Fabry disease in patients receiving maintenance dialysis

Background. Fabry disease is an X-linked disorder resulting from a deficiency of lysosomal α-galactosidase. Renal insufficiency is one of its most important manifestations and affects the prognosis of the disease. We clarified the incidence of Fabry disease in patients receiving maintenance dialysis. Methods. We measured plasma α-galactosidase activity in 722 patients (male 440, female 282) receiving maintenance dialysis. Clinical manifestations were assessed, and the patients were to be screened for mutations in the α-galactosidase gene. Results. Two male patients had low plasma α-galactosidase activity. One patient had a C-to-T transition at codon 357, resulting in substitution of the predictable termination for glutamine. The other patient died suddenly during hemodialysis, due to arrhythmia. We could not carry out further evaluation, but his daughter had moderate reduction of α-galactosidase activity in leukocytes. She was, likely, an asymptomatic heterozygote. Conclusions. Two male patients with Fabry disease were found among 440 male patients who were receiving maintenance dialysis. Fabry disease should be considered in the etiology of end-stage renal failure. Received: January 6, 1999 / Accepted: June 14, 1999     

Fabry Disease in Hemodialysis Patients in Southern Brazil: Prevalence Study and Clinical Report

Background. Fabry disease (FD) is a lysosomal storage disorder caused by a deficiency of α-Galactosidase A (α-Gal A). Fabry nephropathy typically progresses throughout the fifth decade to end-stage renal disease (ESRD), requiring hemodialysis and/or kidney transplantation. Objective. To estimate the prevalence of FD among ESRD males on hemodialysis treatment in Rio Grande do Sul, the southernmost state of Brazil. Methods. Screening for α-Gal A activity was performed by a dried blood spot (normal reference value: >1.5 nmoles/hour/mL). Positive screening results were confirmed by plasma α-Gal A activity assay (reference value: >3.3 nmoles/hour/mL). Results. Five hundred fifty-eight male patients on hemodialysis were evaluated. Of these, only two had low α-Gal A activity and were diagnosed with Fabry disease (0.36%). One of these, age 42, had left ventricular hypertrophy and renal manifestations of Fabry disease without the classic symptoms. The other, age 46, had the classical manifestations of angiokeratomas, acroparesthesias, hypohidrosis, and ocular opacities. Conclusions. Although the prevalence of Fabry disease was very low in our study (0.36%), routine screening of male hemodialysis patients would enable earlier identification of many other affected relatives in their families who might benefit from specific clinical treatment.     

Screening Fabry’s disease in chronic kidney disease patients not on dialysis: a multicenter study

Objectives: Fabry's disease is an X-linked inherited, rare, progressive, lysosomal storage disorder, affecting multiple organs due to the deficient activity of α-galactosidase A (α-Gal A) enzyme. The prevalence has been reported to be 0.15–1% in hemodialysis patients; however, the information on the prevalence in chronic kidney disease not on dialysis is lacking. This study aimed to determine the prevalence of Fabry’s disease in chronic kidney disease.

Methods: The patients older than 18 years, enclosing KDIGO 2012 chronic kidney disease definitions, not on dialysis, were enrolled. Dried blood spots on Guthrie papers were used to analyze α-Gal A enzyme and genetic analysis was performed in individuals with enzyme activity ≤1.2?μmol/L/h.

Results: A total of 1453 chronic kidney disease patients not on dialysis from seven clinics in Turkey were screened. The mean age of the study population was 59.3?±?15.9 years. 45.6% of patients were female. The creatinine clearance of 77.3% of patients was below 60?mL/min/1.73 m², 8.4% had proteinuria, and 2.5% had isolated microscopic hematuria. The mean value of patients’ α-Gal A enzyme was detected as 2.93?±?1.92?μmol/L/h. 152 patients had low levels of α-Gal A enzyme activity (≤1.2?μmol/L/h). In mutation analysis, A143T and D313Y variants were disclosed in three male patients. The prevalence of Fabry’s disease in chronic kidney disease not on dialysis was found to be 0.2% (0.4% in male, 0.0% in female).

