[Show abstract][Hide abstract] ABSTRACT: Mizoribine (MZ) inhibits the proliferation of lymphocytes selectively via inhibition of inosine monophosphate dehydrogenase, like mycophenolate mofetil (MMF). The clinical dosage of MZ (2-5 mg/kg) is much lower than that of MMF (20-60 mg/kg). The purpose of this study was to examine whether high-dose MZ would be effective for treatment of acute humoral rejection. Renal transplantation was performed in a different pig strain combination. Group 1 (n = 2) received no treatment. Group 2 (n = 4) received cyclosporine microemulsion (6 mg/kg) and prednisolone (0.1 mg/kg) as baseline immunosuppression. Groups 3 (n = 4), 4 (n = 4) and 5 (n = 4) were additionally treated with MZ for rescue therapy, 30, 10 and 3 mg/kg, respectively, immediately after rejection was observed. All pigs developed acute vascular rejection between days 4 and 8. Complete reversal of acute rejection including reduction of elevated serum creatinine, suppression of anti-donor antibody production and pathological finding, was obtained in 3/4 (group 3), 1/4 (group 4) and 0/4 (group 5). Rescue with high-dose MZ (30 mg/kg) reversed ongoing acute humoral rejection. Such a high dose of MZ was tolerable for pigs. However, leukocytopenia was observed when MZ trough level was maintained over 10 mug/ml. Treatment with high-dose MZ would be applicable to a clinical trial, if blood level is carefully monitored.
Transplant International 05/2005; 18(4):401-7. DOI:10.1111/j.1432-2277.2004.00042.x · 3.16 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Somatic cells in vitro have a finite life expectancy before entering a state of senescence. If this state has an in vivo counterpart, it could contribute to organ aging. We have previously shown that human kidney cortex displays telomere shortening with age. In the present study, we evaluated the relationship between renal age in humans and a number of phenomena associated with cellular senescence in vitro.
Human kidney specimens were obtained at 8 weeks to 88 years of age and were assessed for changes related to aging.
We found that human kidneys expressed relatively constant levels of mRNAs for genes potentially related to senescence. Among the candidate genes surveyed, the cell cycle regulator p16INK4a emerged with the strongest association with renal aging for both mRNA and protein expression. Proliferation as measured by Ki-67 expression was inversely correlated with p16INK4a expression, compatible with a role for p16INK4a as an irreversible cell cycle inhibitor. Cyclooxygenase 1 and 2 (COX-1 and COX-2) mRNA expression was elevated in older kidneys, associated with increased protein expression. Comparison of gene expression with age-related histologic changes revealed that glomerulosclerosis correlated with p16INK4a and p53, whereas interstitial fibrosis and tubular atrophy were associated with p16INK4a, p53, COX-1, transforming growth factor-beta 1 (TGF-beta 1), and heat shock protein A5 (HSPA5).
We conclude that some changes observed in cellular senescence in vitro do occur in human kidney with age, particularly in the renal cortex, in some cases correlating with histologic features. P16INK4a emerged with the most consistent correlations with age and histologic changes and inversely correlated with cell replication.
Kidney International 03/2004; 65(2):510-20. DOI:10.1111/j.1523-1755.2004.00438.x · 8.52 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: We reported that patients with sodium sensitive type of hypertension exhibited the lack of nocturnal fall in blood pressure with enhanced natriuresis during night. Sodium sensitivity is caused by diminished glomerular filtration capability and/or augmented tubular reabsorption of sodium, and seems tightly linked with glomerular capillary hypertension. In the present study, we investigated the relationship between glomerular filtration rate and circadian rhythms of these parameters in patients with glomerulopathy.
Twenty six patients (15 men and 11 women; aged 17 to 72 years; mean age 47 +/- 3 years), whose diagnosis was confirmed as glomerulopathy with renal biopsy, were studied during hospitalization. Ambulatory blood pressure for 24 hours was monitored, while urinary samples were collected for both daytime (6:00 a.m. to 9:00 p.m.) and nighttime (9:00 p.m. to 6:00 a.m.) to estimate circadian rhythms of urinary sodium and protein excretion rates (UNaV, UproV). Then night/day ratios of mean arterial blood pressure (MAP), UNaV, and UproV were analyzed in relation to 24-hour creatinine clearance as a marker of glomerular filtration rate.
