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nd to maintain the epithelial turnover of the duc-al system.16 EGF has also been shown to have an-iproliferative effects in the developing kidney.19

ur previous study showed that reduced EGF lev-ls would contribute to increased apoptosis in theongenital obstructed kidney in children.20 Bartolit al.21 showed that children with PUJO hadarked reduction of EGF gene expression com-

ared with controls, but it did not correlate withge, differential renal function, or renal thickness.ur study revealed downregulation of EGF expres-

ion in PUJO kidneys, confirming the experimen-al results obtained by other investigators.22 Ourtudy also demonstrated positive granules in theysplastic tubules of two hydronephrotic kidneys.his finding suggests that the abnormal expressionf EGF might alter branching tubulogenesis duringidney development and result in tubular dyspla-ia in congenital hydronephrosis.We also demonstrated positive relationships be-

ween the renal TGF-�1 level and the histologicrade and the drainage clearance half-time, as wells inverse relationships between the EGF level andhe histologic grade and the drainage clearancealf-time, indicating that the alteration of TGF-�1nd EGF might be involved in the pathogenesis ofenal damage.

CONCLUSIONS

The present study has shown increased TGF-�1nd decreased EGF expression in congenital PUJO,nd they might play a key role in the basic mecha-ism that leads to the development of obstructiveephropathy.

REFERENCES1. Mandell GA, Cooper JA, Leonard JC, et al, for the Soci-

ty of Nuclear Medicine: Procedure guideline for diureticenography in children. J Nucl Med 38: 1647–1650, 1997.

2. Elder JS, Stansbrey R, Dahms BB, et al: Renal histolog-cal changes secondary to ureteropelvic junction obstruction.Urol 154(2 Pt 2): 719–722, 1995.

3. Chomczynski P, and Sacchi N: Single-step method ofNA isolation by acid guanidinium thiocyanate-phenol-chlo-oform extraction. Anal Biochem 162: 156–159, 1987.

4. Yang Y, Zhou X, Gao H, et al: The expression of epider-al growth factor and transforming growth factor-beta1 in the

tenotic tissue of congenital pelvi-ureteric junction obstruc-ion in children. J Pediatr Surg 38: 1656–1660, 2003.

5. Diamond JR, Goor HV, Ding G, et al: Myofibroblast inxperimental hydronephrosis. Am J Pathol 146: 121–129,995.

6. Diamond JR, Kees-Folts D, Ding G, et al: Macrophages,onocyte chemoattractant peptide-1, and TGF-�1 in experi-ental hydronephrosis. Am J Physiol 266: 926–933, 1994.

7. Duymelinck C, Dauwe SE, De Greef KE, et al: TIMP-1ene expression and PAI-1 antigen after unilateral ureteralbstruction in the adult male rat. Kidney Int 58: 1186–1201,000.

8. Wen JG, Frokiaer J, Jorgensen TM, et al: Obstructiveephropathy: an update of the experimental research. Urol

es 27: 29–39, 1999. p

ROLOGY 67 (4), 2006

9. Diamond JR, Ricardo SD, and Klahr S: Mechanisms ofnterstitial fibrosis in obstructive nephropathy. Semin Neph-ol 18: 594–602, 1998.

10. Border WA, and Noble NA: Transforming growth fac-or beta in tissue fibrosis. N Engl J Med 331: 1286–1292,994.11. Klahr S: Urinary tract obstruction. Semin Nephrol 21:

33–145, 2001.12. Zeisberg M, and Kalluri R: The role of epithelial-to-esenchymal transition in renal fibrosis. J Mol Med 82: 175–

