Methylglyoxal as a prognostic factor in patients with chronic kidney disease.

AIM: Advanced glycation end products and their precursors cause vascular damage through oxidative stress. We investigated the hypothesis that methylglyoxal (MG), 3-deoxyglucosone (3-DG) and pentosidine influence outcomes of chronic kidney disease (CKD) patients. METHODS: We conducted a 3 years prospective observational study involving 150 outpatients at CKD stages 3-5. At enrolment, MG, 3-DG and pentosidine plasma concentrations were measured; patients were divided into tertiles according to the concentration of each substance. The primary endpoint was death, a cardiovascular event or end-stage renal disease. Survival analysis was performed using the Cox regression model. RESULTS: The patients' mean age was 62 ± 12 years, 97 were men, and 20 had diabetic nephropathy. The mean estimated glomerular filtration rate was 25.0 ± 12.1 mL/min per 1.73 m2 , which negatively correlated with MG but not with 3-DG and pentosidine. Forty-eight patients reached the primary endpoint. Compared with the lowest MG tertile, the hazard ratio for the primary endpoint was 7.57 (95% confidence interval (CI): 1.71-33.54) in the middle tertile and 27.00 (CI: 6.46-112.82) in the highest tertile. When adjusted for characteristics at baseline, the corresponding hazard ratio decreased to 2.09 (CI: 0.37-11.96) and 6.13 (CI: 0.97-38.82), but MG tertile remained an independent risk factor for the primary endpoint. However, 3-DG and pentosidine were not related to the primary outcome. CONCLUSION: Methylglyoxal has a close clinical association with CKD. Higher MG concentrations may contribute renal function deterioration in CKD. In CKD patients, MG concentration might be useful when determining the prognosis.

Clinically diverse phenotypes and genotypes of patients with branchio-oto-renal syndrome.

Branchio-oto-renal (BOR) syndrome is a rare autosomal dominant disorder characterized by branchiogenic anomalies, hearing loss, and renal anomalies. The aim of this study was to reveal the clinical phenotypes and their causative genes in Japanese BOR patients. Patients clinically diagnosed with BOR syndrome were analyzed by direct sequencing, multiplex ligation-dependent probe amplification (MLPA), array-based comparative genomic hybridization (aCGH), and next-generation sequencing (NGS). We identified the causative genes in 38/51 patients from 26/36 families; EYA1 aberrations were identified in 22 families, SALL1 mutations were identified in two families, and SIX1 mutations and a 22q partial tetrasomy were identified in one family each. All patients identified with causative genes suffered from hearing loss. Second branchial arch anomalies, including a cervical fistula or cyst, preauricular pits, and renal anomalies, were frequently identified (>60%) in patients with EYA1 aberrations. Renal hypodysplasia or unknown-cause renal insufficiency was identified in more than half of patients with EYA1 aberrations. Even within the same family, renal phenotypes often varied substantially. In addition to direct sequencing, MLPA and NGS were useful for the genetic analysis of BOR patients.

Proliferative glomerulonephritis with monoclonal IgM deposits without Waldenström's macroglobulinemia: case report and review of the literature.

A 38-year-old man was presented with nephrotic syndrome associated with hematuria and mild hypocomplementemia. Renal biopsy revealed lobular mesangial proliferation, thickened capillary walls, and intraluminal protein thrombi. Immunofluorescence showed marked and mild depositions of immunoglobulin (Ig) M heavy chains and complement C3, respectively, in a peripheral lobular pattern. On light chain staining, only kappa (κ) light and IgM heavy chains showed a similar pattern. Electron microscopy showed fine granular electrondense deposits in subendothelial areas and numerous globular deposits (varying size and density) in glomerular capillary lumens. Serum levels of Ig κ, but not of free κ, light chains were significantly increased. Bone marrow aspiration revealed a normocellular marrow. Waldenström's macroglobulinemia and cryoglobulinemia were ruled out. Clinically, steroid therapy was ineffective and proteinuria persisted. This report demonstrates that glomerular deposition of monoclonal IgM-κ can produce membranoproliferative- like changes in the glomeruli. This condition may be recognized as proliferative glomerulonephritis with monoclonal IgM deposits similar to the recently recognized proliferative glomerulonephritis with monoclonal IgG deposits.

κ I light chain AL amyloidosis presenting with rapidly progressive renal and hepatic failure with unusual renal amyloid distribution.

A 65-year-old man suffering from generalized edema and jaundice was admitted to our hospital. Laboratory findings revealed marked renal dysfunction with heavy proteinuria as well as liver dysfunction with severe obstructive jaundice. On renal biopsy, the diagnosis of AL amyloidosis associated with κ I light chain was made. Interestingly, amyloid deposits were restricted to the glomeruli. Although hemodialysis was initiated, the patient died due to further deterioration of hepatic function. On autopsy, severe intrahepatic cholestasis was observed, and there was marked deposition of AL amyloid in the liver. Literature reviews showed that rapidly progressive renal failure is common in AL amyloidosis patients who presented with acute hepatic failure due to severe intrahepatic cholestasis. However, the detailed renal pathology in this condition has not been documented. The present case is very interesting because rapidly progressive renal and hepatic failure was simultaneously observed, and renal amyloid deposition was restricted to the glomeruli.

