Obstructive Nephropathy Saulo Klahr

REVIEW ARTICLE

Abstract ages. The incidence of hydronephrosis reported by Bell (1) in a series of32,360 autopsies was 3.8% (3.9% in males, 3.6% in Obstructive nephropathy is a relatively commonentity females). The incidence of clinical manifestations of obstruc- that is treatable and often reversible. It occurs at all ages tive uropathy prior to death was not reported, and it is likely from infancy to elderly subjects. Obstructive uropathy is that hydronephrosis was an incidental finding in many of these classified according to the degree, duration and site of the patients. The incidence of hydronephrosis at autopsy is some- obstruction. It is the result of functional or anatomic le- what lower in children than in adults, being 2%in one series of sions located in the urinary tract. The causes of obstructive 16, 100 autopsies (2). Over 80% of children with hydronephro- uropathy are many. Obstruction of the urinary tract may sis at autopsy were less than 1 year old, with the balance of decrease renal blood flow and the glomerular filtration rate. childhood cases being distributed uniformly through the child- Several abnormalities in tubular function mayoccur in hood years. About 166 patients per 100,000 population had a obstructive nephropathy. These include decreased reab- presumptive diagnosis of obstructive uropathy on admission sorption of solutes and water, inability to concentrate the to hospitals in the United States in 1985 (3). Amongmale pa- urine and impaired excretion of hydrogen and potassium. tients with kidney and urologic disorders, obstructive uropa- Renal interstitial fibrosis is a commonfinding in patients thy ranked fourth at discharge (242 patients/100,000 dis- with long-term obstructive uropathy. Several factors: mac- charges). In females with kidney and urologic disorders, ob- rophages, growth factors, hypoxia, cytokines are involved structive uropathy ranked sixth as a diagnosis at discharge (94 in the pathogenesis of interstitial fibrosis. It has been shown patients/100,000 discharges). In the United States in 1985, about that ACEinhibitors ameliorate the interstitial fibrosis in 387 visits per 100,000 population were related to obstructive animals with obstructive uropathy. uropathy (3). Newultrasound techniques have made possible (Internal Medicine 39: 355-361, 2000) the diagnosis of obstructive uropathy in the fetus during pregnancy (4, 5). In the adult, the incidence and causes of urinary Key words: angiotensin II, acute renal failure, interstitial tract obstruction vary with the age and sex of the patient. In fibrosis young and middle-aged males, acute obstruction from renal calculi is commonbut temporary, and such cases would not be included in autopsy surveys. In females of this age group, on the other hand, pelvic cancer is an important cause of obstruc- Introduction tive uropathy. In the older age group, urinary tract obstruction is more commonin the male, resulting from prostatic hyper- Obstructive nephropathy is of great importance to clinicians trophy or malignancy. because it is a commonentity that is treatable and often revers- In 1985, about 80%of the operations for benign prostatic ible. Patients with obstructive nephropathy maybe asymptom- hyperplasia were performed on menage 65 years or older. From atic or mayexhibit a diversity of clinical syndromes (see Table 1989 to 1993, a 5-year span, 4,869 patients with the diagnosis 1). Obstructive uropathy refers to the presence of structural or of obstructive nephropathy began treatment for end-stage re- functional changes in the urinary tract that impedethe normal nal disease (ESRD) in the United States (3). During this pe- flow of urine. Obstructive nephropathy is the renal disease riod, obstructive nephropathy accounted for 2%of the patients caused by impaired flow of urine or tubular fluid. Hydroneph- being treated under Medicare regulations for ESRD. Among rosis denotes dilation of the urinary tract. the 4,869 patients with obstructive nephropathy being treated for ESRD, 6.9% were younger than 20 years of age, 35.7% Incidence and Prevalence of Obstructive were between the ages of 20 and 64 and 57.4% were older than 64 years. Males comprised 73.8%of patients with obstructive Urop athy nephropathy being treated with ESRD. Obstructive uropathy is a commonentity that occurs at all Simon Professor of Medicine, Department of Internal Medicine, Barnes-Jewish Hospital (North Campus) at Washington University School of Medicine, 216 South Kingshighway Boulevard, St. Louis, Missouri 63 100- 1092

