Hirokazu Imai

Association of monocyte chemoattractant protein-1 with renal tubular damage in diabetic nephropathy.

Monocyte chemoattractant protein-1 (MCP-1), is a chemokine that mediates renal interstitial inflammation, tubular atrophy, and interstitial fibrosis by recruiting monocytes/macrophages into renal tubulointerstitium. Recent studies have demonstrated that protein overload in renal tubular cells up-regulates MCP-1 gene and its protein expression. Therefore, we hypothesized that increased expression of MCP-1 in renal tubuli, probably triggered by an increase in the leakage of plasma protein from glomerular capillary to tubular fluid, may contribute to renal tubular damage and accelerate the progression of diabetic nephropathy. To test this hypothesis, we examined urinary excretion levels of MCP-1 and N-acetylglucosaminidase (NAG), a sensitive marker of renal tubular damage, in Japanese Type II diabetic patients with normoalbuminuria (n=29), microalbuminuria (n=25), and macroalbuminuria (n=18). The median urinary excretion level of MCP-1 in patients with macroalbuminuria (394.4 ng/g creatinine) was significantly elevated compared to the levels in patients with normoalbuminuria and microalbuminuria (159.6 and 193.9 ng/g creatinine, respectively). Furthermore, the urinary MCP-1 excretion level was positively correlated with urinary excretion levels of albumin (r=.816, P<.001) and NAG (r=.569, P<.001) in all subjects. These results suggest that MCP-1 is produced in renal tubular cells and released into urine in proportion to the degree of proteinuria (albuminuria), and that increased MCP-1 expression in renal tubuli contributes to renal tubular damage. Therefore, we conclude that heavy proteinuria itself may accelerate the progression of diabetic nephropathy by increasing the MCP-1 expression in renal tubuli.

A multicenter randomized controlled trial of tonsillectomy combined with steroid pulse therapy in patients with immunoglobulin A nephropathy

Background The study aim was, for the first time, to conduct a multicenter randomized controlled trial to evaluate the effect of tonsillectomy in patients with IgA nephropathy (IgAN). Methods Patients with biopsy-proven IgAN, proteinuria and low serum creatinine were randomly allocated to receive tonsillectomy combined with steroid pulses (Group A; n = 33) or steroid pulses alone (Group B; n = 39). The primary end points were urinary protein excretion and the disappearance of proteinuria and/or hematuria. Results During 12 months from baseline, the percentage decrease in urinary protein excretion was significantly larger in Group A than that in Group B (P < 0.05). However, the frequency of the disappearance of proteinuria, hematuria, or both (clinical remission) at 12 months was not statistically different between the groups. Logistic regression analyses revealed the assigned treatment was a significant, independent factor contributing to the disappearance of proteinuria (odds ratio 2.98, 95% CI 1.01–8.83, P = 0.049), but did not identify an independent factor in achieving the disappearance of hematuria or clinical remission. Conclusions The results indicate tonsillectomy combined with steroid pulse therapy has no beneficial effect over steroid pulses alone to attenuate hematuria and to increase the incidence of clinical remission. Although the antiproteinuric effect was significantly greater in combined therapy, the difference was marginal, and its impact on the renal functional outcome remains to be clarified.

Circulating antibodies against α‐enolase in patients with primary membranous nephropathy (MN)

MN is characterized by the glomerular deposition of IgG4 immune complexes. This suggests that nephritogenic immune responses in MN are of the Th2 T helper cell type; however, the pathogenesis of MN is still unknown. In this study we examined sera from patients with primary MN for antibodies to renal proteins. A 47‐kD protein in both human and porcine renal extracts was found by immunoblotting to react specifically with serum IgG from some patients. This protein was purified from porcine kidney and identified as α‐enolase on the basis of its partial amino acid sequences. Sera from 87 patients with primary MN, 24 patients with secondary MN (15 rheumatoid arthritis patients, nine systemic lupus erythematosus patients), and 16 healthy subjects were examined by ELISA using purified α‐enolase. In 60 (69%) patients with primary MN and 14 (58%) patients with secondary MN, the measured optical density values, and hence serum anti‐α‐enolase antibody levels, were greater than the mean + 2 s.d. of healthy subjects. Immunoblot analysis showed that IgG1 or IgG3 was the predominant subclass (Th1 T helper cell type subclass) of antibodies against α‐enolase in patients with primary and secondary MN. Since circulating antibodies against α‐enolase have recently been reported in patients with various autoimmune disorders, our results suggest that a number of patients with presumed primary MN may also have abnormalities in Th1 T helper cell‐mediated immune responses.

