Sacituzumab govitecan in previously treated hormone receptor-positive/HER2-negative metastatic breast cancer: final results from a phase I/II, single-arm, basket trial.

BACKGROUND: Trophoblast cell-surface antigen-2 (Trop-2) is expressed in epithelial cancers, including hormone receptor-positive (HR+) metastatic breast cancer (mBC). Sacituzumab govitecan (SG; Trodelvy®) is an antibody-drug conjugate composed of a humanized anti-Trop-2 monoclonal antibody coupled to SN-38 at a high drug-to-antibody ratio via a unique hydrolyzable linker that delivers SN-38 intracellularly and in the tumor microenvironment. SG was granted accelerated FDA approval for metastatic triple-negative BC treatment in April 2020. PATIENTS AND METHODS: We analyzed a prespecified subpopulation of patients with HR+/human epidermal growth factor receptor 2-negative (HER2-) HR+/HER2- mBC from the phase I/II, single-arm trial (NCT01631552), who received intravenous SG (10 mg/kg) and whose disease progressed on endocrine-based therapy and at least one prior chemotherapy for mBC. End points included objective response rate (ORR; RECIST version 1.1) assessed locally, duration of response (DOR), clinical benefit rate, progression-free survival (PFS), overall survival (OS), and safety. RESULTS: Fifty-four women were enrolled between 13 February 2015 and 1 June 2017. Median (range) age was 54 (33-79) years and all received at least two prior lines of therapy for mBC. At data cut-off (1 March 2019), 12 patients were still alive. Key grade ≥3 treatment-related toxicities included neutropenia (50.0%), anemia (11.1%), and diarrhea (7.4%). Two patients discontinued treatment due to treatment-related adverse events. No treatment-related deaths occurred. At a median follow-up of 11.5 months, the ORR was 31.5% [95% confidence interval (CI), 19.5%-45.6%; 17 partial responses]; median DOR was 8.7 months (95% CI 3.7-12.7), median PFS was 5.5 months (95% CI 3.6-7.6), and median OS was 12 months (95% CI 9.0-18.2). CONCLUSIONS: SG shows encouraging activity in patients with pretreated HR+/HER2- mBC and a predictable, manageable safety profile. Further evaluation in a randomized phase III trial (TROPiCS-02) is ongoing (NCT03901339). TRIAL REGISTRATION: ClinicalTrials.gov NCT01631552; https://clinicaltrials.gov/ct2/show/NCT01631552.

Characterization of immune responses to anti-PD-1 mono and combination immunotherapy in hematopoietic humanized mice implanted with tumor xenografts.

BACKGROUND: The success of agents that reverse T-cell inhibitory signals, such as anti-PD-1/PD-L1 therapies, has reinvigorated cancer immunotherapy research. However, since only a minority of patients respond to single-agent therapies, methods to test the potential anti-tumor activity of rational combination therapies are still needed. Conventional murine xenograft models have been hampered by their immune-compromised status; thus, we developed a hematopoietic humanized mouse model, hu-CB-BRGS, and used it to study anti-tumor human immune responses to triple-negative breast cancer (TNBC) cell line and patient-derived colorectal cancer (CRC) xenografts (PDX). METHODS: BALB/c-Rag2nullIl2rγnullSIRPαNOD (BRGS) pups were humanized through transplantation of cord blood (CB)-derived CD34+ cells. Mice were evaluated for human chimerism in the blood and assigned into experimental untreated or nivolumab groups based on chimerism. TNBC cell lines or tumor tissue from established CRC PDX models were implanted into both flanks of humanized mice and treatments ensued once tumors reached a volume of ~150mm3. Tumors were measured twice weekly. At end of study, immune organs and tumors were collected for immunological assessment. RESULTS: Humanized PDX models were successfully established with a high frequency of tumor engraftment. Humanized mice treated with anti-PD-1 exhibited increased anti-tumor human T-cell responses coupled with decreased Treg and myeloid populations that correlated with tumor growth inhibition. Combination therapies with anti-PD-1 treatment in TNBC-bearing mice reduced tumor growth in multi-drug cohorts. Finally, as observed in human colorectal patients, anti-PD-1 therapy had a strong response to a microsatellite-high CRC PDX that correlated with a higher number of human CD8+ IFNγ+ T cells in the tumor. CONCLUSION: Hu-CB-BRGS mice represent an in vivo model to study immune checkpoint blockade to human tumors. The human immune system in the mice is inherently suppressed, similar to a tumor microenvironment, and thus allows growth of human tumors. However, the suppression can be released by anti-PD-1 therapies and inhibit tumor growth of some tumors. The model offers ample access to lymph and tumor cells for in-depth immunological analysis. The tumor growth inhibition correlates with increased CD8 IFNγ+ tumor infiltrating T cells. These hu-CB-BRGS mice provide a relevant preclinical animal model to facilitate prioritization of hypothesis-driven combination immunotherapies.

