Clinical Presentation of Obstruction

Prenatal ultrasonographic diagnosis has radically altered the clinical presentation of obstructive conditions, and today most of these conditions are detected before birth and many have no apparent clinical signs. Those that present as clinical manifestations are often severe obstructive conditions, such as posterior urethral valves or massive hydronephrosis. Children are still found with clinical signs of obstruction, usually infection or pain and, rarely, hypertension. In the child with obstruction of the entire urinary tract, even when the obstruction is relieved the functional abnormalities inform urologists of the effects of obstruction on developing kidneys. Reduced filtration function as manifest by a rising serum creatinine concentration is associated with glomerular injury, acidosis is due to tubular injury, and nephrogenic diabetes insipidus is secondary to collecting duct abnormalities. In extreme cases these may all be present, but on occasion they are noted in isolation and will often persist after correction of the obstruction (Hutcheon et al, 1976). Obstructive hypertension appears to be renin mediated (Riehle and Vaughan, 1981; Urata et al, 1985; Mizuiri et al, 1992) and may be reversible with surgical repair (de Waard et al, 2008).

The pathologic correlates of these functional alterations have been described in the congenitally obstructed kidney to varying degrees (Elder et al, 1995; Stock et al, 1995; Han et al, 1998; Poucell-Hatton et al, 2000; Zhang et al, 2000; Huang et al, 2006). The pathologic changes associated with lesser degrees of obstruction have been less thoroughly investigated, and a spectrum of qualitatively similar alterations have been described. In the absence of overt functional alterations and in unilateral conditions, determining the state of the affected kidney becomes a clinical challenge. This challenge is often tied to the question of whether surgical intervention is appropriate, and much controversy has emerged from this question. Clinical imaging studies are currently the only widely used modality to make this assessment, and their interpretation is not uniform. The natural history of many conditions in the spectrum of obstruction is not well described yet is the essence of the question. It should be clearly seen that the spectrum of obstruction is wide, involves conditions that do not require intervention as well as others that produce profound renal injury, and may change with age and persistence of the condition.

Progressive Renal Dysfunction

A major concern regarding obstructive conditions in the urinary tract is the potential for a progressive situation leading to ever more loss of renal function. Progression may be seen in two forms, one with the uncorrected partially obstructive lesion (i.e., ureteropelvic [UPJ] obstruction) and the second with the previously obstructed but corrected obstruction that has produced some degree of renal damage (i.e., posterior urethral valves). In the first, renal function may initially appear intact on imaging tests yet in time there will be progressive loss of absolute and relative function of the kidney affected by the obstruction. If this were known prospectively, intervention would be appropriate and should be performed early. The challenge is in predicting this situation, and few markers are available to do this. The frequency of progressive deterioration in unilateral obstruction likely ranges from 20% to 40%, but duration of follow-up will significantly affect this rate. Every prospective study of obstructive conditions has documented the potential for progressive loss (Palmer et al, 1998; Parkhouse et al, 1988; Koff and Campbell, 1992; Koff, 2000).

The second situation reflects the fact that the damaged kidney does not have the functional reserve of a normal kidney by which it may maintain its absolute function over time. These kidneys will demonstrate a steady decline in function over time, and this is usually evident in bilateral obstruction. The mechanism may be hyperfiltration of remnant renal units, and clinically this is most often seen with posterior urethral valves (Parkhouse et al, 1988; Nguyen and Peters, 1999). These children may show very adequate renal function early in life yet demonstrate a delayed and inexorable progression into renal failure in adolescence (Fig. 113–1). Whether earlier intervention would have protected their renal function is uncertain, but that possibility cannot be neglected.

Figure 113–1 Graph depicting the progressive deterioration in renal function as indicated by a rising serum creatinine concentration in patients with posterior urethral valves despite surgical relief of obstruction.

(From Roth KS, Carter WH Jr, Chan JCM. Obstructive nephropathy in children: long-term progression after relief of posterior urethral valve. Pediatrics 2001;107:1004–10.)

