Clinical Study Transperitoneal Calcium Balance in Anuric Continuous Ambulatory Peritoneal Dialysis and Automated Peritoneal Dialysis Patients

Backgrounds. Calcium (Ca) and bone metabolism in continuous ambulatory peritoneal dialysis (CAPD) and hemodialysis (HD) patients show a remarkable difference depending on dialysis modalities. The levels of serum Ca and phosphate (P) in HD patients fluctuate contributing to the intermittent and rapid removal of plasma solute unlike in CAPD. Characteristics of plasma solute transport in automated peritoneal dialysis (APD) patients are resembled with that in HD. The purpose of the present study was to examine the difference of transperitoneal Ca removal between APD and CAPD anuric patients. Subjects and Methods. Twenty-three APD anuric patients were enrolled in this study. Biochemical parameters responsible for transperitoneal Ca removal in 24-hour and 4-hour peritoneal effluents were analyzed on CAPD and APD. Results. Transperitoneal Ca removal on APD was smaller compared with that on CAPD. The Ca removal was related to the ultrafiltration during short-time dwell. Decrease of the Ca removal during NPD induced by short-time dialysate dwell caused negative or small Ca removal in APD patients. The levels of intact PTH were increased at the end of PET. Conclusion. It appears that short-time dwell and frequent dialysate exchanging might suppress the transperitoneal Ca removal in anuric APD patients

Effect of NK-104 on proliferation of cells

AbstractObjectiveProducts of intracellular mevalonate metabolism are essential for cell growth and proliferation. Inhibition of mevalonate synthesis by statins has been shown to suppress mesangial cell proliferation associated with various glomerular diseases. In this study, we investigated the effect of a new synthetic 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor, NK-104, on cultured rat mesangial cell proliferation.MethodsThe cultured rat mesangial cells were stimulated by 10% fetal calf serum or platelet-derived growth factor in the absence or presence of NK-104 and mevalonate metabolites. 5-bromo- 2-deoxyuridine incorporation was used to assess DNA synthesis. In other experiments, Ras processing and mitogen-activated protein kinase activation were analyzed by Western blotting.ResultsNK-104 inhibited fetal calf serum- or platelet-derived growth factor-stimulated Ras processing and mitogen-activated protein kinase activation. NK-104 also caused inhibition of fetal calf serum- or platelet-derived growth factor-stimulated 5-bromo-2-deoxyuridine incorporation and cell proliferation. Mevalonic acid, farnesyl pyrophosphate, and geranylgeranyl pyrophosphate significantly prevented these inhibitory effects of NK-104.ConclusionThe present results suggest that NK-104, by inhibiting the synthesis of isoprenoid metabolites of mevalonate, may modulate Ras-mediated signaling events associated with mesangial cell proliferation

Different Pathological Roles of Toll-Like Receptor 9 on Mucosal B Cells and Dendritic Cells in Murine IgA Nephropathy

Although pathogenesis of IgA nephropathy (IgAN) is still obscure, pathological contribution of mucosal immunity including production of nephritogenic IgA and IgA immune complex (IC) has been discussed. We have reported that mucosal toll-like receptor (TLR)-9 is involved in the pathogenesis of human and murine IgAN. However, cell-type expressing TLR9 in mucosa remains unclear. To address this, we nasally challenged cell-specific CpG DNA ((i): dendritic cell: (DC), (ii): B cell, (iii): both), known as ligand for TLR9, to IgAN prone mice and analyzed disease phenotype of each group. After 8 times of the weekly administration, every group showed deterioration of glomerular damage. However, CpG-A-group showed clear extension of mesangial proliferative lesions with increase of serum IgA-IgG2a IC and its glomerular depositions, while CpG-B-group showed extent of glomerular sclerotic lesions with increase of serum and glomerular IgA and M2 macrophage infiltration. Present results indicate that mucosal TLR9 on B cells and DC may differently contribute to the progression of this disease via induction of nephritogenic IgA or IgA-IgG IC, respectively. This picture is suggestive for the pathological difference between child and adult IgAN

