Yoshihiro Takamitsu

Significantly rapid relief from steroid-resistant nephrotic syndrome by LDL apheresis compared with steroid monotherapy

Rapid amelioration of hypercholesterolemia by LDL apheresis (LDL-A) was performed for long-standing nephrotic syndrome (NS) with hyperlipidemia due to focal segmental glomerulosclerosis (FGS) and the clinical data and prognosis were compared between LDL-A-treated and nontreated groups. Seventeen steroid-resistant NS patients treated with LDL-A (LDL-A group) and 10 NS patients treated with steroids only (steroid-monotherapy (SM) group) were compared. Serum cholesterol and phospholipid levels were significantly lowered only in the LDL-A group (p < 0.01, respectively). The LDL-A group showed a significant decrease of urinary protein (UP, p < 0.01) and increase of serum albumin (p < 0.05). Average time needed to achieve a decrease of UP to less than nephrotic range (< 3.5 g/day) was significantly shorter in the LDL-A group than in the SM group (p < 0.01). Although this is not a prospective study, it is highly expected that a rapid improvement of hypercholesterolemia by LDL-A in steroid-resistant NS will provide more rapid relief from NS than steroid therapy alone.

Total and Split Renal Function Assessed by Ultrasound Doppler Techniques

We evaluated total and split renal functions from the pattern for renal arterial blood flow detected by ultrasound Doppler in healthy subjects and patients with varying degrees of renal function and disorders other than renovascular hypertension or severe aortic valvular disease. A renal-time pulsed ultrasonic echo-Doppler device at 2.5 MHz was used with a translumbar approach. The ratio of peak diastolic (D) to systolic (S) velocity correlated well with both p-aminohippurate clearance and creatinine clearance. Acceleration time was correlated with the clearance of neither compound. To evaluate the clinical usefulness of ultrasound Doppler in the assessment of split renal function, we compared the D/S ratio with the renal function obtained by radionuclide methods for individuals. The split renal glomerular filtration rate, calculated by a method which makes use of the early renal uptake of 99mTc-diethylenetriam-inepentaacetic acid, correlated well with the D/S ratio. These results indicate that the ultrasonic measurement of renal arterial blood flow by the pulsed Doppler method should be useful for assessment of total and split renal functions.

Sequential changes in the plasma concentration of risperidone following intentional overdose.

Risperidone (RIS) is a novel antipsychotic agent whose pharmacokinetics have yet to be fully determined. In particular, little is known about RIS following an overdose. We report the pharmacokinetics following ingestion of a high dose of RIS by serially measuring the plasma concentration in two patients. These patients were admitted in a comatose state following an intentional overdose of RIS; all patients survived. In the first patient, 14 mg of RIS had been ingested 2 hr before the first blood sample was obtained. The second patient ingested an estimated 90 mg of RIS. Seven time-points were determined. The maximum concentration of unaltered RIS was 325 ng/mL and that of the principal metabolite (9-hydroxy-risperidone: 9-OH RIS) was 139 ng/mL. By plotting the time-concentration curve for the active fraction (RIS plus 9-OH-RIS) in the first and second patients, the half-life of RIS following overdose was determined and was approximately 12.7 hr and 17.8 hr, respectively. These values are similar to the half-life of RIS in healthy individuals ingesting a therapeutic dose. Two patients did not developed parkinsonism nor dystonia, and were discharged without sequelae.