Predictors of ongoing progression of renal injury secondary to either ongoing or prior renal obstruction are of critical importance, yet there are few to rely on. The most evident one is altered absolute renal function, as clinically indicated by a creatinine clearance or serum creatinine value. This is relatively insensitive in early stages of progression. Radionuclide imaging may be helpful in some cases, but there is no gold standard as to the best interpretation of potentially progressive disease.

Definition of Obstruction

Although it may not be difficult to diagnose the potentially obstructed urinary tract, usually by ultrasonographic identification of hydronephrosis, the determination of whether this particular condition requires surgical intervention to protect renal function and development is much more difficult. The frequently quoted definition of congenital obstruction (Koff, 1987), which is “a condition producing a restriction of urinary flow that will lead to deterioration in renal function,” is too limited. In the growing child, renal function is expected to increase markedly, initially in excess of body mass and subsequently in parallel to it. If this increase in function does not occur, renal functional potential is lost, which may be of greater consequence than losing absolute function. Therefore the impairment of renal functional development should be considered as a determinant of obstruction that warrants intervention (Peters, 1995).

If this is the case, then an obstructive or hydronephrotic condition that has already resulted in less than normal function should be considered as obstructive and warranting intervention. The child with significant hydronephrosis with a kidney contributing significantly less than the anticipated 50% on a radionuclide renal scan has already suffered an impairment of functional potential and should perhaps be considered as having sufficient obstruction to warrant intervention to limit further impairment.

A critical element of congenital urinary obstruction is the recognition that it is distinct from acquired obstruction in the mature animal (or mature kidney). The fact that obstruction develops at the same time the kidney is in the process of formation creates an entirely different paradigm for congenital urinary obstruction as compared with obstruction of the mature kidney (Peters, 1997). The patterns of renal development are affected by obstruction, and this produces the ultimate functional effects. The mechanisms for these alterations are therefore wholly distinct from mature obstruction. Although there is likely to be some overlap in the critical mechanisms of change, many will be different. It cannot be assumed that the principles relevant to mature obstruction are applicable to congenital obstruction. This will clearly impact the interpretation of experimental data in the postnatal and mature animal, as well as the selection and application of experimental systems.

One of the frustrations in the management of clinical congenital obstruction is the dichotomy between therapeutic options, which are currently limited to either observation or surgery. Although the surgical options have expanded somewhat, the large gap between these divergent options creates a great deal of tension in the minds of the patient and family as well as physicians. The absence of any medical or pharmacologic therapy to ameliorate or prevent the complications of obstruction has been a major factor in the controversy between those who choose to correct a problem and those who believe it is better to await spontaneous resolution or unambiguous evidence of obstructive injury. The horizon holds promise for medical therapies that might prevent renal injury in various ways, but it will be essential to more completely understand the nature of congenital urinary obstruction to permit such specific treatment.

General Observations

In an attempt to understand the pathophysiology of congenital urinary obstruction, examination of obstructed renal tissues has shown disorganization of structure with primitive forms of renal tissues—dysplasia. Although the definition of dysplasia is not universally agreed on, evidence of altered renal development in association with obstruction is frequently reported (Bernstein, 1971; Matsell, 1998; Tarantal et al, 2001; Matsell et al, 2002; Matsell and Tarantal, 2002). Dysplasia is often considered to be an embryonic process and irreversible, yet this is not proven. It is clear that some dysplasias are due to very early abnormalities of renal development (Winyard and Chitty, 2008), unrelated to obstruction, but it is equally clear that obstructive processes can produce dysplasia. Whether there are subtle differences between these patterns is unclear, but it should not be difficult to understand that several underlying causes may produce similar outcomes when renal developmental patterns are disrupted.

In some cases, however, usually in lesser degrees of obstruction, there is no dysplasia (Bonsib, 1998; Zhang et al, 2000). In such cases the mechanisms of obstructive effect may be similar but to a lesser degree or they may be entirely different. It is important to recognize the variability of the patterns of response to obstruction.

