Impact of the new risk stratification in the 2011 Japanese Society of Nephrology clinical guidelines for IgA nephropathy on incidence of early clinical remission with tonsillectomy plus steroid pulse therapy.

BACKGROUND: In 2011, the Japanese Society of Nephrology (JSN) published new clinical guidelines for IgA nephropathy (IgAN) with a new risk stratification based on clinical and histological severity. For classification, patients are divided into four groups (low, medium, high, and very high risk). However, differences in responsiveness to each treatment among different groups remain unclear. We evaluate the responsiveness of tonsillectomy plus steroid pulse (TSP) therapy using the new risk stratification. METHODS: We retrospectively reviewed 111 IgAN patients with TSP therapy between January 2003 and January 2013. Study patients were divided into three groups [low- (n = 40), medium- (n = 43) and high-/very high-risk group (n = 28)]. The primary outcome was clinical remission (CR). The observation period was 1 year following tonsillectomy. RESULTS: 57 out of 111 patients (51.4 %) reached CR. The CR incidence was 70.0, 41.9 and 39.3 % (the low-, the medium- and the high-/very high-risk group, respectively). The incidence of CR was significantly higher in the low-risk group (P = 0.013). In a multivariate logistic regression analysis, both the medium- and the high-/very high-risk group showed significantly lower incidence of inducing CR than the low-risk group [(odds ratio 0.324; 95 % confidence interval 0.106-0.939, P = 0.041) (odds ratio 0.239; 95 % confidence interval 0.058-0.910, P = 0.040), respectively]. CONCLUSIONS: The new risk stratification in the 2011 JSN clinical guidelines for IgAN had a positive impact on early CR of TSP therapy.

Regulation of chemokine CCL5 synthesis in human peritoneal fibroblasts: a key role of IFN-γ.

Peritonitis is characterized by a coordinated influx of various leukocyte subpopulations. The pattern of leukocyte recruitment is controlled by chemokines secreted primarily by peritoneal mesothelial cells and macrophages. We have previously demonstrated that some chemokines may be also produced by human peritoneal fibroblasts (HPFB). Aim of our study was to assess the potential of HPFB in culture to release CCL5, a potent chemoattractant for mononuclear leukocytes. Quiescent HPFB released constitutively no or trace amounts of CCL5. Stimulation of HPFB with IL-1ß and TNF-α resulted in a time- (up to 96 h) and dose-dependent increase in CCL5 expression and release. IFN-γ alone did not induce CCL5 secretion over a wide range of concentrations (0.01-100 U/mL). However, it synergistically amplified the effects of TNF-α and IL-1ß through upregulation of CCL5 mRNA. Moreover, pretreatment of cells with IFN-γ upregulated CD40 receptor, which enabled HPFB to respond to a recombinant ligand of CD40 (CD40L). Exposure of IFN-γ-treated HPFB, but not of control cells, to CD40L resulted in a dose-dependent induction of CCL5. These data demonstrate that HPFB synthesise CCL5 in response to inflammatory mediators present in the inflamed peritoneal cavity. HPFB-derived CCL5 may thus contribute to the intraperitoneal recruitment of mononuclear leukocytes during peritonitis.

Human peritoneal fibroblasts are a potent source of neutrophil-targeting cytokines: a key role of IL-1beta stimulation.

Polymorphonuclear leukocyte (PMN) infiltration is a cardinal feature of peritonitis. CXC chemokine ligands 1 and 8 (CXCL1 and CXCL8), and the cytokine granulocyte colony-stimulating factor (G-CSF) are the key mediators of PMN accumulation. Increasing evidence points to an important role of human peritoneal fibroblasts (HPFB) in the response of the peritoneum to infection. We have examined the synthesis of PMN-targeting cytokines by HPFB exposed to intraperitoneal milieu as represented by peritoneal dialysate effluent (PDE) from patients undergoing peritoneal dialysis. PDE obtained during peritonitis, but not during infection-free periods, significantly increased production of CXCL1, CXCL8, and G-CSF by HPFB. The effect was largely blocked by antibodies to interleukin-1beta (IL-1beta), whereas neutralization of tumor necrosis factor-alpha (TNFalpha) had no major effect. Similar pattern of inhibition was observed when HPFB were exposed to conditioned media from endotoxin-stimulated peritoneal macrophages. Significance of IL-1beta stimulation was further shown in experiments with recombinant cytokines. Compared with TNFalpha, exposure of HPFB to recombinant IL-1beta resulted in a much higher release of PMN-targeting cytokines. The assessment of mRNA degradation revealed that the IL-1beta-induced transcripts of CXCL1, CXCL8, and G-CSF were more stable compared with those induced by TNFalpha. These data indicate that HPFB can be a significant source of PMN-targeting cytokines when stimulated with IL-1beta in the inflamed peritoneum.

