Spontaneous splenic rupture in a patient with light-chain deposition disease undergoing autologous peripheral blood stem cell transplantation.

Light-chain deposition disease (LCDD) is a rare plasma cell neoplasm that secretes an abnormal immunoglobulin light chain, which is deposited in tissues, leading to organ dysfunction. Spontaneous splenic rupture is a rare and life-threatening complication of treatment with granulocyte colony-stimulating factor (G-CSF). Herein, we describe spontaneous splenic rupture after the administration of lenograstim to a patient with LCDD undergoing autologous stem cell transplantation (ASCT). The patient was successfully treated by transcatheter embolization of the splenic artery, and long-term stringent complete remission was attained. Plasma cell neoplasms, including multiple myeloma with amyloidosis, are among the most commonly reported conditions associated with spontaneous splenic rupture in patients undergoing ASCT. This finding suggests that, in addition to the effect of G-CSF on the spleen, a combination of factors, including tissue vulnerability induced by the infiltration of abnormal immunoglobulins, may be involved in the pathogenesis of spontaneous splenic rupture. Notably, splenomegaly is not always evident in these patients. Surgical treatment may not be an option, because of severe myelosuppression, and thus less invasive treatment using transcatheter embolization may be feasible.

Cerebral oxidative stress induces spatial working memory dysfunction in uremic mice: neuroprotective effect of tempol.

BACKGROUND: Chronic kidney disease (CKD) is frequently associated with uremic encephalopathy and cognitive impairment. Recent studies have demonstrated that cerebral oxidative stress contributes to cognitive dysfunction. Although oxidative stress has been reported to increase in the uremic rat brain, the relationship between increased oxidative stress and cognitive impairment in uremia is unclear. In the present study, the effects of tempol (TMP), an antioxidant drug, were investigated in uremic mice. METHODS: CKD was induced in male C57BL/6 mice (n = 8) by left nephrectomy and 2/3 electrocoagulation of the right renal cortex. Working memory performance was tested by the radial arm water maze test. We have prepared two protocols ('time course study' and 'treatment study'). First, we examined the working memory test and histological examination of mouse brains after 4 and 8 weeks. Next, we investigated the effect of TMP (3 mM) against uremia-induced neurodegeneration and oxidative stress in the mouse brain. RESULTS: Eight weeks after CKD induction, vehicle-treated mice made significantly more errors than sham-operated control mice, while TMP improved working memory performance in CKD mice. CKD was associated with accumulation of 8-hydroxy-2'-deoxyguanosine in the hippocampal neuronal cells, but not in TMP-treated CKD mice. Increased numbers of pyknotic neuronal cells were observed in the hippocampus of CKD mice at 8 weeks, but pyknotic neuronal cell numbers were decreased under the influence of TMP in uremic mice. CONCLUSIONS: The present study provided evidence that uremia is associated with spatial working memory dysfunction in mice and that treatment with TMP protects against cerebral oxidative stress and improves cognitive dysfunction in uremic mice, suggesting their potential usefulness for the treatment of cognitive dysfunction in uremia.

Spironolactone inhibits hyperglycemia-induced podocyte injury by attenuating ROS production.

BACKGROUND: Accumulating evidence suggests that mineralocorticoid receptor (MR) blockade effectively reduces proteinuria in diabetic nephropathy although the renin-angiotensin-aldosterone system is generally suppressed in diabetes. The present study was designed to confirm the antiproteinuric effect of MR blockade in diabetic rats and elucidate its mechanism. METHODS: The present study investigated whether MR blockade inhibits hyperglycemia-induced podocyte injury, focusing on the involvement of reactive oxygen species (ROS) production, in diabetic rats and cultured podocytes. Sprague-Dawley rats were divided into three groups: control, streptozotocin (STZ; 75 mg/kg)-injected diabetic and STZ treated with spironolactone (SPL; 50 mg/kg/day) and sacrificed after 8, 16 and 24 weeks. RESULTS: Rats gradually developed proteinuria from 8 weeks after induction of diabetes. Immunostaining for Wilms' tumor-1 (WT1) and synaptopodin, markers of podocytes, was attenuated, whereas immunostaining for desmin, a marker of podocyte damage, and 8-hydroxy-2'-deoxyguanosine, a marker of oxidative stress, was up-regulated in the glomeruli of diabetic rats. Diabetic rats showed hypoaldosteronemia compared to the control, whereas SPL decreased proteinuria, ROS production and podocyte damage. To elucidate the paradox between hypoaldosteronemia and effect of SPL under hyperglycemia, the role of high glucose in MR activation and podocyte injury was explored. In cultured MR-expressing podocytes, high glucose significantly enhanced Sgk1 expression, activated nicotinamide adenine dinucleotide phosphate (NADPH) oxidase and ROS production and induced podocyte apoptosis. All these effects were inhibited by SPL. CONCLUSION: We conclude that hyperglycemia in diabetes, independent of plasma aldosterone concentration, induces podocyte injury through MR-mediated ROS production and leads to proteinuria. SPL inhibits hyperglycemia-induced podocyte injury by attenuating ROS production.

