Chronically Elevated Levels of Short-Chain Fatty Acids Induce T Cell-Mediated Ureteritis and Hydronephrosis.

Short-chain fatty acids (SCFAs) are major products of gut microbial fermentation and profoundly affect host health and disease. SCFAs generate IL-10(+) regulatory T cells, which may promote immune tolerance. However, SCFAs can also induce Th1 and Th17 cells upon immunological challenges and, therefore, also have the potential to induce inflammatory responses. Because of the seemingly paradoxical SCFA activities in regulating T cells, we investigated, in depth, the impact of elevated SCFA levels on T cells and tissue inflammation in mice. Orally administered SCFAs induced effector (Th1 and Th17) and regulatory T cells in ureter and kidney tissues, and they induced T cell-mediated ureteritis, leading to kidney hydronephrosis (hereafter called acetate-induced renal disease, or C2RD). Kidney hydronephrosis in C2RD was caused by ureteral obstruction, which was, in turn, induced by SCFA-induced inflammation in the ureteropelvic junction and proximal ureter. Oral administration of all major SCFAs, such as acetate, propionate, and butyrate, induced the disease. We found that C2RD development is dependent on mammalian target of rapamycin activation, T cell-derived inflammatory cytokines such as IFN-γ and IL-17, and gut microbiota. Young or male animals were more susceptible than old or female animals, respectively. However, SCFA receptor (GPR41 or GPR43) deficiency did not affect C2RD development. Thus, SCFAs, when systemically administered at levels higher than physiological levels, cause dysregulated T cell responses and tissue inflammation in the renal system. The results provide insights into the immunological and pathological effects of chronically elevated SCFAs.

Testicular inflammation as a new manifestation of IgG4-associated disease.

IgG4-related disease has properties of a systemic disorder but simultaneously is associated with a growing list of organ-specific manifestations including autoimmune pancreatitis, IgG4-associated cholangitis, IgG4-related kidney disease, and IgG4-associated prostatitis. In this study, we present, to the best of our knowledge, the first case of a patient with multiorgan IgG4-related disease who lost his testes because of IgG4-related testicular inflammation. We postulate that IgG4-related disease in the urogenital tract is not restricted to IgG4-related kidney disease and prostatitis, but that this rare disorder may also affect the testis.

A case of IgG4-related tubulointerstitial nephritis with left hydronephrosis after a remission of urinary tract tuberculosis.

IgG4-related systemic disease encompasses multi-organ disorders, including tubulointerstitial nephritis. This disease is accompanied by a high serum IgG4 concentration and IgG4-positive plasma cell infiltration. We herein describe a 63-year-old woman with renal failure and dryness of the eyes and mouth, who had been treated with antituberculosis agents for urinary tract tuberculosis. She had a negative finding for a PCR analysis for Mycobacterium tuberculosis, a positive QuantiFERON-TB test, high serum IgG4 concentrations (2,660 mg/dl), and low serum IgM and IgA concentrations (34 and 82 mg/dl, respectively). Imaging tests revealed swelling in the submandibular glands, pancreas, and right kidney. A renal biopsy showed IgG4-positive plasma cell infiltration in the interstitium and tubular atrophy. This case was diagnosed as IgG4-related systemic disease. Corticosteroid therapy improved renal failure and swelling in the submandibular glands, pancreas, and right kidney. The case suggests that an abnormal reaction to tuberculosis may be associated with a predominance of type-2 helper T-cell immunity, thus resulting in IgG4-related systemic disease.

[IgG4-related prostatitis associated with retroperitoneal fibrosis: a case report].

A 70-year-old male was referred to our hospital because of an abnormally high prostate specific antigen (PSA) level (4.4 ng/ml) associated with lower urinary tract symptoms. Needle biopsy of the prostate did not reveal any malignant tissue. Four months later, the patient presented again with hydronephrosis, which was diagnosed using ultrasonography. Furthermore, contrast-enhanced computed tomography (CT) and magnetic resonance imaging (MRI) revealed left hydronephrosis caused by a soft tissue mass around the left iliac artery compressing the left ureter. Serum IgG4 level was 918 mg/dl. On immunohistochemical reevaluation of the prostate biopsy specimens, the samples were positive for IgG4 immunostaining. The patient was finally diagnosed with IgG4-related prostatitis with retroperitoneal fibrosis. With steroid therapy, the hydronephrosis and urinary symptoms were ameliorated. Our experience with this case suggests that in a male patient with urinary symptoms, biopsy of the prostate may be useful for exact diagnosis when IgG4-related disease is suspected.

