Izaya Nakaya

Blockade of IP-10/CXCR3 Promotes Progressive Renal Fibrosis

Background/Aim: Fibrosis is a hallmark of progressive organ disease. The 10-kDa interferon-inducible protein IP-10/CXCL10 is a potent chemoattractant for activated T lymphocytes, natural killer cells, and monocytes. However, the involvement of IP-10 in the pathogenesis of renal diseases viaits receptor, CXCR3, remains unclear. To contribute to the clarification of this issue was the aim of this study. Methods: The impacts of IP-10 on renal fibrosis were investigated in a unilateral ureteral obstruction model in CXCR3-deficient mice and mice treated with anti-IP-10-neutralizing monoclonal antibody. Anti-IP-10 monoclonal antibody (5 mg/kg/day) was injected intravenously once a day until sacrifice on days 1, 4, or 7 after treatment. The effects of IP-10 were confirmed in cultured tubular epithelial cells. Results: IP-10 and CXCR3 were upregulated in progressive renal fibrosis. Blockade of IP-10/CXCR3 promotes renal fibrosis, as evidenced by increases in interstitial fibrosis and hydroxyproline contents, concomitant decrease in hepatocyte growth factor expression, and converse increase in transforming growth factor-β1 in diseased kidneys. IP-10 blockade affected neither macrophage nor T cell infiltration in diseased kidneys. Conclusion: These results suggest that blockade of IP-10 via CXCR3 contributes to renal fibrosis, possibly by upregulation of transforming growth factor-β1, concomitant with downregulation of hepatocyte growth factor.

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. Waldenströms 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.

Potential Benefit Associated With Delaying Initiation of Hemodialysis in a Japanese Cohort

Introduction Late referral to a nephrologist, the type of vascular access, nutritional status, and the estimated glomerular filtration rate (eGFR) at the start of hemodialysis (HD) have been reported as independent risk factors of survival for patients who begin HD. The aim of this study was to clarify the influence of the HD-free interval from the time of an eGFR of 10 ml/min per 1.73 m2 (IGFR10-HD) on patient outcome. Methods We enrolled 124 patients aged older than 20 years who had HD initiated in a general hospital. The predictive factor was the HD-free IGFR10-HD. The primary outcome was the relationship of the HD-free interval on death or the onset of a cardiovascular event. Survival analysis was performed using the Cox regression model. Results The median IGFR10-HD was 159 days (range: 2–1687 days). The median eGFR at the initiation of HD was 5.48 ml/min per 1.73 m2. Sixty-seven of 124 patients (54.0%) reached the primary outcome. Of these, 29 died and 38 experienced a cardiovascular event. In univariate analysis, older age, a history of cardiovascular disease, nephrologic care for <6 months, higher modified Charlson comorbidity index score, poor performance status, temporary catheter, edema, diabetic retinopathy, and nonuse of erythropoiesis-stimulating agent were statistically related to the primary outcome. The unadjusted hazard ratio per log-transformed IGFR10-HD was 0.393 (95% confidence interval [CI]; 0.244−0.635; P < 0.001) and the hazard ratio adjusted for confounding factors was 0.507 (95% CI: 0.267−0.956; P = 0.036). Discussion A longer HD-free IGFR10-HD was associated with a lower risk of death or a cardiovascular event. The interval could be considered an independent prognostic factor for outcomes in patients on HD.

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.

Crystalline cast nephropathy in a patient with IgD lambda myeloma

A 72-year-old woman was admitted at our department for renal dysfunction with general fatigue and loss of appetite for 2 months. She had no remarkable past medical history except hypertension, which was treated with angiotensin-converting enzyme inhibitor and a calcium channel blocker. Physical examination was unremarkable, except for pale conjunctivae. Urinary protein to creatinine ratio was 9.5 g/gCr, revealing a large discrepancy from the result of mild proteinuria by urinary dipstick (2?; indicating 100–300 mg/L). No hematuria was found. Serum creatinine level was increased to 1.90 mg/ dL associated with anemia (hemoglobin 7.3 g/dL). Other findings were total protein 6.8 g/dL, serum albumin 4.67 g/ dL, serum IgG 516 mg/dL (normal 870–1700 mg/dL), serum IgA 17 mg/dL (normal 110–410 mg/dL), serum IgM 5 mg/ dL (normal 34–220 mg/dL), and serum IgD 306 mg/dL (normal 0–9 mg/dL). Serum and urine electrophoresis revealed a monoclonal spike and an IgD-type monoclonal k band, respectively. The free k light chain level was 3720 mg/ L; serum j/k ratio was 0.0017. On the 5th day after admission, kidney biopsy was performed (Fig. 1). On light microscopy, minor glomerular abnormalities were observed; furthermore, diffuse mononuclear cell infiltration in the interstitium and crystalline casts in the proximal tubules were observed. These crystalline casts were hematoxylin and eosin positive but periodic acid-Schiff (PAS) negative. Moreover, only k light chain staining was positive. On electron microscopy, crystalline casts were found to form gigantic plate-shaped crystalline structures. Bone marrow aspiration cytology confirmed the diagnosis of multiple myeloma. She received bortezomib–dexamethasone therapy and achieved complete remission with normal renal function for 2 years. Cast nephropathy is the most common renal complication [1]. In rare cases, the casts exclusively comprise crystals. Myeloma-free light chains (MFLCs) are usually absorbed by proximal tubular cells, leading to acute proximal tubular damage associated with needle-shaped crystals in epithelial cells. This condition is well known as acquired light chain-related Fanconi syndrome [2]. Conversely, MFLCs that are not absorbed by the proximal tubules are distributed to the distal tubules and the ascending loop of Henle, where Tamm–Horsfall protein (THP) casts are exclusively synthesized [3]. These casts usually comprise needle-shaped or rhomboid crystals. THP is one of the glycoproteins, which is invariably PAS positive. The crystalline casts that were observed in this case were PAS negative and were distributed in the proximal tubule lumen. This is understandable, considering the site of THP synthesis. Some reports described crystal formation in organs except the kidneys. In these organs, crystal formation occurred in microvasculature due to low tissue temperature and/or blood circulation stasis; however, the precise mechanism is uncertain [4]. The characteristics of this case emphasized that MFLCs may form crystals independently or at least, without THP participation. Some have reported factors that may contribute to explain MFLC precipitation for crystal formation: a large MFLC amount & Satoshi Kumakura satoshi.kuma.714@gmail.com

