Mechanisms of renal injury and progression of renal disease in congenital obstructive nephropathy

Abstract

Congenital obstructive nephropathy accounts for the greatest fraction of chronic kidney disease in children. Genetic and nongenetic factors responsible for the lesions are largely unidentified, and attention has been focused on minimizing obstructive renal injury and optimizing long-term outcomes. The cellular and molecular events responsible for obstructive injury to the developing kidney have been elucidated from animal models. These have revealed nephron loss through cellular phenotypic transition and cell death, leading to the formation of atubular glomeruli and tubular atrophy. Altered renal expression of growth factors and cytokines, including angiotensin, transforming growth factor-beta, and adhesion molecules, modulate cell death by apoptosis or phenotypic transition of glomerular, tubular, and vascular cells. Mediators of cellular injury include hypoxia, ischemia, and reactive oxygen species, while fibroblasts undergo myofibroblast transformation with increased deposition of extracellular matrix. Progression of the lesions involves interstitial inflammation and interstitial fibrosis, both of which impair growth of the obstructed kidney and result in compensatory growth of the contralateral kidney. The long-term outcome depends on timing and severity of the obstruction and its relief, minimizing ongoing injury, and enhancing remodeling. Advances will depend on new biomarkers to evaluate the severity of obstruction, to determine therapy, and to follow the evolution of lesions.

Timing and Outcome of Renal Replacement Therapy in Patients with Congenital Malformations of the Kidney and Urinary Tract

“…Ample experimental and clinical evidence suggests that renal function is commonly reduced at birth in patients with urinary tract malformation, secondary to a common underlying genetic abnormality or to early intrauterine urinary tract obstruction altering kidney development (16,17). Hence, bilateral renal hypoplasia or dysplasia is a far more likely cause of ESRD in most RRT patients classified as having "pyelonephritis" due to obstruction, reflux, or neurogenic bladder disorder, even more so as antibiotic prophylaxis and early corrective urologic surgery have greatly reduced the incidence of upper urinary tract infections in this population in the past three decades (18,19).…”

Chemokines as Potential Markers in Pediatric Renal Diseases

“…In this regard, chemokines like CCL2/MCP-1, CCL5/ RANTES, macrophage inflammatory protein-2 (CXCL2/ MIP-2), and -interferon-inducible protein (CXCL10/IP-10) have been evaluated in experimental hydronephrosis [49][50][51][52][53]. CCL2/MCP-1 is an inflammatory chemokine that attracts and activates monocytes, T-cells, and natural killer cells [4,54].…”

Ulinastatin attenuates renal interstitial inflammation and inhibits fibrosis progression in rats under unilateral ureteral obstruction

“…The unilateral ureteral obstruction (UUO) model is a classic animal model that is used to study obstructed renal interstitial inflammation and fibrosis (3). The renal damaging effects caused by UUO mainly include interstitial inflammatory response, apoptosis and progressive interstitial fibrosis (4). Among these, inflammatory responses are characterized by an excessive generation of cytokines, including interstitial pro-inflammatory cytokines and growth factors, as well as reactions involving inflammatory cell packages, actuate renal tubular atrophy and interstitial fibrosis.…”