Serum creatinine and creatinine clearance were 1.1 +/- 0.1 mg/dL and 89 +/- 7 mL/min/1.73 m2. There were significant day-night differences in MAP (96 +/- 2 mm Hg vs. 92 +/- 2 mm Hg; P= 0.006), UNaV (6.7 +/- 0.9 mmol/hour vs. 3.6 +/- 0.3 mmol/hour; P= 0.003), and UproV (161 +/- 27 mg/hour vs. 128 +/- 28 mg/hour; P= 0.02). Creatinine clearance had significantly negative relationships with night/day ratios of MAP (r=-0.49; P= 0.01), UNaV (r=-0.43; P= 0.03,) and UproV (r=-0.41; P= 0.04). In addition, night/day ratio of MAP had significantly positive relationships with night/day ratios of UNaV (r= 0.49; P= 0.01) and UproV (r= 0.45; P= 0.02).
Our results show that as renal function deteriorates in glomerulopathy the nocturnal dip in blood pressure is lost, resulting in enhanced urinary sodium and protein excretions during night. These findings are compatible with our proposal that impaired natriuresis during daytime makes nocturnal blood pressure elevated to compensate for diminished natriuresis by pressure natriuresis. We speculate that nocturnal glomerular capillary hypertension contributes, at least in part, to enhanced urinary sodium and protein excretions during night.
Kidney International 03/2004; 65(2):621-5. DOI:10.1111/j.1523-1755.2004.00419.x · 8.52 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Expression of class II transactivator (CIITA), the transcriptional regulator that controls all class II expression, is controlled in cell lines in vitro by three promoters: the dendritic cell promoter PI, the B cell promoter PIII, and the interferon-gamma (IFN-gamma)-inducible promoter, PIV. The authors examined the promoter usage in vivo in mouse kidney in the basal state and in response to IFN-gamma, endotoxin, allostimulation, and renal injury. Genetically modified mice were used to examine the dependency of each promoter on IFN-gamma and on the transcription factor interferon regulatory factor 1 (IRF-1). Usage of distinct CIITA promoters was monitored by real-time reverse transcriptase polymerase chain reaction (RT-PCR) using the unique sequences in the 5' end of the transcript from each promoter. Kidneys in both control mice and IFN-gamma knockouts expressed chiefly PI- and PIV-related products. Administration of recombinant IFN-gamma activated only promoter PIV. Endotoxin or allogeneic stimulation elevated the PIV-related mRNA, dependent on IFN-gamma and on IRF-1. Ischemic renal injury, however, increased the PI- and PIV-driven mRNA expression in wild-type but also in IFN-gamma-deficient mice. Thus the in vivo control of CIITA promoters in kidney is similar to that observed in vitro (i.e., basal-state usage of PI and IFN-gamma-dependent usage of PIV during inflammation), but it also shows additional levels of control: IFN-gamma-independent basal activity of PIV and IFN-gamma-independent induction of PIV during tissue injury.
Journal of the American Society of Nephrology 11/2003; 14(11):2823-32. DOI:10.1097/01.ASN.0000094084.18567.CC · 9.47 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: We recently found regional differences in the incidence of end-stage renal disease (ESRD) in Japan, which is generally ethnically homogeneous, suggesting that factors other than genetic may contribute to the difference. Here, we examined regional differences in the amounts of expenses spent on antihypertensives, especially angiotensin-converting enzyme (ACE) inhibitors, in our search for an explanation.
Annually, the Japanese Society for Dialysis Therapy reports the numbers of patients entering maintenance dialysis in each prefecture of Japan since 1982. We used the findings for 1995 to 2000 to calculate the annual incidence of ESRD in each of the 11 regions of Japan. In addition, regional differences in annual amounts paid for antihypertensive drugs, presumably corresponding to the amounts used, during the same 6 years, corrected for population, were estimated.
As in our 1982 to 1998 study, the incidence of ESRD was high in Okinawa, Kyushu, and Shikoku, while low in Hokuriku, Koshinetsu, and Tohoku (P < 0.0001) [one-way repeated measures analysis of variance (ANOVA)]. We found regional differences in the corrected sum paid for total antihypertensive drugs, ACE inhibitors and calcium antagonists. Only ACE inhibitors were negatively correlated with the incidence of ESRD by linear and multiple regression analyses.
