. Waldo R, Kohaut E (1987) Therapy of focal segmental glomerulosclerosis with cyclosporin A. Pediatr Nephrol 1: 180-182 4. Niaudet P, Habib R, Tete M-J, Hinglas N, Broyer M (1987) Cyclosporin in the treatment of idiopathic nephrotic syndrome in children. Pediatr Nephrol 1: 566-573 5. Schnaper HW, Aunne TM (1985) Identification of the lymphokine soluble immune response suppressor in urine of nephrotic children. J Clin Invest 76: 341- 349 6. Tejani A, Khalid B, Trachtman H, Suthanthiran M, Rosenthal C, Khawm M (1988) Cyclosporin A induced remission of relapsing nephrotic syndrome in children. Kidney Int 33 : 729-734 7. Barnett HL, Schoeneman M, Bernstein J, Edehnann CM (1978) Pediatric kidney diseases. Little Brown & Co, Boston, pp 695-711
8. Wiesinger D, Borel JF (1979) Studies on the mechanisms of action of cyclosporin A. Br J Pharmacol 66:66-67 9. Bunjes D, Hardt C, Solbach W (1982) Studies on the mechanism of action of cyclosporin A in the murine and human T-cell response in vitro. In: White DJG (ed) Cyclosporin A. Proceedings of the International Congress on Cyclosporin A. Elsevier Amsterdam, pp 261- 280 10. Abb J, Abb H (1983) Effect of cyclosporine on human leukocyte interferon production: selective inhibition of IFN-gamma synthesis. Transplant Proc 15:2380-2383 11. Textor SC, Margolin K, Blayney D, Carlson J, Doroshow J (1987) Renal, volume and hormonal changes during therapeutic administration of recombinant interleukin-2 in man. Am J Med 83:1055-1061 12. Cornaby A, Simpson M, Vann Rice R, Dempsey RA, Madras PN, Monaco AP (1988) Interleukin-2 production in plasma and urine, plasma interleukin-2 receptor level, and urine cytology as a means of monitoring renal allograft recipients. Transplant Proc 20: 108-110
Ask the expert* What are the indications, if any, for urinary diversion in the prune-belly syndrome? Key words: Agenesis of anterior abdominal muscles - Urinary diversion Many patients with prune-belly syndrome have large, f l a b b y bladders with hydronephrosis. Their bladders empty slowly, infrequently and often incompletely. Historically, these dysmorphic and sluggish urinary tracts attracted urological interest, which naturally led to aggressive surgical reconstruction, aimed at restoring urinary tract anatomy to normal. Unfortunately, the results have typically been temporary, and have provided no better improvement in renal function than nonoperative management. Consequently and appropriately, a more conservative surgical approach to this condition has evolved. Occasionally, however, urinary diversion must be considered in a patient with prune-belly syndrome who has poor bladder emptying associated with urinary infection, pro-
*The editors invite questions for this section
gressive hydronephrosis or deteriorating renal function. This situation may occur in two clinical contexts: (1) the newborn with a greatly deformed urinary tract and very poor renal function, where urinary tract obstruction is suspected; and (2) the older child with a stable dysmorphic urinary tract who develops bladder decompensation. Successful long-term management depends first on excluding obstruction and then on recognizing the often temporary nature of bladder decompensation in these patients. Consequently, short-term solutions such as intermittent catheterization should first be utilized, especially in the older child, where compensated bladder function is delicately balanced, and may return after a brief period of bladder drainage. When tubeless surgical urinary diversion is required, a temporary, reversible technique such as cutaneous vesicostomy should likewise be given first consideration. Stephen A. Koff Section Chief, Pediatric Urology Children's Hospital 700 Columbus Drive Columbus, OH 43205, USA
Pediatr Nephrol (1990) 4:166-168 9 IPNA 1990
Brief report Serum interleukin-2 levels in a patient with focal segmental glomerulosclerosis Relationship to clinical course and cyclosporin A therapy Stanley C. Jordan, Uwe Querfeld, Mieko Toyoda, and John Prehn Pediatric Renal Immunology Laboratory, Ahmanson, Pediatric Center, Cedars-Sinai Medical Center, Los Angeles, California, USA Received December 29, 1988; accepted June 1, 1989
