Katsuyuki Nagatoya

Inhibitory effects of T/L-type calcium channel blockers on tubulointerstitial fibrosis in obstructed kidneys in rats.

OBJECTIVESnTo examine the effect of L- and T/L-type calcium channel blockers on interstitial fibrosis in chronic unilateral ureteral obstruction (UUO). Tubulointerstitial fibrosis is a common outcome of several progressive renal diseases. Calcium channel blockers are widely used for the treatment of hypertension with renal diseases; however, the direct effect of calcium channel blockers on renal diseases independent of lowering blood pressure has not been fully elucidated.nnnMETHODSnSprague-Dawley rats were divided into 3 treatment groups: (1) vehicle control; (2) nifedipine, an L-type calcium channel blockers; and (3) efonidipine, a T/L-type calcium channel blockers. Treatment was initiated 1 day before and continued until 6 days after creation of the UUO.nnnRESULTSnTubulointerstitial fibrosis in the obstructed kidney was significantly increased compared with that in the contralateral unobstructed kidney. Furthermore, the increased fibrosis was accompanied by increased fibrogenic signaling expressed by transforming growth factor β1 and connective tissue growth factor mRNA levels, increased oxidative stress expressed by p22phox, p47phox and gp91phox mRNA level. Moreover, treatment with a nonhypotensive dose of efonidipine but not nifedipine in the obstructed kidney significantly suppressed the fibrogenic signaling and the oxidative stress, resulting in reduced tubulointerstitial fibrosis. The plasma aldosterone level in efonidipine-treated animals was increased compared with vehicle-treated animals, although not significantly. The increased plasma aldosterone level did not increase sgk-1 mRNA level in efonidipine but not in nifedipine treated animals.nnnCONCLUSIONSnTreatment with efonidipine improved tubulointerstitial fibrosis more effectively than treatment with nifedipine in UUO. The antifibrogenic effect by efonidipine was obtained through suppression of fibrogenic signaling.

Voriconazole-associated salt-losing nephropathy

A 74-year-old man was diagnosed with nephrotic syndrome due to focal segmental glomerulosclerosis, and steroid therapy was initiated. Subsequently, he was affected by deep mycosis, and hence, voriconazole (VRCZ) was administered. On the 16th day, he was transferred to our hospital because of somnolence and malaise. His systolic blood pressure was approximately 80xa0mmHg, and he showed decreased skin turgor, indicating volume depletion. Laboratory analysis revealed hyponatremia and liver dysfunction. Discontinuation of VRCZ and drip infusion of normal saline improved the consciousness disorder, hyponatremia, and liver dysfunction. The levels of antidiuretic hormone (ADH) and plasma renin activity were elevated. This patient showed high excreted urine sodium, despite volume depletion and low serum osmolality. Therefore, this patient was diagnosed with salt-losing nephropathy (SLN). SLN should be considered for treatment of VRCZ-associated hyponatremia, together with syndrome of inappropriate secretion of ADH.

A case report of successful treatment with plasma exchange for hemophagocytic syndrome associated with severe systemic juvenile idiopathic arthritis in an infant girl.

Abstract:u2002 An infantile case of hemophagocytic syndrome (HPS) with systemic juvenile idiopathic arthritis (s‐JIA), refractory to methylprednisolone pulse therapy and cyclosporine A administration, was successfully treated by plasma exchange. The patient was a one‐year‐old Japanese girl who had developed recurrent steroid‐dependent signs, including fever, skin eruption, and hepatopathy, while in France, where she had been diagnosed as having s‐JIA at eight months of age. As a high fever and rheumatoid rash were evident on arrival at our hospital, she was admitted and given intravenous methylprednisolone pulse therapy and cyclosporine A. She developed pancytopenia with a generalized clonic seizure, high fever, and liver dysfunction after her cytomegalovirus (CMV) titer became positive during the course of treatment; therefore, she was treated with ganciclovir. She was subsequently diagnosed as having HPS complicating s‐JIA from the findings of a bone marrow aspirate. At this time, her blood examination data including a high level of C‐reactive protein and hyperferritinemia, suggested that her s‐JIA was very active, and the pancytopenia continued after her CMV titer became negative. Therefore, CMV infection against a background of active s‐JIA could have triggered the HPS in this case. Because the HPS was resistant to an immunosuppressive regime of methylprednisolone pulse therapy and cyclosporine A, plasma exchange therapy was started. After three sessions of this therapy, the patients symptoms and laboratory data were markedly improved. Our experience suggests that plasma exchange should be considered as a therapeutic tool for HPS refractory to conventional therapy.

Successful treatment for thrombotic thrombocytopenic purpura complicated with myeloperoxidase anti-neutrophil cytoplasmic autoantibody-associated vasculitis

Thrombotic thrombocytopenic purpura (TTP) complicated with myeloperoxidase anti-neutrophil cytoplasmic autoantibody (MPO-ANCA)-associated vasculitis is rare and generally has a serious prognosis. We report a case wherein TTP was successfully treated with repeated plasma exchange (PE) and MPO-ANCA-associated vasculitis with corticosteroids. The renal function consequently improved such that haemodialysis could be discontinued and the patient was discharged without any significant complications.