Spironolactone suppresses inflammation and prevents L-NAME-induced renal injury in rats.

Chronic inhibition of nitric oxide synthase by N(omega)-nitro- L-arginine methyl ester (L-NAME) causes progressive renal injury with systemic hypertension and interstitial macrophage infiltration. We have previously shown that there is local activation of the renin-angiotensin-aldosterone system in the renal cortex as a major pathogenic feature of macrophage infiltration. In this study, we measured the effects of the aldosterone antagonist, spironolactone, on renal injury in L-NAME-treated male Wistar rats. After 12 weeks of L-NAME-treatment, rats had increased systolic blood pressure, urinary protein excretion, and serum creatinine and histological analysis showed glomerulosclerosis, interstitial fibrosis, and macrophage infiltration. Treatment with spironolactone significantly prevented these renal changes, whereas treatment with hydralazine had no effect. The cortical expression of osteopontin was significantly elevated in L-NAME-treated rats, and expression of its mRNA significantly correlated with the number of infiltrating macrophages and degree of interstitial fibrosis. Spironolactone treatment markedly suppressed osteopontin expression. Our results suggest that reduced nitric oxide bioavailability caused renal inflammation and fibrosis through an aldosterone receptor-dependent mechanism associated with osteopontin expression independent of its systemic hemodynamic effects.

Severe anasarca due to beriberi heart disease and diabetic nephropathy.

A 40-year-old man was transferred to our hospital because of severe anasarca. He was a heavy drinker for more than 20 years, and diagnosed with diabetes mellitus 8 years earlier and treated with retinal photocoagulation 8 months earlier. He reported loss of appetite after divorce 10 months prior to admission. On admission, he presented with systemic edema and dyspnea. Chest radiography showed massive pleural effusion and cardiomegaly. Serum total protein was 5.6 g/dl, albumin 2.6 g/dl, and urinary protein excretion was 5.3 g/day. Glucose tolerance test showed normal pattern. Ultrafiltration and continuous hemofiltration resulted in loss of 40 kg body weight in 5 days. Echocardiography revealed high-output heart failure and blood tests showed low serum thiamine level of 12 ng/ml (normal, >28 ng/ml). Accordingly, the diagnosis was established as beriberi heart disease complicated with nephrotic syndrome. Treatment with 50 mg/day thiamine intravenously and 80 mg/day furosemide resulted in increase in urine output, decrease in cardiac output, resolution of pulmonary effusion, and about 70 kg body weight loss. Percutaneous renal biopsy showed nodular glomerulosclerosis, mesangial matrix expansion, and thickening of glomerular basement membrane (GBM). Immunofluorescence study showed no glomerular deposition of immunoglobulin or complement. Electron microscopy showed GBM thickening and mesangial matrix deposition without electron-dense deposits or fibrils. These findings were compatible with diabetic glomerulosclerosis. In this patient, extreme malnutrition altered glucose tolerance but, on the other hand, nephrotic syndrome associated with diabetic nephropathy made the diagnosis of beriberi heart disease difficult.

Systemic Aldosterone, But Not Angiotensin II, Plays a Pivotal Role in the Pathogenesis of Renal Injury in Chronic Nitric Oxide-Deficient Male Rats.