Abstract. We describe a patient with steroid-resistant focal segmental glomerulosclerosis (FSGS) whose serum interleukin-2 (IL-2) levels were markedly elevated in association with disease activity. With cyclosporin A (CsA) treatment, the patient entered remission and serum IL-2 fell to undetectable levels. After cessation of CsA, the patient relapsed and the serum IL-2 levels were elevated again. Reinstitution of CsA therapy was followed by a partial remission and disappearance of detectable serum IL-2 levels. Key words: Interleukin-2 -
Focal segmental glomerulosclerosis - Cyclosporin A
Introduction Dysfunctional T-cell activation is thought to be important in the genesis of both focal segmental glomerulosclerosis (FSGS) and minimal change nephrotic syndrome (MCNS) [1-6]. Corticosteroids and cytotoxic drugs readily induce remissions of proteinuria in MCNS, although only 10%-20% of patients with FSGS respond [6]. The pathogenesis of both conditions remains unclear, but the nephrotic range proteinuria may result from a loss of anionic charge on the glomerular basement membrane [1] mediated by abnormal lymphokine(s) produced by activated lymphocytes. Schnaper and Aunne [5] recently identified a lymphokine in MCNS patients, designated sol-
Offprint requests to: S. C. Jordan, Cedars-Sinai Medical Center, 8700 Beverly Boulevard, Los Angeles, CA 90048, USA
uble immune response suppressor factor (SIRS). It was present in all steroid-responsive MCNS patients tested, but was no longer detectable after steroid-induced remissions. Neither the mechanism(s) responsible for dysfunctional T-cell activation in MCNS or FSGS, nor how lymphokines may mediate these disorders [1-6], however, have been delineated by these previous studies. Cyclosporin A (CsA) is a potent immunosuppressive agent which modifies T-cell functions [8, 9], inhibiting mitogen- and antigen-induced T-cell proliferation, IL-2 production and gamma interferon production [8-10]. It may be effective in treating steroid-resistant MCNS and FSGS [1-3, 6] although the mechanism is unknown. IL-2 is a lymphokine required for the initiation and maintenance of many normal T- and B-cell functions. IL-2 infusions have been given to humans with malignancies, and have been associated with edema formation, salt retention and hypoalbuminemia [11]; however, there have been no reports of IL-2 infusions causing albuminuria. In this report, we describe a patient with steroid-resistant FSGS whose serum IL-2 levels were elevated during two periods of disease activity and fell during remissions following treatment with CsA.
Case report A 14-month-old Hispanic male was admitted to CSMC with generalized edema, ascites, hypertension, and proteinuria. The child's past medical history was significant for recurrent urinary tract infections, otitis media, and failure to thrive. There was no evidence of infection at the time of presentation. The patient's height, weight, and head circumference were all below the 5th percentile for age. Pertinent initial laboratory values showed: serum albumin of 1.0 g/dl, urine protein of 20 g/day, normal C3, C4, CH 50, ASO and antinuclear anti-
167 body titers. The patient was treated with a salt-restricted diet, salt-poor albumin (25%) infusions, methylprednisolone (2 mg/ kg per day) and intravenous gamma globulin for a serum IgG level below 100 mg/dl. The patient did not respond to this treatment and remained hospitalized for approximately 1 month. At that time a renal biopsy was performed and revealed FSGS. Subsequently steroid dosage was tapered and therapy with CsA (3.5 mg/kg twice daily) initiated. Within 10 days of initiation of CsA therapy, the patient improved and remission occurred after 2.5 weeks of CsA therapy. CsA therapy was continued for 2 months and the patient was tapered off the drug (duration of therapy: 15 weeks). Two weeks after discontinuation of CsA therapy, the patient relapsed. He was treated initially with methylprednisolone (2 mg/kg per day) for 3 weeks, but failed to respond. Steroid therapy was again tapered and CsA was initiated at a dose of 5 mg/kg per day. Proteinuria decreased gradually over the next month. The patient is currently free of edema with 1 + proteinuria and no hypertension.