Conclusion: Fabry’s disease should be considered in the differential diagnosis of chronic kidney disease with unknown etiology even in the absence of symptoms and signs suggestive of Fabry’s disease.     

Anderson–Fabry disease: a case-finding study among male kidney transplant recipients in Austria

The diagnosis of Anderson–Fabry disease is often delayed or even missed. As severe renal manifestations are a hallmark of alfa-galactosidase A (AGAL) deficiency, we tested the hypothesis that Anderson–Fabry disease is under-recognized among male kidney transplant recipients. This nation-wide study in Austria enrolled 1306 patients (ca 65% of all kidney transplanted males) from 30 kidney centers. AGAL activity was determined from filter paper dried blood spots by a fluorescence assay. A positive screening test was defined by an AGAL activity below 1.5 nmol/h/ml. In patients with a positive blood spot-screening test, AGAL activity was re-examined in peripheral blood leukocytes. Genetic testing for mutations in the GLA gene was performed by sequencing to confirm the diagnosis of Anderson–Fabry disease. Two previously not recognized cases with Anderson–Fabry disease were identified. Our study is the first showing that a diagnosis of Anderson–Fabry disease can be missed even in patients who undergo kidney transplantation. Case-finding strategies may be considered a useful tool for diagnosis of this rare disease that may be somewhat more prevalent among kidney transplant recipients compared with dialysis populations.     

Thalidomide blocking of particle-induced TNFα release in vitro

 Tumor necrosis factor-α (TNFα) and interleukin-6 (IL-6), pleiotropic cytokines with osteotropic activities, are produced by multiple cells in the skeletal tissue, including macrophages and osteoblasts. They are thought to be pivotally involved in pathological bone resorption, such as that seen with aseptic loosening. Thalidomide is reported to have antiinflammatory, immunomodulatory effects in a number of inflammatory diseases. We investigated the effect of thalidomide on titanium (Ti) particle-induced TNFα and IL-6 production by both human macrophage U937 and osteoblast MG-63 cell lines. They were stimulated with 1 × 10⁷ Ti particles/ml and treated simultaneously with or without various concentrations of thalidomide (from 2.5 ng/ml to 25 μg/ml) for 24, 48, or 72 h. Cell viability and proliferation were measured. TNFα and IL-6 in the supernatant of the culture media were also analyzed with an enzyme-linked immunosorbent assay. We found that with a concentration of thalidomide of less than 2.5 μg/ml the viability of the two cell lines did not differ significantly from that of controls treated simultaneously with 1 × 10⁷ Ti particles/ml. Cell proliferation was inhibited to some extent when they were treated with thalidomide 2.5 μg/ml co-cultured with 1 × 10⁷ Ti particles/ml. Thalidomide treatment was found to inhibit TNFα production in a dose-dependent manner in human macrophages exposed to Ti particles. At the clinically achievable drug dose of 2.5 μg/ml, 34.4% TNFα inhibition occurs. Thalidomide had no effect on IL-6 secretion in these cultures. These data support the idea that thalidomide may have potential for treating prosthetic loosening in humans. Received: February 13, 2002 / Accepted: August 1, 2002 Acknowledgments. The authors thank Guangrong Sun, Patricia Redecha, and Bruce Rapuano for their technical help and assistance. Offprint requests to: M.P.G. Bostrom     

Prevalence of Fabry disease in dialysis patients: Japan Fabry disease screening study (J-FAST)

Background

In Fabry disease, progressive glycolipid accumulation leads to damage in kidney and other organs. This study was designed to determine the prevalence rate of Fabry disease in Japanese dialysis patients.

Methods

All dialysis patients agreeing to Japan Fabry disease screening study (J-FAST) with informed consent were selected except for Fabry disease. The screening was performed by a method of measuring plasma and/or leukocytes lysosomal α-galactosidase A protein level and α-galactosidase A activity. If positive, genetic analysis was carried out upon patient’s agreement.