Carbamylated Hemoglobin as a Therapeutic Marker in Hemodialysis

Carbamylation requires isocyanic acid derived from urea. Carbamylation of hemoglobin (Hb) produces carbamylated Hb (carbHb), which could serve as a marker of posttranslational protein modification possibly associated with such uremic complications as atherosclerosis. Since relative carbHb levels are determined by mean urea concentration and duration of exposure, they could be used to assess the adequacy of a patient’s hemodialysis (HD) regimen. We therefore determined the relationship between carbHb and urea kinetics in patients with chronic renal failure (CRF) undergoing maintenance HD. In pre-HD determinations as well as in nondialyzed subjects including healthy subjects and CRF patients without dialysis, carbHb correlated well with blood urea nitrogen (BUN) concentrations, especially with BUN averaged for the preceding 1–3 months. In HD patients, carbHb correlated significantly with urea kinetics (time-averaged concentration of urea, or TACurea, Kt/V and urea reduction rate). The estimated mean urea concentration in HD patients calculated from the relationship between carbHb and averaged BUN over 3 months in the nondialyzed groups was lower than TACurea, suggesting that TACurea may be an overestimate. Pre-HD BUN is not a good nutritional index since detrimental decreases in urea elimination from the body can elevate pre-HD BUN independently of nutrition. We therefore devised a new nutritional index, BUN/carbHb, which correlated significantly with serum albumin as well as the normalized protein catabolic rate. These results demonstrate that carbHb accurately reflects uremic control and the BUN/carbHb ratio could serve as an index of nutritional state in HD patients.

Impairment of Vascular Responses to Reactive Hyperemia and Nitric Oxide in Chronic Renal Failure

Background: Cardiovascular events are the leading cause of morbidity and mortality in patients with end-stage renal disease. The role of endothelial dysfunction, an early marker of arteriosclerosis, in patients with chronic renal failure (CRF) before the initiation of maintenance hemodialysis (HD), and the factors affecting endothelial dysfunction in the setting of chronic renal failure remain poorly understood. Methods: We evaluated endothelial function by measuring flow-mediated vasodilation (%FMD) during reactive hyperemia in healthy individuals (HCS) and patients with chronic renal failure with (HD) or without (ND) hemodialysis. Nonspecific endothelium-independent vasodilation (%NTG) was measured after the administration of sublingual glyceryl trinitrate spray (0.3 mg). Factors affecting %FMD and %NTG were also tested. Results: In ND and HD, plasma homocysteine, cysteine and stable NO metabolite (NO–3) concentrations were significantly elevated. In ND and HD, reactive hyperemia as well as %NTG and %FMD were attenuated to a similar degree. On multivariate regression analysis, NO–3 concentration was directly correlated with both %FMD and %NTG, while the glutathione (GSH) concentration correlated with only %NTG. Conclusion: Our findings indicate that chronic renal failure before the initiation of maintenance hemodialysis impairs endothelial function and/or the response to NO, which is accompanied by the attenuated reactive hyperemia. Furthermore, the impairment might be related to the decreased synthesis or the dissipation of NO.

Elevated Serum Pepsinogens in Chronic Renal Failure Patients

Human pepsinogens, the precursors of pepsin, originating from the stomach mucosa, are classified into two biochemically distinct groups, namely pepsinogen I (PG I) and pepsinogen II (PG II). We studied the serum levels of PG I and II in 51 normal volunteers, 23 chronic glomerulonephritis patients, 21 continuous ambulatory peritoneal dialysis (CAPD) patients and 40 hemodialysis patients. Serum pepsinogen levels were measured with a competitive binding double antibody radioimmunoassay. In the group of chronic glomerulonephritis patients, a positive correlation between the serum creatinine and the pepsinogen levels were found. The serum pepsinogen levels were remarkably elevated in CAPD and hemodialysis patients. The median levels of post-hemodialysis PG I (265.4 +/- 165.2 ng/ml) and PG II (41.7 +/- 38.0 ng/ml) were significantly higher than prehemodialysis values (PG I 207.4 +/- 127.5 ng/ml, PG II 29.0 +/- 16.6 ng/ml). Pepsinogen release by isolated gastric glands of guinea pigs was suppressed by guanidinosuccinic acid and was facilitated by calcium. The data suggest that both removal of guanidinosuccinic acid and infusion of calcium during hemodialysis contribute to the raised serum levels of these pepsinogens after hemodialysis.

Role of Taurine in the Kidney: Osmoregulatory Taurine Accumulation in Renal Medulla

Comparative studies of a wide variety of organisms indicate that almost all cells that are able to adapt to a high-salt environment do so by balancing the increased extracellular osmolality with high intracellular concentrations of certain organic solutes (“organic osmolytes”). The organic osmolytes fall mainly into three groups: polyols (such as sorbitol and myo-inositol), methylamines (such as glycerophosphorylcholine and betaine), and amino acids (such as taurine, glycine and proline). Cells apparently use these organic compounds to adjust their intracellular osmolality because, unlike “perturbing” solutes such as NaCl, KCl, and urea, the organic osmolytes inhibit enzymes and other cellular processes relatively little even at high concentrations (17).