355 Internal Medicine Vol. 39, No. 5 (May 2000) Klahr

Table 1. Clinical Presentation of Obstructive Nephropathy Pre sentation C ause Acute renal failure Complete bilateral obstruction (or complete obstruction of a solitary kidney) Chronic renal failure Severe partial bilateral obstruction Rank pain and/or enlarged, Unilateral obstruction partial or complete tender kidney

Polyuria, polydipsia, sodium Chronic partial obstruction or post- wasting, and/or renal tubular obstructive diuresis acidosis H ypertension Increased ECF volume (bilateral obstruction): increased renin-angiotensin (unilateral obstruction) Polycythem ia Increased renal production of erythropoietin (presumably due to renal ischemia during obstruction) Bladder Symptoms: hesitancy, Obstruction of lower urinary tract (bladder incontinence, decreased caliber neck, bladder pathology) of urine stream Repeated or refractory urinary Any obstructive lesion but most commonly tract infections lower urinary tract

Thecausesof upperurinary tract obstructioncan be intrin- Classification and Pathogenesis sic or extrinsic. Intrinsic causesare either intraluminalor intramural, withrenal calculi beingthe maincauseof intralumi- Anatomicor functional factors are importantin establish- nal obstruction. Theintramural causes of obstruction are ei- ing the causeof the obstruction.Thelevel at whichthe ob- ther anatomicor functional.Anatomiclesionsof the upperuri- struction occurs in the urinary tract, and whether it is intralu- nary tract, a less commoncauseof obstruction, include ure- minal, intramural (intrinsic), or extramural (extrinsic) are help- teral strictures, benignor malignanttumorsof the renal pelvis ful. Theimportant levels of obstruction in the urinary tract are and ureter, ureteral valves and polyps. The functional disor- the urethraandthe bladderneck,the bladderandthe ureterovesi- ders include vlsicoureteral reflux andadynamicureteral seg- cal junction, the ureter, and the renal pelvis andureteropelvic ments.Themostcommonsite of functionalobstructionin the junction. ureters is a functional defect at the ureteropelvic junction. This Obstructive uropathy is classified according to the degree, is usually a diseaseof infants. Thesecondmostcommoncause duration, andsite of the obstruction.Thedegreesof obstruc- is a functional defect at the ureterovesical junction. This is a tion are said to be highgrade whenit is complete,and low disease primarily of malechildren. Theextrinsic causes of ob- gradewhenpartial or incomplete.Whenthe obstructionis of structive uropathyare best classified underthe systemof ori- short duration it is said to be acute. Mostoften this is dueto gin of the obstructing lesion. Thelesions causing obstruction stones. Obstruction that develops slowly and is long lasting is mayoriginatein the reproductivesystem,the vascularsystem, said to be chronic,as in congenitalureterovesicalabnormali- the gastrointestinal tract, or the retroperitoneal space(see Table ties and retroperitoneal fibrosis. Obstructive uropathyis due to 2). functional or anatomiclesions that can be located anywherein Thecausesof lower urinary tract obstruction include lesions the urinary tract from the renal tubules (crystals) to the ure- of the urethra, prostate, and bladder. Anatomicalor functional thral meatus. Obstructive uropathyaffecting the lumenof the abnormalitiesof the bladdermayresult in obstruction. Ure- renal tubules is said to be intrarenal, and those causes of ob- thral strictures usually result fromchronicinstrumentationor struction that arise in the urinarytract are referredto as extra- gonococcalinfections. In males, benign prostatic hyperplasia renal. Extrarenal obstruction in turn is divided into upperuri- andprostatic cancer, particularly in the elderly, are majorcauses nary tract obstruction (above the ureterovesical junction), which of lowerurinary tract obstruction. is usually unilateral in nature, andlowerurinary tract obstruction, which by definition is bilateral.