Mast cell activation and degranulation promotes renal fibrosis in experimental unilateral ureteric obstruction.

Progressive renal fibrosis is the final common pathway leading to renal failure irrespective of the initiating cause. Clinical studies of renal fibrosis found that prominent mast cell accumulation correlated with worse outcomes. Mast cells are pluripotent innate immune cells that synthesize and secrete profibrotic mediators. Here we use mast cell-deficient (Kit(W-sh/W-sh)) mice to define a functional pathogenic role for these cells in the development of renal fibrosis. Intrarenal collagen deposition was significantly decreased in mast cell-deficient compared to wild-type mice 7 and 14 days after unilateral ureteric obstruction. The intrarenal expression of mRNAs for transforming growth factor-ß, α-smooth muscle actin, chemokines, and renal macrophages and CD4(+) T cells were also decreased in mast cell-deficient mice. Reconstitution of the mast cell population in mast cell-deficient mice with wild-type bone marrow-derived mast cells restored the pattern and intensity of renal fibrosis to levels seen in wild-type mice following ureteric ligation. Interestingly, the mast cells were recruited, activated, and degranulated within 6 h of ureteric ligation. A mast cell stabilizer that impairs degranulation, disodium chromoglycate, significantly attenuated renal fibrosis following ureteric ligation in wild-type mice. Thus, mast cells promote renal fibrosis and their targeting may offer therapeutic potential in the treatment of renal fibrosis.

Urinary cytokine profiles in unilateral congenital hydronephrosis.

BACKGROUND: We aimed to evaluate possible clinical application of urinary monocyte chemotactic protein-1 (MCP-1), osteopontin (OPN), and regulated upon activation, normal T-cell expressed and secreted (RANTES) chemokine as useful noninvasive markers in children with congenital hydronephrosis (HN) caused by ureteropelvic junction obstruction (UPJO). METHODS: The study cohort consisted of surgical cases (study group 1), comprising 15 children with severe HN who required surgery (median age 1.03 years), conservative cases (study group 2), comprising 21 patients with mild, nonobstructive HN, and control group, comprising 19 healthy children. All children had normal renal function. Urinary (u) concentrations of MCP-1, OPN, and RANTES were measured using immunoenzymatic enzyme-linked immunosorbent assay (ELISA) commercial kits and were expressed in nanograms per milligram creatinine. Increased levels of MCP-1 and OPN were found in children with HN in comparison with study group 2 and controls (p < 0.05). UMCP-1/Cr correlated with half-time (T(1/2)) of the elimination phase of tracer excretion of technetium-99m-mercaptoacetyltriglycine ((99m)Tc-MAG-3) (p < 0.05). RESULTS: Receiver operator characteristic (ROC) analyses revealed good diagnostic profile for uMCP-1 only in identifying children (<40 %) with abnormal differential renal function (DRF) [area under the curve (AUC) 0.862], and in detecting kidney injury in all examined children (AUC 0.704). CONCLUSIONS: Additional studies with larger number of patients are required to confirm a potential application of uMCP-1 as a promising parameter for early identification of kidney obstruction.

Antimyeloperoxidase antibodies rapidly induce alpha-4-integrin-dependent glomerular neutrophil adhesion.