Is 2.5 mEq/L the Optimal Calcium Concentration of Dialysate in the Use of Sevelamer Hydrochloride? A Study of the Dialysate Calcium Concentration Recommended by K/DOQI Guidelines

Abstract:  We tested the effect of three different dialysate calcium concentrations on calcium–phosphorus metabolism during the use of sevelamer hydrochloride. After a calcium‐containing phosphate binder was switched to sevelamer, the serum calcium, phosphorus, and intact parathyroid hormone levels and the markers of bone turnover were measured in the patients whose dialysate calcium concentrations were 2.5, 2.75, and 3.0 mEq/L. As a result, in the 2.75‐mEq/L group, the serum calcium concentrations decreased and the intact parathyroid hormone level increased significantly. In the 2.5‐mEq/L group, transient hypocalcemia occurred and the levels of both bone‐alkaline phosphatase and osteocalcin increased. In the 3.0‐mEq/L group, the serum calcium concentrations did not change significantly and only bone‐alkaline phosphatase increased. If a calcium‐containing phosphate binder is completely switched to sevelamer, dialysis using a dialysate calcium concentration below 3.0 mEq/L may result in hypocalcemia and acceleration  of  bone  turnover.  

A Nitric Oxide-Generating Beta-Blocking Agent Prevents Renal Injury in the Rat Remnant Kidney Model

Background: The L-arginine-nitric oxide (NO) pathway plays an important role in the modulation of glomerular disease. We investigated whether β-blocking agents, with and without an NO-generating function, had renoprotective effects in the 5/6 nephrectomized rats (Nx), an animal model of glomerulosclerosis. Methods: Nipradilol, a β-blocker with an ONO2 group (5, 10 or 15 mg/kg/day) and propranolol, a β-blocker without this group (50 mg/kg/day) were administered for 12 weeks to Nx together with and without nitro-L-arginine methyl ester (L-NAME). We evaluated the effects of both drugs on proteinuria, hypertension, renal function, glomerulosclerosis and urinary excretion of NO metabolites (UNOx) and cyclic GMP (UcGMP). Results: Both drugs similarly attenuated the elevated blood pressure in Nx. However, nipradilol, at doses of 10 and 15 mg/kg/day, significantly decreased proteinuria and glomerulosclerosis, while propranolol did not. Nx showed reduced UNOx in comparison with the sham-operated rats. Nipradilol increased UNOx and UcGMP significantly and in a dose- dependent manner, whereas propranolol reduced them to levels lower than those in Nx. Nx receiving L-NAME reduced UNOx. The addition of nipradilol increased UNOx and decreased urinary protein excretion and glomerulosclerosis, suggesting that the NO released from the drug contributed to its renoprotective effect. Conclusion: These findings indicate that nipradilol exerts its renoprotective effect through NO generation, and not by lowering blood pressure. The β-adrenergic blocking action per se does not seem to be related to the renoprotective effect of these agents.

Influence of Magnesium Deficiency on Concentration of Calcium in Soft Tissue of Uremic Rats

The influence of magnesium (Mg) deficiency on the concentration of calcium (Ca) in the aorta, heart, and kidney was evaluated in uremic rats. A total of 32 rats were randomly assigned to two groups: one group made uremic by the 5/6 nephrectomy method, and the other serving as sham-operated controls. Both groups were randomly assigned to two subgroups: one group given a Mg-deficient diet and the other fed a Mg-supplemented diet. After 12 weeks on the regimen, all animals were sacrificed. In Mg-supplemented uremic rats, the concentration of Ca in the aorta was higher than in Mg-supplemented control rats. The concentration of Ca in the aorta was further increased in Mg-deficient uremic rats. The concentrations of Ca in the heart and the kidney were also increased in Mg-deficient uremic rats, as compared with Mg-supplemented uremic rats. The concentration of Mg was decreased in the aorta and increased in the kidney of Mg-deficient rats. There was no significant influence of Mg deficiency on the concentration of phosphate in tissue. Results suggest that Mg deficiency in uremia may increase aortic calcification.