Materials and methods IL-2 assay. Weekly serum samples were obtained from the patient and normal controls, and were analyzed for IL-2 using a modified enzyme-linked immunosorbent assay (ELISA) system (Genzyme, Boston, Mass.). Results
D a t a f o r m the entire t r e a t m e n t course are s h o w n in Fig. 1. After 4 weeks o f daily p r e d n i s o l o n e thera p y (2 m g / k g per day), the patient's serum alb u m i n was 1 g / d l , a n d the serum IL-2 level was 16 u n i t s / m l ( n o r m a l : < 1 u n i t / m l ) . After the initiation o f CsA t h e r a p y a n d tapering o f the steroid dosage the patient rapidly d e v e l o p e d a clinical a n d biochemical remission. This was a c c o m p a nied by a rapid and steady weekly decrease in the serum IL-2 level t o w a r d s normal. T h e initial urine protein excretion was greater than 20 g / d a y , and did not r e s p o n d to steroid therapy. Two weeks after starting CsA therapy, the urine protein excretion was greater than 2 g / d a y and 200 m g / d a y at 4 weeks. T r e a t m e n t with CsA was c o n t i n u e d for 4
_.J~
oo
2~
c-
15
3
.s
10
2
~
5
1
O.
. . . . . . . . Dec Jan Feb Mar Apr May Jun Jul
I
CSA
I
I
0
E~
2
15 weeks. Within 3 weeks o f cessation o f CsA therapy, and 1 week prior to d e v e l o p m e n t o f a full biochemical and clinical relapse, the patient's serum IL-2 level was 20.0 u n i t s / m l . Discussion
This is the first study to d e m o n s t r a t e a b n o r m a l levels o f l y m p h o k i n e s in the serum o f patients with either M C N S or FSGS. Our study was carried out to d e t e r m i n e if elevated serum IL-2 levels might serve as a m a r k e r for dysfunctional T-cell activation in n e p h r o t i c s y n d r o m e and if levels would r e s p o n d to t r e a t m e n t with the T-cell inhibitory drug CsA. Although this r e p o r t details our experience with only o n e patient, we believe these observations are o f interest and m a y be relevant to determining which steroid-resistant patients might r e s p o n d to CsA. Serum and urine levels o f IL-2 have p r o v e n useful in diagnosing allograft rejection, a n o t h e r condition where a b n o r m a l T-cell activation occurs [12]. These investigators also showed that patients with CsA toxicity had u n d e t e c t a b l e levels o f IL-2 in their urine and serum. Tejani et al. [6] r e p o r t e d that pre-therapy IL-2 p r o d u c t i o n by p e r i p h e r a l b l o o d m o n o n u clear cells was s u p r a n o r m a l in six o f eight F S G S patients who r e s p o n d e d to CsA. Published reports o f CsA t r e a t m e n t for steroid-resistant M C N S a n d F S G S have shown variable results; however, the patients who derived the most benefit were treated within 6 m o n t h s o f diagnosis [ 1 - 4 , 6]. The relationship between T-cell activation, l y m p h o k i n e s and n e p h r o t i c s y n d r o m e is obscure, but the response o f patients with M C N S and F S G S to agents k n o w n to m o d i f y T-cell functions (steroids and CsA) suggests that this relationship is a strong one. Since IL-2 p r o d u c t i o n is essential for T-cell activation and proliferation, detection o f IL-2 in biological fluids should be a g o o d marker for T-cell activation. H o w e v e r , one must always be cautious, since c o n c o m i t a n t infection could also increase IL-2 levels. T h e patient presented here showed a g o o d correlation between s y m p t o m s o f the n e p h r o t i c s y n d r o m e , IL-2 levels, a n d response o f b o t h to CsA therapy.
~
Aug
CSA ~ 1
Time (months)
Acknowledgements. This work was supported by the Rebecca Sakai Memorial Fund, by a grant (DK-38831) from the NIDDK of the NIH and a Research Career Development Award (DK-01183)to Dr. Jordan.