Patients with antineutrophil cytoplasmic antibodies (ANCAs) frequently develop severe vasculitis and glomerulonephritis. Although ANCAs, particularly antimyeloperoxidase (anti-MPO), have been shown to promote leukocyte adhesion in postcapillary venules, their ability to promote adhesion in the glomerular vasculature is less clear. We used intravital microscopy to examine glomerular leukocyte adhesion induced by anti-MPO. In mice pretreated with LPS, 50 microg anti-MPO induced LFA-1-dependent adhesion in glomeruli. In concert with this finding, in mice pretreated with LPS, more than 80% of circulating neutrophils bound anti-MPO within 5 minutes of intravenous administration. However, even in the absence of LPS, more than 40% of circulating neutrophils bound anti-MPO in vivo, a response not seen in MPO(-/-) mice. In addition, a higher dose of anti-MPO (200 microg) induced robust glomerular leukocyte adhesion in the absence of LPS. The latter response was beta2-integrin independent, instead requiring the alpha4-integrin, which was up-regulated on neutrophils in response to anti-MPO. These data indicate that anti-MPO antibodies bind to circulating neutrophils, and can induce glomerular leukocyte adhesion via multiple pathways. Lower doses induce adhesion only after an infection-related stimulus, whereas higher doses are capable of inducing responses in the absence of an additional inflammatory stimulus, via alternative adhesion mechanisms.

Leukocyte recruitment to the inflamed glomerulus: a critical role for platelet-derived P-selectin in the absence of rolling.

The renal glomerulus is one of the few sites within the microvasculature in which leukocyte recruitment occurs in capillaries. However, due to the difficulty of directly visualizing the glomerulus, the mechanisms of leukocyte recruitment to glomerular capillaries are poorly understood. To overcome this, we rendered murine kidneys hydronephrotic to allow the visualization of the functional glomerular microvasculature during an inflammatory response. These experiments demonstrated that following infusion of anti-glomerular basement membrane (GBM) Ab, leukocytes became adherent in glomerular capillaries via a process of immediate arrest, without undergoing prior detectable rolling. However, despite the absence of rolling, this recruitment involved nonredundant roles for the P-selectin/P-selectin glycoprotein ligand-1 and beta2 integrin/ICAM-1 pathways, suggesting that a novel form of the multistep leukocyte adhesion cascade occurs in these vessels. Anti-GBM Ab also increased glomerular P-selectin expression and induced a P-selectin-independent increase in platelet accumulation. Moreover, platelet depletion prevented both the increase in glomerular P-selectin, and the leukocyte recruitment induced by anti-GBM Ab. Furthermore, depletion of neutrophils and platelets also prevented the increase in urinary protein excretion induced by anti-GBM Ab, indicating that their accumulation in glomeruli contributed to the development of renal injury. Finally, infusion of wild-type platelets into P-selectin-deficient mice restored the ability of glomeruli in these mice to support leukocyte adhesion. Together, these data indicate that anti-GBM Ab-induced leukocyte adhesion in glomeruli occurs via a novel pathway involving a nonrolling interaction mediated by platelet-derived P-selectin.

Hydronephrosis associated with antiurothelial and antinuclear autoantibodies in BALB/c-Fcgr2b-/-Pdcd1-/- mice.

Because most autoimmune diseases are polygenic, analysis of the synergistic involvement of various immune regulators is essential for a complete understanding of the molecular pathology of these diseases. We report the regulation of autoimmune diseases by epistatic effects of two immunoinhibitory receptors, low affinity type IIb Fc receptor for IgG (FcgammaRIIB) and programmed cell death 1 (PD-1). Approximately one third of the BALB/c-Fcgr2b(-/-)Pdcd1(-/-) mice developed autoimmune hydronephrosis, which is not observed in either BALB/c-Fcgr2b(-/-) or BALB/c-Pdcd1(-/-) mice. Hydronephrotic mice produced autoantibodies (autoAbs) against urothelial antigens, including uroplakin IIIa, and these antibodies were deposited on the urothelial cells of the urinary bladder. In addition, approximately 15% of the BALB/c-Fcgr2b(-/-)Pdcd1(-/-) mice produced antinuclear autoAbs. In contrast, the frequency of the autoimmune cardiomyopathy and the production of anti-parietal cell autoAb, which were observed in BALB/c-Pdcd1(-/-) mice, were not affected by the additional FcgammaRIIB deficiency. These observations suggest cross talk between two immunoinhibitory receptors, FcgammaRIIB and PD-1, on the regulation of autoimmune diseases.

