Shuichi Hisanaga

Incidence of ANCA-Associated Primary Renal Vasculitis in the Miyazaki Prefecture: The First Population-Based, Retrospective, Epidemiologic Survey in Japan

Clinicoepidemiological manifestations of the vasculitides differ geographically. According to a nationwide, hospital-based survey in Japan, the prevalence of microscopic polyangiitis (MPA) and/or renal-limited vasculitis (RLV) is much higher than that of Wegeners granulomatosis (WG). However, little is known about the incidence of antineutrophil cytoplasmic autoantibodies (ANCA)-associated primary renal vasculitis (PRV) in Japan. The incidence of PRV was retrospectively determined by a population-based method in Miyazaki Prefecture in Japan between 2000 and 2004. PRV was defined according to the following criteria from the European Systemic Vasculitis Study Group: (1) new patients with WG, MPA, Churg-Strauss syndrome (CSS), or RLV, (2) renal involvement attributable to active vasculitis, and (3) ANCA considered positive if the disease was not histologically confirmed. The numbers of patients with PRV in the years 2000, 2001, 2002, 2003, and 2004 were 9, 9, 9, 16, and 13, respectively. The male to female ratio was 24:32 and the average age was 70.4 +/- 10.9 (mean +/- SD) yr. The estimated annual incidence of PRV was 14.8 (95% confidence interval [CI] 10.8 to 18.9) and 44.8 (95% CI 33.2 to 56.3) per million adults (>15 yr old) and seniors (>65 yr old), respectively. Ninety-one percent of the patients were myeloperoxidase (MPO)-ANCA positive, but none were positive for proteinase 3 (PR3)-ANCA. There were no WG or CSS patients. The incidence of PRV did not differ between Japan and Europe, but WG was not widespread in Japan. Furthermore, the ratio of serum MPO to PR3-ANCA among Japanese with PRV was much higher than that found among European and US patients.

Minimal Change Nephrotic Syndrome in Adults: Response to Corticosteroid Therapy and Frequency of Relapse

Rate of response to a corticosteroid and frequency of relapse were studied in 33 patients with adult-onset minimal change nephrotic syndrome (MCNS). Of these, 28 patients were treated with oral prednisolone (PSL) at 1 mg/kg/d for from 4 to 8 weeks depending on their response, followed by PSL, at gradually tapering doses for 1 year. Five severely nephrotic patients received 1 g of methylprednisolone intravenously (IV) for 3 days, followed by 40 mg/d oral PSL for 4 to 8 weeks and finally PSL in gradually reduced doses. Sixteen patients (48%) were free of proteinuria within 4 weeks, and 25 (76%) within 8 weeks. Two patients required cyclophosphamide for induction of remission. Age at presentation was not significantly correlated with response time to corticosteroid therapy. Thirty-two (97%) went into remission, and relapse occurred in 11 (34%) of these. As assessed by the life-table method, 84% of patients were still in remission at 6 months after induction of remission, 75% after 1 year, and 63% during the follow-up period (mean, 47.1 +/- 29.1 months; range, 6 to 123 months). Incidence of relapse was not correlated with remission induction time, ie, earlier (less than or equal to 4 weeks) or later (greater than 4 weeks), but was greater in younger (less than 30 years of age) patients than older (greater than or equal to 30 years) patients (P less than 0.03). At the last follow-up, 31 patients (94%) were in complete remission and had normal renal function.(ABSTRACT TRUNCATED AT 250 WORDS)

Plasma and Urine Levels of Uroguanylin, a New Natriuretic Peptide, in Nephrotic Syndrome

Uroguanylin, a new natriuretic peptide originally isolated from urine, stimulates the membrane guanylate cyclase C receptor. No information, however, is available on the plasma and urine levels of uroguanylin in nephrotic syndrome (NS), the state associated with sodium and water retention. Using a sensitive radioimmunoassay, we measured the plasma and urine concentrations of immunoreactive (ir-)uroguanylin in NS patients and compared them with those of patients with non-nephrotic glomerulonephritis. Plasma ir-uroguanylin, blood pressure and the cardiothoracic ratio were higher, and urine excretion of ir-uroguanylin was lower in the NS patients. Plasma ir-uroguanylin in the NS patients significantly decreased during remission as compared with findings on admission. There was a significant inverse correlation between the concentration of plasma ir-uroguanylin and that of serum total protein or albumin. Moreover, fluid retention in the NS patients was correlated with the changes in plasma ir-uroguanylin between admission and remission, indicative that the plasma concentration increases with the severity of the nephrotic state. Taking into account its potent natriuretic effect, these findings suggest that uroguanylin may function in the pathophysiological mechanism in NS.

