Takashi Nakamichi

Characteristics of the antibodies of two patients who developed daytime hyperglycemia and morning hypoglycemia because of insulin antibodies

We encountered two patients who developed daytime hyperglycemia and early morning hypoglycemia because of insulin antibody (IA) that the affinity was extremely lower and the capacity extremely higher than those of IA in the insulin autoimmune syndrome, after their insulin treatment were changed from human insulin to analog insulin.

Losartan modulates muscular capillary density and reverses thiazide diuretic-exacerbated insulin resistance in fructose-fed rats

The renin–angiotensin system (RAS) is involved in the pathogenesis of insulin sensitivity (IS). The role of RAS in insulin resistance and muscular circulation has yet to be elucidated. Therefore, this study sought to determine the mechanisms of angiotensin II receptor blockers (ARBs) and/or diuretics on IS and capillary density (CD) in fructose-fed rats (FFRs). Sprague-Dawley rats were fed either normal chow (control group) or fructose-rich chow for 8 weeks. For the last 4 weeks, FFRs were allocated to four groups: an FFR group and groups treated with the thiazide diuretic hydrochlorothiazide (HCTZ), with the ARB losartan, or both. IS was evaluated by the euglycemic hyperinsulinemic glucose clamp technique at week 8. In addition, CD in the extensor digitorum longus muscle was evaluated. Blood pressure was significantly higher in the FFRs than in the controls. HCTZ, losartan and their combination significantly lowered blood pressure. IS was significantly lower in the FFR group than in the controls and was even lower in the HCTZ group. Losartan alone or combined with HCTZ significantly increased IS. In all cases, IS was associated with muscular CD, but not with plasma adiponectin or lipids. These results indicate that losartan reverses HCTZ-exacerbated insulin resistance, which can be mediated through the modulation of muscular circulation in rats with impaired glucose metabolism.

Blockade of angiotensin II type-1 receptor increases salt sensitivity in Sprague―Dawley rats

This study determined the role of angiotensin II type-1 (AT1) receptor in the salt sensitivity of blood pressure. The mean arterial blood pressure (MAP) of Sprague–Dawley rats was monitored by radio telemetry and, after baseline measurements, rats were treated either with (1) vehicle, (2) AT1 receptor blocker (ARB) olmesartan (OLM, 100 nmol kg−1 h−1, subcutaneously), (3) OLM with hydrochlorothiazide (HCTZ, 40 mg kg−1 day−1, orally), (4) angiotensin II (AngII, 100 ng kg−1 min−1, subcutaneously) or with (5) AngII with OLM. Rats were fed a 0.5% salt diet during the baseline and first 7 days of treatment period, and the diet was then switched to one containing 8% salt for another 7 days. Urinary samples were collected in a metabolic cage at the end of each period. MAP of the vehicle group did not change throughout the study. In AngII-infused rats, BP increased only when rats were fed an 8% salt diet. OLM and OLM with AngII significantly reduced MAP when rats were on a 0.5% salt diet, but not on an 8% salt diet, indicating an enhanced salt sensitivity by OLM. Co-treatment with HCTZ reduced the salt sensitivity of OLM. The urinary level of the oxidative stress marker was increased by an 8% salt diet and was not altered by either OLM alone or in combination with HCTZ. However, OLM attenuated the salt-induced renal NAD(P)H (nicotinamide adenine dinucleotide phosphate) oxidase activity. These results indicate that AT1 receptor blockade increases salt sensitivity, which is reversed by diuretics. We conclude that OLM and HCTZ could be a useful combination for reduction of blood pressure even under high salt intake without changes in urinary oxidative stress levels.

Fabry's disease discovered with chance urinary mulberry cells: a case report

Fabry’s disease (FD) is a rare X-linked lysosomal storage disorder. Novel enzyme replacement therapy (ERT) at an early stage can slow the progression of cardiovascular and renal dysfunction. Urinary mulberry cells are occasionally found in renal FD. We report a case of variant FD in which detection of urinary mulberry cells led to an early diagnosis. A 36-year-old Japanese man was referred to our hospital because mulberry cells had been detected during urinalysis. Proteinuria and renal dysfunction were not observed. His plasma alpha-galactosidase activity was very low. Renal biopsy revealed typical foamy changes in the glomerular podocytes and tubular epithelial cells that are found in renal FD. Based on the detection of urinary mulberry cells, we successfully started ERT before the patient’s renal function deteriorated. Clinical nephrologists and laboratory technicians should recognize the importance of screening for mulberry cells during urinalysis as this is a simple, inexpensive, and non-invasive method for diagnosing FD.