If obstruction can produce dysplasia or abnormal developmental patterns, the particular mechanisms of obstructive effects may be identifiable. These include the fundamental processes of development, and by examining these specifically we may be able to understand the critical mechanisms of obstructive nephropathy. Development is the controlled process of growth and differentiation of tissues in the formation of an organ or tissue. The forces that regulate these processes are likely targets of obstructive effects.

Structural alterations with obstruction are obviously evident with hydronephrosis, but this is largely a distortion of normal architecture and relative alterations in the amounts of elements of renal tissues. There may be subtle changes, however, that are functionally important. Other alterations include fibrosis and increased interstitial tissues, as well as the presence of abnormal tubules and glomeruli. The normal layered organization of the kidney with the cortical and medullary areas with inner and outer stripes is often distorted or absent (Zhang et al, 2000). Less obvious will be changes in the differentiation of the individual renal cell types that make up the nephron (Huang et al, 2006). Cells are unlikely to perform their normal functions, including communicating with neighboring cells in an integrated fashion. Function will therefore be disrupted.

Closely tied with these altered patterns of structure are distortions of normal growth regulation with either increased or decreased growth of specific structures. In some cases, obstructed kidneys are markedly smaller than normal and in a developmental context this does not represent atrophy but hypoplasia. The distinction is important in that renal tissue mass has not been lost but has never been formed. This is growth failure not atrophy, and the mechanisms are likely distinct.

These observations are supported by both clinical and experimental work. Several biopsy studies have shown patterns indicative of altered differentiation and growth in various levels of obstruction, including both upper (UPJ obstruction) (Elder et al, 1995; Stock et al, 1995; Zhang et al, 2000; Huang et al, 2006) and lower (posterior urethral) valves (Poucell-Hatton et al, 2000; Haecker et al, 2002). These variations are not well explained, and correlation with clinical parameters is often imperfect. Experimental studies, however, have shown similarly that obstruction during development will produce changes in patterns of renal differentiation and in growth regulation (Beck, 1971; Steinhardt et al, 1988; Gonzalez et al, 1990; Peters et al, 1992; Wen et al, 2002; Cachat et al, 2003; Mure et al, 2006b). These can be seen to vary depending on the time of onset in experimental models, as well as the severity of obstruction (Fig. 113–2) (Chevalier et al, 1988, 1999c; Thornhill et al, 2005). The latter is difficult to measure accurately. The validity of any of these model systems must be challenged, however, until we have more definite correlations. Nonetheless it is clear that induced obstruction can produce such severe abnormalities of differentiation as to be considered dysplasia and to produce clear disruptions of growth regulation (Peters et al, 1992). It is therefore reasonable to examine the specific patterns observed and the potential mechanisms of those changes, all of which are likely contributing factors in the development of obstructive nephropathy.

Figure 113–2 Interval change in kidney weight between 2 and 4 weeks of age in rats subjected to experimental unilateral ureteral obstruction (UUO) at birth. The sharp drop in weight with decreasing luminal diameter of the ureter suggests a threshold effect on the obstructive effects on renal growth regulation.

(Modified from Thornhill BA, Burt LE, Chen C, et al. Variable chronic partial ureteral obstruction in the neonatal rat: a new model of ureteropelvic junction obstruction. Kidney Int 2005;67:42–52.)

Patterns of Effect

The effects of obstruction on the developing kidney may be summarized as producing alterations in the regulation of growth, tissue differentiation, extracellular matrix (ECM), and fibrosis and in altering the functional integration of the kidney (Fig. 113–3). The latter is largely a result of the first three major factors and refers to the mechanisms producing vascular, neural, and humoral homeostasis and in the regulation of inflammatory cascades. Understanding the mechanisms by which these systems are dysregulated by obstruction will permit a better understanding of the outcomes of obstruction, which should improve our diagnostic, prognostic, and therapeutic abilities.

Figure 113–3 Diagram of the key patterns of effect due to obstruction during fetal life. UPJ, ureteropelvic junction.