356 Internal Medicine Vol. 39, No. 5 (May 2000) Obstructive Nephropathy

Table 2. Causes of Urinary Tract Obstruction Upper urinary tract Lower urinary tract

Intrinsic causes 1. Phimosis, meatal stenosis, paraphimosis 2. Urethra: strictures, stones, diverticulum, 1. Intralum inal posterior or anterior ureteral valves, periure- 1. Intratubular deposition of crystals (uric acid) thral abscess, urethral surgery 2. Ureter: urolithiasis, blood clots, papillary tissue 3. Prostate: benign prostatic hyperplasia, 2. Intramural prostatic calculi, abscess, prostatic carcinoma 1. Dysfunction at the ureteropelvic or ureterovesical 4. Bladder junction a. Neurogenic bladder: spinal cord defect or 2. Ureteral valve, polyp, or stricture trauma, diabetes, multiple sclerosis, cerebrovascular accidents, Parkinsons's Extrinsic causes disease . Reproductive system b. Bladder neck dysfunction a. Uterus: pregnancy, prolapse, tumors, endometriosis c. Bladder calculus b. Ovary: abscess, tumors, ovarian remnants d. Bladder cancer c. Gartner's duct cyst, tubuloovarian abscess 5. Trauma 2. Vascular lesions a. Straddle injury a. Aneurysm: abdominal aorta, iliac vessels b. Pelvic fracture b. Aberrant vessels: ureteropelvic junction c. Venous: retrocaval ureter, ovarian vein thrombophle- bitis d. Fibrosis following vascular reconstructive surgery 3. Gastrointestinal tract: Crohn's disease, diverticulitis, appendiceal abscess, tum ors, pancreatic tum ors, abscess, cysts 4. Diseases of the retroperitoneum a. R etroperitoneal fibrosis (idiopathic, radiation) b. Inflammatory: tuberculosis, sarcoidosis c. Hematomas d. Primary retroperitoneal tumors (lymphoma, sarcoid, etc.) e. Tumor metastatic to the retroperitoneum (cervix, bladder, colon, prostate, etc.) f. Lymphocele g. Pelvic lipom atosis

crease in the net hydraulic pressure gradient across glomerular BloodFlow,Glomerularand Tabular Function capillaries, resulting in a decline in GFR.Thedecrease in whole in Obstructive Nephropathy kidney GFRafter ureteral ligation is due to both a decrease in single nephronGFRand a decreasein the numberof filtering In experimentalanimals,acute ureteral obstructioncausesa nephrons. transient increase in blood flow to the affected kidney, followed Several abnormalities in tubular function mayoccur in ob- by progressive vasoconstriction. Local production of structive nephropathy.Someof the abnormalitiesinclude: de- eicosanoids, especially prostacyclin andprostaglandinE may creased reabsorption of solutes andwater, inability to concen- accountfor the increased renal bloodflow observedafter the trate the urine, impairedexcretion of hydrogenand potassium. onset of obstruction. Usually3 to 5 hoursafter the onset of the Impairedability to concentratethe urineis evidentafter relief obstruction there is an increase in intrarenal resistance. This of obstruction in both animals and humansubjects. Vasopressin vasoconstrictionis mediatedby severalvasoactivecompoundsadministration does not correct the defect (9, 10). Adecrease such as angiotensin II, (6) thromboxane A2(7) and antidiuretic in the solute contentof the papillary interstitium maybe a major hormone(8). In addition, decreased production of nitric oxide factor underlyingthis abnormality.Adecreasedexpressionof mayalso havea role in the increasein vascularresistance. aquoporinsin the distal tubule maybe also a contributory fac- Glomerular filtration rate (GFR)declines progressively af- tor. ter the onset of completeureteral obstruction.Thereis anin- Thefractional excretion of potassiumis decreasedin pa- crease in pressure in the proximaltubule. This results in a de- tients with obstructive uropathy. Thus, patients with this disor-