Role of specific T-type calcium channel blocker R(-) efonidipine in the regulation of renal medullary circulation.

Objectives: Blockade of the T-type calcium channel (TCC), which is expressed in the renal efferent arterioles of the juxtamedullary nephron and vasa recta, has been shown to protect against renal injury. Studies were designed to determine the effects of a specific TCC blocker, R(−) efonidipine [R(−)EFO], on the regulation of renal circulation. Methods and results: Renal medullary blood flux (MBF) and cortical blood flux (CBF) were simultaneously monitored using laser-Doppler flowmetry in Sprague-Dawley rats. Responses were also determined in rats with angiotensin II (AngII) induced renal ischemia. Intravenous (i.v.) or renal interstitial (r.i.) infusion of R(−)EFO (0.25 mg/h, i.v. or r.i.) significantly increased MBF by 24.0 ± 7.0 and 21.0 ± 4.4%, respectively, but without changing CBF or mean arterial pressure. The nitric oxide (NO) synthase inhibitor NG-nitro-L-argininemethylester (L-NAME, 1 &mgr;g/kg per min, i.v. or r.i.) significantly attenuated R(−)EFO-induced increase in MBF. R(−)EFO inhibited the AngII-mediated (50 ng/kg per min, i.v.) reduction of MBF (28.4 ± 1.7%), which was associated with increased urinary NO2− + NO3− excretion and decreased urinary hydrogen peroxide (H2O2) excretion. Intracellular H2O2 fluorescence (real-time fluorescence imaging) in the epithelial cells of isolated medullary thick ascending limb (mTAL) significantly increased following AngII stimulation (1 &mgr;mol/L, 235 ± 52 units), which was significantly inhibited by pre and coincubation with R(−)EFO. R(−)EFO stimulation also increased the intracellular NO concentration in the epithelial cells of mTAL (220 ± 62 units). Conclusion: These results suggest that TCC blockade with R(−)EFO selectively increases MBF, an effect that appears to be mediated by changes in renal NO and oxidative stress balance, which may protect against ischemic renal injury in the renal medullary region.

Synovitis in a Patient with IgG4-related Disease

A 71-year-old man was admitted to our department due to arthralgia and renal dysfunction. A physical examination disclosed swelling of the right shoulder and left wrist joints. Laboratory tests showed elevated serum IgG4 and creatinine levels, and magnetic resonance imaging of the wrist revealed bone erosion and synovitis. In addition, fluorodeoxyglucose positron emission tomography showed uptake in the submandibular glands, pancreas, kidneys, and affected joints and a renal biopsy revealed tubulointerstitial nephritis with the infiltration of IgG4+ plasma cells. The patient was subsequently diagnosed with IgG4-related disease (IgG4-RD) and successfully treated with corticosteroid therapy. This case suggests that erosive arthritis may occur in patients with IgG4-RD.

Focal Segmental Glomerulosclerosis Associated with Chronic Progressive External Ophthalmoplegia and Mitochondrial DNA A3243G Mutation

Focal segmental glomerulosclerosis (FSGS) is caused by various etiologies, with mitochondrial dysfunction being one of the causes. FSGS is known to be associated with mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS), which is a subclass of mitochondrial disease. However, it has rarely been reported in other mitochondrial disease subclasses. Here, we reported a 20-year-old man diagnosed with FSGS associated with chronic progressive external ophthalmoplegia (CPEO) due to mitochondrial DNA (mtDNA) 3243A>G mutation. He presented with left ptosis, short stature, mild sensorineural deafness, and cardiac conduction block. A renal biopsy sample showed segmental sclerosis and adhesions between capillaries and Bowman’s capsule, indicating FSGS. Electron microscopy demonstrated abnormal aggregated mitochondria in podocytes, and the basement membrane and epithelial cells of Bowman’s capsule. Skeletal muscle biopsy also showed accumulation of abnormal mitochondria. mtDNA analysis identified heteroplasmic mtDNA 3243A>G mutation with no large-scale deletions. From these findings, we diagnosed the case as CPEO with multi-organ involvement including FSGS. Our report demonstrates that CPEO, as well as MELAS, can be associated with FSGS. Because mitochondrial disease presents with a variety of clinical symptoms, atypical cases with non-classical manifestations are observed. Thus, mitochondrial disease should be considered as an underlying cause of FSGS with systemic manifestations even with atypical phenotypes.