Growth

Growth regulation is a critical part of development, and the obstructed kidney may evidence impaired or accelerated growth. It is important to recognize that the small, obstructed kidney is not atrophic, as might be seen in the adult, but is hypoplastic. The growth it should have experienced never occurred. This can be readily seen on prenatal ultrasound evaluation and has been shown repeatedly experimentally (Peters et al, 1992; Mandell et al, 1994). This seems usually to be a generalized impairment of all parts of the kidney, with both reduced numbers of nephrons as well as smaller nephrons. Differential growth impairment within the nephron segments may be present as well (Cachat et al, 2003; Huang et al, 2006). The functional effects of significant growth impairment are obvious because there are fewer and smaller nephron units. There may be compensatory responses to these changes, and it is difficult to assess their long-term impact. Reduced renal mass can be associated with hypertension as well as reduced filtration function, and loss of tubular mass will affect electrolyte and acid-base homeostasis, as well as water balance.

Growth acceleration can be seen in the larger than normal hydronephrotic kidney, although this is difficult to prove in humans, because few of those kidneys are removed. In animal experiments, fetal partial obstruction can increase renal mass (Gobet et al, 1999a; Ayan et al, 2001). This is not seen with dysplastic changes and is not a product of edema, because the total protein and DNA are increased as well. The factors that predict altered growth appear to be the severity of obstruction and timing of the obstructive effect, although the latter is difficult to ascertain in human situations. The functional consequences of accelerated growth are not known, and this may correlate with the occasional hyperfunction measured on renal scans that is seen in some patients with hydronephrosis (Moon et al, 2003; Maenhout et al, 2005). Compensatory effects with obstruction may not be benign; growth enhancement of the glomeruli occurs in early diabetes and is later associated with glomerular sclerosis.

Growth Regulation

Regulation of renal growth is extremely complex and dynamic through development. A variety of growth factors are known to influence kidney growth at various stages of renal development and act at different loci of the nephron. Obstructive conditions have been shown to alter expression of growth-regulatory genes as well as the presence of the proteins coded by these genes (Chevalier, 1996). Some of the factors known to be altered in renal obstruction (not all in early or fetal models) are listed in Table 113–1. Epidermal growth factor (EGF) has been shown to reduce some of the growth effects of obstruction when administered exogenously (Kennedy et al, 1997; Chevalier et al, 1998, 1999a). Many studies have focused on specific growth factors, but it is evident from the complexity of renal development and growth regulation that the interactions of multiple factors and their signaling pathways will be of greater relevance.

Table 113-1 Key Factors in Congenital Urinary Obstruction

Differentiation

Differentiation is the process of cells attaining specific functional traits to permit specialized functions and organization into tissues. It is the basis for renal function, in its many aspects. Obstruction affects these finely tuned patterns, as can be seen histologically in a severely obstructed kidney with dysplasia. More subtle effects may require assessment of tubular or glomerular function, but all are a result of altered differentiation. Disruption of differentiation may begin as early as induction of the nephron or later in development with injury to renal collecting duct cells that regulate urinary concentrating ability. Some of these changes may be reversible, but it is usually presumed that many are not, in that some cells will undergo terminal differentiation, and if that does not occur at a particular time point in development there will not be another opportunity for it to occur. Disruption of normal differentiation of renal elements is unique to congenital obstruction and does not occur in a major way in adult obstruction. Abnormal epithelial-mesenchymal transformation (EMT) is one alteration in differentiation that does occur in the adult and can be reversible (Hay and Zuk, 1995; Yang et al, 2005; Docherty et al, 2006b; Forino et al, 2006; Higgins et al, 2007; Ivanova et al, 2008). A variety of mediators of EMT have been described, including transforming growth factor-β (TGF-β), plasminogen (Zhang et al, 2007), and leukocytes (Lange-Sperandio et al, 2007), as well as inhibitors, such as hepatocyte growth factor (HGF) (Yang et al, 2005) (Fig. 113–4). It is likely to be an important factor in fetal obstruction as well, although little is known about its role. Most adult cells may be injured and lose their differentiated capacity, but the cell types rarely change their behavior once differentiated. Understanding the patterns of altered differentiation and its regulators is critical to understanding congenital obstructive nephropathy.