Pathological Role of Tonsillar B Cells in IgA Nephropathy

Although impaired immune regulation along the mucosa-bone marrow axis has been postulated to play an important role, the pathogenesis of IgA nephropathy (IgAN) is unknown; thus, no disease-specific therapy for this disease exists. The therapeutic efficacy of tonsillectomy or tonsillectomy in combination with steroid pulse therapy for IgAN has been discussed. Although randomized control trials for these therapies are ongoing in Japan, the scientific rationale for these therapies remains obscure. It is now widely accepted that abnormally glycosylated IgA1 and its related immune complex (IC) are probably key molecules for the pathogenesis, and are thus considered possible noninvasive biomarkers for this disease. Emerging evidence indicates that B cells in mucosal infections, particularly in tonsillitis, may produce the nephritogenic IgA. In this paper, we briefly summarize characteristics of the nephritogenic IgA/IgA IC, responsible B cells, and underlying mechanisms. This clinical and experimental information may provide important clues for a therapeutic rationale

Distinct contribution of Fc receptors and angiotensin II-dependent pathways in anti-GBM glomerulonephritis

Distinct contribution of Fc receptors and angiotensin II-dependent pathways in anti-GBM glomerulonephritis.BackgroundThe contribution of antibody and/or immune-complex to the pathogenesis of immunologically-mediated glomerulonephritis is not fully understood, although it has been recently clarified that Fc receptors (FcRs) play critical roles in the inflammatory cascade. We therefore re-evaluated the classical model of glomerulonephritis, anti-glomerular basement membrane antibody-induced glomerulonephritis (Anti-GBM GN), from the standpoint of FcRs and also investigated the residual FcR-independent mechanisms.MethodsWe adopted an Anti-GBM GN mouse model that has two strains deficient in the FcR γ chain [γ(-/-)] or FcγRIIB [RII(-/-)], and analyzed functional (urinary protein, serum creatinine, BUN) and pathological changes of the glomeruli. For the analyses of FcR-independent mechanisms, several doses of nephrotoxic serum were applied, and then mice were treated either with cobra venom factor or an angiotensin II type 1 receptor antagonist in γ(-/-) mice.ResultsIn γ(-/-) mice, renal injuries were dramatically attenuated with an absence of polymorphonuclear cell (PMN) influx, while RII(-/-) mice suffered accelerated glomerular injuries in spite of a normal PMN influx. In the absence of FcR-dependent effects in γ(-/-) mice, the FcR-independent pathway lead to chronic renal damage characterized by mesangial proliferation and progressive expansion of mesangial area, with monocyte/macrophage accumulation and with the expression of α smooth muscle actin in the mesangial cells and interstitium. Those injuries in γ(-/-) mice were not attenuated by the decomplementation, but completely abolished by using an angiotensin II type 1 receptor antagonist.ConclusionsOur results clearly demonstrate that FcRs play a pivotal role in Anti-GBM GN, especially in its acute phase. We further clarified the existence of FcR and complement-independent but antibody-dependent pathway. Furthermore, we found that those pathological changes were strongly related to the renin-angiotensin system

Gene expression profile in diabetic KK/Ta mice

Gene expression profile in diabetic KK/Ta mice.BackgroundTo identify susceptibility genes for diabetic nephropathy, GeneChip® Expression Analysis was employed to survey the gene expression profile of diabetic KK/Ta mouse kidneys.MethodsKidneys from three KK/Ta and two BALB/c mice at 20weeks of age were dissected. Total RNA was extracted and labeled for hybridizing to the Affymetrix Murine Genome U74Av2 array. The gene expression profile was compared between KK/Ta and BALB/c mice using GeneChip® expression analysis software. Competitive reverse transcription-polymerase chain reaction (RT-PCR) was used to confirm the results of GeneChip® for a selected number of genes.ResultsOut of 12,490 probe pairs present on GeneChip®, 98 known genes and 31 expressed sequence tags (ESTs) were found to be differentially expressed between KK/Ta and BALB/c kidneys. Twenty-one known genes and seven ESTs that increased in expression and 77 known genes and 24 ESTs that decreased in KK/Ta kidneys were identified. These genes are related to renal function, extracellular matrix expansion and degradation, signal transduction, transcription regulation, ion transport, glucose and lipid metabolism, and protein synthesis and degradation. In the vicinity of UA-1 (quantitative trait locus for the development of albuminuria in KK/Ta mice), candidate genes that showed differential expression were identified, including the Sdc4 gene for syndecan-4, Ahcy gene for S-adenosylhomocysteine hydrolase, Sstr4 gene for somatostatin receptor 4, and MafB gene for Kreisler leucine zipper protein.ConclusionThe gene expression profile in KK/Ta kidneys is different from that in age-matched BALB/c kidneys. Altered gene expressions in the vicinity of UA-1 may be responsible for the development of albuminuria in diabetic KK/Ta mice