Palbociclib:CDK4/6 inhibition in the treatment of ER-positive breast cancer.

Maintaining cell-cycle control has become a mainstay in treatment for many cancers. Cell-cycle manipulation can be especially valuable in breast cancer tumor cells that will often express hormone receptors that are amenable to anti-hormone receptor-targeted therapies. Despite these treatments, patients often progress, leading to other targeted agents being investigated to help promote progression-free survival. Cyclin-dependent kinases (CDKs) have been identified as contributors in the process of cell division. Combining inhibitors of CDKs with traditional endocrine treatments has shown significant progression-free survival in patients with metastatic breast cancer. One such CDK inhibitor, palbociclib, has shown great promise in the treatment of hormone receptor-positive breast cancer. In this article we review the traditional hormonal treatments of breast cancer, how CDK inhibition is beneficial in the treatment of this disease, and the preclinical and clinical data supporting the use of this medication.

Medullary thyroid cancer and pseudocirrhosis: case report and literature review.

Pseudocirrhosis is a rare form of liver disease that can cause clinical symptoms and radiographic signs of cirrhosis; however, its histologic features suggest a distinct pathologic process. In the setting of cancer, hepatic metastases and systemic chemotherapy are suspected causes of pseudocirrhosis. Here, we present a patient with medullary thyroid carcinoma metastatic to the liver who developed pseudocirrhosis while on maintenance sunitinib after receiving 5-fluorouracil, leucovorin, and oxaliplatin (folfox) in combination with sunitinib. Cirrhotic change in liver morphology was accompanied by diffusely infiltrative carcinomatous disease resembling the primary tumor. We discuss the diagnosis of pseudocirrhosis in this case and review the literature regarding pseudocirrhosis in cancer.

Increased renal expression of monocyte chemoattractant protein-1 and osteopontin in ADPKD in rats.

BACKGROUND: Human autosomal-dominant polycystic kidney disease (ADPKD) is variable in the rate of deterioration of renal function, with end-stage renal disease (ESRD) occurring in only approximately 50% of affected individuals. Evidence suggests that interstitial inflammation may be important in the development of ESRD in ADPKD. Han:SPRD rats manifest ADPKD that resembles the human disease. Homozygous cystic (Cy/Cy) rats develop rapidly progressive PKD and die near age 3 weeks. Heterozygous (Cy/+) females develop slowly progressive PKD without evidence of renal dysfunction until the second year of life, whereas heterozygous (Cy/+) males develop more aggressive PKD with renal failure beginning by 8 to 12 weeks of age. METHODS: To examine the relationship between proinflammatory chemoattractants and the development of interstitial inflammation and ultimately renal failure in ADPKD, we evaluated monocyte chemoattractant protein-1 (MCP-1) and osteopontin mRNAs and proteins in kidneys from Han:SRPD rats. RESULTS: MCP-1 and osteopontin mRNAs, expressed at low levels in kidneys from normal (+/+) animals at all ages, were markedly elevated in kidneys from 3-week-old Cy/Cy animals. In kidneys from heterozygous (Cy/+) adults of either gender, MCP-1 and osteopontin mRNAs were more abundant than normal; MCP-1 mRNA was more abundant in Cy/+ males than in females. Thus, chemoattractant mRNA expression correlated with the development of renal failure in Cy/Cy and Cy/+ rats. Osteopontin mRNA, localized by in situ hybridization, was moderately expressed in the renal medulla of normal animals; however, this mRNA was expressed at very high levels in the cystic epithelia of Cy/+ and Cy/Cy animals. MCP-1 and osteopontin proteins, localized by immunohistochemistry, were weakly detected in +/+ kidneys but were densely expressed in Cy/Cy and in adult Cy/+ kidneys, primarily over cystic epithelium. Increased expression of chemoattractants was associated with the accumulation of ED-1 positive cells (macrophages) in the interstitium of cystic kidneys. CONCLUSIONS: We suggest that proinflammatory chemoattractants have a role in the development of interstitial inflammation and renal failure in ADPKD.