Blood purification therapies in methotrexate-induced acute kidney injury: four case reports

BackgroundMethotrexate (MTX), a folic acid antimetabolite, is administered at a high dose for the treatment of diseases such as leukemia and malignant lymphoma. Often, an effort is made to reduce the adverse effects of MTX by monitoring MTX concentration in the blood and administering a high dose of leucovorin. However, side effects of MTX are still reported. MTX is metabolized in the liver and eliminated via the kidneys; hence, blood purification therapy is useful for the reduction of MTX blood concentration in case of renal impairment.Case presentationWe performed various types of blood purification therapies in four cases of MTX poisoning that accompanied renal impairment.ConclusionsBased on our results, we concluded that hemodialysis or hemoperfusion with an activated carbon absorption column was useful for the elimination of MTX from the blood. It is important to choose an appropriate blood purification method understanding the characteristics of each blood purification method.

Pro)renin receptor is involved in mesangial fibrosis and matrix expansion

Abstract(Pro)renin receptor [(P)RR] is expressed in the kidney and is involved in renal injury. Although (P)RR is activated by indoxyl sulfate (IS) and may be related to renal injury, the details remain unclear. We used mouse mesangial cell line SV40 MES13 to investigate the association of (P)RR with mesangial fibrosis or expansion. Furthermore, we examined the correlation between serum soluble (P)RR [s(P)RR] and various laboratory data including serum IS, a uremic toxin that induces renal fibrosis through (P)RR, and pathological indices in chronic kidney disease and particularly in IgA nephropathy patients. In vitro study using SV40 MES13 cells revealed that (P)RR expression significantly increased in the presence of IS. IS stimulated the fibrotic factors’ expression, which was significantly suppressed by (P)RR knockdown. Moreover, it significantly increased the expression of matrix metalloproteinase 9 and tissue inhibitor of metalloproteinase 1 via the ERK1/2 pathway. In addition, the s(P)RR level significantly correlated with serum IS and mesangial injury markers in our patients. Our results suggest that (P)RR is associated with mesangial fibrosis and matrix expansion through the IS-(P)RR-ERK1/2 pathway. Clinically, s(P)RR may be a biomarker of mesangial fibrosis and matrix expansion.

747 URINARY ANGIOTENSINOGEN ASSOCIATE WITH URINARY ALBUMIN EXCRETION AND BLOOD PRESSURE IN COMMUNITY HEALTH CHECKUP –KAWASAKI STUDY-

Background: Recent studies evaluated that inappropriate activation of the intrarenal RAS is an important contributor for the pathogenesis of hypertension and renal injury. Urinary angiotensinogen (U-AGT) has been demonstrated to be an indicator for intrarenal RAS. Therefore the present study was designed to evaluate whether U-AGT excretion would associate the pathogenesis of hypertension. Association between U-AGT excretion, blood pressure and urinary albumin excretion (UAE) in the parameters of the community health checkup was determined. Methods: 434 adults (men; 204, women: 230, age: 66.1 ± 14.7 years) who have taken health checkup in Kawasaki town were enrolled for the study. U-AGT excretion and U-MCP-1 excretion, a marker for inflammation, was analyzed by ELISA. Correlations were determined among the parameters in the community health checkup. Results: Significant positive correlation (p < 0.05) between systolic blood pressure (SBP) and U-albumin excretion was observed in both men and women. There was a significant negative correlation between SBP and estimated GFR (eGFR) only in men but not in women. U-AGT had a positive correlation between SBP, HBA1c and UAE, negative correlation with eGFR. Although U-MCP-1 had strong correlation between U-AGT, it did not have correlation between SBP, HBA1c, UAE and eGFR. Significant correlation was observed between eGFR and HBA1c, SBP, U-AGT, UAE and age. Conclusions: Results in the present study indicate that renal RAS as indicated by U-AGT excretion have an association with hypertension and renal injury. We conclude that U-AGT excretion would be a good marker for predicting the pathogenesis of hypertension and renal injury.