Results

J-FAST dealt with 8547 patients (male 5408, female 3139). At the tertiary examination, 26 out of 8547 patients were found to be positive. Six out of 26 patients could not accept genetic analysis because of death. Remaining 20 patients agreed with genetic analysis; then 2 patients (male 2, female 0) had a variation of the α-Gal gene and 11 patients showed E66Q variations. Therefore, the frequency of Fabry disease in J-FAST was 0.04 % (2/5408) in males and 0 % (0/3139) in females, and then 0.02 % (2/8547) in all patients. The presumptive clinical diagnoses of end-stage kidney disease (ESKD) were 10 chronic glomerulonephritis, 7 diabetic nephropathy, 3 unknown etiology, 3 nephrosclerosis, 1 gouty nephropathy, 1 autosomal dominant polycystic kidney disease and 1 renal tuberculosis among 26 tertiary positive patients. Two male Fabry patients were initially diagnosed as nephrosclerosis and chronic glomerulonephritis.

Conclusions

The prevalence rate of Fabry disease in J-FAST was 0.02 %. Moreover, Fabry disease could not be ruled out as the clinical diagnosis of ESKD.

     

Pharmacokinetics of the antithyroid drug thiamazole in a chronic hemodialysis patient with hyperthyroidism

 There has been little information regarding the pharmacokinetics of antithyroid drugs in patients with endstage renal disease (ESRD). We report here the pharmacokinetics and dialyzability of the antithyroid drug thiamazole in a chronic hemodialysis patient with hyperthyroidism. The patient was a 46-year-old woman who complained of palpitations 3 years after starting chronic hemodialysis therapy, followed by several episodes of pulmonary edema. A diagnosis of hyperthyroidism due to Graves' disease was confirmed by a laboratory test for thyroid function and anti-thyroid-stimulating hormone (TSH) receptor antibodies. The plasma concentration of thiamazole was measured before and at 1, 3, 4, 5, 6, and 24 h after administration of the drug. The dialyzability of the drug was investigated during hemodialysis therapy. On the non-dialysis day, the serum half-life of thiamazole (6.4 h) was similar to that in healthy subjects (4–6 h). Further, thiamazole was removed via the dialyzer during dialysis therapy. The initial dose of thiamazole was set at 15 mg/day for the patient. Free thyroid hormone levels began to decrease 2 weeks after the initiation of thiamazole, followed by the normalization of the values after 1 month. The patient's symptoms also subsided. Several confirmations of the concentration of thiamazole in the plasma in the morning on the first dialysis day of the week did not disclose a trend of accumulation in the blood. Although this is a single case report, it is suggested that thiamazole can be used for patients with ESRD. Careful monitoring of thyroid function, however, is recommended, because the intrathyroid action of thiamazole in uremia is unknown. Received: September 20, 2001 / Accepted: May 20, 2002     

Effect of renal pelvic and ureteral distension on the striated urethral sphincter with recognition of the “reno-vesico-sphincteric reflex”

Renal pelvic and ureteral distension occurs in physiologic (diuresis) and pathologic (calculus) conditions. Its effect on the vesical and posterior urethral pressures as well as on the electromyographic (EMG) activity of the striated urethral sphincter (SUS) was investigated. The renal pelvis of 10 healthy volunteers (7␣men, 3 women; mean age 35.8 ± 8.6 years) was distended by means of a 4-F balloon-tipped catheter in␣increments of 2 ml of saline up to 10 ml and the response of the vesical and posterior urethral pressures and SUS EMG activity was recorded. The test was repeated with ureteral distension in increments of 0.25 ml up to 1 ml. The response of the aforementioned parameters was also registered after anesthetization of the renal pelvis, ureter and SUS. Two rates of renal pelvic and ureteral distension were tested: rapid (1 ml/s) and slow (1 ml/min). Renal pelvic distension with large volumes effected an increase of the renal pelvic and urethral pressures (P < 0.05, P < 0.05, respectively), a vesical pressure drop (P < 0.05) and increased EMG activity of the SUS. Ureteral distension caused a rise of ureteral and urethral pressures as well as of SUS EMG activity. With rapid distension, the aforementioned parameters responded at smaller volumes than with slow distension. Renal pelvic, ureteral or SUS anesthetization effected no urethral or SUS EMG response. It is suggested that the reaction of above parameters to distension indicates a mechanism regulating the urine flow so as to protect the renal pelvis and the ureter from being overloaded. The vesical pressure drop with increased SUS EMG activity on renal pelvis distension postulates a reflex relationship that we call the “reno-vesico-sphincteric reflex”. The role of this reflex in urine transport requires further study. Received: 2 December 1997 / Accepted: 31 March 1998     