Figure 113–4 Renal cellular interactions in obstructive nephropathy. The interstitium is infiltrated by monocytes, which are “classically” activated to macrophages, which release cytokines such as transforming growth factor (TGF)-β1 and tumor necrosis factor (TNF)-α. In turn, TGF-β1 promotes a phenotypic response of tubular epithelial cells either to undergo apoptosis (leading to tubular atrophy) or to undergo epithelial-mesenchymal transition (EMT), becoming fibroblasts that migrate to the interstitium. Angiotensin II (ANG II), produced by the activation of monocytes, stimulates the production of nuclear factor kappa B (NFκB), which leads to the recruitment of more macrophages, as well as to the production of reactive oxygen species (ROS), which aggravates renal tubular injury. In contrast, alternatively activated macrophages can enhance tubular cell survival and proliferation. Endothelial cells can undergo endothelial-mesenchymal transition (EndMT) or apoptosis, which leads to capillary loss and secondary renal ischemia and hypoxia. Resident pericytes and infiltrating hematopoietic stem cells can also differentiate into fibroblasts. Under the stimulus of cytokines such as TGF-β1 produced by macrophages or other cells, fibroblasts synthesize stress fibers and undergo further differentiation to become myofibroblasts. The myofibroblasts are contractile and augment the deposition of extracellular matrix (ECM), leading to progressive interstitial fibrosis. This process is augmented by a decrease in ECM degradation, mediated by plasminogen activator inhibitor-1 (PAI-1) and tissue-type plasminogen activator (tPA).

(From Chevalier RL, Forbes MS, Thornhill BA. Ureteral obstruction as a model of renal interstitial fibrosis and obstructive nephropathy. Kidney Int 2009;75:1145–52.)

Induction Process

Renal differentiation begins with induction and from then on is exquisitely sensitive to various outside effects that may disrupt the normal sequence of cellular changes that results in a kidney. When these may be disturbed by obstruction is unclear, but it can be presumed that some of the variation in the spectrum of obstruction is due to different times of onset of the obstructive effect and to different degrees of severity. The pattern of effect is likely to reflect the time of onset and be reflected in the number of nephron generations and the degree of dysplastic transformation. Controversy remains as to whether obstruction can produce dysplasia, and it is often stated that if dysplasia is present, then it was due to abnormal induction and not obstruction. Abnormal induction and nephrogenesis may be produced by various factors, including genetic ones, or due to cellular disruption from mechanical forces with subsequent cellular responses. The study of Maizels and Berman is often cited to indicate that dysplasia in the chick kidney (a mesonephric kidney) was only produced with mechanical disruption of the mesenchyme and not hydronephrosis. The production of “obstruction” in that elegant study was by necessity rather crude, and several of the preparations were not obstructed. It is unclear whether they all were to a sufficient degree. It also suggests that mechanical forces can, in fact, disrupt nephronogenesis enough to produce dysplasia, and there is no inherent reason to believe that this cannot be from obstruction as well. Later mammalian studies in fetal sheep have shown dysplastic changes produced by obstruction (Steinhardt et al, 1988; Peters et al, 1992; Matsell et al, 1996), and this has also been shown in rodent studies (Thomasson et al, 1970).

The critical determinant of dysplasia in animal studies has been complete obstruction early in gestation. In the fetal sheep this was only seen when the obstruction was induced before 50% of gestation (70 days in most sheep species, which have a gestation from 140 to 145 days). Obstruction induced after that point only produces hydronephrotic changes, albeit severe ones (Beck, 1971). Partial obstructions produced hydronephrosis only, without apparent disruption of the renal architecture. The reason for this is presumably altered sensitivity of the developing nephrons to obstructive effects at this point. Alternatively, the particular signaling systems that are active in the early phases of renal development begin to fade away with ongoing development. It is possible that the pathways sensitive to obstruction that would inherently alter the pattern of development have run their course of expression and activity by mid gestation. Expression of recognized mediators of renal development have been shown to be affected in models of fetal obstruction, including WT1 (Liapis, 2003), the Wnt gene family (Nguyen et al, 1999), and PAX2 (Attar et al, 1998; Mure et al, 2006b; Cohen et al, 2007).

