Osamu Saito

Microscopic Hematuria and Diabetic Glomerulosclerosis – Clinicopathological Analysis of Type 2 Diabetic Patients Associated with Overt Proteinuria

Background/Aims: The information available concerning the qualitative and quantitative clinical variables in cases with pathologically defined diabetic glomerulosclerosis (DGs) has been insufficient so far. In addition, the prevalence and composition of nondiabetic renal disease (NDRD) among proteinuric diabetics still remain to be delineated. Methods: The glomerular pathology, clinical correlates, and the prevalence of NDRD were retrospectively analyzed in 50 type 2 proteinuric diabetics who underwent a renal biopsy between 1990 and 2006. The patients were divided into two groups according to clinical and pathological features. Thereafter, the diagnostic contribution of the laboratory and clinical variables that were significant between the two groups were determined by logistic regression analysis. Results: There were 34 cases with pure DGs and 15 cases (30%) had NDRD with or without DGs. Although the difference in the prevalence of microscopic hematuria between these two groups was significant, it was no longer statistically significant when the patients were limited to nephrotic cases. We identified 14 hematuric cases with pathologically defined DGs, and they all had a significantly lower renal function than nonhematuric patients with DGs. The prevalence of nephrotic syndrome and retinopathy were significantly higher in the cases with hematuric DGs than in the cases with nonhematuric DGs. Based on a logistic regression analysis, the presence of nephrotic syndrome and known duration of diabetes were identified to be significant predictors for hematuria with DGs. Conclusions: Our observations suggest that the presence of hematuria may be a common feature for DGs with nephrotic syndrome.

The Impact of Nephrectomy and Renal Transplantation on Serum Levels of Soluble Klotho Protein

BACKGROUND Klotho, a single-pass transmembrane protein primarily expressed in the kidneys, parathyroid glands, and choroid plexus of the brain, has a short cytoplasmic tail and a long extracellular domain, which can be cleaved and released as a soluble form. However, information regarding the origins and kinetics of soluble serum Klotho remains poorly understood. We evaluated serial changes in serum Klotho levels among living donors before and after retroperitoneoscopic nephrectomy as well as in their renal transplant recipients. METHODS The levels of soluble Klotho in serum obtained from 10 living donors and their renal transplant recipients were determined using a sandwich enzyme-linked immunosorbent assay system. RESULTS Serum soluble Klotho was detectable in all subjects. The baseline serum Klotho concentrations in the living donors ranged from 726.4 to 1417.1 pg/mL (median, 909.8 pg/mL; interquartile ranges [IR], 754.8-1132.4), whereas that in the concomitant renal transplant recipients ranged from 397.5 to 1047.2 pg/mL (median, 613.0 pg/mL; IR, 445.9-750.8; P = .003). The levels of soluble serum Klotho measured 5 days after retroperitoneoscopic nephrectomy (median, 619.0 pg/mL; IR, 544.6-688.5; P = .001) were significantly lower than the baseline values. Among the renal transplant recipients, no significant changes in serum Klotho levels were observed during the observation period. CONCLUSION Our data regarding soluble serum Klotho levels obtained from living donors support the idea that the kidneys are a major source of soluble serum Klotho in human subjects without a deterioration of renal function. In recipients, concomitant acute kidney injuries and immunosuppressive protocols might modulate the release of soluble Klotho from the grafts into the circulation.

Matrix metalloproteinase levels in the drained dialysate reflect the peritoneal solute transport rate: a multicentre study in Japan

BACKGROUND Long-term peritoneal dialysis (PD) leads to peritoneal injury with high solute transport of the peritoneal membrane. At worst, peritoneal injury leads to encapsulating peritoneal sclerosis with an extremely high mortality rate. To perform PD safely and adequately, it is necessary to monitor peritoneal injury. The aim of this study was to investigate the potential of matrix metalloproteinases (MMPs) as new indicators of peritoneal injury. METHODS The subjects included 215 PD patients with end-stage renal disease at 20 centres in Japan. MMPs or tissue inhibitors of MMP (TIMPs) in the drained dialysate were quantified with enzyme-linked immunosorbent assay. The peritoneal solute transport rate was assessed to estimate peritoneal injury and PD efficiency by the peritoneal equilibration test (PET). RESULTS MMP-2, MMP-3 and TIMP-1 levels in the drained dialysate obtained by the PET were correlated with the D/P Cr ratios (ρ = 0.69, ρ = 0.52, ρ = 0.55, respectively) and the D/D0 glucose ratios (ρ = -0.60, ρ = -0.47, ρ = -0.48, respectively). The measured D/S ratios of MMP-2 and TIMP-1 were significantly higher than the expected D/S ratios when MMP-2 and TIMP-1 would have been transported from only the circulation. The measured D/S ratios of MMP-3 nearly corresponded to the expected ratios. MMP-1 and TIMP-2 in the drainage were undetected in most patients. CONCLUSIONS From these results, most MMP-2 in the drained dialysate may be produced from the peritoneum, and MMP-2 is expected to be a useful marker of peritoneal injury or change in peritoneal solute transport.