The frequency of Fabry disease with the E66Q variant in the α-galactosidase A gene in Japanese dialysis patients: a case report and a literature review

Fabry disease (FD) is an Xlinked disorder resulting in a deficiency in α-galactosidase A (α-Gal) activity. FD is one of the causes of progressive renal dysfunction, but its diagnosis is often delayed or missed completely. We herein report the case of a 70-year-old male who had been receiving hemodialysis (HD) for 23 y who was diagnosed with FD after his participation in a screening program for plasma α-Gal activity for 892 HD patients. He had a low plasma α-Gal activity level and was demonstrated to have an E66Q mutation in exon 2 of the α-Gal gene. One of his daughters had the same mutation. The proband died due to aspiration pneumonia before receiving enzyme replacement therapy. We reviewed previous studies and found E66Q mutation in 36% of Japanese FD patients on HD including the present case. The clinical characteristics of E66Q variant are also discussed.     

The effect of caffeic acid phenethyl ester on ischemia-reperfusion injury in comparison with alpha-tocopherol in rat kidneys

Oxygen-derived free radicals have been implicated in the pathogenesis of renal injury after ischemia-reperfusion. Caffeic acid phenethyl ester (CAPE), an active component of propolis extract, exhibits antioxidant and anti-inflammatory properties. To determine whether CAPE offers any advantage over α-tocopherol, we compared their effects on an in vivo model of renal ischemia-reperfusion injury in rats. CAPE at 10 μmol/kg or α-tocopherol at 10 mg/kg was administered intraperitoneally before reperfusion. Acute administration of CAPE suppressed ischemia-reperfusion induced renal lipid peroxidation and tissue injury more than α-tocopherol. CAPE may therefore offer a therapeutic advantage in acute injury settings. Received: 9 October 2000 / Accepted: 23 February 2001     

The effect of α-human atrial natriuretic peptide on the incidence of acute renal failure in cadaveric kidney transplantation

In previous studies in humans, mannitol (20%, 250 ml) has been shown to reduce the incidence of acute renal failure (ARF) after transplantation from 54% to 19%. In rats, atrial natriuretic peptide appears to prevent ischemia-induced ARF. We therefore decided to evaluate the effects of α-human atrial natriuretic peptide (α-h-ANP) both alone and combined with mannitol during transplantation in humans. First, we demonstrated that systemic α-h-ANP infusion during kidney transplantation was safe in dosages up to 0.08 μg/kg per minute. In these patients the calculated metabolic clearance rate of α-h-ANP was relatively low ranging from 0.68 to 1.80 l/min. In a second study of 11 renal graft recipients, no mannitol was used and α-h-ANP (0.05 μg/kg per minute) was infused into the donor kidney artery during transplantation for 46±2 min, followed by IV administration for 71±2 min. Our aim was to reduce the incidence of ARF. Nevertheless, ARF occurred immediately after surgery in four of the patients (36%) in this group and, as a result, mannitol was reintroduced. A third group of nine renal graft recipients received α-h-ANP (total dose 400 μg) as five IV injections within 90 min after transplantation. ARF occurred in four of these patients (44%). We conclude that α-h-ANP, administered according to the aforementioned protocols in such small groups of patients, does not seem to be of value in the prevention of ARF after transplantation.     