Holter Electrocardiogram Monitoring in Nephrotic Patients during Methylprednisolone Pulse Therapy

We assessed the effect of intravenous methylprednisolone pulse therapy (IMPT) on cardiac rhythm and electrolyte metabolism in patients with nephrotic syndrome. A total of 25 patients had valid evaluations with continuous ambulatory electrocardiograms, and 20 of these had simultaneous sodium and potassium clearances. No significant difference of frequency in complex ventricular arrhythmias (Lowns grades 3-5) between the control and the therapy period was observed; however, 4 patients showed complex ventricular arrhythmias including ventricular tachycardia (2 patients) during the course of therapy. Fractional excretion of potassium and serum potassium significantly increased from baseline after IMPT. Complex ventricular arrhythmias, sometimes leading to sudden death, might ensue from IMPT. These dysrhythmias may be related to an abrupt change in potassium reflux from the cell.

Peritonitis Increases MMP-9 Activity in Peritoneal Effluent from CAPD Patients

Patients undergoing long-term continuous ambulatory peritoneal dialysis (CAPD) sometimes experience ultrafiltration failure. Mesothelial basement membrane thickening and the accumulation of submesothelial fibrotic tissue are common features of the diseased peritoneum. Peritonitis can lead to ultrafiltration failure, but the precise mechanism is not clear. The key enzymes in extracellular matrix (ECM) remodeling, namely matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs), are produced by human peritoneal mesothelial cells. Using peritoneal effluent from 13 CAPD patients with peritonitis and 7 noninfected CAPD control individuals, we examined MMP and TIMP activities by gelatin and reverse zymography. Latent and activated types of MMP-2 and -9, and TIMP-1 and -2 were identified in peritoneal effluent (from all CAPD patients). Levels of latent and activated type MMP-9, as well as of TIMP-1 activities were higher at the onset of peritonitis than either during the recovery phase of peritonitis and/ or in control individuals. Activated MMP-9 activity positively correlated with leukocyte numbers and IL-6 levels in peritoneal effluent. Activities of MMP-2 and TIMP-2 in peritoneal effluent did not change between the onset of peritonitis and recovery. We concluded that increased MMP-9 and TIMP-1 levels might be associated with peritoneal ECM remodeling during peritonitis.

Plasma and urine levels of adrenomedullin and proadrenomedullin N-terminal 20 peptide in chronic glomerulonephritis

Proadrenomedullin N-terminal 20 peptide (PAMP) is a novel hypotensive peptide present in the precursor of adrenomedullin (AM), a vasodilative and natriuretic peptide. We examined the plasma and urinary levels of these peptides in patients with chronic glomerulonephritis (CGN). The mean plasma AM concentration of the patients with CGN did not differ from that of control subjects (4.17 +/- 0.17 v 3.87 +/- 0.21 fmol/mL, respectively), whereas urinary AM excretion was significantly less in the patients with CGN (5.96 +/- 0.95 v control, 8.93 +/- 1.02 fmol/mg of creatinine; P < 0.05). Plasma concentrations and urinary excretion of PAMP were significantly less for the patients with CGN compared with control subjects (0.91 +/- 0.08 v 1.23 +/- 0.20 fmol/mL; P < 0.05 and 25.0 +/- 3.0 v 35.0 +/- 3.6 fmol/mg of creatinine, respectively; P < 0. 05). The plasma AM concentration was negatively correlated with plasma renin activity (r = -0.58; P < 0.01) and aldosterone concentration (r = -0.40; P < 0.05). Urinary excretions of AM and PAMP showed significant correlations with urine excretion of sodium (r = 0.39; P < 0.05 and r = 0.49; P < 0.01, respectively). These findings suggest that AM and PAMP may have roles in the regulation of sodium in patients with CGN.

Elevated Osteoprotegerin Levels Predict Cardiovascular Events in New Hemodialysis Patients

Background: Patients on hemodialysis (HD) frequently experience cardiovascular events associated with vascular calcification. We investigated the involvement of osteoprotegerin (OPG), an inhibitor of vascular calcification, in the incidence of cardiovascular events and mortality among new HD patients. Methods: We conducted a prospective cohort study of the association of serum OPG levels with morbidity and mortality in subjects who became new HD patients between June 2000 and May 2006. Results: A total of 99 patients (age 58.9 ± 14.6 years, 65 male, 34 female) were prospectively followed up for 41.5 ± 20.2 months. During this period, 27 patients developed cardiovascular events and 12 died of causes related to cardiovascular disease. When divided into 2 groups according to OPG levels, the high OPG group showed a higher prevalence of cardiovascular morbidity and mortality compared with the low OPG group. Cox’s proportional hazards analysis associated the new onset of cardiovascular events with the high OPG group (HR 2.88, 95% CI 1.09–7.62, p = 0.033). Furthermore, the high OPG group at the start of HD was significantly associated with older age, male gender and a high aortic calcification index. Conclusions: Elevated levels of serum OPG in new HD patients may predict subsequent cardiovascular events.