Pulmonary hypertension confirmed histologically five months prior to scleroderma renal crisis onset.

A 69-year-old man presented shortness of breath and acute renal failure. He had undergone pulmonary partial resection for lung cancer 5 months prior. On examination, severe hypertension, skin sclerosis of his forearms, and anticentromere antibody were observed. A renal biopsy specimen showed characteristic findings for scleroderma renal crisis, and a right heart catheterization revealed severe pulmonary arterial hypertension. Re-examination of the resected lung specimen revealed sclerodermatous vascular involvement was present.

[Massive colonic bleeding and crescentic glomerulonephritis in an elderly man with Henoch-Schönlein purpura].

A 79-year-old man with an artificial anus constructed during surgical repair of colon perforation of unknown etiology in 1995 was admitted to our hospital for sudden appearance of purpura in the lower extremities. Two weeks before admission, he complained of flu-like symptoms and abdominal pain. He was diagnosed with Henoch-Schonlein purpura (HSP), which responded to treatment with 30 mg day oral prednisolone (PSL). Subsequently, however, rapid deterioration of renal function associated with severe hematuria and proteinuria was noted. Renal biopsy on hospitalization day 14 showed cellular crescent formation in more than half of the glomeruli with granular deposits of IgA, C3 and fibrinogen in the mesangium and on the capillary walls. PSL was tapered to 20 mg day from hospitalization day 14 because of a further decrease in purpura and a decrease in C-reactive protein. On hospitalization day 19, serum creatinine increased to 3.1 mg dL and a massive bloody stool was observed. Colonoscopy revealed extensive oozing from the colonic mucosa around the artificial anus. Since the bleeding was considered to result from HSP activity, methylprednisolone pulse therapy was applied, followed by increasing the dose of oral PSL to 30 mg/day. Co-administration of cyclophosphamide (25 mg day) from hospitalization day 39 led to improvement of renal dysfunction and a decrease in proteinuna at the outpatient clinic.

Immunoglobulin A nephropathy with massive paramesangial deposits caused by anti-vascular endothelial growth factor therapy for metastatic rectal cancer: a case report and review of the literature.

BACKGROUND: Bevacizumab, a recombinant humanized monoclonal antibody for vascular endothelial growth factor, has been widely used in various cancers offering substantial clinical benefit. It is reportedly associated with development of high-grade proteinuria and nephrotic syndrome with the histology of thrombotic microangiopathy, but there has been no report describing the development of immunoglobulin A nephropathy in bevacizumab-treated patients. CASE PRESENTATION: A 68-year-old man with metastatic rectal cancer was treated with bevacizumab. He presented with hematuria and proteinuria 15 and 17 months, respectively, after bevacizumab initiation. Bevacizumab was stopped at 17 months. Renal biopsy at 19 months revealed immunoglobulin A nephropathy, with numerous paramesangial hemispherical deposits and thrombotic microangiopathy. Electron microscopy showed numerous paramesangial electron-dense deposits of various sizes, and subendothelial injuries. Proteinuria almost completely resolved 8 months after bevacizumab cessation, although hematuria persisted. Follow-up renal biopsy 11 months after bevacizumab cessation showed a marked decrease in mesangial immunoglobulin A deposits and paramesangial electron-dense deposits, which correlated with a gradual decrease in serum immunoglobulin A. CONCLUSION: This is the first case report that confirmed histologically the development and resolution of immunoglobulin A nephropathy during and after bevacizumab therapy. This case shows that there may be other mechanisms of glomerular injury by bevacizumab besides glomerular endothelial injury leading to thrombotic microangiopathy.

Long-term outcome and efficacy of cyclophosphamide therapy in Japanese patients with ANCA-associated microscopic polyangiitis: a retrospective study.

OBJECTIVE: The aim of this study was to elucidate the efficacy of cyclophosphamide (CY) in Japanese patients with antineutrophil cystoplasmic antibody (ANCA)-associated microscopic polyangiitis (MPA). METHODS: Sixty-four patients, newly diagnosed with ANCA-associated MPA were included in this retrospective study. The patients were divided into two groups based on whether they received combination therapy of CY and corticosteroid (CS) (CY group, n=29) or CS alone (CS group, n=35) for remission induction. The primary outcome was all-cause mortality. RESULTS: Most patients in the CY group were treated with oral CY. Between the two groups, there were no differences in the baseline characteristics except for a higher proportion of male patients in the CY group. The remission rate was not substantially different between the two groups (86.2% in the CY group vs. 91.4% in the CS group). The survival rate was slightly higher in the CY group than in the CS group (not statistically significant; 0.86 vs. 0.77 at 1 year and 0.73 vs. 0.64 at 5 years, p=0.648). In the CY group, the hazard ratio after adjusting for age, sex, Birmingham vasculitis activity score values, serum albumin levels and C-reactive protein (CRP) levels was 0.657 (95% CI, 0.254-1.699; p=0.386). CONCLUSION: We observed no increased efficacy of CY in ANCA-positive MPA in the Japanese patients, and hence, its efficacy may be limited in these patients.