Different concentrations of two small stress proteins, αB crystallin and HSP27 in human urological tumor tissues

Concentrations of two small stress proteins, αB crystallin and the 27-kDa heat shock protein (HSP27) were quantitated in tissues of the human normal genitourinary system and their tumors. Levels of HSP27 in renal cell carcinomas (mean ± SE: 1450 ± 262 ng/mg protein, n = 15) were significantly higher than in normal kidney (the cortex: 540 ± 99 ng/mg protein, n = 13; the medulla: 600 ± 106 ng/mg protein, n = 13) while those of αB crystallin tended to be increased without statistical significance. These findings were similar to those previously reported for renal cell tumors chemically induced in rats. Concentrations of αB crystallin in prostatic carcinoma tissues (410 ± 129 ng/mg protein, n = 10) were also significantly higher than in benign prostatic hyperplasia (54 ± 12 ng/mg protein, n = 14), whereas αB crystallin levels in testicular tumors including seminomas (2.1 ± 0.8 ng/mg protein, n = 11) and non-seminomas (5.2 ± 2.3 ng/mg protein, n = 9) were significantly lower than in normal testicular tissues (29.7 ± 6.2 ng/mg protein, n = 5). Both αB crystallin and HSP27 could be immunohistochemically localized in the normal kidney and renal cell carcinoma tissues. Received: 1 December 1997 / Accepted: 16 June 1998     

Early post-operative ACTH and cortisol as predictors of remission in Cushing’s disease

Summary Aim. To study the value of early (24 h) post-operative ACTH and serum cortisol as predictors of remission after transsphenoidal surgery in Cushing’s disease. Methods. We prospectively studied 44 patients who underwent transsphenoidal surgery for Cushing’s disease between 1997 and 2005. The mean follow-up period of patients after surgery was 49 months (19–102 months). The predictive value of clinical characteristics, pre-operative hormonal studies, radiological, surgical and histological findings, and post-operative hormonal studies were analysed. For the post-operative hormonal study plasma ACTH and serum cortisol were determined at 8.00 a.m. the day after surgery. Results. After surgery, Cushing’s disease remitted in 39 patients (89%) and persisted in 5 patients (11%). Three patients relapsed during the follow-up period. Only three study variables were predictive of persistence of Cushing’s disease after surgery: the non identification of the adenoma in histology (an adenoma was found in 87% of the patients in remission, and in 20% of treatment failures, p = 0.01), the early post-operative plasma ACTH (patients in remission: 2 pmol/L (1.1–10.8 pmol/L), treatment failures: 8.2 pmol/L (1.1–12 pmol/L), p = 0.019), and the early post-operative serum cortisol (patients in remission: 128.4 nmol/L (27.6–4644 nmol/L), treatment failures: 797 nmol/L (606–1037 nmol/L), p = 0.003). ROC curves indicated that plasma ACTH ≤7.55 pmol/L distinguished patients in remission from treatment failures with 80% sensitivity and 97.4% specificity, and serum cortisol ≤585 nmol/L with 100% sensitivity and 90% specificity. Conclusions. Twenty-four hours after transsesphenoidal surgery for Cushing’s disease, and without glucocorticoids replacement, patients with serum cortisol concentrations higher than 585 nmol/L, and/or plasma ACTH higher than 7.55 pmol/L, and/or those in which an adenoma is not identified in the histological study, have a high risk of treatment failure.     