Increased plasma levels of mature adrenomedullin in chronic glomerulonephritis.

Adrenomedullin (AM) is a potent vasodilative and natriuretic peptide that is processed from its precursor as the intermediate form, AM-glycine-COOH (iAM). Subsequently, iAM is converted to the biologically active mature form, AM(1-52)-CONH2 (mAM), by enzymatic amidation. Using immunoradiometric assays that recognize total AM (tAM) and only mAM, we determined the plasma and urinary levels of mAM and iAM in patients with chronic glomerulonephritis (CGN). The plasma mAM concentration was significantly higher in the patients than in the controls (1.8 ± 0.1 vs. 1.3 ± 0.1 fmol/ml, p < 0.01), whereas the plasma iAM concentration of the CGN patients did not significantly differ from that of the controls (9.4 ± 0.5 vs. 8.9 ± 0.5 fmol/ml). Levels of urinary mAM excretion in the patients did not statistically differ from those of the controls (1.6 ± 0.4 vs. 2.0 ± 0.3 fmol/mg creatinine), whereas urinary iAM excretion was significantly lower in the CGN patients (3.7 ± 0.7 vs. 5.6 ± 0.8 fmol/mg creatinine, p < 0.05). Urinary excretion levels of mAM significantly correlated with those of sodium (r = 0.47, p < 0.05), whereas those of iAM did not. In conclusion, the plasma ratio of mAM to iAM is augmented in CGN patients, and mAM appears to be involved in the regulation of sodium. Therefore, determination of the mAM in addition to the tAM concentration is essential in CGN patients.

Nephrotic Syndrome Associated with Recombinant Interleukin-2

Adoptive immunotherapy using recombinant interleukin-2 (rIL-2) has recently been demonstrated to have antitumor effects in man. Adverse effects have included an apparent increase in capillary permeability (vascular leak syndrome) and a decrease in glomerular flow rate. To our knowledge, nephrotic syndrome (NS) associated with rIL-2 has not been reported. We would like to report a case of NS with human rIL-2 treatment

Exercise-induced renal failure in a patient with hyperuricosuric hypouricemia

Shuichi Hisanaga, MD, Shinseikai Dai-ichi Hospital, 1-3-2, Tamamizu-cho, Mizuho-ku, Nagoya 467 (Japan) Dear Sir, Renal isolated hypouricemia is a rare condition. The patient is asymptomatic, and the main complication is known as urolithiasis. We experienced a case of exercise-induced acute renal failure who had renal isolated hypouricemia. A 14-year-old girl was referred to our hospital on September 13,1991, because of acute renal failure. On September 11, she complained of nausea and abdominal pain while she took lessons in an athletic meeting. She consulted her familial doctor, and protein-uria, but not hematuria, and renal dysfunction (blood urea nitrogen 22.6 mg/dl and serum creatinine 2.3 mg/dl, were first pointed out. On admission, she was normally developed and well nourished, and physical examination revealed no abnormalities. Urinalysis showed a 1+ test for protein and no hemoglobinuria, and the sediment was normal. Blood chemistry findings showed renal failure (blood urea nitrogen 24.7 mg/dl, serum creatinine 3.4 mg/dl, sodium 140 mEq/1, potassium 5.1 mEq/1, chloride 106 mEq/1, calcium 9.7 mg/dl and phosphate 4.4 mg/dl), but her serum uric acid was within normal limits (2.3 mg/dl). Serum creatinine kinase was 57 IU/1. Serum and urinary myoglobin were 42 ng/ml and less than 5 ng/ml, respectively. The concentrations of C3 and C4 were normal, and the titer of antinucleatic antibody was normal. Renal echography showed no evidence ofurolithiasis and hydronephrosis. Thus, collagen diseases and rhabdomyolysis were denied. She received sufficient transfusion, and her serum creatinine decreased to 1.0 mg/dl on September 20, 1991. Simultaneously, her serum uric acid decreased to 0.8 mg/dl. Urinary excretion of uric acid was 320 mg/day. Fractional excretion of uric acid (FEua; Cua/ Ccr) was high (55%). Neither glycosuria nor aminoaciduria was shown. To evaluate the disturbance in the renal handling of uric acid, a benzbromarone (100 mg)-pyrazinamide (3.0 g) test was done on March 20,1992, when she had normal renal function (serum creatinine 0.6 mg/dl and serum uric acid 0.8 mg/dl). FEua was not affected by either drug and was maintained at high levels (62-68%). The pattern of renal defect was classified as presecretory reabsorption defect [1]. Thereafter, she stopped moderate to severe exercises, and she did not meet with an episode of acute renal failure.