Kazuhiko Hora

A case of mitochondrial cytopathy with a typical point mutation for MELAS, presenting with Severe focal-segmental glomerulosclerosis as main clinical manifestation

A 27-year-old female with short stature and mild hearing loss was diagnosed as having focal-segmental glomerulosclerosis by renal biopsy at our hospital. One year later she developed progressive renal dysfunction and cardiac failure and was admitted again to our hospital for evaluation. Though her only neurological disorder was mild hearing loss, her short stature and elevated lactate and pyruvate values in cerebrospinal fluid suggested mitochondrial cytopathy. A muscle biopsy specimen of the left biceps brachii, using modified Gomori trichrome stain, showed a typical image of ragged-red fibers, and an increased number of giant mitochondria with paracrystalline inclusions were visible by electron microscopy. Mitochondrial DNA from the skeletal muscle showed an A-to-G transition at 3243 of transfer RNALeu(UUR), the common point mutation for mitochondrial myopathy, encephalopathy, lactic acidosis, and strokelike episodes. These data confirmed the diagnosis of atypical mitochondrial cytopathy with renal and heart involvement. Mitochondrial cytopathies are often associated with hypertrophic cardiomyopathy but rarely with renal disease. Among the few reported cases with associated renal disease, most included renal tubular disorders; few cases with focal glomerular sclerosis are known. The present case of atypical mitochondrial cytopathy was characterized by a unique clinical course and rare complications with focal-segmental glomerulosclerosis.

Identification of Functions of Peroxisome Proliferator-Activated Receptor α in Proximal Tubules

Peroxisome proliferator-activated receptor alpha(PPARalpha) is a member of the steroid/nuclear receptor superfamily that is intensively expressed in the kidney, but its physiologic function is unknown. In this study, PPARalpha-null mice were used to help clarify the function. Starved PPARalpha-null mice were found to secrete significantly more quantities of urine albumin than starved wild-type mice. Furthermore, the appearance of giant lysosomes, marked accumulation of albumin, and an impaired ability concerning albumin digestion were found only in proximal tubules of the starved PPARalpha-null mice. These abnormalities were probably derived from ATP insufficiency as a result of the starvation-induced decline of carbohydrate metabolism and a lack of PPARalpha-dependent fatty acid metabolism. It is interesting that these abnormalities disappeared when glucose was administered. Taken together, these findings demonstrate important functions of PPARalpha in the proximal tubules, the dynamic regulation of the protein-degradation system through maintenance of ATP homeostasis, and emphasize the importance of the fatty acid metabolism in renal physiology.

PPAR Protects Proximal Tubular Cells from Acute Fatty Acid Toxicity

Fatty acids bound to albumin are filtered through glomeruli, reabsorbed by proximal tubular epithelial cells, and metabolized. Because albumin serves as a carrier, an increase in delivery of fatty acids to the proximal tubule may occur in proteinuric states, possibly leading to toxic effects. At

PPARα attenuates the proinflammatory response in activated mesangial cells

The activated mesangial cell is an important therapeutic target for the control of glomerulonephritis. The peroxisome proliferator-activated receptor alpha (PPARalpha) has attracted considerable attention for its anti-inflammatory effects; however, its roles in the mesangial cells remain unknown. To determine the anti-inflammatory function of PPARalpha in mesangial cells, wild-type and Ppara-null cultured mesangial cells were exposed to lipopolysaccharide (LPS). LPS treatment caused enhanced proinflammatory responses in the Ppara-null cells compared with wild-type cells, as revealed by the induction of interleukin-6, enhanced cell proliferation, and the activation of the nuclear factor (NF)-kappaB signaling pathway. In wild-type cells resistant to inflammation, constitutive expression of PPARalpha was undetectable. However, LPS treatment induced the significant appearance and substantial activation of PPARalpha, which would attenuate the proinflammatory responses through its antagonizing effects on the NF-kappaB signaling pathway. The induction of PPARalpha was coincident with the appearance of alpha-smooth muscle actin, which might be associated with the phenotypic changes of mesangial cells. Moreover, another examination using LPS-injected wild-type mice demonstrated the appearance of PPARalpha-positive cells in glomeruli, suggesting in vivo correlation with PPARalpha induction. These results suggest that PPARalpha plays crucial roles in the attenuation of inflammatory response in activated mesangial cells. PPARalpha might be a novel therapeutic target against glomerular diseases.