Hyperinsulinemia in pediatric patients with chronic kidney disease: the role of tumor necrosis factor-α

We sought to determine the prevalence of hyperinsulinemia and insulin resistance in pediatric patients with chronic kidney disease (CKD) stages 2–4. Data were collected on 43 subjects, aged 6–21 years with mean glomerular filtration rate (GFR) = 47 ml/min per 1.73 m² body surface area. Patients were grouped by body mass index (BMI) as either non-lean (>85th percentile) or lean (≤85th percentile). Fourteen (33%) subjects had hyperinsulinemia, and seven (16%) had elevated homeostasis model assessment of insulin resistance (HOMA-IR). Non-lean subjects had a higher serum insulin level (21.0 μU/ml vs 13.4 μU/ml, P < 0.0001) and HOMA-IR (4.9 vs 3.2, P < 0.001) than lean subjects had. The prevalence of hyperinsulinemia was higher in non-lean patients (40%) than in lean patients (29%) but was not statistically significant. High HOMA-IR was present in six (40%) non-lean subjects and in one lean subject (P < 0.001). Correlation analysis demonstrated that serum insulin level was significantly associated with BMI, leptin and tumor necrosis factor (TNF)-α. Stepwise regression determined that increased BMI (P = 0.003) and TNF-α (P = 0.01) independently predicted higher insulin level in the whole cohort. Separate analysis for lean subjects showed no significant associations between serum insulin level and BMI; TNF-α was the only independent predictor of serum insulin (β = 1.11, P = 0.01). We conclude that hyperinsulinemia and insulin resistance are frequent in pediatric CKD. In lean patients inflammation appears to be an important determinant of serum insulin level.     

Screening for Fabry disease in male patients with end-stage renal disease in western France

ContextFabry disease is a rare X-linked genetic disease due to pathogenic variants in the GLA gene. Classic Fabry disease is characterized by glycosphingolipids accumulation in all organs including the kidney, resulting in end-stage renal disease in a subset of male patients. Fabry disease should therefore be considered in the differential diagnosis of patients with unexplained end-stage renal disease.ObjectiveWe performed a prospective screening study in Western France to determine the prevalence of Fabry disease in a large population of dialyzed and transplanted patients.Patients and methodsPatients meeting the inclusion criteria (males, 18-70 years with end-stage renal disease of unknown or vascular origin) were selected from the REIN® registry and the CRISTAL® database. Screening on filter papers was performed after patient consent was obtained during either a dialysis session or a transplantation follow-up visit.ResultsOne thousand five hundred and sixty-one end-stage renal disease male patients were screened and 819 consented (dialysis: n = 242; transplant: n = 577). One single patient was found with decreased alpha-galactosidase levels <25%. GLA sequencing identified the p.Phe113Leu variant in favor of an unknown superimposed kidney disease responsible for end-stage renal disease since this GLA pathogenic variant is associated with a later-onset cardiac form of Fabry disease with minimal kidney involvement. Family cascade genotyping revealed a previously undiagnosed affected brother.ConclusionThe prevalence of Fabry disease in end-stage renal disease patients was 0.12%, questioning the efficacy of this screening strategy with respect to the low prevalence. However, beside the benefit for the patient and his family, the increased awareness of Fabry disease among participating nephrologists may be of interest for future patients.     

Parameters of Inflammation in Morbid Obesity: Lack of Effect of Moderate Weight Loss

Background  Obesity has been associated with a chronic activation of the acute-phase response. The aims of our study were to investigate whether levels of inflammatory cytokines are higher in obese patients, to evaluate their relationship with metabolic syndrome, and to analyze the effect of moderate weight loss upon their levels. Methods  Sixty-seven severe or morbid obese patients were compared with 67 controls. Patients were submitted to a 4-week very low calorie diet followed by a low calorie diet for 2 months. Exclusion criteria were organic disease, ischemic heart disease or stroke, diabetes mellitus, hyperlipidemia, and hypertension. An evaluation was performed before and after the diet, in which fibrinogen, blood count, high-sensitive C-reactive protein (CRP), interleukin 6 (IL-6), and tumoral necrosis factor α (TNF-α) were measured. The Student t test was employed to compare differences between the groups and Pearson correlation coefficients were calculated. Results  Obese patients showed higher levels of CRP (P < 0.001), IL-6 (P < 0.001), TNF-α (P < 0.001), leukocyte (P = 0.001), and neutrophil count (P < 0.001) than controls. In obese patients, inflammatory parameters were significantly correlated with anthropometric parameters and did not differ between obese subjects with or without metabolic syndrome. Moderate weight loss (excess weight loss 19.6%) was achieved through dieting, but no change was observed in any inflammatory parameter. Conclusions  Obesity is associated to a chronic inflammatory state that seems to be due to an increased secretion of cytokines, and this state is not related to the presence of metabolic syndrome. Moderate weight loss does not ameliorate this inflammatory state in the short term.     