81, 2004.13. Diamond JR: Macrophages and progressive renal dis-

ase in experimental hydronephrosis. Am J Kidney Dis 26:33–140, 1995.14. Fisher DA, Salido EC, and Barajas L: Epidermal growth

actor and the kidney. Annu Rev Physiol 51: 67–80, 1989.15. Jung JY, Song JH, Li C, et al: Expression of epidermal

rowth factor in the developing rat kidney. Am J Physiol Renalhysiol 288: F227–F235, 2005.16. Gesualdo L, Di Paolo S, Calabro A, et al: Expression of

pidermal growth factor and its receptor in normal and dis-ased human kidney: an immunohistochemical and in situybridization study. Kidney Int 49: 656–665, 1996.17. Harris RC: Potential physiologic roles for epidermal

rowth factor in the kidney. Am J Kidney Dis 17: 627–630,991.18. Goodyer PR, Mulligan L, and Goodyer CG: Expression

f growth-related genes in human fetal kidney. Am J Kidneyis 17: 608–610, 1991.19. Gattone VH II, Sherman DA, Hinton DA, et al: Epider-al growth factor in the neonatal mouse salivary gland and

idney. Biol Neonate 61: 54–67, 1992.20. Yang Y, Ji S, Wang C, et al: Apoptosis of renal tubular

ells in congenital hydronephrosis. Chin Med J (Engl) 114:02–505, 2001.21. Bartoli F, Gesualdo L, Paradies G, et al: Renal expres-

ion of monocyte chemotactic protein-1 and epidermalrowth factor in children with obstructive hydronephrosis.Pediatr Surg 35: 569–572, 2000.22. Walton G, Buttyan R, Garcia-Montes E, et al: Renal

rowth factor expression during the early phase of experimen-al hydronephrosis. J Urol 148(2 Pt 2): 510–514, 1992.

EDITORIAL COMMENTThe role of TGF-� as a mediator of renal injury is well

stablished. In brief, TGF-� binds to the TFG-� type II recep-or, resulting in activation (phosphorylation) of the TGF-�ype I receptor. The activated type I receptor, in turn, triggersytoplasmic proteins (Smads) to complex, enter the nucleus,nd upregulate transcription of pro-fibrotic target genes. Thend result is extracellular matrix deposition, characteristic ofnd-stage renal disease. EGF is also thought to play a role inegulating renal injury. Interestingly, a recent publication hasescribed opposing, species-specific, effects on renal function.1

Regarding TGF, the question remains, will it prove to be ofiagnostic, prognostic, or therapeutic value?The authors assert that the renal TGF-� levels correlate

ith clinical-pathologic parameters such as renal function andistologic features. This is exciting, but must be confirmed byubsequent studies. Others have reported that urinary TGFan be used as a biomarker for obstruction; however, fol-ow-up publications evaluating the specificity and sensitivityre lacking. Complicating matters is the ubiquitous nature ofGF-�. The authors have previously reported that TGF-� islso elevated in the renal pelvic tissue of obstructive systems.2

his raises the question, can urinary levels reliably predictenal parenchymal damage?

Interference of TGF-� signaling has significant therapeutic

otential, but its multiple biologic functions make develop-

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ent of inhibitors challenging. Current approaches includenti-TGF antibodies, antifibrotic agents, such as pirfenidone,hown to be effective in obstruction models, and antagonizersf TGF such as BMP-7, which can accelerate renal recovery, toame but a few.3,4

One can envision a day when a urinary biomarker aids in theiagnosis of obstruction and medical therapy is given to pro-ect renal function and accelerate its recovery after interven-ion. More thoughtful work is needed to make this a reality.

REFERENCES1. Kiley SC, Thornhill BA, Belyea BC, et al: Epidermal

rowth factor potentiates renal cell death in hydronephroticeonatal mice, but cell survival in rats. Kidney Int 68: 504,005.2. Yang Y, Zhou X, Gao H, et al: The expression of epider-al growth factor and transforming growth factor-beta1 in the

tenotic tissue of congenital pelvi-ureteric junction obstruc-ion in children. J Pediatr Surg 38: 1656, 2003.

3. Negri AL: Prevention of progressive fibrosis in chronicenal diseases: antifibrotic agents. J Nephrol 17: 496, 2004.

4. Gagliardini E, and Benigni A: Role of anti-TGF-beta an-ibodies in the treatment of renal injury. Cytokine Growthactor Rev 2006 Feb–Apr;17(1–2): 89–96. Epub 2005 Oct 28.

Fernando Ferrer, M.D.Department of Pediatric Urologic Surgery and Oncology

Connecticut Children’s Medical CenterUniversity of Connecticut Health Center

Hartford, Connecticut

doi:10.1016/j.urology.2005.12.044© 2006 ELSEVIER INC.