Serum adiponectin and markers of endothelial injury in hemodialysis patients with arteriosclerosis obliterans

BackgroundArteriosclerosis obliterans (ASO) in hemodialysis patients is the dominant cause of morbidity evolving from arteriosclerosis. Adiponectin is an adipose-derived cytokine which, because of its modulation of endothelial adhesion molecules, has potential anti-inflammatory and anti-atherogenic properties. However, the implications of adiponectin and endothelial function in ASO of hemodialysis patients has not been fully elucidated.MethodsIn this study we measured serum levels of adiponectin, adhesion molecules (VCAM-1 and ICAM-1), and an endothelial cell injury marker (CD146) in patients with ASO. We sought to determine clinical and laboratory correlates of ASO in ESRD patients. A total of 80 hemodialysis patients and 82 patients with normal serum creatinine levels were enrolled. Serum levels of adiponectin, ICAM-1, VCAM-1, and CD146 were measured by ELISA.ResultsSerum adiponectin levels in 41 hemodialysis patients with ASO were significantly lower than in 39 patients without ASO. Serum CD146 levels in hemodialysis patients with ASO were significantly higher than in patients without ASO. There were no significant differences between levels of ICAM-1 and VCAM-1 in these two groups. Similar results were obtained for patients with normal renal function. Serum adiponectin was related to hemodialysis duration and BMI in hemodialysis patients. In patients with normal renal function, adiponectin was related to HDL-cholesterol, triglyceride, and ICAM-1.ConclusionA decrease in serum adiponectin levels and an increase in serum CD146 may be closely associated with the development of ASO, regardless of renal function. However, there are different mechanisms determining serum adiponectin levels in patients with normal kidney function and in hemodialysis patients.

Metabolic and hemodynamic advantages of an acetate-free citrate dialysate in a uremic case of congenital methylmalonic acidemia.

ethylmalonic acidemia (MMA) is an or-ganic acidemia in the class of diseasescaused by enzymatic defects in the catabolism ofbranched-chain amino acids (valine, isoleucine,methionine, and threonine), odd-chain fatty ac-ids,andcholesterol.MMAisanautosomalreces-sive disorder caused by a deficiency in methyl-malonyl–coenzyme A (CoA) mutase (encoded bythe

Renal failure caused by plasma cell infiltration in multiple myeloma

We report on a case of severe renal failure in a 61-year-old female with multiple myeloma (MM). Two months prior to admission, the patient was diagnosed to have anemia and progressive renal failure associated with urinary Bence Jones protein and was referred to our hospital. A bone marrow biopsy revealed 40% plasma cells with κ light chain restriction. Thus, she was considered to have MM. A renal biopsy revealed neoplastic plasma cell infiltration within the kidney, moderate interstitial fibrosis, tubular atrophy, and punctate, electron-dense material along the peripheral capillary walls, tubular basement membrane, and in the interstitium of the kidney. This suggested that a combination of compression of the tubules and the microvasculature by the infiltrative process, and local light chain deposition-mediated tissue damage might be implicated in the development of renal failure in this patient. Despite a remission of bone marrow plasmacytosis with a bortezomib-based regimen, her renal function gradually deteriorated and a periodic hemodialysis program was finally required. Although the clinical impact of the direct kidney infiltration of neoplastic plasma cells on the longitudinal changes in renal function remains to be delineated, it is reasonable to consider that the infiltration of neoplastic plasma cells associated with local light chain depositions may result in irreversible renal injuries. Obviously, further studies and accumulation of additional experience with renal biopsy are required to better determine the precise and prognostic relationship between renal outcome and morphological alterations among MM patients with varying degrees of renal impairment.