Possible IgG4-related kidney disease requiring a differential diagnosis of membranous lupus nephritis.

A 25-year-old woman presented with fever, arthralgia and proteinuria exhibiting leukopenia, hypocomplementemia, increased serum IgG and IgG4, and positive antinuclear and anti-double-stranded DNA antibodies. Renal biopsy revealed membranous nephropathy with tubulointerstitial nephritis. IgG subclass immunofluorescence revealed intense IgG4 expression in glomeruli, but no expression of IgG2. Observations resembled membranous lupus nephritis with tubulointerstitial nephritis; however, elevated IgG4, low titers of antinuclear and anti-double-stranded DNA antibodies, IgG4-bearing cell infiltration, and characteristic IgG subclass deposition in glomeruli prompted diagnosis of IgG4-related tubulointerstitial nephritis with membranous nephropathy. It is challenging but important to distinguish lupus nephritis from IgG4-related kidney disease.

Systemic and rapidly progressive light-chain deposition disease initially presenting as tubulointerstitial nephritis.

A 42-year-old woman was admitted to a hospital after first-time detection of proteinuria and hematuria during a routine medical check-up. Because her serum creatinine level had rapidly increased from 0.9 to 3.2 mg/dl since measurement 3 months earlier, she was referred to our hospital. Renal biopsy revealed extensive tubular atrophy and interstitial fibrosis with mild leukocyte infiltration. Glomeruli showed minimal changes, and no immunoglobulin or complement deposition was observed by immunofluorescence. Oral prednisolone was commenced under the diagnosis of chronic tubulointerstitial nephritis, and she discharged once. However, its effects were transient; her renal function deteriorated rapidly and hemodialysis was initiated 5 months after her initial check-up. On readmission, urinary Bence-Jones protein κ-type was detected, and examination of bone marrow led to a diagnosis of Bence-Jones κ-type multiple myeloma. Light-chain staining using a renal biopsy specimen obtained 2 months earlier showed κ-light-chain deposition on tubular basement membranes but not glomeruli. Despite undergoing chemotherapy with vincristine, doxirubicin, and dexamethasone, the patient died suddenly from a cardiac arrhythmia. Autopsy showed κ-light-chain deposition in the heart, thyroid, liver, lungs, spleen, and ovaries. Congo red staining yielded negative results. Typical light-chain deposition disease (LCDD) characterized by nodular glomerulosclerosis was observed in the kidneys. This case demonstrates that tubulointerstitial nephritis can be an early pathological variant of LCDD, which may be followed by accelerated and massive light-chain deposition in glomeruli.

A case of γ1-heavy chain deposition disease successfully treated with melphalan and prednisolone therapy.

Heavy chain deposition disease (HCDD) is characterized by glomerular and tubular deposition of non-amyloidotic monoclonal heavy chains without associated light chains. We describe a case of gamma1-HCDD who presented with nephrotic syndrome, microhematuria, and hypocomplementemia. Renal biopsy showed lobular and nodular glomerulosclerosis along with IgG and C3 deposition. Electron microscopy revealed electron-dense deposits on the glomerular and tubular basement membranes and mesangium. Congo red staining was negative. Staining was positive for IgG1 on glomerular and tubular basement membranes but negative for IgG2-4, kappa and lambda light chains. Staining for the constant heavy chain domains showed the deletion of the first constant heavy chain domain. Thus, we diagnosed gamma1-HCDD. She was considered to be early-stage HCDD because proteinuria and hematuria were not observed before the nephrotic syndrome onset. Melphalan and prednisolone (MP) therapy reduced proteinuria as well as improved renal function and complement levels. Although renal prognosis of HCDD is poor, aggressive chemotherapy with MP may be effective in early-stage HCDD patients.

Isolated granulomatous renal arteritis: a variant form of giant cell arteritis with few macrophages.

A 64-year-old woman with hypertension and hyperlipidemia was admitted to our hospital for the investigation and management of general fatigue, anorexia, a 5-kg weight loss, and a 4-week history of high-grade fever. She had no symptoms of headache, myalgia, or arthralgia, and the physical examination was unremarkable. The laboratory tests revealed renal dysfunction with urine abnormalities that had not been observed 1 year earlier. A renal biopsy showed granulomatous small arteritis without necrotic lesions or glomerular pathology. An immunohistochemical study of the infiltrating leukocytes showed a predominance of CD4+ T cells followed by CD8+ T cells, and only a few macrophages. The condition drastically improved after treatment with 30 mg/day of oral prednisolone. The granulomatous renal arteritis was considered a variant of giant cell arteritis, because it showed the peculiar finding of a few macrophages in the granulomatous lesions.