One of the histologic hallmarks of renal dysplasia is fibromuscular collars surrounding tubular structures, so-called primitive ducts. These have a characteristic appearance, and the smooth muscle surrounding the tubules stains for α-smooth muscle actin (α-SMA) (Fig. 113–5). This pattern suggests an abnormality in the regulation of EMT (Butt et al, 2007; Baum et al, 2008). The mesenchymal structures of the primitive nephrogenic blastema and the epithelium of the ureteral bud processes interact, and there is differentiation from an epithelial to mesenchymal phenotypes and the reverse. It is uncertain whether the presence of the primitive tubules suggests persistence of mesenchyme that should have transformed to epithelium or inappropriate EMT. Understanding the signaling pathways involved in these processes will directly impact our understanding of obstructive processes (Roberts et al, 2006; Bani-Hani et al, 2008). Persistent expression of α-SMA can be seen in partial obstruction without dysplastic patterns and thus may be important at several levels of severity (Gobet et al, 1999; Mure et al, 2006a). α-SMA expression is regulated by TGF-β1, linking these two proteins to growth as well as to fibrotic changes.

Figure 113–5 Histologic views of the kidneys of normal and obstructed full-term sheep showing the abnormal structural pattern, increased interstitial fibrosis and cells, as well as abnormally persistent α-smooth muscle actin (brown stain).

(From Gobet R, Bleakley J, Cisek L, et al. Fetal partial urethral obstruction causes renal fibrosis and is associated with proteolytic imbalance. J Urol 1999;162:854–60.)

Development of the glomerulus is a tightly regulated process that involves interaction of the mesenchyme and epithelium with a very specific pattern of growth and formation of intermediate structures such as the S-shaped body. In general, primitive glomeruli are not evident in obstructive changes but markedly abnormal glomeruli are seen as well as hypoplastic glomerular structures (Matsell et al, 2002). In some cases, glomeruli may be enlarged in obstruction, suggestive of the changes seen in hyperfiltration that lead to glomerulosclerosis. Dissociation of the glomerulus from the tubules can be seen in early neonatal rodent obstruction (Thornhill et al, 2007), suggesting severe disruption of the developmental program.

Key Points: Growth and Differentiation

• The effect of growth impairment includes fewer nephron units and delayed nephron maturation.

• Obstructive conditions have been shown to alter the expression of growth-regulating genes, as well as the presence of proteins coded by these genes.

• Congenital obstruction increases apoptosis and cellular patterns characteristic of apoptosis, with enhanced expression of apoptosis-regulating molecules.

• The ultimate cellular effects of such stimuli, however, depend on the summation of competing pro-apoptotic signals and antiapoptotic signals, as well as growth stimulation.

• Alteration in the differentiation of cells is unique to congenital obstruction and does not occur in a major way in adult obstruction.

• The critical determinant of dysplasia in animal studies has been complete obstruction early in gestation.

Evidence and Patterns

Increased interstitial connective tissue is a hallmark of various renal pathologic processes (Eddy, 1996), including obstruction. Although it is unclear if the mechanisms of fibrotic change are universal, they are believed to interfere with intercellular signaling and thus with functional integration (Fig. 113–6). The most likely causes of excessive connective tissue include abnormal accumulation due to imbalance of synthesis and breakdown. It may also represent abnormal inductive signaling that produces excessive conversion of epithelium to mesenchymal tissue and connective tissues (Bascands and Schanstra, 2005; Burns et al, 2007; Zhang et al, 2007). These processes may be normal developmental sequences that persist due to the obstructive effect.

Figure 113–6 Diagram illustrating the various cytokines with reported effects on specific nephron segments. See text for details and references.