Transmission of and liver injury by TT virus in patients on maintenance hemodialysis

Abstract: To study the prevalence and clinical significance of TT virus (TTV) infection in hemodialysis patients, we tested for TTV DNA in serum, using the nested polymerase chain reaction. The prevalence of TTV DNA in 352 hemodialysis patients was 32%, significantly higher than that in 50 healthy blood donors (12%). The prevalence increased with age (P = 0.0098); it was 20% (22/110) in patients aged less than 49 years, 37% (69/188) in those aged 50–69 years, and 41% (22/54) in those aged over 70 years. Other clinical features and the prevalence of other hepatitis viral markers tested did not differ between patients with TTV DNA and those without it. The detection rate of hepatitis C virus (HCV) and hepatitis G virus (HGV) viremias increased with duration of hemodialysis and with the number of blood transfusion units, but the prevalence of TTV viremia did not. Twenty-nine of 91 patients followed for 5 years were initially positive for TTV DNA. Of these 29 patients, 17 (59%) carried this viremia for at least 5 years. Fourteen of the 62 patients (23%) who were initially negative for TTV DNA acquired TTV viremia. Serum alanine aminotransferase (ALT) levels were elevated in patients with HCV viremia but not in patients with HGV or TTV viremia. However, the mean ALT level in patients with all three viremias (HCV, HGV, and TTV) was significantly higher than that in patients with one or two of the viremias. More than 30% of the hemodialysis patients had TTV viremia and the carrier state was maintained for years. The hemodialysis procedures, including blood transfusion, did not seem to be crucial for the transmission of TTV. The pathogenic effects of TTV on hepatitis appear to be limited.

Pharmacokinetics of Temocapril and Enalapril in Patients with Various Degrees of Renal Insufficiency

SummaryTemocapril is a novel ACE inhibitor that is cleared via dual excretion routes in humans. Borderline or mildly hypertensive patients with normal renal function [group 1, creatinine clearance (CLcr) >70 ml/min (4.2 L/h), n = 12], moderate renal impairment [group 2, CLcr 30 to 70 ml/min (1.8 to 4.2 L/h), n = 12] or severe renal impairment [group 3, CLcr <30 ml/min (1.8 L/h), n = 12] received a single oral dose of either temocapril 1mg (n = 6, each group) or enalapril 5mg (n = 6, each group).These 2 drugs gave similar values for the area under the plasma concentration-time curve (AUC) of the active diacids. The maximum plasma concentration of enalapril diacid was increased 2- and 6-fold in moderate and severe renal impairment, respectively, whereas that of temocapril diacid was not altered. The AUC of enalapril diacid increased 13-fold at CLcr values <30 ml/min, but that of temocapril diacid increased only 2-fold.The duration of plasma ACE inhibition due to enalapril was greatly prolonged by the impairment of renal function, whereas that due to temocapril was affected very little. Urinary recovery of temocapril diacid was decreased markedly in patients with severe renal dysfunction, most probably because the diacid was excreted through the biliary route. On the other hand, urinary recovery of enalapril diacid remained fairly high even in patients with severe renal impairment, because of extremely high plasma diacid concentrations resulting from the lack of biliary excretion. These observations suggest that temocapril is beneficial in the treatment of hypertension in patients with severely impaired renal function.

Effects of PMX-DHP Treatment for Patients With Directly Induced Acute Respiratory Distress Syndrome

Abstract:  Endotoxin‐removal direct hemoperfusion column containing polymyxin B immobilized fibers (PMX‐DHP) is an effective procedure for the treatment of sepsis‐induced acute respiratory distress syndrome (ARDS). We investigated retrospectively the effects and appropriate timing of PMX‐DHP induction for directly induced ARDS in 38 patients. PMX‐DHP was carried out twice for two hours. Blood pressure, heart rate (HR) and PaO2/FIO2 (PF) ratio, leukocytes, platelets, endotoxin, inflammatory cytokines and clusters of differentiated peripheral neutrophils and monocytes were measured before and after PMX‐DHP. Acute Physiology and Chronic Health Evaluation (APACHE) II scores, Sequential Organ Failure Assessment (SOFA) scores and lung injury scores (LIS) were determined at the time of starting PMX‐DHP. The underlying causes of ARDS were pneumonia in 29 patients and aspiration pneumonia in 9 patients. The patients were divided into Survivors (n = 21) and Nonsurvivors (n = 17). Mortality was 45% at 30 days after PMX‐DHP. The APACHE II and SOFA scores and the LIS were not significantly different between the two groups. The time from the onset of ARDS to the start of PMX‐DHP was significantly delayed between the two groups. PMX‐DHP significantly improved the PF ratio, HR and systolic blood pressure in the Survivors compared to the Nonsurvivors. The function of active monocytes in the peripheral blood was significantly suppressed after PMX‐DHP. This early induction of PMX‐DHP is indicated for directly induced ARDS. In the Nonsurvivors, this delay could have led to undesirable responses to oxygenation and circulation after PMX‐DHP.