[Correlational studies of urine interleukin 6, interleukin 8 and nitric oxide in the patients with pyelonephritis and hydronephrosis].

The urine concentration of IL-6, IL-8 and nitric oxide (NO) were determined in the patients with pyelonephritis and hydronephrosis. Correlations between urine levels of IL-6 and IL-8 and amount of nitric oxide in the hydronephrosis patients were not found. However, in the patients with both acute and chronic pyelonephritis the coefficient of correlation was high, r((IL-6/NO)) = 0,94 and r((IL-8/NO)) = 0,86 for acute and r((IL-6/NO)) = 0,72 and r((IL-8/NO)) = 0,40 for chronic forms, respectively. These data suggest that secretion of NO during hydronephrosis has a compensatory character and acted on renal microvascular tone, whereas during pyelonephritis NO produced inflammatory mediators by recruiting leukocytes and has pathogenic character.

Giant hydronephrosis with increased carbohydrate antigen 19-9 both in serum and fluid.

We report a case of right giant hydronephrosis. A 68-year-old man was admitted to our hospital with chief complaints of general fatigue, loss of appetite and a one-year history of progressive fullness on whole abdomen. Abdominal computed tomography scan exhibited a huge, homogeneous, low density mass originating from the right kidney. We performed right percutaneous nephrostomy and drained over 6,500 ml bloody fluid. Cytological examination of the drained fluid revealed atypical nuclear appearance defined as class III. Increased values of carbohydrate antigen 19-9 were observed both in the fluid as well as in the serum. We performed right nephrectomy. Macroscopic appearance of the resected kidney showed marked stenosis at the portion of ureteropelvic junction. Histological analysis of the stenotic portion demonstrated marked fibrosis without findings of malignancy.

[Immune disorders in congenital hydronephrosis complicated by obstructive pyelonephritis]. / Immunnye nausheniia pri vrozhdennom gidronefroze, oslozhnennom obstruktivnym pielonefritom.

Congenital hydronephrotic transformation complicated by obstructive pyelonephritis with intact renal function in children exhibited association with some antigens of the major histocompatibility system and their combinations, changes in immunity and nonspecific resistance. Marked and stable shifts in immune reactivity give grounds for inclusion of immunomodulating drugs in combined treatment of the above patients.

MP84 expression in pyelonephritis and hydronephrosis kidney biopsy sections.

MP84 is a novel antigen expressed in the primary glomerulonephritis kidney biopsy section and stimulated mesangial cells and matrix but not in the normal kidney and other tissue sections or any other cell lines tested except Bewo choriocarcinoma cell line. This is the first report of MP84 expression in pyelonephritis and hydronephrosis kidney sections. The distribution of the antigen is different from the primary glomerulonephritis kidney sections studied previously such as membranous, minimal change, focal and segmental, and IgA nephropathy. This may have an important correlation with the pathological concept underlying the disease.

[Hydronephrosis associated with elevated serum levels of CA 125 antigen. Report of a case]. / Idronefrosi associata ad elevati livelli sierici dell'antigene CA 125. Descrizione di un caso.

High level of the CA 125 serum antigen is typically associated with ovarian malignancies. However the CA 125 antigen can also be found in association with inflammation or neoplasms of tissues other than ovaries, i.e. mesothelial cells, mullerian duct derivatives and gastroenteric tract. Therefore the marker is not specific for ovarian neoplasms. In childhood there is not a large experience about clinical meaning of high CA 125 serum levels. We report a case in a 14-year-old patient, female, affected by hydronephrosis. Our case confirms that high CA 125, especially in childhood, is not necessarily associated with ovarian or pelvic diseases. Moreover the review of literature suggests the opportunity to investigate CA 125 serum levels in children affected by hydronephrosis.

[A case of hydronephrosis with high level of serum Span-1 antigen and CA19-9].