The renal protective effects of ACE inhibitors have been established by results with animal models of progressive nephropathy and large-scale clinical trials. Our epidemiologic results for Japan as a whole show the same protective effects still more convincingly from a different approach.
Kidney International 11/2003; 64(4):1445-9. DOI:10.1046/j.1523-1755.2003.00221.x · 8.52 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Acute humoral rejection (AHR) is the most important risk factor for early graft loss in ABO-incompatible (ABO-i) kidney transplantation (RTx). The pathogenesis and diagnostic criteria for AHR after ABO-i RTx remain unclear. Complement fragment C4d deposition in peritubular capillaries (PTC), which is a sensitive indicator for activation of the classical complement pathway, was studied to establish the pathologic diagnostic indicator of AHR.
Forty-four graft biopsy specimens from 19 patients with ABO-i living donors were analyzed within 90 days after RTx. Nineteen biopsy specimens with acute rejection after ABO-compatible (ABO-c) living-related RTx were used as controls. Diffuse and bright C4d deposition in PTC was considered significantly positive.
All of 8 recipients with AHR showed significantly positive C4d in PTC in the ABO-i group, but 9 of 11 recipients without AHR were negative. In the ABO-c RTx group, 16 of 19 recipients were negative for C4d in PTC. The prevalence of C4d in PTC was significantly higher in ABO-i RTx (P<0.05).
C4d deposition is valuable as a specific and sensitive indicator for AHR, even of mild severity, in ABO-i RTx.
[Show abstract][Hide abstract] ABSTRACT: The pathogenesis of antibody-mediated rejection has been investigated, but the precise mechanism of chronic glomerular rejection remains unclear. We have followed the clinicopathological course of a patient with pre-existing anti-donor antibody only detected by flow-cytometry crossmatch for over 3 years. Glomerular endothelial injuries and peculiar glomerular lesions were noted in biopsy specimen of postoperative year 3; however, both typical chronic vascular rejection lesions and peritubular capillary multilayered lesions were not revealed. We consider that the presence of weak anti-donor antibody leading early onset of acute humoral rejection played a role in the pathogenesis of early onset of chronic transplant glomerulopathy.
[Show abstract][Hide abstract] ABSTRACT: Hyperhomocysteinaemia, which is considered to be induced by impairment of the remethylation pathway in patients with chronic renal failure (CRF), cannot be cured solely by folic acid therapy. In the present study, we investigated the additional benefit of administration of methylcobalamin, which is a co-enzyme in the remethylation pathway, on lowering total homocysteine (tHcy) plasma concentrations in haemodialysis (HD) patients receiving high-dose folic acid supplementation.
In order to assess the efficacy on lowering plasma tHcy levels (fasting concentration), 21 HD patients, were randomly assigned and provided folic acid supplementation: 15 mg/day orally (group I, n=7); methylcobalamin 500 mg intravenously after each HD, in addition to folic acid (group II, n=7); or vitamin B(6) (B(6)), 60 mg/day orally, in addition to folic acid and methylcobalamin (group III, n=7). All patients were treated for 3 weeks. A methionine-loading test was conducted before and after supplementation. The following measurements were also made before and after supplementation for each group: serum folic acid, B(6), and vitamin B(12) (B(12)) concentrations (including measurement of proportion of methylcobalamin fraction). Twelve HD patients receiving methylcobalamin alone served as the HD control group and seven healthy volunteers served as the normal control group for this study.
In our randomized HD patients the proportions of methylcobalamin fraction (48.3+/-7.5%) and plasma vitamin B(6) concentration (2.9+/-1.1 ng/ml) were significantly lower than in the normal controls (methylcobalamin 58.7+/-2.2%, P<0.01; B(6) 20.1+/-10.8 ng/ml, P<0.01), while folic acid and vitamin B(12) were not significantly different from the normal controls. Mean percentage reduction in fasting tHcy was 17.3+/-8.4% in group I, 57.4+/-13.3% in group II, 59.9+/-5.6% in group III, and 18.7+/-7.5% in HD controls. The power of the test to detect a reduction of tHcy level was 99.6% in group II and 99.9% in group III when type I error level was set at 0.05. Groups II and III had normal results for the methionine-loading test after treatment. Treatment resulted in normalization of fasting tHcy levels (<12 ng/ml) in all 14 patients treated by the combined administration of methylcobalamin and supplementation of folic acid regardless of whether there was supplementation of vitamin B(6).
