One-year results of an open-label study on antiproteinuric effect of benidipine in elderly patients with chronic kidney disease.

BACKGROUND: The long-term antiproteinuric effects of benidipine, a calcium channel blocker (CCB), have not been evaluated in detail in hypertensive patients with chronic kidney disease (CKD). METHODS: Benidipine (4 mg/day) was administered to previously untreated hypertensive patients with CKD, or hypertensive patients with CKD not achieving target blood pressure (BP) despite taking an angiotensin II receptor blocker (ARB). The patients were followed up for 1 year. If target BP was not achieved by 2 weeks after the start of benidipine treatment, the dosage was increased to 8 mg/day. The urinary protein to creatinine (UP/cre) ratio was evaluated before and after benidipine treatment. RESULTS: This study evaluated 65 hypertensive patients with CKD. BP (systolic/diastolic) decreased from 154 ± 19 / 91 ± 12 mm Hg before treatment to 134 ± 16 / 78 ± 10 mm Hg at 1 year after treatment (p<0.001). The UP/cre ratio decreased significantly from 2.21 ± 2.47 g/g creatinine (g/g cre) before treatment to 1.43 ± 2.21 g/g cre after treatment (p<0.001). In both the untreated and ARB-treated groups, the BP and UP/cre ratio decreased significantly at 1 year after treatment. The percentage change in the UP/cre ratio was significantly greater in patients aged 65 years or older than in those less than 65 years (79.1% vs. 48.7%, p=0.038). CONCLUSIONS: Benidipine treatment reduced the UP/cre ratio in hypertensive patients with CKD, and the percentage decrease of the UP/cre ratio was greater in elderly patients, suggesting that benidipine may have more potent antiproteinuric effects in elderly hypertensive patients with CKD.

Down-regulation of core 1 beta1,3-galactosyltransferase and Cosmc by Th2 cytokine alters O-glycosylation of IgA1.

BACKGROUND: Patients with IgA nephropathy (IgAN) have an increased amount of abnormally O-glycosylated IgA1 in circulation, in glomerular deposits and produced by tissue cells in vitro. Although increased production of Th2 cytokines by peripheral blood lymphocytes and a functional abnormality of core 1 ß1,3-galactosyltransferase (C1ß3Gal-T) have been proposed as mechanisms underlying pathogenesis of IgAN, they are still obscure and are not connected. METHODS: To clarify the effect of T-cell cytokines, we analysed the mRNA levels of C1ß3Gal-T and its molecular chaperone Cosmc, C1ß3Gal-T activity and subsequent O-glycosylation of IgA1 in a human B-cell line stimulated with these cytokines. The surface IgA1-positive human B-cell line was cultured with recombinant human IFN-γ, IL-2, IL-4 or IL-5. The production and glycosylation of IgA1 were determined by sandwich ELISA and enzyme-linked lectin binding assay, respectively. The mRNA levels of C1ß3Gal-T and Cosmc were quantitatively measured by real-time PCR. C1ß3Gal-T activity was analysed using high-performance liquid chromatography. RESULTS: IgA1 production by IL-4-stimulated cells was significantly higher than controls or after IFN-γ or IL-5. The terminal glycosylation of secreted IgA1 was altered in response to IL-4. IL-4 stimulation significantly decreased the mRNA levels of both C1ß3Gal-T and Cosmc and of C1ß3Gal-T activity. IL-4 stimulation was clearly blocked by recombinant human IL-4 soluble receptor. CONCLUSIONS: It appears that Th2 cytokine IL-4 may play a key role in controlling glycosylation of the IgA1 hinge region.

Antiproteinuric effect of olmesartan in patients with IgA nephropathy.

BACKGROUND: IgA nephropathy is one of the most common primary glomerulonephritides, and the clinical course of almost 40% of the patients progresses to end-stage renal disease (ESRD) within 20 years. Angiotensin-converting enzyme (ACE) inhibitors and/ or angiotensin II receptor blockers (ARBs) induce a marked renoprotective effect in nondiabetic chronic proteinuric nephropathies including IgA nephropathy. However, in Japan, ACE inhibitors and ARBs are not used for normotensive patients. The purpose of the present study was to evaluate the antiproteinuric effect of olmesartan, one of the ARBs, in normotensive patients with IgA nephropathy in Japan. METHODS: Olmesartan was given to 25 patients for 16 weeks. The initial dose was 5 mg and was increased stepwise to 10 mg, 20 mg and 40 mg. RESULTS: Final doses were 40 mg (n=11), 20 mg (n=5), 10 mg (n=7) and 5 mg (n=2). The change in urinary protein to creatinine ratio was -56.2%+/-22.8% at week 16. Creatinine clearance showed no changes throughout the study period. Blood pressure (systolic/diastolic) was 118.9+/-7.0 / 76.8+/-7.4 mm Hg in the lead-in period and decreased to 107.0+/-10.1/66.3+/-7.8 mm Hg at week 16. At the end of treatment with olmesartan, no correlation was observed between changes in the urinary protein to creatinine ratio and mean blood pressure based on investigation of dispersion diagrams. CONCLUSIONS: Olmesartan monotherapy showed robust reduction of urinary protein in normotensive IgA nephropathy patients, suggesting that this effect is independent of its blood pressure-lowering properties.