Abnormal accumulation may represent simply excessive synthesis with no change in ECM breakdown. Increased collagen synthesis has been shown by upregulation of collagen gene expression in obstructive models (Liapis et al, 1994; Fu et al, 2006). Collagen synthesis is regulated in part by various cytokines, including TGF-β and the renin-angiotensin system (RAS). Reduced fibrosis may be seen when angiotensinogen activity is downregulated in an obstructed system (Fern et al, 1999; Kellner et al, 2006). Similar approaches have been demonstrated in nonobstructive fibrosis as well.

The role of TGF-β is complex and context dependent, yet inhibition of activity will produce less fibrosis as well (Isaka et al, 2000; Miyajima et al, 2000; El Chaar et al, 2007). There is evidence that TGF-β interacts and regulates the activity of the RAS, as well as regulating cellular growth dynamics. Fetal obstruction induces increased expression of TGF-β1 (Medjebeur et al, 1997; Ayan et al, 2001). As reviewed earlier, TGF-β1 regulates EMT, thereby contributing to renal dysplasia (Yang et al, 2000). There is considerable interest in the role of TGF-β1 in promoting EMT of differentiated renal tubular epithelial cells in response to chronic ureteral obstruction. As shown in Figure 113–4, renal interstitial fibroblasts, through transformation to myofibroblasts, play a pivotal role in the deposition of ECM in a hydronephrotic kidney. There is growing evidence that, in addition to proliferation of resident interstitial fibroblasts and transformation of hematopoietic stem cells, renal tubular epithelial cells can undergo EMT and migrate to the interstitium to contribute to the pool of fibroblasts (Iwano et al, 2002). Many of the steps involved in the transformation of tubular epithelial cells are regulated by TGF-β1; these steps include loss of cell adhesion, expression of α-SMA, disruption of tubular basement membrane, and cell migration to the interstitium (Liu, 2004). Signaling by TGF-β1 is mediated in part by Smads, which are both profibrotic (Smad2 and Smad3) and inhibitory (Smad7). Thus targeted deletion of Smad3 reduces apoptosis and fibrosis in mice with ureteral obstruction, whereas gene therapy with Smad7 also reduces fibrosis (Lan et al, 2003; Sato et al, 2003). TGF-β1 also acts through downregulation of transcriptional corepressors of the Smads: SnoN and Ski (Yang et al, 2003b). In contrast, HGF blocks EMT by blocking Smad2 and Smad3 and gene therapy with HGF reduces fibrosis in rats with ureteral obstruction (Gao et al, 2002; Yang and Liu, 2003). HGF also acts by upregulating the Smad corepressors SnoN and Ski, countering the action of TGF-β1 (Yang et al, 2005). These complex networks of counterbalancing factors provide many potential opportunities for therapeutic intervention to prevent the progression—or even promote the reversal—of interstitial fibrosis resulting from obstructive nephropathy (Fogo, 2003).

Nitric oxide has also been shown to regulate the development of obstructive fibrosis in postnatal animals and may play a similar role prenatally (Huang et al, 2000; Felsen et al, 2003). Increased nitric oxide generation reduces the degree of interstitial fibrosis (Ito et al, 2004), and in animals without the gene to produce nitric oxide synthase, unilateral obstruction produces a greater degree of fibrosis than in those animals with this enzyme intact (Hochberg et al, 2000). Data suggest a greater potential role for nitric oxide derived from endothelial nitric oxide synthase (eNOS) than inducible nitric oxide synthase (iNOS) (Huang et al, 2000; Chang et al, 2002).

Hypoxia may be a factor in the development of tissue fibrosis as well, in response to induction of hypoxia-inducible factors-1 and 2 (HIF-1, HIF-2) (Higgins et al, 2008). In-vitro stimulation of renal epithelia with HIF-1 increases EMT, known to induce fibrosis. Genetic models that do not express HIF-1α develop less fibrosis and inflammatory infiltration in response to ureteral obstruction in postnatal models (Higgins et al, 2007). The role in prenatal obstruction remains undefined but potentially relevant.