Membranous nephropathy in an HIV-positive patient complicated with hepatitis B virus infection

In ordinary settings, human immunodeficiency virus (HIV)-associated nephropathy should be considered when HIV infection is associated with heavy proteinuria. On the other hand, hepatitis B virus (HBV) may also play a role in the development of glomerular injury among patients with HIV infection, since HIV and HBV infections commonly occur together due to shared modes of transmission. We present here a case of nephrotic syndrome in an HIV-positive patient complicated with HBV infection. A renal biopsy revealed sparse granular deposits of immunoglobulin G in the subepithelial region, consistent with membranous nephropathy (MN) stage I. Moreover, immunostaining exhibited weak anti-hepatitis B core activity within glomeruli. These results led us to consider that HBV-associated MN might play a role in the development of nephrotic syndrome. Although anti-viral treatment for patients with HBV-associated MN has been suggested to be clinically effective, the use of two anti-HIV agents (tenofovir and emtricitabine), both of which have anti-HBV activities, was not effective for the patient’s nephrotic syndrome, despite obtaining a decrease in the serum HBV-DNA levels. A lack of prospective data suggests that many decisions on the treatment of glomerulopathies with HIV infections are potentially empirical. Obviously, further studies and accumulated clinical experience are required to better determine the pathogenesis and management of HBV-associated MN among patients with HIV infections.

Henoch–Schönlein purpura complicated with severe gastrointestinal bleeding

Bleeding from the gastrointestinal tract is one of the common determinants of morbidity and mortality in the ordinary clinical setting. The gastrointestinal involvement of Henoch–Schönlein purpura (HSP) has often been described as self-limiting, with no long-term morbidity. In this report, we describe our experience with a male HSP patient who presented with abdominal pain, loss of appetite and deteriorated renal function associated with nephrotic syndrome. Despite the use of aggressive immunomodulatory treatments, including corticosteroids and plasmapheresis, he developed lethal gastrointestinal hemorrhage. We believe that the accumulation of more experience with additional cases similar to ours is mandatory for the establishment of optimal management for HSP patients with severe gastrointestinal manifestations.

Rituximab Treatment for PR3-ANCA-Positive Membranoproliferative Glomerulonephritis Associated with Adult-Onset Periodic Fever Syndrome

We report the case of a 36-year-old Japanese woman with nephrotic syndrome due to membranoproliferative glomerulonephritis (MPGN) Type I diagnosed after a 5-year history of periodic fever syndrome (PFS). Hypocomplementemia and elevation of anti-proteinase 3 anti-neutrophil cytoplasmic autoantibody (PR3-ANCA) were observed. HIV, and hepatitis B and C serology were negative. Nephrotic syndrome and periodic fever did not respond to oral steroid and intravenous steroid pulse therapies combined with cyclosporine, dipyridamole, warfarin and losartan. We tried immunotherapy using rituximab, a human-mouse chimeric monoclonal antibody directed against the CD20 antigen on mature B cells. This therapeutic approach led to improvement of renal function and remission of nephrotic syndrome and hypocomplementemia. However, it did not have a beneficial effect on periodic fever. Suspecting adult-onset hereditary PFS, we analyzed her genetic alteration of MEFV and TNFRSF1A genes. A rare genotype in intron 6 of TNFRSF1A was revealed. The etiological relationship between periodic fever and MPGN is discussed. Rituximab is a hopeful choice of induction therapy for refractory MPGN.

Reversible acute renal failure associated with clomipramine-induced interstitial nephritis

We describe a 41-year old man with obsessive-compulsive neurosis who developed acute renal failure (ARF) due to acute interstitial nephritis (AIN) during 6 weeks of treatment with clomipramine hydrochloride (CPH). He had a slight fever, mild arthralgia, appetite loss, and diarrhea after taking CPH. On admission, he showed serum creatinine (sCr) of 7.31 mg/dl, and creatinine clearance (Ccr) of 2.5 ml/min. He subsequently became anuric and required hemodialysis. Renal biopsy revealed AIN with diffuse mononuclear cell infiltration. After the withdrawal of CPH and treatment with prednisolone (PSL) 0.5 mg/kg per day, his urinary output improved, along with improvement of his renal function; therefore hemodialysis was finally discontinued. To our knowledge, this is the first case report of AIN induced by clomipramine.