Serum Levels of Erythropoietin as a Novel Marker Reflecting the Severity of Diabetic Nephropathy

Erythropoietin (EPO) is reported to be mainly produced by renal peritubular interstitial cells. Serum levels of EPO may provide new information on the tubulointerstitial lesions in patients with diabetic nephropathy. We determined EPO, hemoglobin (Hb), and Hb x EPO in 63 diabetic patients who showed normo-, micro- or macroalbuminuria with normal or reduced renal function (creatinine clearance, Ccr, > or = 60 ml/min or < 60 ml/min). In addition, we followed up Ccr during a mean of 26 months in 13 patients with overt nephropathy and normal renal function. The following results were obtained: (1) Hb, EPO, and Hb x EPO values gradually decreased along with advancing stages of nephropathy, and (2) 6 patients with rapidly decreasing renal function showed significantly lower initial EPO and Hb x EPO values than 7 patients without it (p < 0.01). We conclude that EPO and Hb x EPO values may be a new marker predicting future chronic renal failure in diabetic overt nephropathy.

Carbamazepine-Induced Granulomatous Nectrotizing Angiitis with Acute Renal Failure

A 42-year-old male treated with carbamazepine developed a skin eruption in the trunk, followed by acute renal failure. Laboratory data revealed leukocytosis (15,700/mm3) with eosinophilia (37%). A renal biopsy disclosed granulomatous necrotizing angiitis that differed from classic periateritis nodosa and hypersensitivity angiitis. All drugs were discontinued immediately, and there was a gradual improvement of the renal function. A carefully performed provocation test using carbamazepine was positive. We made a diagnosis of carbamazepine-induced granulomatous necrotizing angiitis. Only 6 cases of drug-induced granulomatous angiitis have been reported prior to the present case. Drug-induced granulomatous angiitis is often fatal. The present report suggests the importance of making a diagnosis quickly, and providing adequate treatment in order to prevent a fatal course.

Disappearance of nodular mesangial lesions in a patient with light chain nephropathy after long-term chemotherapy

A 64-year-old man developed multiple myeloma (kappa light chain type), nephrotic syndrome, and renal insufficiency in 1993. A renal biopsy showed typical histological findings of light chain nephropathy: nodular glomerulosclerosis with deposition of kappa light chains in the mesangial area and subendothelial space of the glomerular capillary walls. Long-term intermittent MEVP chemotherapy (melphalan, 4 mg/d for 4 days; cyclophosphamide, 100 mg/d for 4 days; vincristine, 1 mg/d; prednisolone, 40 mg/d for 4 days) diminished proteinuria and improved renal function. In April 1999, a follow-up biopsy showed remarkable diminution of nodular lesions and disappearance of kappa light chain deposits. Although the prognosis of light chain nephropathy has been considered poor, long-term successful chemotherapy can clear light chain deposits and restore renal function.

Cobalt chloride decreases EC-SOD expression through intracellular ROS generation and p38-MAPK pathways in COS7 cells.

It is known that cells suffer a chronic hypoxic condition during the development of proximal tubulointerstitial disease. However, it is accepted that extracellular-superoxide dismutase (EC-SOD) protects the cells from oxidative stress. The purpose of this study was to elucidate the regulation of EC-SOD expression in cells under hypoxia. The results show that the expressions of EC-SOD mRNA and protein in cobalt chloride (CoCl2)-treated COS7 cells decreased in a dose- and time-dependent manner, whereas the expressions of other SOD isoforms (Cu/Zn-SOD and Mn-SOD) were not changed. The down-regulation of EC-SOD mRNA was suppressed by pre-treatment with the antioxidant trolox and the p38 mitogen-activated protein kinase (p38-MAPK) inhibitor SB203580. It is concluded that the expression of EC-SOD is decreased through ROS and p38-MAPK signalling cascades and that the down-regulation of EC-SOD leads to a decrease in the resistance to oxidative stress of COS7 cells under hypoxia induced by CoCl2.