Suppressive activity of pemirolast potassium, an antiallergic drug, on glomerulonephritis. Studies in glomerulonephritis model rats and in patients with chronic glomerulonephritis concurrently affected by allergic rhinitis.

BACKGROUND: It is still difficult to manage chronic glomerulonephritis with corticosteroids because of safety concerns, especially for patients with mild symptoms and infants. Therefore, an alternative approach is greatly required. Pemirolast potassium (CAS 100299-08-9) is an antiallergic drug with high safety. METHODS: Two glomerulonephritis rat models were prepared to examine the pharmacological actions of pemirolast potassium: one reversible model prepared with the anti-Thy-1 antibody, and another irreversible model by unilateral nephrectomy and with the anti-Thy-1 antibody. Pemirolast potassium was administered to 10 Japanese chronic glomerulonephritis patients concurrently affected by allergic rhinitis in order to examine its efficacy for mild proteinuria. RESULTS: Pemirolast potassium 1 and 10 mg/kg markedly inhibited proteinuria in the reversible model. In the irreversible model, pemirolast potassium 3 mg/kg showed a significant decrease in the incidence of glomerulosclerosis. In chronic glomerulonephritis patients, pemirolast potassium, 10 mg twice daily, for 6 months, significantly reduced the severity of proteinuria. CONCLUSION: Our research suggested the efficacy of pemirolast potassium in glomerulonephritis. A well-controlled study is considered necessary to validate pemirolast potassium as a therapeutic drug for glomerulonephritis.

Fc alpha receptor I activation induces leukocyte recruitment and promotes aggravation of glomerulonephritis through the FcR gamma adaptor.

Myeloid cells bear Fc receptors (FcR) that mediate inflammatory signaling through the ITAM-containing FcRgamma adaptor. They express FcRgamma-associated FcalphaRI, which modulate either activating or inhibitory signaling depending on the type of ligand interaction. The role of FcalphaRIgamma in disease progression remains unknown, notably in IgA nephropathy (IgAN), one of major causes of end-stage renal disease, in which large amounts of circulating IgA-immune complexes (IC) may mediate receptor activation. To analyze the involvement of FcalphaRI activation in glomerulonephritis (GN), we generated Tg mice expressing a mutated, signaling-incompetent, human FcalphaRI(R209L) that cannot associate with FcRgamma. Like FcalphaRI(wt)-Tg mice, they developed mesangial IgA deposits but not macrophage infiltration. FcalphaRI activation in FcalphaRI(wt), but not in FcalphaRI(R209L), Tg mice resulted in marked inflammation with severe proteinuria and leukocyte infiltration in spontaneous IgAN or anti-glomerular basement membrane Ab-induced GN models. Receptor triggering of syngenically transferred FcalphaRI(wt) Tg macrophages into non-Tg animals induced their recruitment into injured kidneys during GN development. FcalphaRI(wt) cross-linking on macrophages activated MAP kinases and production of TNF-alpha and MCP-1. Moreover, IgA-IC from IgAN patients activated FcalphaRI and induced TNF-alpha production. Thus, FcalphaRI activation mediates GN progression by initiating a cytokine/chemokine cascade that promotes leukocyte recruitment and kidney damage.

FcgammaRIIa-131R allele and FcgammaRIIIa-176V/V genotype are risk factors for progression of IgA nephropathy.

BACKGROUND: Fcgamma receptors (FcgammaRs) may play an important role in positive and negative regulation of immune cell responses and immune complex (IC) clearance. Mesangial IgG deposition and circulating IgG/IgA-IC in sera are observed in patients with IgA nephropathy (IgAN). Therefore, the pathological roles of IgG-IC in IgAN have been discussed. On the other hand, several studies have identified FcgammaR polymorphisms (FcgammaRIIa, FcgammaRIIIa and FcgammaRIIIb) that determine susceptibility to autoimmune diseases such as systemic lupus erythematosus and rheumatoid arthritis. The objective of the present study was to clarify whether FcgammaR polymorphisms influence susceptibility to IgAN, clinical features or severity in patients with IgAN. METHODS: Japanese patients with IgAN (n = 124) and healthy controls (n = 100) were genotyped for FcgammaR polymorphisms (FcgammaRIIa-131H or R, FcgammaRIIIa-176F or V and FcgammaRIIIb-NA1 or -NA2). The genotyping of these polymorphisms was performed using allele-specific polymerase chain reaction (PCR) methods. Associations among FcgammaR polymorphisms and susceptibility, age of onset, levels of serum immunoglobulins, intensity of glomerular IgG deposition and pathological severity were analysed. RESULTS: These three FcgammaR polymorphisms showed no significant differences in genotype and allele frequencies between the IgAN patients and healthy controls. Each FcgammaR polymorphism had no influence on age of onset, serum levels of IgG and glomerular IgG deposition in IgAN. However, FcgammaRIIa-131R (R/R or H/R) or FcgammaRIIIa-176V homozygous carriers (V/V) showed significantly more severe injury than FcgammaRIIa-131H homozygous (H/H) (P < 0.03) or FcgammaRIIIa-176F carriers (F/F or F/V) (P < 0.03), respectively. CONCLUSION: The present study shows that polymorphisms of FcgammaRIIa and FcgammaRIIIa influence the severity of IgAN in Japanese patients but not the incidence, suggesting that IgG-IC may play important roles in the progression and prognosis of this disease via FcgammaRs.