Internal Medicine Vol. 39, No. 5 (May 2000) 357 Klahr der may develop hyperkalemic/hyperchloremic acidosis, par- compartment by macrophages (19). Since the macrophage is a ticularly those with chronic obstruction (1 1). An inability to rich source of numerous peptide growth factors, it is not unex- acidify the urine is seen after release of obstruction in both pected that such compoundshave a pivotal role in initiating humans and experimental animals ( 1 2-16). Although this acidi- and maintaining the fibrogenesis of the tubulointerstitium. Also, fying defect is reversible in most instances, it may persist in the cortical tubular cells in the kidney are capable of elaborat- some patients (12). In animals with ureteral obstruction, there ing a numberof peptide growth factors in response to the me- is a decreased numberof H+ATPasepumpsin the apical sur- chanical perturbation that occurs after ureteral obstruction ( 1 8). face of intercalated cells. This event mayaccount for the acidi- Macrophagesand renal tubular cells are a source of a number fying defect seen after release of ureteral obstruction (17). of growth factors and inflammatory agents such as, interleukin 1 and interleukin 6, transforming growth factor p (TGF-p), Mechanisms of Interstitial Fibrosis in tumor necrosis factor (TNF), platelet-derived growth factor Obstructive Nephropathy (PDGF) and fibroblast growth factor (PGF). The deposition and accumulation of extracellular matrix Interstitial fibrosis is a commonfinding in the kidney with (ECM)following tubulo-interstitial injury represents an im- long-term ureteral obstruction ( 1 8). The process of fibrosis, in balance between deposition and removal of collagen and other part, represents an imbalance betweenextracellular matrix pro- compounds.There is a down-regulation of proteases which de- tein synthesis and degradation. Anearly event in the intersti- grade matrix components.Onthe other hand, the upregulation tial fibrosis process is the infiltration of the tubulointerstitial of TGF-presults in a variety of cellular responses that pro- mote fibrosis, including stimulation of ECMgenes, down regulation of degradative matrix metalloproteinases and up-regu- Table 3. Factors whoseExpression is Increased in the lation of tissue inhibitor of metalloproteinase (TIMP) 1 (20, Kidney with Ureteral Obstruction 21). Transforming growth factor p (TGF-(3,) Recent studies have suggested that tension stress (22), hy- Protein 53 (p53) poxia (23), macrophage infiltration (24), and increased pro- Protein 21 [p21, (WAFl)] duction of cytokines (25-27) mayaffect the redox state in vitro. Tissue inhibitors of metalloproteinases- 1 (TIMP- 1 ) To investigate the potential role of oxidative stress, Kawadaet Decorin al (28) examined the levels of distribution of NGcarboxy- methyl-lysine (CML) in the kidney with ureteral obstruction. Nuclear factor-KB (NF-kB) They found CMLin the interstitium of the obstructed kidney Tumornecrosis factor-a (TNF-a) 10 days after ligation of the ureter. HemeoxygenasemRNA Vasoactive compounds was upregulated 12 hours after ureteral obstruction. These re- Angiotensinogen sults indicate the presence of oxidative stress in the intersti- Angiotensin II Endothelin tium of the obstructed kidney. Oxidative stress and the produc- Thromboxane A2 tion of several active oxidative products mayplay an impor- Prostagl andi ns tant role in interstitial inflammation and fibrosis. Proto-oncogenes Reactive oxygenspecies stimulate nuclear factor-kappa B c-fos, c-jun, jun B, c-myc, cH-Ras (NF-kB) and compounds that restore the "redox balance" of Growthfactors the cell ultimately inhibit NF-kB (29). The components of the Interleukin-6 (IL-6) NF-kB family of transcription factors are designated p50, p52, Platelet activating factor (PAF) p65 (Rel A), c-Rel and Rel B; each derives from a separate Basic fibroblast growth factor (BFG) gene product (30). This family forms dimeric protein com- Proteins involved in apotosis Clusterin (SGP-2) plexes, is constitutively present in the cytoplasm of cells, and Osteopontin upon activation, translocates to the nucleus, where it, in turn Chemoattractants controls genes contributing to tissue inflamation, cellular proliferation and cellular differentiation (30). NF-kBcan be acti- Monocyte chemoattractant peptide- 1 (MCP-1 ) Osteopontin vated by a number of stimuli including angiotensin II (3 