The benefit of methylcobalamin administration on lowering plasma tHcy levels in HD patients was remarkable. Our study suggested that both supplementations of high-dose folic acid and methylcobalamin are required for the remethylation pathway to regain its normal activity. This method could be a therapeutic strategy to combat the risk associated with atherosclerosis and cardiovascular disease in patients with chronic renal failure.
[Show abstract][Hide abstract] ABSTRACT: We report the case of a young pregnant woman with bilateral renovascular hypertension due to renal microaneurysms from an unknown cause, who had a successful delivery. Pregnancy did not affect the disease activity even in the postpartum period. Her blood pressure was maintained within the normal range by administration of labetalol. Although the angiographic appearance of the symmetrical aneurysms in both renal artery beds from the interlobular to arcuate artery levels suggested polyarteritis nodosa of multiple microaneurysms in the bilateral interlobular arteries, the clinical features suggested other causes of renovascular hypertension, such as fibromuscular dysplasia and/or congenital microaneurysms. We were thus unable to reach a definitive diagnosis.
Hypertension Research 02/2001; 24(1):83-5. DOI:10.1291/hypres.24.83 · 2.94 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Despite recent medical advances, the number of patients beginning dialysis annually is increasing in both the United States and Japan. The ethnically homogeneous population of Japan presents an opportunity to study the presence of factors other than race/ethnicity that might contribute to incidence of end-stage renal disease (ESRD).
To determine if and where regional differences exist in ESRD in Japan.
Analysis of data reported by the Japanese Society for Dialysis Therapy based on the annual number of patients with ESRD beginning maintenance dialysis therapy in all 47 prefectures of Japan from 1982 to 1998.
Mean annual ESRD incidence and increasing rate of ESRD in each of 11 predefined areas making up the entire country.
Incidence of ESRD increased approximately 3-fold in Japan during the study years, from 81.3 per 1 million in 1982 to 237.6 per 1 million in 1998. Significant regional differences were found in both measures. The mean (SEM) annual ESRD incidence (P<.01) and increasing rate of ESRD (P<.01), respectively, were significantly different across Japan. Koshinetsu (140  per 1 million and 9.1 [0.6] per 1 million/y) and Hokuriku (141  per 1 million and 9.7 [0.5] per 1 million/y) were the areas with the lowest incidence and increasing rate of incidence, while Okinawa (188  per 1 million and 13.4 [0.6] per 1 million/y) and Kyushu (179  per 1 million and 12.0 [0.6] per 1 million/y) were the areas with the highest incidence and increasing rate of incidence.
We found definite and significant regional differences in incidence and increasing rate of incidence of ESRD in Japan. Further analyses are needed to identify factors that contribute to these regional differences and thereby improve strategies for treatment of renal disease. JAMA. 2000;284:2622-2624.
JAMA The Journal of the American Medical Association 01/2000; 284(20):2622-4. · 30.39 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Typical chronic rejection showing prominent glomerular and/or arterial lesions is less common in renal allograft patients treated with cyclosporin A (CsA). We investigated the value of peritubular capillary lesions as a criterion for chronic rejection in the CsA era. A total of 129 renal graft biopsies, taken from recipients showing graft dysfunction after more than 2 months post-operatively, were examined by electron microscopy, and peritubular capillary lesions were studied, especially multi-layered basement membrane lesions (MLPTC). Eighty-two biopsy specimens taken from non-transplantation patients were also studied as a control. Five biopsies (6%) showed mild and atypical MLPTC in the control group. Of the 129 allograft biopsies, MLPTC was seen in 55 (42.6%). The prevalence showed no significant relationship to the interval from operation to biopsy. MLPTC was either typical (n = 10) or incomplete (n = 45). Concomitant membrane disruption, edema and lymphocyte infiltration of the subendothelial space, reflecting acute cellular rejection, were occasionally noted in both groups. Incomplete MLPTC often developed within 1 yr after surgery, in association with acute rejection. It was found in 26-50% of biopsies at any time up to 5 yr post-operatively. The incidence of typical MLPTC was 5.7-12.8% over 1 yr post-operatively. These findings suggest that the development of chronic rejection is closely related to relapsing acute tubulo-interstitial allograft rejection which is often clinically silent. We concluded that MLPTC is useful as a specific criterion for chronic rejection.