Pioglitazone attenuates TGF-beta(1)-induction of fibronectin synthesis and its splicing variant in human mesangial cells via activation of peroxisome proliferator-activated receptor (PPAR)gamma.

The peroxisome proliferator-activated receptor (PPAR)gamma is expressed not only in adipose tissue but also in macrophages/monocytes and plays important roles in acute/chronic inflammation. Transforming growth factor (TGF)-beta is a common pathogenic indicator of sclerosis because it induces the accumulation of extracellular matrix (ECM) in the glomerular mesangium of the kidney. Among components of the ECM, fibronectin (FN) is an acute reactant in inflammation, and isoforms of it produced by splicing of gene variants appear during abnormal conditions such as wound healing. In this study, we examined the effects of pioglitazone, a PPARgamma agonist, on TGF-beta(1)-induced FN synthesis in cultured mesangial cells using RT-PCR and Western blot analysis. We also analyzed its splicing variant, extra domain (ED) A, containing FN (EDA(+)FN). TGF-beta(1) enhanced the production of both FN and EDA(+) FN and down-regulated PPARgamma expression. Pioglitazone reversed both these effects of TGF-beta(1). These findings suggest that PPARgamma activation by pioglitazone may affect the TGF-beta(1)-induced FN accumulation observed in the glomerular mesangium in cases of glomerulosclerosis, although further in vivo experiments are needed to evaluate this inference.

Using protein/creatinine ratios in random urine.

We assessed the new test paper Multistix PRO IOLS, in which the +/-region of the conventional test for protein was altered so that creatinine correction became possible. Urinary samples from 235 patients with various renal diseases were obtained from the Juntendo University Hospital. We examined 1) the correlation between qualitatively measured values of urinary protein by the new test paper and the conventional test paper, and 2) the correlation between qualitative and quantitative values of protein (P), creatinine (C), and the P/C ratio measured by the new test paper. There was a good correlation between the P/C ratio observed with the new test paper and that observed by quantitative analysis. There was also a good correlation of the P/C ratio between 24-hr urine and urinary samples obtained at any time of day. Thus, it appears that the results obtained from urinary samples any time of day can predict the amount of protein excreted during the day.

Pathogenic significance of IgA receptor interactions in IgA nephropathy.

IgA nephropathy (IgAN), the most common primary glomerulonephritis worldwide, frequently progresses to renal failure. The pathogenesis of this disease involves the deposition of undergalactosylated IgA1 complexes in the glomerular mesangium. How the IgA1 complexes are generated and why they are deposited in the mesangium remains unclear. We propose a model wherein two types of IgA receptors participate in sequential steps to promote the development of IgAN, with FcalphaRI (CD89) being initially involved in the formation of circulating IgA-containing complexes and, subsequently, transferrin receptor (CD71) in mediating mesangial deposition of IgA1 complexes.

FcRn-mediated transcytosis of immunoglobulin G in human renal proximal tubular epithelial cells.

In the kidney, proteins filtered through glomeruli are reabsorbed by endocytosis along the proximal tubules to avoid renal loss of large amounts of proteins. Recently, neonatal Fc receptor (FcRn), which is involved in the transport of IgG across several epithelial and endothelial cells, was reported to be expressed in renal proximal tubular epithelial cells (RPTECs). However, there has been no direct evidence for receptor-mediated endocytosis of IgG in human RPTECs. To explore physiological roles of FcRn in the proximal tubules, we used the human RPTECs to examine IgG transport. FcRn was expressed in RPTECs and physically associated with beta(2)-microglobulin, preserving the capacity of specific pH-dependent IgG binding. Human IgG was bound to the cell surface of RPTECs in a pH-dependent manner. The human IgG transport assay revealed that receptor-mediated transepithelial transport of intact IgG in RPTECs is bidirectional and that it requires the formation of acidified intracellular compartments. With the use of double immunofluorescence, the internalized human IgG was marked in cytoplasm of RPTECs and colocalized with FcRn. These data define the mechanisms of FcRn-associated IgG transport in RPTEC monolayers. It was suggested that the intact pathway for human IgG transepithelial transport may avoid lysosomal degradation of IgG.