A sixty-year-old woman visited our hospital with a complaint of left flank pain. Laboratory data showed a high level of serum CA19-9. Computerized tomography and ultrasonography revealed left hydronephrosis and hydroureter. No tumors were found in the liver, pancreas, gallbladder, gastrointestinal tract or genitourinary tract. The serum SPan-1 antigen level was elevated to 250 U/ml, and the serum CA19-9 level was also elevated to 580 U/ml. Since urological malignancy was not excluded from these findings, left nephroureterectomy was performed. Pathological findings revealed chronic inflammation, and malignant cells were not found in the resected specimens. Although high levels of SPan-1 antigen and CA19-9 have been reported in benign diseases, both are usually less than 100 U/ml. In this case, serum SPan-1 antigen and CA19-9 levels were extremely high (more than 1,000 U/ml). Since the serum SPan-1 antigen and CA19-9 levels were gradually reduced to normal levels within 4 months after the operation, a possible explanation for the high levels of the two tumor markers is hydronephrosis in the left kidney. We report this interesting hydronephrosis associated with high levels of serum SPan-1 antigen and CA19-9.

Tissue factor expression in an animal model of hydronephrosis.

BACKGROUND: Hydronephrosis is associated with interstitial fibrosis and occlusion of renal capillaries by fibrin. However, the mechanisms leading to fibrin formation is unknown. METHODS AND RESULTS: Twenty days after unilateral ligation of the ureter, interstitial fibrosis occurred in the ligated kidney. Fibrosis was preceded by infiltration of inflammatory cells (macrophages, B and T lymphocytes). Staining with an antibody against von Willebrand factor demonstrated newly formed capillaries in the fibrosing tissue as well as prominent fibrin deposition. Fibrin staining was found around vessels, in the interstitium, the glomeruli, and tubuli. Fibrin deposition was less prominent in the non-ligated kidney and almost absent in sham-operated animals. The expression of tissue factor, the central initiator of coagulation, was induced within 5 days after ligation in the operated kidney but not in the sham-operated animals. Tissue factor positivity was observed by immunohistochemistry in vascular endothelial cells, the vessel wall, tubular epithelial cells, glomerular capsular cells, Bowman's space and in the interstitium. Tissue factor induction was due to increased transcription, since in-situ hybridization showed increased levels of mRNA in the ligated kidney compared to sham-operated rats. The tissue factor gene is under control of the transcription factors activator protein-1 (AP-1) and nuclear factor-kappa B (NF-kappa B). When extracts of operated organs were compared with kidneys of sham-operated rats or contralateral kidneys in electrophoretic mobility shift assays, an increase in AP-1 and NF-kappa B binding activity to their respective binding sites in the tissue factor gene was observed in the operated, but not in the contralateral kidney or kidneys of sham-operated animals. CONCLUSION: Ureteral ligation leads to infiltration of inflammatory cells, increased AP-1 and NF-kappa B expression in the kidney, resulting in increased tissue factor transcription and translation, and ultimately in increased fibrin deposition.

[A case of hydronephrosis caused by renal stones with elevated serum levels of CA-19-9 and CA-125].

A case of hydronephrosis caused by renal stones with elevated serum levels of carbohydrate antigens 19-9 (CA-19-9) and 125 (CA-125) is reported. A 74-year-old woman was hospitalized with pyelonephritis. The results of computerized tomography and endoscopy suggested that the patient did not have pancreatic or ovarian cancer, but laboratory tests were significant for serum CA-19-9 greater than 1,000 U/ml (normal less than 37) and serum CA-125 78 U/ml (normal less than 35), which are markers for such tumors. Abdominal X-ray films showed stones in the pelvis of the right kidney. Excretory urography showed that the right kidney was not functioning. Computerized tomography showed severe right hydronephrosis with a thin renal cortex. Complete obstruction of the ureteropelvic junction of the kidney was seen by retrograde pyelography. During percutaneous pyelography, aspiration of the pelvic urine was done, and the sample had a high concentration of CA-19-9 (250,000 U/ml), but no cancer cells. The patients underwent right nephrectomy. The pelvic urine was tested for both CA-19-9 and CA-125 this time, and both were high (190,000 U/ml and 5,100 U/ml, respectively). Pathological evaluation showed no evidence of a malignant tumor. The epithelium lining the renal pelvis was stained for both CA-19-9 and CA-125 using the avidin-biotin-peroxidase complex method. Serum levels of the markers returned to normal after nephrectomy.