Masaya Yamato

Retinoids Regulate the Repairing Process of the Podocytes in Puromycin Aminonucleoside-induced Nephrotic Rats

The foot processes forming the slit diaphragm are disrupted in diseases associated with proteinuria. Although they are often repairable, regulators for the repairing process remain unknown. By extrapolating from the fact that vitamin A is essential for the nephrogenesis, this study examined whether or not injured podocytes in the middle of the repairing process require retinaldehyde dehydrogenase type 2 (RALDH2), one of the key enzymes to produce all-trans-retinoic acid (ATRA). RALDH2 was dramatically upregulated in podocytes of puromycin aminonucleoside-induced nephrosis (PAN nephrosis) rats. On day 5 of PAN nephrosis, RALDH2 showed the remarkable induction, whereas glomerular expression levels of nephrin and midkine, one of the ATRA target genes, were downregulated. Daily administration of ATRA ameliorated proteinuria, which was accompanied by the improvement in the effacement of the foot processes and by the induction of nephrin and midkine. In contrast, recovery from PAN nephrosis was delayed in rats fed with a vitamin A-deficient diet. Consistently, the promoter region of human nephrin gene (NPHS1) contained three putative retinoic acid response elements (RARE) and showed the enhancer activity in response to ATRA in a dose-dependent manner. This transcriptional activation was regulated through the receptors for retinoids because BMS-189453, an antagonist to the retinoid receptors, counteracted it in a dose-dependent manner. In conclusion, active metabolites of vitamin A, especially ATRA produced by RALDH2 play relevant roles during the repairing process of injured podocytes. The results obtained from PAN nephrosis rats might be applicable to human renal diseases.

Plasma B-type natriuretic peptide level predicts kidney prognosis in patients with predialysis chronic kidney disease

BACKGROUND As a cardiorenal syndrome, there is a dynamic interplay between the heart and the kidney. We conducted a prospective study to evaluate the prognostic impact of plasma B-type natriuretic peptide (BNP) level, a cardiac biomarker, on the long-term kidney prognosis in chronic kidney disease (CKD) patients. METHODS We prospectively enrolled 508 patients with CKD Stages 3, 4 and 5 not on dialysis, from a single nephrology department between 2004 and 2010. The exclusion criteria were over 90 years of age, malignancy, active infection, low cardiac ejection fraction and rapid progressive glomerulonephritis. Relationships between BNP and kidney end point [defined as doubling of baseline serum creatinine and end-stage kidney disease (ESKD) requiring kidney replacement therapy] were measured using Cox models for case-mix and laboratory variables. RESULTS The final analysis covered 485 participants with no loss to follow-up. The median follow-up period was 3.2 years. Two hundred and twenty-eight of the 485 patients reached ESKD requiring dialysis, and baseline serum creatinine levels doubled in another 31. The kidney end point was significantly poorer among patients with plasma BNP levels above, compared with below a cut-off value of 86.1 pg/mL indicated from receiver operating characteristic analysis. Multivariable Cox regression analysis identified the common logarithm BNP as a predictor of kidney end point (adjusted hazard ratio 1.78, 95% CI: 1.28-2.46, P < 0.01). CONCLUSIONS Elevation of BNP level is associated with an increased risk for accelerated progression of CKD ultimately to ESKD. Monitoring the BNP level could be helpful in the management of combined heart and kidney disease.

A case of Wegener's granulomatosis with pulmonary bleeding successfully treated with double filtration plasmapheresis (DFPP)

We report a case of a 41-year-old Japanese man who presented with rapidly progressive glomerulonephritis, chronic sinusitis, and positive cytoplasmic-antineutrophil cytoplasmic antibody (c-ANCA). Renal biopsy showed crescentic glomerulonephritis, and he was diagnosed as having Wegener’s granulomatosis. During the clinical course, he suffered from pulmonary bleeding, and combination therapy of steroid, immunosuppressant, and double filtration plasmapheresis (DFPP) was started. He rapidly entered remission after assistance through DFPP, suggesting the potential efficacy of DFPP for Wegener’s granulomatosis, especially with pulmonary bleeding.