1) and Adhesion Proteins tumor necrosis factor alpha (TNF-cc). Transcription factors of Intercellular adhesion molecule 1 (ICAM-1) the NF-kB family can directly or indirectly influence cellular Vascular cell adhesion molecule 1 (VCAM-1) events leading to tissue fibrosis. Fibronectin alternate splice forms Matrix/basement membraneproteins Collagen types I, III and IV TYimorNecrosis Factor-oc There are two membersof the tumor necrosis factor (TNF) Adapted from Klahr S. ; Obstructive Nephropathy (Neph- family: TNF-a and TNF-p. The discussion in this article will rology Forum) Used with permission from Kidney In- be confined to TNF-a. Activation of the human TNF-a gene ternational 54: 286-300, 1998. Reference 1 8. leads to the production of a protein with 233 amino acids. The 358 Internal Medicine Vol. 39, No. 5 (May 2000) Obstructive Nephropathy signal sequence of full length TNF-a is unusually long (76 RANTESmRNAin a murine mesangial cell line and in vivo in aminoacids). This signal sequence provides a mechanismby rat kidneys perfused with TNF-a. Mulligan et al (38) reported which TNF-occan exist as an integral membraneprotein, with that anti- TNF-aor soluble recombinant humanTNFR1 blocked the carboxy-terminus extracellular. MatureTNF-occonsists of the upregulation of intercellular adhesion molecule 1 (ICAM- 157 amino acids with a molecular mass of 17 kDa. Fully ma- 1), endothelial leukocyte adhesion molecule 1 (ELAM-1), and ture TNF-ocprotein self-assemble as homotrimers with masses vascular adhesion molecule 1 (VCAM-1)in nephrotoxic ne- of 51 kDa. The macrophage is a major source ofTNF-cc, but phritis. The above data support the concept that TNF-acon- TNF-oc is also produced by resident renal cells (32, 33). Two tributes to the increased macrophage migration into the renal TNF-ocreceptors have been described: one with a molecular interstitium of the affected kidney. Wefound that macroph- weight of 55 kDa (TNFR1) and the other with a molecular ages infiltrated the interstitium of the obstructed kidney cortex weight of 75 kDa (TNFR2) (34). Binding ofTNF-a to its re- as early as 4 hours after the onset of unilateral ureteral obstruc- ceptors activates a numberof signal transduction pathways that tion, and by 24 hours the influx was at a level approximately result in the expression of a variety of transcription factors, 10-fold greater than normal (39). Taken together, these obser- cytokines, growth factors, receptors, cell adhesion molecules, vations suggest that an early increase in TNF-aafter ureteral mediators of inflammatory processes, acute phase proteins, and obstruction of the kidney upregulates the production of a major histocompatibility complex proteins (34). Lipopolysac- chemoattractant(s) for monocytes and contributes to the infil- charide (LPS)-induced renal injury is associated with increased tration of the obstructed kidney by leukocytes. expression of TNF-aby renal cells. Proximal tubular cells ex- The binding of TNF-a to a cell surface receptor results in press TNF-a when stimulated with interleukin- la or LPS (35). intracellular metabolic changes that mediate apoptotic and ne- Also, mRNAtranscripts of TNF-a are found in cortical tu- crotic cell death (40, 41). Although the mechanism of the cyto- bules of mice injected with LPS. Thus, resident renal cells cidal action of TNF-a has not been completely elucidated, the (glomerular mesangial cells and tubular epithelial cells) are TNFR1receptor has been shown to have a cytoplasmic do- sources of TNF-a production in renal injury. Wefound (36) main sequence similar to the Fas antigen receptor, which is that in normal rats TNF-a mRNAwas more abundant in glom- considered to mediate apoptosis (42). Someinvestigators have erulitis than in renal cortical tubules. Wemeasured TNF-a reported apoptosis of renal tubular cells in the obstructed kid- mRNAin the renal cortex of rats at different times after the ney one week after ureteral ligation (43, 44). onset of unilateral ureteral obstruction and determined whether angiotensin