Altered regulation of ECM breakdown, the proteolytic balance, is a potential mechanism for interstitial fibrosis of obstruction as well, although less explored. Connective tissue breakdown is controlled by the MMPs, of which there are at least 15 having specific activity toward particular connective tissue proteins. MMP-1, for instance, is a collagenase (Pardo and Selman, 2005), whereas MMP-2 specifically degrades gelatin. Their expression and activity are both subject to close regulation, because it is crucial to appropriate ECM homeostasis. Too much activity will degrade the tissues, whereas too little permits accumulation of abnormal amounts of ECM. These pathologic alterations have been described in a variety of disease states, including arthritis and pulmonary fibrosis (Corbel et al, 2002; Vincenti and Brinckerhoff, 2002). One of the means by which their activity is regulated is through endogenous TIMPs. These are less varied and may have less specific activity over the MMPs in their environment and serve to check the degradative activity of the MMPs. Their expression and activity are closely regulated and their net activity is the proteolytic balance. The role of the proteolytic balance in a wide variety of disease states has been the subject of active research (Diamond et al, 1998; Vincenti, 2001).

Altered activity and regulation of the MMPs and TIMPs have been studied in the kidney (Eddy, 1996) in several conditions, and it is clear that they are important regulators of the state of the ECM. Their expression has been shown in the developing kidney as well, and in postnatal obstruction they are altered in activity. In prenatal obstruction increased expression (Ayan et al, 2001; Mure et al, 2006a) and activity (Gobet et al, 1999a) have been shown, as well as in congenital reflux-related fibrosis (Gobet et al, 1998). The precise regulators of the MMPs and TIMPs in development and obstruction are not well defined but are likely to be an important element in the development of pathologic fibrosis. There also is some evidence of regulation by the RAS and TGF-β, which opens therapeutic options for the treatment of fibrosis (Diamond et al, 1998; Ding et al, 2005; Bolbrinker et al, 2006; Yang et al, 2007).

Fibrosis is clearly a major component of the pathophysiology of congenital obstruction. Understanding the role and activities of the various components of this system may permit more specific diagnosis through urinary biomarkers reflecting the elements of the system. These elements may also be relevant targets of therapeutic intervention to modulate ECM homeostasis.

Vascular Development

The developing vascular tree plays a critical role in renal development, and any disruption could be associated with a wide variety of abnormalities, ranging from lack of development of the glomerulus to aberrant regulation of renal blood flow. Sensitivity to humoral and neural regulation of blood flow may be altered as well, which may be a permanent effect.

Expression of renal renin is increased in the obstructed kidney (el-Dahr et al, 1993; Gobet et al, 1999b; Ayan et al, 2001) and decreased in the contralateral kidney. Renin-secreting renal cortical cells appear to be recruited with obstruction as well (Norwood et al, 1994). Expression of receptors for the RAS is altered in specific patterns in neonatal obstruction. Angiotensin I, which mediates vasoconstriction (as well as growth alterations) (Chung et al, 1995; Yoo et al, 1998) increases whereas the levels of angiotensin II, which acts in a contrary manner, are decreased. These alterations suggest a role for a local renal RAS in obstruction-mediated vasoconstriction and that are independent of the systemic RAS.

Altered sensitivity of both kidneys to renin-mediated vasoconstriction has been shown to occur with unilateral obstruction. Interaction with nitric oxide has been seen to be important in regulation of both glomerular and tubular function in early obstruction (Eskild-Jensen et al, 2007b). After release of obstruction, sensitivity to angiotensin II–mediated vasoconstriction was reduced in the obstructed kidney but increased in the contralateral kidney (Chevalier and Gomez, 1988). These observations indicate the sensitivity of renal vascular regulation to obstruction as well as the importance of recognizing the interaction of the two developing kidneys. The role of renal counterbalance in obstruction has been recognized but only investigated to a limited degree. A possible mechanism for these observations is through neural regulation of renin expression (Chevalier and Thornhill, 1995a).

Neural Development

Renal innervation is an important regulator of vascularity and perfusion and is associated with expression of renin in the kidney (el-Dahr et al, 1991). Sympathetic denervation, both mechanical and chemical, has been shown to reduce the expected increase in renin expression in the setting of obstruction (Chevalier and Thornhill, 1995b

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