Chemokine expression in the obstructed kidney.

Chemokines are chemotactic cytokines that are important mediators of leukocyte extravasation and chemotaxis. Herein, we provide evidence that after 1 day of unilateral ureteral obstruction (UUO), the mouse obstructed kidney (OBK) expresses MCP-1 (monocyte chemoattractant protein-1), RANTES (Regulated on activation normal T-cell expressed and secreted) and IP-10 (interferon-gamma-induced protein-10). In addition, by day 7, MIP-2 (macrophage inflammatory protein-2) expression is elevated in the obstructed kidneys compared to the contralateral control kidneys (CLK). After 7 days of obstruction, RANTES was the most abundant of the four chemokines detected in the OBK. In situ hybridization results indicate that several cellular compartments contribute to the expression of RANTES in the OBK. However, clearly cortical tubules within the OBK contribute substantially to the elevated expression of RANTES. These data support the contention that the cortical tubular epithelium plays a pivotal role in the inflammation associated with experimental hydronephrosis.

Variation in the PPARalpha gene is associated with altered function in vitro and plasma lipid concentrations in Type II diabetic subjects.

AIMS/HYPOTHESIS: Peroxisome proliferator activated receptor alpha (PPARalpha) regulates genes involved in lipid metabolism, haemostasis and inflammation, in response to fatty acids and fibrates, making it a candidate gene for risk of dyslipidaemia, atherosclerosis and coronary artery disease. Plasma non-esterified fatty acids are increased in subjects with Type II (non-insulin-dependent) diabetes mellitus, suggesting that PPARalpha could link Type II diabetes and dyslipidaemia, and affect response to fibrates. This has been investigated in association studies in healthy and diabetic subjects and in vitro studies. METHODS: The human PPARalpha gene was isolated and screened for variation by single strand conformation polymorphism analysis. Genotypes were determined for 129 Type II diabetic subjects and 2508 healthy men. The association with plasma lipid concentrations was examined. The function of the V162 variant was examined in co-transfection assays. RESULTS: We identified two polymorphisms, one in intron 3 and a missense mutation, leucine 162 to valine, in the DNA binding domain. In Type II diabetic patients, V162 allele carriers had higher total cholesterol, HDL cholesterol and apoAI whereas intron 3 rare allele carriers had higher apoAI concentrations. By contrast, no effect was observed in healthy rare allele carriers. In vitro, the V162 variant showed greater transactivation of a reporter gene construct. CONCLUSION/INTERPRETATION: Naturally occurring variation alters PPARalpha function, influencing plasma lipid concentrations in Type II diabetic patients but not healthy people. This demonstrates that PPARalpha is a link between diabetes and dyslipidaemia, and so could influence the risk of coronary artery disease, the greatest cause of morbidity and mortality in Type II diabetes.

Angiotensinogen and AT(1) antisense inhibition of osteopontin translation in rat proximal tubular cells.