Spontaneous intracranial hypotension in a case of systemic lupus erythematosus

and lateral ventricle narrowing (Figure 1a). MR myelography suggested CSF leakage at C1 – 3 levels (Figure 1b). After admission, prednisolone was increased from 20 to 30 mg/day, combined with cyclosporine 100 mg/day and mizoribine 150 mg/day following one course of methylprednisolone pulse therapy (500 mg/day) for three consecutive days. Immunoabsorption was performed weekly. These therapies attenuated serological SLE indicators. Although her headache and cognitive dysfunction improved, she transferred to another hospital ’ s neurosurgical department to determine the requirement of autologous blood injection into the epidural space in October 2012. Her CSF pressure decreased to 10 mm H 2 O, fulfi lling the criteria for intracranial hypotension. However, CSF leakage was not confi rmed using CT myelography or radioisotope cisternography. Then, she did not undergo autologous blood injection into the epidural space. CSF leakage possibly stopped before she was transferred. CSF leakage was not confi rmed using MR myelography in December 2012 (Figure 1c), and MRI in July 2013 revealed improvements of subdural hygroma and lateral ventricle narrowing (Figure 1d). SLE patients manifest various central nervous system abnormalities. Intracranial hypertension has been reported to be found in 17% CNS lupus cases with intractable headaches [2]. In contrast, only one SIH case with SLE has been reported [3]. Intracranial hypertension in SLE was believed to occur because of an arachnoid occlusion by granulation or immune complex deposition in the choroid plexus [4]. In addition, hypertrophic pachymeningitis, which shows dural thickening and neurological symptoms, should be considered to be a diff erential diagnosis in intractable headache in SLE [5]. However, in this case, low CSF pressure and subdural hygoma were incompatible with hypertrophic pachymeningitis. Furthermore, the possibility of coincidence of SIH due to CSF leakage could not be denied in this case, but clinical symptoms such as headache, gait disturbance, and cognitive dysfunction and imaging results improved in correlation with SLE serological disease activity, suggesting an Mod Rheumatol, 2014; Early Online: 1–2

Isolated Renal Sarcoidosis Presenting with Granulomatous Interstitial Nephritis: A Case Report and Review of the Literature

Background: Sarcoidosis is a multi-system disorder characterized by noncaseating epitheloid granuloma in multiple organs. However, granulomatous interstitial nephritis in the absence of extrarenal renal lesions is very rare. Case presentation: A 64-year-old male presented with a weight loss of 10 kg and an increase in serum creatinine from 1.1 to 4.8 mg/dl over a 1-year period. At admission, no proteinuria or hematuria was found, although serum creatinine was 5.1 mg/dl and was associated with slight increases in serum angiotensin converting enzyme and calcium levels. Renal biopsy revealed granulomatous interstitial nephritis with noncaseating epitheloid cells. The patient was diagnosed with sarcoidosis, although no extrarenal sarcoid lesion was found. Oral prednisolone was effective, with normalization of serum creatinine levels 2 weeks later. A review of the literature showed that isolated granulomatous renal sarcoidsosis preferentially affected elderly males, and their serum angiotensin converting enzyme levels were normal or mildly increased in many cases. Conclusions: This paper describes a rare case of isolated renal sarcoidosis with acute granulomatous interstitial nephritis. This case and a relevant review of the literature demonstrate that sarcoid granulomatous interstitial nephritis should be considered as one of differential diagnoses in elderly male patients with suspected tubulointerstitial nephritis irrespective of angiotensin converting enzyme levels.

Classic polyarteritis nodosa presenting with rapidly progressive renal insufficiency

Rapidly progressive renal insufficiency is rare in patients with classic polyarteritis nodosa (cPAN). We describe two cases of cPAN who presented with rapid and progressive deterioration of renal function. Renal biopsies showed severe necrotizing vasculitis in medium-sized arteries but no changes in glomeruli. Combination therapy of corticosteroid and cyclophosphamide resulted in marked improvement of clinical symptoms, amelioration of renal function and lack of subsequent relapse of vasculitis. These findings suggest good prognosis of patients with cPAN who show rapid and progressive deterioration of renal function who respond to immunosuppressive therapy.