A strict low protein diet during the predialysis period suppresses peritoneal permeability at induction of peritoneal dialysis.

BACKGROUND: The factors that predict baseline peritoneal permeability remain largely unknown. We noticed that patients that adhered to a strict low protein diet (LPD) during the predialysis period seldom showed high peritoneal permeability on the peritoneal equilibration test (PET) at the introduction of peritoneal dialysis (PD). Therefore, we investigated whether a strict LPD during the predialysis period affects peritoneal permeability. METHOD: We retrospectively analyzed 37 patients that started PD in a single Japanese center. Patients were divided into group A and group B by the median amount of daily protein intake (PI) during the predialysis period using urine collected over 24 hours. RESULTS: There were no differences between groups A and B in age, gender, proportion of diabetic nephropathy, blood pressure, body mass index, or body surface area. There were also no differences between the groups in laboratory findings, including hematocrit, serum albumin, and serum creatinine. The PETs showed a significantly lower dialysate-to-plasma ratio of creatinine at 4 hours (Cr D/P) for group A than for group B (p = 0.02). Furthermore, a significant positive correlation between Cr D/P and PI was observed (r = 0.53, p < 0.01). CONCLUSION: It is suggested that a strict LPD during the predialysis period may suppress peritoneal permeability at induction of PD.

Collagenofibrotic glomerulopathy with a widespread expression of type-V collagen.

Collagenofibrotic glomerulopathy is considered as a form of glomerulopathy in which organized collagen type III progressively deposits. We report a case of this disease with widespread expression of collagen type V. A 65-year-old woman was admitted to our hospital for further evaluation of nephrotic-range proteinuria. The patient had had anemia and hypertension for 9 years, and proteinuria for 3 years. A renal biopsy specimen showed a remarkable mesangial expansion with Congo red-negative and periodic acid-Schiff-positive deposits. At the ultrastructural level, two forms of bundling fibers were found in the mesangium and subendothelial side of the glomerular basement membranes (GBM). The GBM itself appeared normal. Immunohistochemical investigation showed that the glomerular lesions were strongly reactive with both anti-collagen type-III and -V antibodies. Immunoelectron microscopy demonstrated collagen type V in both forms of bundling fibers. Despite therapy, her renal function declined. The clinical course and renal pathology of this case were in accordance with collagenofibrotic glomerulopathy except for the widespread expression of collagen type V. Collagen type V is a fibrillar collagen capable of forming banding fibrils. This report poses the question whether collagen type V accumulates only in this particular case or whether it is a normal component in collagenofibrotic glomerulopathy.

Renal sarcoidosis with limited lung manifestations expressing Propionibacterium acnes antigens in the affected tubulointerstitium.

Sarcoidosis is a granulomatous multisystemic disorder of unknown origin that can affect the kidneys. Previous reports from Japan and Europe have indicated a link between Propionibacterium acnes infections and sarcoidosis. Here, we present the case of a 68-year-old woman with hypercalcemia and renal failure. A kidney biopsy was performed, which showed granulomatous tubulointerstitial nephritis with a large nonnecrotic nodule that contained mononuclear inflammatory cells and multinucleated giant cells. Subsequent immunohistochemical analysis revealed intracytoplasmic structures, which strongly indicated the presence of the P acnes antigen. Treatment with methylprednisolone ameliorated the patient's hypercalcemia and renal failure. This case report emphasizes the potential of chronic P acnes infection to cause sarcoidosis.

Aldosterone mediates glomerular inflammation in experimental mesangial proliferative glomerulonephritis.

BACKGROUND: The renoprotection of the mineralocorticoid receptor antagonist (MRA) is considered to be mainly via its antifibrotic activity, and the possibility that it may also have antiinflammatory effects has not been studied. We tested the hypothesis that MRA might influence the inflammatory changes that accompany experimental glomerular injury. METHODS: Administration of vehicle (control) or a selective MRA, eplerenone (50 mg/kg x 2 times/day) was started 7 days (-7d) before induction of anti-Thy-1.1 glomerulonephritis. Kidney samples were evaluated serially over a 12-day period for the presence of cell proliferation, macrophage infiltration, mesangial cell phenotypic activation and expression of the chemokine monocyte chemoattractant protein-1 (MCP-1). RESULTS: MRA did not prevent the mesangiolysis associated with anti-Thy-1 antibody. However, MRA significantly inhibited MCP-1 expression, glomerular macrophage infiltration and mesangial phenotypic activation (alpha-smooth muscle actin expression). CONCLUSION: MRA alters glomerular inflammation and mesangial cell activation in experimental glomerular injury. MRA may be a novel way to treat acute glomerular diseases.