Prospective follow-up study of hepatitis C virus infection in patients undergoing maintenance haemodialysis: comparison among haemodialysis units.

A prospective follow‐up study on hepatitis C virus (HCV) infection was conducted in seven haemodialysis units from April 1990 to March 1995. A total of 634 patients were undergoing maintenance haemodialysis in the seven units. Of those, 302 patients participated in the follow‐up study; 179 were initially HCV antibody negative and 123 were initially positive. Nine of the 179 initially negative patients became positive for HCV antibody during the follow‐up period. In accordance with the appearance of HCV antibody, indicating new infection of HCV, all nine of these patients were diagnosed with HCV viraemia. As no other routes were apparent, HCV infection in all nine patients was likely due to nosocomial transmission. Prevalence of HCV antibody at the start of follow up was significantly higher (P < 0.001) in haemodialysis units A‐C (37.9%) than in haemodialysis units D‐G (17.0%). Incidence of new HCV infection was significantly higher (P= 0.005) in the former units (2.2% per year) than in the latter (0.2% per year). Ten of the 123 patients who were initially positive for the HCV antibody exhibited a loss of reactivity during the follow‐up period; of these 10 patients, nine were negative for HCV‐RNA from the start of the study. In conclusion, the incidence of new HCV infection seen in patients undergoing haemodialysis suggests that their risk of acquiring HCV infection is directly related to the prevalence of HCV antibody positive patients being treated in the units.

Peroxisome Proliferator-Activated Receptor Protects against Glomerulonephritis Induced by Long-Term Exposure to the Plasticizer Di-(2-Ethylhexyl)Phthalate

Safety concerns about di-(2-ethylhexyl)phthalate (DEHP), a plasticizer and a probable endocrine disruptor, have attracted considerable public attention, but there are few studies about long-term exposure to DEHP. DEHP toxicity is thought to involve peroxisome proliferator–activated receptor α (PPARα), but this contention remains controversial. For investigation of the long-term toxicity of DEHP and determination of whether PPARα mediates toxicity, wild-type and PPARα-null mice were fed a diet that contained 0.05 or 0.01% DEHP for 22 mo. PPARα-null mice that were exposed to DEHP exhibited prominent immune complex glomerulonephritis, most likely related to elevated glomerular oxidative stress. Elevated NADPH oxidase, low antioxidant enzymes, and absence of the PPARα-dependent anti-inflammatory effects that normally antagonize the NFκB signaling pathway accompanied the glomerulonephritis in PPARα-null mice. The results reported here indicate that PPARα protects against the nephrotoxic effects of long-term exposure to DEHP.

Chronic Inhibition of Nitric Oxide Production Aggravates Diabetic Nephropathy in Otsuka Long-Evans Tokushima Fatty Rats

Background: Nitric oxide (NO) is known to play a role in diabetic nephropathy, but the molecular basis for this effect remains unclear. Method: Otsuka Long-Evans Tokushima Fatty spontaneous diabetic rat models were used along with Long-Evans Tokushima Otuska rat models as age-matched controls. Either L-arginine (a NO precursor) or L-NAME (a nitric oxide synthase inhibitor) was administered from the age of 22 weeks. Clinical parameters and serum and urinary NO2+NO3 levels were measured, in addition to renal histological findings and ED-1-positive cell counts in glomeruli. Results: There were no significant differences in creatinine clearance between any of the groups at any point. The levels of urinary NO2+NO3 in the diabetic group were significantly lower than those in the control groups after 40 weeks; that in the L-NAME diabetic group was significantly lower than in the other diabetic groups at 52 weeks. Compared with the other diabetic groups, the L-NAME diabetic group had significantly higher urinary protein excretion levels, histological scores, and numbers of ED-1-positive cells in glomeruli. Diabetic rats administered L-arginine excreted more urinary protein than the diabetic controls. Conclusion: Diabetic nephropathy was exacerbated drastically by a nitric oxide synthase inhibitor and mildly by a NO precursor. These data suggested that NO may modify type 2 diabetic nephropathy in Otuska Long-Evans Tokushima Fatty rats through factors other than hemodynamics.