Antisense oligonucleotide inhibition of angiotensinogen and ANG II type 1 receptor (AT(1)) mRNA translation in rat proximal tubules (PT) was examined to provide direct evidence for a role of the renin-angiotensin system (RAS) in upregulated osteopontin expression observed following mechanical cell stretch. Male Sprague-Dawley rats underwent unilateral ureteral obstruction (UUO) under Brevital anesthesia. In situ hybridization and Western blot analysis demonstrated angiotensinogen mRNA and angiotensin converting enzyme (ACE) protein localized to PTs and upregulated in obstructed kidneys, respectively, confirming an increased expression of renal RAS in vivo. In vitro studies were performed to provide mechanistic insight into ANG II-dependent osteopontin expression following mechanical cell stretch, which putatively mimics the increased PT luminal pressure post-UUO. A cationic transfection method was used to introduce either angiotensinogen or AT(1) antisense oligonucleotide into cultured rat PT cells prior to 1 h of cyclic mechanical cell stretch. Northern blot analysis revealed that PT cells subjected to cyclic mechanical stretch with/without prior transfection with a sense oligonucleotide exhibited increased osteopontin mRNA expression compared with unstretched cells. Blockade of either angiotensinogen or AT(1) mRNA translation by antisense oligonucleotide inhibition prior to cell stretch was found to significantly decrease osteopontin mRNA levels 2.4-fold (P<0.004) and 1.6-fold (P<0.001), respectively, compared with values observed in control unstretched cells. This study provides evidence that stretch-induced upregulation of osteopontin mRNA expression is mediated, in part, via production of ANG II. These results lend insight into upregulation of osteopontin via a local PT RAS leading to macrophage infiltration in the tubulointerstitium in experimental hydronephrosis.

Alpha macroglobulins and the low-density-lipoprotein-related protein/alpha-2-macroglobulin receptor in experimental renal fibrosis.

In this study, we evaluated the location of non-specific proteinase inhibitors and their receptor in experimental glomerular and interstitial fibrosis. The alpha macroglobulins alpha-2-macroglobulin (alpha2M) and alpha-1-inhibitor 3 (alpha1I3) are proteinase inhibitors, including metalloproteinases and serine proteases. Using immunohistochemistry, we detected alpha1I3 in the glomerular mesangium in control rats. In acute and chronic fibrosis, the alpha1I3 protein expression was dramatically increased throughout the glomerulus and at sites of increased extracellular matrix deposition in the interstitium. The presence of alpha1I3 in normal and nephrotic kidneys was confirmed by Western blotting. Under chemically reducing conditions, we found that, in contrast to native alpha1I3, kidney-derived alpha1I3 has reacted upon by proteinases, thereby revealing a functional role for this macroglobulin under normal and pathological conditions. Double staining revealed that high amounts of glomerular alpha1I3 were present in sclerotic lesions. alpha2M was absent in glomeruli and interstitium from control rats, but present in small amounts in glomerular mesangial areas of acute nephrotic rats. alpha2M was also present in significant amounts in glomeruli from rats with chronic fibrosis. The receptor mediating the uptake of proteinase inhibitor-proteinase complexes, the low-density-lipoprotein-related protein/alpha-2-macroglobulin receptor, was found in the glomerular mesangium and tubulo-interstitium from control rats. Significant increments in receptor expression were found in glomeruli and interstitium of rats with chronic fibrosis, with a preferential localization in fibrotic areas. Interstitial staining for low-density-lipoprotein-related protein/alpha-2-macroglobulin receptor was attributed to fibroblasts, since double staining ruled out dendritic cells and macrophages. In conclusion, these studies demonstrate the intrarenal presence of plasma-derived proteinase inhibitors together with their receptors. These findings may point to a novel mechanism for renal fibrosis wherein matrix-degrading proteinases are inhibited, resulting in renal fibrosis.

Regulation of proximal tubular osteopontin in experimental hydronephrosis in the rat.