Fig. 1. The relationship of serum interleukin-2 (IL-2) levels
(bars) and serum albumin (solid line) in response to cyclosporin A (CsA) therapy in a patient with steroid-resistant focal segmental glomerulosclerosis. High levels of IL-2 were observed with disease activity; levels decreased with clinical remissions of the nephrotic syndrome
References
1. Meyrier A, Simon P, Perret G, Condamin MC (1986) Remission of idiopathic nephrotic syndrome after treatment with cyclosporin A. Br Med J 292:789-792
168 2. Tejani A, Butt K, Trachtman H, Suthanthiran M, Rosenthal C, Khawar MR (1987) Cyclosporin-induced remission of relapsing nephrotic syndrome in children. J Pediatr l l l : 1056-1061 3. Waldo R, Kohaut E (1987) Therapy of focal segmental glomerulosclerosis with cyclosporin A. Pediatr Nephrol 1: 180-182 4. Niaudet P, Habib R, Tete M-J, Hinglas N, Broyer M (1987) Cyclosporin in the treatment of idiopathic nephrotic syndrome in children. Pediatr Nephrol 1: 566-573 5. Schnaper HW, Aunne TM (1985) Identification of the lymphokine soluble immune response suppressor in urine of nephrotic children. J Clin Invest 76: 341- 349 6. Tejani A, Khalid B, Trachtman H, Suthanthiran M, Rosenthal C, Khawm M (1988) Cyclosporin A induced remission of relapsing nephrotic syndrome in children. Kidney Int 33 : 729-734 7. Barnett HL, Schoeneman M, Bernstein J, Edehnann CM (1978) Pediatric kidney diseases. Little Brown & Co, Boston, pp 695-711
8. Wiesinger D, Borel JF (1979) Studies on the mechanisms of action of cyclosporin A. Br J Pharmacol 66:66-67 9. Bunjes D, Hardt C, Solbach W (1982) Studies on the mechanism of action of cyclosporin A in the murine and human T-cell response in vitro. In: White DJG (ed) Cyclosporin A. Proceedings of the International Congress on Cyclosporin A. Elsevier Amsterdam, pp 261- 280 10. Abb J, Abb H (1983) Effect of cyclosporine on human leukocyte interferon production: selective inhibition of IFN-gamma synthesis. Transplant Proc 15:2380-2383 11. Textor SC, Margolin K, Blayney D, Carlson J, Doroshow J (1987) Renal, volume and hormonal changes during therapeutic administration of recombinant interleukin-2 in man. Am J Med 83:1055-1061 12. Cornaby A, Simpson M, Vann Rice R, Dempsey RA, Madras PN, Monaco AP (1988) Interleukin-2 production in plasma and urine, plasma interleukin-2 receptor level, and urine cytology as a means of monitoring renal allograft recipients. Transplant Proc 20: 108-110
Ask the expert* What are the indications, if any, for urinary diversion in the prune-belly syndrome? Key words: Agenesis of anterior abdominal muscles - Urinary diversion Many patients with prune-belly syndrome have large, f l a b b y bladders with hydronephrosis. Their bladders empty slowly, infrequently and often incompletely. Historically, these dysmorphic and sluggish urinary tracts attracted urological interest, which naturally led to aggressive surgical reconstruction, aimed at restoring urinary tract anatomy to normal. Unfortunately, the results have typically been temporary, and have provided no better improvement in renal function than nonoperative management. Consequently and appropriately, a more conservative surgical approach to this condition has evolved. Occasionally, however, urinary diversion must be considered in a patient with prune-belly syndrome who has poor bladder emptying associated with urinary infection, pro-
*The editors invite questions for this section
gressive hydronephrosis or deteriorating renal function. This situation may occur in two clinical contexts: (1) the newborn with a greatly deformed urinary tract and very poor renal function, where urinary tract obstruction is suspected; and (2) the older child with a stable dysmorphic urinary tract who develops bladder decompensation. Successful long-term management depends first on excluding obstruction and then on recognizing the often temporary nature of bladder decompensation in these patients. Consequently, short-term solutions such as intermittent catheterization should first be utilized, especially in the older child, where compensated bladder function is delicately balanced, and may return after a brief period of bladder drainage. When tubeless surgical urinary diversion is required, a temporary, reversible technique such as cutaneous vesicostomy should likewise be given first consideration. Stephen A. Koff Section Chief, Pediatric Urology Children's Hospital 700 Columbus Drive Columbus, OH 43205, USA