ALL RIGHTS RESERVED

REPLY BY THE AUTHORSRecent evidence has suggested that the progression of renal

brosis is a reversible process, at least in experimental models.any strategies that have been explored in the past few yearsere aimed at antagonizing the fibrotic action of TGF-� and

hey appear to give the most promising results. Two endoge-ous factors, namely HGF and BMP-7, have been demon-trated to be potent inhibitors that effectively block epithelial-o-mesenchymal transition both in vivo and in vitro. Althoughome studies have demonstrated improvement of renal func-ion in congenital hydronephrosis after surgical intervention,ther studies revealed renal damage progression despite im-rovement of renal function after relief of unilateral ureteralbstruction in animal models.1 Medical therapy is needed torotect renal function and reverse renal damage progressionfter surgical intervention. Our study showed increased ex-ression of TGF-�1 and decreased expression of EGF in chil-ren with hydronephrosis. These findings suggest that strate-ies to antagonize the fibrotic action of TGF-� and use thentiapoptotic effect of EGF could be explored in children withongenital hydronephrosis after intervention to attenuate re-al fibrosis and renal atrophy.A recent publication noted that the effects of EGF on growth

re organ specific and developmentally determined and that

22

pecies-specific differences in the response to EGF are due toariations in receptor signaling.2 Our previous study showedhat the reduced EGF expression would contribute to in-reased apoptosis in the congenitally obstructed kidney inhildren.3 This report also demonstrated positive granulesn the dysplastic tubules of two hydronephrotic kidneys. Thisnding suggested that during nephrogenesis the expression ofGF might alter branching tubulogenesis and result in tubularysplasia, but after nephrogenesis completion, EGF has anntiapoptotic role in congenital hydronephrosis. The resultslso suggested that the maturational stage of the kidney affectshe tubular response to EGF, so the therapy strategies of renalamage aimed at EGF must be based on a thorough under-tanding of EGF signaling.

At present, two puzzling issues of congenital hydronephro-is need to be elucidated. One is the diagnosis of obstructiondistinguishing an obstructed from a nonobstructed collectingystem), and the other is the existence and definition of ao-return point of reversal of fibrosis. Our study showed aositive relationship between TGF-�1 level and histologicrade and drainage clearance half-time and inverse relation-hips between EGF level and histologic grade and drainagelearance half-time. Our previous study also showed an in-reased level of TGF-�1 and decreased level of EGF in theenal stenotic tissue of congenital hydronephrosis.4 This sug-ested that the renal levels of TGF-�1 and EGF could predictenal parenchymal damage and the degree of obstruction. Be-ause circulating TGF-�1 and EGF also contribute to urinaryevels, whether urinary levels can reliably predict renal dam-ge also needs further study. To answer the question ofhether a TGF-�1/EGF mRNA ratio in renal parenchyma orrine could predict whether renal function can recover, a fol-

ow-up study and large samples are needed. I believe thoseuestions could be answered in our future study.

REFERENCES1. Ito K, Chen J, El Chaar MR, et al: Renal damage

rogresses despite improvement of renal function after relieff unilateral ureteral obstruction in adult rats. Am J Physiolenal Physiol 287: 1283–1293, 2004.2. Kiley SC, Thornhill BA, Belyea BC, et al: Epidermal

rowth factor potentiates renal cell death in hydronephroticeonatal mice, but cell survival in rats. Kidney Int 68: 504–14, 2005.3. Yang Y, Ji S, Wang C, et al: Apoptosis of renal tubular

ells in congenital hydronephrosis. Chin Med J (Engl) 114:02–505, 2001.4. Yang Y, Zhou X, Gao H, et al: The expression of epider-al growth factor and transforming growth factor-beta1 in the

tenotic tissue of congenital pelvi-ureteric junction obstruc-ion in children. J Pediatr Surg 38: 1656–1660, 2003.

Yi Yang, M.D.Department of Pediatric Surgery

Second Affiliated Hospital of China Medical UniversityShenyang City, China

doi:10.1016/j.urology.2006.01.012© 2006 ELSEVIER INC.

ALL RIGHTS RESERVED

UROLOGY 67 (4), 2006