BACKGROUND: Osteopontin is a tubular-derived glycoprotein with macrophage chemoattractant properties. Our previous observations demonstrate that osteopontin is involved in the accumulation of macrophages within the renal cortex of rats following unilateral ureteral obstruction (UUO). METHODS: The present study performed Northern and Western blot analyses of isolated proximal tubular cells exposed to exogenous angiotensin II, and cultured rat proximal tubular cells subjected to one hour of cyclic mechanical stretch, which provided insight into mechanisms involving the proximal tubular renin-angiotensin system in the increased expression of cortical osteopontin following hydronephrosis. RESULTS: In situ hybridization, using a 35S-labeled antisense riboprobe, showed osteopontin mRNA transcription localized to the cortical tubules of the obstructed kidney. Freshly isolated proximal tubules incubated with angiotensin II (10-5 M) for one hour had increased osteopontin mRNA and protein expression by Northern and Western blot analyses, respectively. Pre-treatment of proximal tubules with losartan (10-5 M) for one hour prior to the addition of exogenous angiotensin II (10-5 M) decreased osteopontin mRNA and protein expression. Rat proximal tubule cells subjected to cyclic mechanical stretch for one hour exhibited a 2.1-fold increment in osteopontin mRNA levels, which was normalized following pre-treatment with losartan. CONCLUSIONS: This study provides evidence that angiotensin II, produced by the proximal tubule in the obstructed kidney as a result of mechanical injury, possibly mechanical stretch, may stimulate angiotensin II type I receptor activation, leading to up-regulated osteopontin expression and secretion by the proximal tubule, thereby facilitating macrophage recruitment into the renal interstitium.

Mechanisms of interstitial fibrosis in obstructive nephropathy.

Numerous pathological processes are involved in the renal tubulointerstitial fibrogenic reaction that occurs after ureteral ligation. Central to these maladaptive events is a florid interstitial monocytic infiltration of the tubulointerstitium, which is preceded by a proximal tubular up-regulation of macrophage chemoattractants. Once within the peritubular and periglomerular space, these macrophages are capable of releasing a potent armamentarium of peptide growth factors. TGF-beta has been singled out as a pivotal growth factor mediating fibrogenesis owing to its multifaceted effects on fibroblasts, tubular cells, matrix metalloproteinases, and TIMPs. A growing body of experimental studies using the rat hydronephrosis model is now demonstrating that angiotensin II may, in addition to its well-known hemodynamic effect, also be pro-inflammatory and pro-fibrogenic.

The role of macrophages and reactive oxygen species in experimental hydronephrosis.

A common feature to a number of immune and non-immune renal diseases of diverse etiology is the infiltration of the glomerular and tubulointerstitial compartments by infiltrating macrophages. This review will focus on experimental data supporting the role of the infiltrating renal macrophage as a mediator of interstitial fibrosis during the course of obstructive nephropathy as it pertains to the unilateral ureteral obstruction model in the rat. The mechanical disturbance resulting from complete ureteral obstruction causes tubular injury/dysfunction resulting in a florid pro-inflammatory and fibrogenic response. The central pathobiological theme drawn from data in this model is that macrophage-derived pro-inflammatory mediators, including fibrogenic cytokines and reactive oxygen species, represent pivotal links between the pro-inflammatory state of ureteral obstruction and the late development of interstitial fibrosis. We propose that increased intrarenal oxidant stress, owing to an overproduction of reactive oxygen species and dysregulated tubular antioxidant enzymes, can induce overexpression of fibrogenic cytokines and chemoattractants, as well as increased transcription and synthesis of extracellular matrix proteins, leading to tubular loss and fibrogenesis.

Cardiovascular outcomes in type 2 diabetes. A double-blind placebo-controlled study of bezafibrate: the St. Mary's, Ealing, Northwick Park Diabetes Cardiovascular Disease Prevention (SENDCAP) Study.