Kid-1 participates in regulating ERK phosphorylation as a part of the circadian clock output in rat kidney

Circadian clock genes play a role for the regulation of cell cycle, but the factors connecting clock to cell cycle are not fully understood. We found that mRNA of Kid-1— a zinc-finger-type transcriptional repressor was localized to cortical and juxtamedullary segments of tubules but not to glomeruli in the rat kidney. Kid-1 mRNA showed robust circadian oscillation with a peak at ZT16. Under temporal restricted feeding, the phase of the oscillation shifted along with mRNAs of the clock genes—Per1 and Per2. The rhythm of S-phase in cell cycle disappeared in the kidney under the restricted feeding. The level of phosphorylation of extracellular signal-regulated kinase (ERK) 1/2 was rhythmic with a peak at ZT16 in the kidney. We found that knockdown and overexpression of Kid-1 in NRK52E (normal rat kidney epithelial) cells induced and reduced the phosphorylation of ERK1/2, respectively. The data suggest that clock-controlled Kid-1 regulates the cell cycle of proliferating renal tubular epithelial cells through ERK phosphorylation.

Rhabdomyolysis caused by peripheral T-cell lymphoma in skeletal muscle

We report a rare case of rhabdomyolysis caused by peripheral T-cell lymphoma (PTCL) in skeletal muscle. A 62-year-old man was admitted with complaints of sudden muscle weakness. Laboratory abnormalities were identified including markedly elevated creatinine-phosphokinase, peaking at 62,640 IU/L and serum creatinine (Cr) at 5.0 mg/dL. Computed tomography scans revealed tumorous swelling of the right psoas major muscle and the obturator internus muscles. Consequently, he was diagnosed with acute renal failure caused by rhabdomyolysis and was treated with hydration and continuous hemodiafiltration, which resulted in significant improvement in renal function (Cr 1.79 mg/dL). However, the cause of the rhabdomyolysis remained unclear, and he suddenly developed a remittent fever and suffered from hemophagocytic syndrome. Serum ferritin level dramatically increased to 104,707.0 ng/mL and creatinine level to 4.09 mg/dL. We performed a biopsy of inguinal lymph nodes, leading to a diagnosis of PTCL. Finally, he was diagnosed with rhabdomyolysis caused by PTCL. Methylprednisolone pulse therapy markedly improved his general condition and renal function (Cr 1.48 mg/dL), and computed tomography scans revealed that tumorous swelling was greatly diminished. Except when the cause of rhabdomyolysis is readily apparent, such as in cases of trauma, drug and thrombophlebitis, one should consider that rhabdomyolysis may be a sequel of lymphoma.

Atypical hemolytic uremic syndrome with MCP mutations preceded by respiratory infection

A 14-year-old boy was referred to our hospital with general fatigue and sore throat. A chest X-ray and computed tomography revealed diffuse bilateral bronchitis. A laboratory examination showed anemia, thrombocytopenia, and renal insufficiency. He had a past medical history of hemolytic uremic syndrome (HUS) without diarrhea at the age of 3; moreover, his elder brother suffered from HUS at the age of 12. These findings indicated that the patient had a familial relapsing form of HUS (atypical HUS). Therefore, he was immediately treated with plasma exchange (PE), as suggested by guidelines, obtaining complete remission. Fifteen months later, he suffered another relapse of atypical HUS preceded by respiratory infection and was cured again with PE. His ADAMTS-13 activity was normal and its inhibitory antibody was undetectable. Two different mutations were found in the gene encoding membrane cofactor protein (MCP). Respiratory infections preceded all three episodes of HUS, but we could not detect the pathogenic agent. Although the long-term outcomes of patients with atypical HUS who have mutations in the MCP gene appear favorable, recurrences are nevertheless frequent. Few reports have described Japanese patients with atypical HUS and complement regulatory abnormalities. This is the first report of a Japanese patient with atypical HUS and mutations in the MCP gene.

Unusual abdominal masses

A 66-year-old afebrile man presented with a 10-day history of general fatigue. He had a history of autoimmune pancreatitis and tubulointerstitial nephritis diagnosed from a kidney biopsy of the left kidney. He had been treated with oral glucocorticoids (prednisolone 25 mg/day) for 3 months. He had normal hepatic function, renal insufficiency (creatinine 122 lmol/L) and a leucocyte concentration of 31.4 3 10/L with predominant neutrophils. There were no abdominal symptoms. An emergency computed tomography (CT) scan was performed to determine the cause of the inflammation. The CT scan revealed a large solid mass in the pelvis and a solid mass in the right retroperitoneal space (Figure 1A and B, indicated by arrows). Gram staining of the grey fluid aspirated from the right retroperitoneal mass (Figure 1C) revealed positive branching rods suggestive ofActinomyces (Figure 1D). We cultured the organism and identified Actinomyces. Intravenous cefotaxime was started, as our patient’s bacterium was ampicillin resistant, and treatment was continued for