Effects of raloxifene on bone metabolism in postmenopausal women on chronic hemodialysis

BackgroundPostmenopausal women with end-stage renal failure are at an increased risk of fracture because of the effects of secondary hyperparathyroidism and postmenopausal osteoporosis. In the present study, we investigated the feasibility of using raloxifene to prevent fractures in postmenopausal women with end-stage renal failure on hemodialysis.MethodsThis study was conducted using a multicenter, single-arm, prospective design. Raloxifene was administered to postmenopausal women aged ≥50xa0years who were on maintenance hemodialysis and met any of the following criteria after a 24-week run-in period: an alkaline phosphatase level (bone formation marker) of ≥6.18xa0µkat/L (≥370xa0U/L), a bone-specific alkaline phosphatase (BAP; bone formation marker) level of ≥0.59xa0µkat/L (≥35.4xa0U/L), or a bone-derived tartrate-resistant acid phosphatase (TRACP-5b; bone resorption marker) level of ≥4.2xa0U/L.ResultsA total of 48 individuals were eligible for study inclusion. Of them, 30 individuals participated in this study. The BAP levels were significantly decreased at week 4, but returned to the baseline levels at week 24. Similarly, the TRACP-5b levels were significantly decreased at week 4, but returned to the baseline levels at week 24. The serum calcium value decreased consistently after the start of raloxifene therapy. The intact parathyroid hormone (iPTH) levels were likely increased at week 4. The ratio of BAP to iPTH levels and the ratio of TRACP-5b to iPTH levels both showed significant decreases over time. During the raloxifene therapy, no thrombosis or other drug-related adverse events developed.ConclusionThe study results indicated that raloxifene can transiently reduce the levels of bone metabolism markers and might be useful for preventing fractures in postmenopausal women with end-stage renal failure, although raloxifene use over the long term may not have adequate efficacy in the absence of appropriate concomitant active vitamin D therapy.

Coincidental finding of Fabry's disease in a patient with IgA nephropathy.

We present the case of a woman with IgA nephropathy and concomitant Fabry’s disease. She was referred to our hospital with proteinuria and haematuria. A renal biopsy showed findings indicating IgA nephropathy under light and immunofluorescence microscopy. Electron microscopy, however, showed laminated inclusion bodies characteristic of Fabry’s disease. The α-galactosidase activity in her serum was low, and the diagnosis of Fabry’s disease was confirmed by genetic analysis. Fabry’s disease in a patient with IgA nephropathy is a very rare occurrence, and Fabry’s disease diagnosed only by electron microscopy has not been previously reported.

Influence of sevelamer on mineral metabolism and hyperparathyroidism in Japanese hemodialysis patients.

Abstract:u2002 In June 2003, sevelamer hydrochloride became widely available in Japan and was expected to control hyperphosphatemia in hemodialysis patients without inducing hypercalcemia. To evaluate the impact of sevelamer therapy on mineral metabolism, we recruited 954 hemodialysis patients from 21 renal units just before the general release of sevelamer in Japan. The serum calcium, phosphate, and parathyroid hormone levels determined on enrollment were compared with those later measured in June 2004. Sevelamer was prescribed for 169 of the 859 patients for whom data were available in 2004. The mean calcium level, phosphate level, and calciumu2003×u2003phosphate product were all significantly reduced during the 12‐month study period, but the intact parathyroid hormone (iPTH) level did not change. As a result, the percentage of patients who achieved a calciumu2003×u2003phosphate product of <55 mg2/dL2 was significantly increased, but there were no changes in that of patients who achieved the target ranges for phosphate (3.5–5.5u2003mg/dL) or iPTH (150–300u2003pg/mL). Among sevelamer‐treated patients, iPTH significantly increased, and this change was more marked in the patients with an initial iPTH level <150u2003pg/mL. Sevelamer was useful for reducing the serum calcium level and calciumu2003×u2003phosphate product, but hyperphosphatemia and hyperparathyroidism were not improved in our study population at 12u2003months after the release of sevelamer. A decrease in the calcium load might result in the exacerbation of hyperparathyroidism. However, among patients with relative hypoparathyroidism, sevelamer therapy may be beneficial for the prevention of adynamic bone disease.

Antineutrophil cytoplasmic antibody-associated crescentic glomerulonephritis with membranous nephropathy treated using thiamazole

A 21-year-old woman with nephrotic syndrome was referred to our hospital. She had congenital diaphragmatic hernia, hypoxic ischemic encephalopathy, and mental retardation, and had been treated for hyperthyroidism with thiamazole in another hospital. Serum creatinine was 37.8xa0μmol/L and antineutrophil cytoplasmic antibody against myeloperoxidase (MPO-ANCA) was 39xa0EU. Urinalyses were 3+ for proteins and 3+ for occult blood. A renal biopsy was performed. An examination using light microscopy (LM) revealed necrotizing glomerulonephritis with crescent formation. Immunofluorescence microscopy showed granular staining with immunoglobulin G and complement component 3 along the capillary walls. Electron microscopy (EM) disclosed subepithelial dense deposits. A renal biopsy suggested necrotizing glomerulonephritis with membranous nephropathy (MN) in stages I or II. Since many cases of drug-induced ANCA-associated glomerulonephritis (AAG) have been reported, we stopped thiamazole and treated with corticosteroid. The MPO-ANCA titer became negative 49xa0days after the initiation of treatment. Two years after the first treatment, the MPO-ANCA titer became elevated again and was 82xa0EU. The patient was administered cyclophosphamide and prednisone. However, the MPO-ANCA titer did not decrease. A renal biopsy was performed again 3xa0years after the first renal biopsy. LM revealed no crescentic formation but demonstrated spike formations along the glomerular basement membrane. EM also disclosed subepithelial dense deposits, but less than the first biopsy. The renal biopsy suggested MN in stages II or III. AAG was regarded as inactive after corticosteroid treatment. Therefore, ciclosporin administration was started. In conclusion, we experienced a rare case of AAG complicated with MN. The histopathologic results showed that immunosuppressive therapy seemed to be effective in treating crescentic glomerulonephritis; furthermore, it reduced proteinuria but could not reduce the MPO-ANCA titer.