II inhibition or total body irradiation affected the Effect of Pharmacologic Interventions in mRNAlevels of TNF-a (36). Cortical tubules obtained from Obstructive Nephropathy the kidney with ureteral obstruction had a marked increase in TNF-a mRNAexpression, whereas the glomeruli obtained from Administration of an ACEinhibitor or an angiotensin II re- the same kidneys did not. Thus, upregulation of TNF-a ex- ceptor (ATI ) antagonist, to rats with unilateral ureteral obstruc- pression wasconfined to renal tubular cells of the obstructed tion, ameliorated the increase in interstitial volume and attenu- kidney. Levels of TNF-a mRNAare significantly increased in ated the increased expression of TGF-pj in tubular cells, the the obstructed kidney at 1 hour (x 2), 2 hours (x 2.7), 4 hours increased production of extracellular matrix protein, the acti- (x 3.6), 24 hours (x 2.7), 72 hours (x 1.8) and 120 hours (x vation of NF-kB,the proliferation of fibroblasts and the con- 2.8) after ureteral ligation whencomparedto the contralateral version of their phenotype to myofibroblasts (45). Amono- kidney of the samerats or to the control kidney of normal rats. cyte/macrophage infiltrate was present in the obstructed kid- Administration of enalapril, an ACEinhibitor, before and dur- ney of untreated rats and in the obstructed kidney of rats treated ing unilateral ureteral obstruction decreased TNF-a mRNA with the angiotensin II receptor antagonist. By contrast, this levels in the obstructed kidney by about 40% at 4 hours after infiltrate was markedly decreased in the obstructed kidney of the onset of obstruction. Total body irradiation, which prevents rats treated with an ACEinhibitor. This difference may be owing the migration of macrophages to the obstructed kidney, did not to greater generation of nitric oxide related to increased levels affect the upregulation of TNF-a mRNAexpression at 4 hours of bradykinin during ACEinhibition (46). In fact, rats with after unilateral ureteral obstruction. Thus, TNF-a may have a unilateral obstruction given both an ACEinhibitor and (L- role in initiating tubulointerstitial injury in the obstructed kid- NAME)(an inhibitor of NOformation) had a substantial mac- ney. Leukocytes, infiltrating the renal interstitium of the ob- rophage infiltrate. Administration of L-arginine in the drink- structed kidney, do not appear to contribute to the increased ing water significantly blunted the increases in interstitial vol- expression of TNF-amRNA.Angiotensin II seems to contrib- ume, monocyte infiltration, interstitial collagen IV and a- ute, at least in part, to the early increase in expression of TNF- smooth muscle actin expression (47). However, in contrast to a mRNAin the obstructed kidney. ACEinhibitors, arginine administration did not decrease the TNF-ahas a role in the recruitment of inflammatory cells expression of TGF-(3, mRNAin the kidney with ureteral liga- in animal models of glomerular injury. It stimulates the pro- tion. Wealso found a 10-fold increase in TIMP-1 mRNAin the duction of chemotactic factors by resident cells and upregulates obstructed kidney. Administration of an ACEinhibitor blunted monocyte chemoattractant protein-1 (MCP-1) mRNAin hu- this increase, by 40 % (p<0.001). The addition of L-NAMEto man mesangial cells. Wolf et al (37) found that TNF-a increases the ACEinhibitor prevented the decrease in TIMP-1 mRNA. Internal Medicine Vol. 39, No. 5 (May 2000) 359 Klahr