The HLA-DRB1 * 1501 allele is prevalent among Japanese patients with anti-glomerular basement membrane antibody-mediated disease

BACKGROUND We aimed to clarify the relationship between HLA-DRB1(*)1501 and anti-glomerular basement membrane (GBM) antibody-mediated disease in Japanese patients. MATERIALS Samples were collected from 16 anti-GBM antibody-positive patients who were admitted to our department or related hospitals from December 1990 to October 2005. We analysed clinical and laboratory data, kidney biopsy findings, and the HLA-DR phenotypes and HLA-DRB1 alleles of the patients. RESULTS Among the 16 patients, 15 had HLA-DR15 [the phenotype frequency (PF) was 93.8%], 7 were positive for DR4 (the PF was 43.8%) and 5 were positive for DR9 (the PF was 31.3%). The allele frequency of HLA-DRB1(*)1501 was 46.4% (13/28), which was significantly different from Japanese controls (11.6%) (P < 0.001). In contrast, the frequency of HLA-DRB1(*)1502 was not different from controls (0/28). The odds ratio of HLA-DRB1(*)1501 in these patients was 6.4 (95% CI: 2.4-16.5). CONCLUSION The present study demonstrated that Japanese patients with anti-GBM antibody-mediated disease are very likely to carry the HLA-DRB1(*)1501 but not the HLA-DRB1(*)1502 allele.

Increased Urinary Excretion of Monocyte Chemoattractant Protein-1 in Proteinuric Renal Diseases

Monocyte chemoattractant protein-1 (MCP-1) is a chemokine that is produced mainly by tubular epithelial cells in kidney and contributes to renal interstitial inflammation and fibrosis. More recently, we have demonstrated that urinary MCP-1 excretion is increased in proportion to the degree of albuminuria (proteinuria) and positively correlated with urinary N-acetylglucosaminidase (NAG) levels in type 2 diabetic patients. Based on these findings, we have suggested that heavy proteinuria, itself, probably aggravates renal tubular damage and accelerates the disease progression in diabetic nephropathy by increasing the MCP-1 expression in renal tubuli. In the present study, to evaluate whether urinary MCP-1 excretion is increased in the proteinuric states not only in diabetic nephropathy but also in other renal diseases, we examined urinary MCP-1 levels in IgA nephropathy patients with macroalbuminuria (IgAN group; n = 6), and compared the results with the data obtained from type 2 diabetic patients with overt diabetic nephropathy (DN group; n = 23) and those without diabetic nephropathy (non-DN group; n = 27). Urinary MCP-1 excretion levels in non-DN, DN, IgAN groups were 157.2 (52.8–378.5), 346.1 (147.0–1276.7), and 274.4 (162.2–994.5) ng/g creatinine, median (range), respectively. Expectedly, urinary MCP-1 and NAG excretion levels in DN and IgAN groups were significantly elevated as compared with non-DN group. Therefore, we suggest that MCP-1 expression in renal tubuli is enhanced in proteinuric states, irrespective of the types of renal disease, and that increased MCP-1 expression probably contributes to renal tubular damage in proteinuric states.

Case Report: Intestinal Infarction After an Aneurysmal Occlusion of Superior Mesenteric Artery in a Patient With Behçet’s Disease

A patient with Behçets disease, accompanied by a large aneurysm of superior mesenteric artery, developed an ischemic enteritis with multiple perforated ulcers. The ischemic necrosis of the intestine preceded by recurrent abdominal pain was due to an aneurysmal occlusion of superior mesenteric artery, but not entero-Behçets disease. This is the first case report of intestinal infarction that occurred in a patient with vasculo-Behçets disease involving the superior mesenteric artery. Vasculo-Behçets disease should be included in a differential diagnosis of acute mesenteric artery thrombosis.