Chronic inhibition of nitric oxide synthase by N(ω)-nitro-L-arginine methyl ester (L-NAME) causes progressive renal injury and systemic hypertension. Angiotensin II (Ang II) has been conventionally regarded as one of the primary causes of renal injury. We reported previously that such renal injury was almost completely suppressed by both an Ang II type I receptor blocker and an aldosterone antagonist. The aldosterone antagonist also inhibited the systemic Ang II elevation. Therefore, it remains to be elucidated whether Ang II or aldosterone directly affects the development of such renal injury. In the present study, we investigated the role of aldosterone in the pathogenesis of renal injury induced by L-NAME-mediated chronic nitric oxide synthase inhibition in male Wistar rats (aged 10 wk). Serial analyses demonstrated that the renal injury and inflammation in L-NAME-treated rats was associated with elevation of both Ang II and aldosterone. To investigate the direct effect of aldosterone on the renal injury, we conducted adrenalectomy (ADX) and aldosterone supplementation in L-NAME-treated rats. In ADX rats, aldosterone was undetectable, and renal injury and inflammation were almost completely prevented by ADX, although systemic and local Ang II and blood pressure were still elevated. Aldosterone supplementation reversed the beneficial effect of ADX. The present study indicates that aldosterone rather than Ang II plays a central and direct role in the pathogenesis of renal injury by L-NAME through inflammation, independent of its systemic hemodynamic effects.

Factors Contributing to Erythropoietin Hyporesponsiveness in Patients on Long-Term Continuous Ambulatory Peritoneal Dialysis: A Cross-Sectional Study.

BACKGROUND: Factors contributing to erythropoietin (EPO) hyporesponsiveness in patients on long-term continuous ambulatory peritoneal dialysis are not well understood. Therefore, we investigated the factors contributing to EPO hyporesponsiveness using the EPO resistance index (ERI). METHODS: A total of 14 patients (7 males and 7 females, age 65.0 ± 11.9 years) were selected for this study. We defined ERI as the weekly dose of EPO per body weight divided by hemoglobin (U/kg/g/dl/week). Bioelectrical impedance analysis was used to assess the patients' body composition and fluid status. We examined associations between ERI and clinical parameters, such as physiological, chemical and nutrition status, by correlation and multiple linear regression analyses. RESULTS: Peritoneal dialysis duration was 95 ± 23 months, and all patients underwent peritoneal dialysis for >5 years. Hemoglobin, blood pressure and ultrafiltration volume of peritoneal dialysis were 11.5 ± 1.2 g/dl, 123 ± 14/72 ± 8 mm Hg and 834 ± 317 ml/day, respectively. Renal Kt/V and peritoneal Kt/V, which are indices of dialysis adequacy, were 0.32 ± 0.31 and 1.70 ± 0.31, respectively. Age and extracellular water/total body water (ECW/TBW) ratio had significant positive correlations with ERI (both p < 0.05). Levels of C-reactive protein, serum albumin, parathyroid hormone and normalized protein catabolic rate were not significantly correlated with ERI. In a multiple regression analysis, ECW/TBW was independently associated with ERI (p < 0.05). CONCLUSIONS: This study demonstrates that ECW/TBW was a factor contributing to ERI and that appropriate maintenance of body fluid volume could contribute to low EPO dosing.

Two Years of Cinacalcet Hydrochloride Treatment Decreased Parathyroid Gland Volume and Serum Parathyroid Hormone Level in Hemodialysis Patients With Advanced Secondary Hyperparathyroidism.

The long-term effect of cinacalcet hydrochloride treatment on parathyroid gland (PTG) volume has been scarcely investigated in patients with moderate to advanced secondary hyperparathyroidism (SHPT). The present study was a prospective observational study to determine the effect of cinacalcet treatment on PTG volume and serum biochemical parameters in 60 patients with renal SHPT, already treated with intravenous vitamin D receptor activator (VDRA). Measurement of biochemical parameters and PTG volumes were performed periodically, which were analyzed by stratification into tertiles across the baseline parathyroid hormone (PTH) level or PTG volume. We also determined the factors that can estimate the changes in PTG volume and the achievement of the target PTH range by multivariable analyses. Two years of cinacalcet treatment significantly decreased the serum levels of PTH, calcium, and phosphate, followed by the improvement of achieving the target ranges for these parameters recommended by the Japanese Society for Dialysis Therapy. Cinacalcet decreased the maximal and total PTG volume by about 30%, and also decreased the serum PTH level independent of the baseline serum PTH level and PTG volume. Ten out of 60 patients showed 30% increase in maximal PTG after 2 years. Multivariable analysis showed that patients with nodular PTG at baseline and patients with higher serum calcium and PTH levels at 1 year were likely to exceed the target range of PTH at two years. In conclusion, cinacalcet treatment with intravenous VDRA therapy decreased both PTG volume and serum intact PTH level, irrespective of the pretreatment PTG status and past treatment history.