A commondenominator of the beneficial effects of ACEinhi- 6) Yarger WE, Schocken DD, Harris RH. Obstructive nephropathy in the bition or arginine and the deleterious effects of L-NAMEdur- rat: possible roles for the renin-angiotensin system, prostaglandins, and thromboxanes in postobstructive renal function. J Clin Invest. 65: 400- ing ACEinhibition may be a result of the increased or decreased 412, 1980. generation of NO (46, 47). 7) Purkerson ML,Klahr S. Prior inhibition of vasoconstrictors normalizes In the above studies the ACEinhibitor was administered GFR in postobstructed kidneys. Kidney Int. 35: 1305-1314, 1989. before or concomitant with the onset of ureteral obstruction. 8) Reyes AA, Robertson G, Klahr S. Role ofvasopressin in rats with bilat- Wealso have examined the effects of ACEinhibition after 3 or eral ureteral obstruction. Proc Soc Exp Biol Med 197: 49-55, 1991. 9) Hanley MJ, Davidson K. Isolated nephron segments from rabbit models 5 days of established unilateral ureteral obstruction in rats. De- of obstructive nephropathy. J Clin Invest 69: 165-174, 1982. layed administration of an ACEinhibitor slowed and in sev- 10) Campbell HT, Bello-Reuss E, Klahr S. Hydraulic water permeability and eral instances halted the progression of fibrosis in the transepithelial voltage in the isolated perfused rabbit cortical collecting tubule following acute unilateral ureteral obstruction. J Clin Invest 75: tubulointerstitium of the kidney with ureteral ligation (48). 219-225, 1985. Pharmacological maneuvers that reduce angiotensin II (ACE 1 1 ) Batlle DC, Arruda JA, Kurtzman NA. Hyperkalemic distal renal tubular inhibitors) or interfere with its action (ATI receptor antago- acidosis associated with obstructive uropathy. N Engl J Med 304: 373- nists) blunt NF-kBactivation and blunt the progression of dis- 380, 1981. ease. Although AT2receptor inhibition decreases NF-kB acti- 12) Gillenwater JY, Westervelt FB Jr, Vaughan ED Jr, Howards SS. Renal vation the effect on NF-kBdimers may be different from those function after release of chronic unilateral hydronephrosis in man. Kid- ney Int7: 179-186, 1975. affected through ATI receptors (45). Indeed, AT2 receptor in- 13) Better OS, ArieffAI, Massry SG, Kleeman CR, Maxwell MH. Studies on hibition in rats (49) or AT2 receptor knockout in mice (50) renal function after relief of complete unilateral ureteral obstruction of exacerbates renal fibrosis consequent to ureteral obstruction. three months' duration in man. AmJ Med 54: 234-240, 1973. Pharmacological maneuversthat reduce the activation of cer- 14) Ericsson NO, Wineberg J, Zetterstrom R. Renal function in infantile ob- tain NF-kB isotypes may extrinsically blunt angiotensin II- structive uropathy. Acta Pediatr Scand 44: 444-459, 1955. 1 5) Berlyne GM. Distal tubular function in chronic hydronepyhrosis. Q J Med mediated effects and also slow the progression of renal dis- 30: 339-355, 1961. ease. 16) Massry SG, Schainuck LI, Goldsmith C, Schreiner GE. Studies on the In summary,angiotensin II regulates a numberof genes as- mechanismof diuresis after relief of urinary-tract obstruction. AnnIntern sociated with the progression of renal disease. The regulation Med 66: 149-158, 1967. of gene expression by angiotensin II occurs through specific 17) Purcell, H, Bastani, B, Harris, KP, Hemken, P, Klahr, S, Gluck, S. Cellu- lar distribution of H (+) -ATPase following acute unilateral ureteral ob- receptors that are ultimately linked to changes in the activity struction in the rat. Am. J Physiol 261: F365-F376, 1991. of transcription factors within the nucleus of target cells. In 18) Klahr S. Obstructive nephropathy. Kidney Int 54: 286-300, 1998 (clini- particular, members of the NF-kB family of transcription fac- cal conference). tors are activated, which, in turn, fuels at least two autocrine 19) Diamond, JR, Ricardo, SD, Klahr S. Mechanisms of interstitial fibrosis reinforcing loops that amplify angiotensin II and TNF-oc for- in obstructive nephropathy. Semin Nephrol 18: 594-602, 1998. 20) Jones CL, Buch S, Post M, McCulloch L, Liu E, Eddy AA. Renal extra- mation. This amplification of the angiotensin II and TNF-a cellular matrix accumulation in acute puromycinaminonucleosideneph- signals to the samecells in an autocrine manneror to adjacent rosis in rats. AmJ Pathol 141: 1381-1396, 1992. cells in a paracrine manner further amplifies NF-kBactivation 21) Sharma K, Ziyadeh FN. The emerging role of transforming growth fac- within the kidney. This leads to fibroblast proliferation and tor-beta in kidney diseases. 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