OBJECTIVE: To determine whether serum lipid intervention, in addition to conventional diabetes treatment, could alter cardiovascular outcomes in type 2 diabetes. RESEARCH DESIGN AND METHODS: There were 164 type 2 diabetic subjects (117 men, 47 women) without a history of clinical cardiovascular disease randomized to receive either bezafibrate or placebo daily on a double-blind basis in addition to routine diabetes treatment and followed prospectively for a minimum of 3 years. Serial biochemical and noninvasive vascular assessments, carotid and femoral artery B-mode ultrasound measurements, and those pertaining to coronary heart disease (CHD)--clinical history, the World Health Organization (WHO) cardiovascular questionnaire, and resting and exercise electrocardiogram (ECG)--were recorded. RESULTS: Bezafibrate treatment was associated with significantly greater reductions over 3 years in median serum triglyceride (-32 vs. 4%, P = 0.001), total cholesterol (-7 vs. -0.3%, P = 0.004), and total-to-HDL cholesterol ratio (-12 vs. -0.0%, P = 0.001), and an increase in HDL cholesterol (6 vs. -2%, P = 0.02) as compared with placebo. There was a trend toward a greater reduction of fibrinogen (-18 vs. -6%, P = 0.08) at 3 years. No significant differences between the two groups were found in the progress of ultrasonically measured arterial disease. In those treated with bezafibrate, there was a significant reduction (P = 0.01, log-rank test) in the combined incidence of Minnesota-coded probable ischemic change on the resting ECG and of documented myocardial infarction. CONCLUSIONS: Improving dyslipidemia in type 2 diabetic subjects had no effect on the progress of ultrasonically measured arterial disease, although the lower rate of "definite CHD events" in the treated group suggests that this might result in a reduction in the incidence of coronary heart disease.

Ureteral obstruction as a complication of renal transplantation: a review.

Ureteral obstruction in a renal allograft, due to a variety of etiologies, is both a challenging diagnostic and therapeutic disorder. Since ureteral obstruction in a renal transplant recipient usually presents as azotemia, it must also be distinguished from acute rejection. Although ultrasound is non-invasive and readily available, the most definitive diagnostic tool is percutaneous nephrostomy tube placement with antegrade nephrostogram. A variety of therapeutic approaches are available to treat ureteral obstruction in a renal allograft. These procedures can be open (e.g., repeat ureteroneocystotomy) or utilize an endourological approach (e.g., transluminal ureteral dilatation). From an experimental standpoint, recent data in rodent models of experimental hydronephrosis demonstrate similar pathobiologic events in both the obstructed kidney and an allograft undergoing the chronic rejection process. To this end, investigation needs to be conducted to assess whether partial, unrecognized ureteral obstruction in an allograft hastens the development of chronic rejection. This would further underscore the importance of ureteral obstruction as a cause for not only acute azotemia in an allograft, but also chronic deterioration in renal transplant function.

Hemolytic uremic syndrome/thrombotic thrombocytopenic purpura (HUS/TTP) complicating adult Still's disease: remission induced with intravenous immunoglobulin G.

Coexistence of hemolytic uremic syndrome/thrombotic thrombocytopenic purpura (HUS/TTP) and adult Still's disease is extremely rare. We describe the case history of a 22-year-old young man who presented with evidence of a thrombotic microangiopathy complicated by dialysis-dependent renal failure, encephalopathy, and an ischemic retinopathy. The most important and novel feature of this case was the dramatic and sustained clinical remission of the TMA induced by intravenous immunoglobulin (IVIg) after failure of plasmapheresis and glucocorticoids to do so.

Antioxidant expression in experimental hydronephrosis: role of mechanical stretch and growth factors.