The antioxidant tempol ameliorates arterial medial calcification in uremic rats: important role of oxidative stress in the pathogenesis of vascular calcification in chronic kidney disease.

Vascular calcification is closely related to cardiovascular morbidity and mortality. Accumulating data indicate that oxidative stress is associated with dysfunction of various organs, including cardiovascular diseases in chronic kidney disease (CKD). However, it remains undetermined if oxidative stress induced by uremia promotes arterial medial calcification. The present study investigated the role of oxidative stress in the pathogenesis of arterial medial calcification in uremic rats. Rats with uremia induced by adenine-rich diet progressively developed arterial medial calcification, which was accompanied by time-dependent increases in both aortic and systemic oxidative stress. Immunohistochemical and biochemical analyses showed that the arterial medial calcification progressed in a time-dependent manner that is parallel to the osteogenic transdifferentiation of vascular smooth muscle cells. Accumulation of oxidative stress was also identified in the calcified regions. Time-course studies indicated that both oxidative stress and hyperphosphatemia correlated with arterial medial calcification. Tempol, an antioxidant, ameliorated osteogenic transdifferentiation of vascular smooth muscle cells and arterial medial calcification in uremic rats, together with reduction in aortic and systemic oxidative stress levels, without affecting serum biochemical parameters. Our data suggest that oxidative stress induced by uremia can play a role in the pathogenesis of vascular calcification in CKD, and that antioxidants such as tempol are potentially useful in preventing the progression of vascular calcification in CKD.

Kienböck's disease: unusual cause of acute onset wrist pain in a dialysis patient.

Kienböck's disease is a rare disorder that presents with wrist pain and limitation of motion and is caused by avascular necrosis of the lunate bone. Dialysis patients occasionally present with wrist pain. However, Kienböck's disease is rarely reported in dialysis patients. We report a case of 52-year-old woman with a 28-year history of hemodialysis who presented with acute wrist pain. T1-weighted magnetic resonance imaging showed diffuse low intensity of the lunate bone, consistent with the diagnosis of Kienböck's disease. Because this disease can lead to chronic debilitating wrist pain, prompt diagnosis, accurate staging, and provision of appropriate treatment is mandatory.

Hemorrhagic shock and obstructive uropathy due to a large rectus sheath hematoma in a patient on anticoagulant therapy.

A 54-year-old woman was transferred to our hospital with disseminated intravascular coagulation, and was treated with heparin. On hospitalization day 13, she developed lower abdominal pain and mass followed by circulatory shock. She became oliguric and laboratory tests showed serum creatinine of 3.5 mg/dL and hemoglobin of 7.4 g/dL. Computed tomography showed hematoma in the left rectus sheath, compressing the urinary bladder exteriorly, which resulted in worsening of bilateral hydronephrosis. Conservative treatment resulted in resolution of the rectus sheath hematoma and improvement of renal function. Rectus sheath hematoma can be treated conservatively without surgical intervention even in complicated cases.

Tubulointerstitial nephritis and IgA nephropathy in a patient with advanced lung cancer treated with long-term gefitinib.

A 52-year-old Japanese female was admitted to our hospital for microhematuria, proteinuria and progressive renal dysfunction. Two years prior to admission, she was diagnosed with lung adenocarcinoma and multiple bone and brain metastases, and was treated with gefitinib (250 mg/day). Treatment for 6 months induced partial response with 30% regression of the primary lung tumor, and resolution of metastatic tumors. After confirmation of the partial remission state, we performed percutaneous renal biopsy. Glomeruli showed mild to moderate mesangial proliferation, segmental endocapillary proliferation and occasional fibrocellular crescent formation. In addition, severe interstitial fibrosis and tubular atrophy relative to the degree of glomerular sclerosis were noted. Immunofluorescence microscopy showed predominant IgA deposition in the mesangial area. Electron microscopy revealed subepithelial and paramesangial electron-dense deposits. In consideration of the prognosis of lung cancer and complication of immunosuppressive treatment, we continued gefitinib only and closely followed-up the clinical course in the outpatient clinic. Sixteen months later, she continued to have proteinuria and microhematuria, and the severity of renal dysfunction was still the same. However, the lung cancer started to increase in size. This is quite an unusual case presenting histologically with tubulointerstitial nephritis and IgA nephropathy in a patient on long-term treatment with gefitinib.