We assessed whether levels of renal reactive oxygen species (ROS) and antioxidant enzymes are perturbed in rats following unilateral ureteral obstruction (UUO). The mechanism of catalase perturbation was investigated using proximal tubule suspensions following stimulation with transforming growth factor (TGF)-beta and interleukin (IL)-1 and in a proximal tubular cell line (OKC) subjected to cyclic mechanical stretch, which mimics the early hydrodynamic derangement after UUO. Levels of catalase and copperzinc superoxide dismutase (Cu,Zn-SOD) mRNA from 96-h UUO rats showed a 5.5-fold (P < 0.001) and 5.0-fold (P < 0.001) decrease, respectively, compared with the contralateral unobstructed kidney (CUK). Levels of superoxide anion and hydrogen peroxide showed a significant 1.8-fold (P < 0.0001) and 14.0-fold (P < 0.0001) increase, respectively, in 96-h UUO kidney slice cultures. In situ hybridization and immunohistochemistry showed Cu,Zn-SOD and catalase mRNA and protein transcription expressed in proximal tubules of UUO and CUK specimens. Catalase mRNA levels were markedly downregulated following a 1-h exposure of isolated proximal tubules to TGF-beta (0.1-10 ng) and IL-1 (1-5 ng), in comparison to control proximal tubular suspensions. OKC subjected to cyclic mechanical stretch for 1-24 h had marked decrements in catalase mRNA levels, compared with unstretched cells at the same time point. These results indicate that a primary downregulation of proximal tubular Cu,Zn-SOD and catalase expression develops in the proximal tubules of UUO with consequent increments in cortical oxidant levels. These findings suggest that either an early mechanical disturbance produced by UUO or local tubular generation of cytokines can reduce tubular catalase expression. The downregulation of catalase mRNA expression, together with increased oxidant stress in the rat renal cortex post-UUO, may amplify the proinflammatory state of experimental hydronephrosis culminating in tubulointerstitial injury and fibrosis.

Increased expression of decorin in experimental hydronephrosis.

Transforming growth factor (TGF)-beta1 is a potential mediator of tubulointerstitial (TI) fibrosis in the rat unilateral ureteral obstruction (UUO) model. Decorin is a protein composed of a core protein and a chondroitin sulfate side chain and is capable of inactivating TGF-beta. Since TGF-beta strongly induces the synthesis of decorin in experimental glomerulonephritis, it was our intent to investigate whether altered decorin expression is operant in the rat UUO model. Renal cortical decorin mRNA levels initially became elevated (2.5-fold) in obstructed kidney (OBK) versus contralateral unobstructed kidney (CUK) 24 hours post-UUO and remained greater in the OBK specimens at 48 (2.3-fold), 96 (2.2-fold), and 168 (1.9-fold) hours post-ureteral ligation. Whole-body X-irradiation 11 days prior to UUO significantly reduced decorin mRNA at 24 and 96 hours post-UUO. On immunolabeling, decorin was only evident in the adventitia of blood vessels in CUK specimens at any time point after UUO. In contrast, OBK specimens initially demonstrated periglomerular and peritubular interstitial localization of decorin at 96 hours post-ureteral ligation, which became even more intense and diffuse in the tubulointerstitium at 168 hours post-UUO. On Western analysis, there were highly significant increases in decorin protein expression in the OBK versus the CUK specimens at 96 and 168 hours post-UUO. Levels of active TGF-beta1 in the renal cortex of OBK were 1.9- and 3.6-fold higher than CUK at 48 and 96 hours post-UUO. In summary, we demonstrated that post-UUO, decorin mRNA and protein expression is up-regulated in the renal cortex of OBK, but not CUK, specimens in a temporal parallel with active TGF-beta1 levels and macrophage infiltration. We postulate that the development of TI fibrosis in this model may be related to only a physiologic induction of decorin by TGF-beta, and that pharmacologic levels may be required to retard or prevent scarring via TGF-beta inhibition.

Obstructive nephropathy as a result of retroperitoneal fibrosis: a review of its pathogenesis and associations.

Retroperitoneal fibrosis is a rare disease, typically with an insidious clinical course. It is thought that this disease process is perhaps an exaggerated reaction to an inciting inflammatory event. In this study, a case of retroperitoneal fibrosis is reported, in which the patient presented with typical symptoms of retroperitoneal fibrosis, along with some atypical vasculitic symptomatology. Retroperitoneal fibrosis is a disease process with an unknown etiology, which has been observed to be associated with a number of different possible inciting factors. Two factors that have been documented in the literature as being associated with retroperitoneal fibrosis include the use of beta-blocking agents, and connective tissue disease processes such as systemic lupus erythematosus. The patient discussed was using beta-blocker medication and also had signs and symptoms suggestive of a lupus syndrome. There are no reported cases of the combined association of beta-blocker usage, lupus, and retroperitoneal fibrosis.