Interferon-α inhibits cyclooxygenase-1 and stimulates cyclooxygenase-2 expression in bladder cancer cells in vitro

The enzymes cyclooxygenase-1 (Cox-1) and cyclooxygenase-2 (Cox-2) catalyze the initial step in the formation of prostaglandins (PGs). PGs are known to be involved in numerous processes, for example inflammation, immune responses, carcinogenesis, and tumor angiogenesis. The formation of PGs is stimulated in various cancers since the expression of Cox-2 is upregulated. Interferon (IFN)-α is used in the treatment of bladder cancer, although not all of the effects of such treatment are thoroughly known. Therefore, we investigated the expression of cyclooxygenases in two bladder cancer cell lines, 5637 and T24, under basal conditions and in the presence of human recombinant IFN-α (100, 1,000, and 10,000 U/ml). The mRNA of Cox-1 and Cox-2 was expressed in both cultured bladder carcinoma cell lines. The level of Cox-1 expression was low in 5637 cells and higher in T24 cells. In contrast, Cox-2 expression was prominent in 5637 cells and low in T24 cancer cells. The highest IFN-α concentration (10,000 U/ml) decreased the expression of Cox-1 to 47 and 28% of the control levels in 5637 and T24 cells, respectively. In contrast, Cox-2 expression increased in both cell lines. In 5,637 cells, Cox-2 expression increased 1.3-fold with 10,000 U/ml of IFN-α. In T24 cells, the maximum effect was achieved by 1,000 U/ml of IFN-α, which increased the expression of Cox-2 up to 2.4-fold. These findings may have relevance in the outcome of patients treated with IFN-α because upregulated Cox-2 expression may suppress the cell-mediated defense system. On the other hand, the inhibition of Cox-1 could be beneficial because Cox-1 is known to stimulate angiogenesis. Received: 5 August 1999 / Accepted: 8 September 2000     

Re-biopsy in a patient with IgA nephropathy showing success of treatment with cyclosporin A and angiotensin-II receptor blocker

We report a patient with IgA nephropathy (IgAN) showing reduction of proteinuria and histological improvement of renal injury with cyclosporin A (CsA) and angiotensin-II receptor blocker (ARB) therapy. The amount of urinary protein was reduced from 4.4 to 1.8 g/24 h after 2 months of CsA (150 mg/day) therapy, and further, to 0.4 g/24 h after 1 month of the combination therapy with ARB (candesartan, 4 mg/day). A renal re-biopsy, after treatment with CsA for 3 months and ARB for 1 month, demonstrated a reduction of IgA deposits, disappearance of crescents, re-separation of foot process fusion and decrease of interstitial cellular infiltration. After CsA therapy for 20 months and ARB for 18 months, the patient currently remains stable without deterioration of serum creatinine (1.7 mg/dl) and urinary protein excretion (0.5 g/day). These findings seem to indicate that combination therapy with CsA and ARB is effective for achieving histological improvement and protecting against deteriorated renal function, in addition to reducing proteinuria, in IgAN. Received: October 1, 2001 / Accepted: April 10, 2002     

Irinotecan plus low-dose cisplatin for alpha-fetoprotein-producing gastric carcinoma with multiple liver metastases: report of two cases

α-Fetoprotein (AFP)-producing gastric carcinoma generally causes multiple liver metastases and has an extremely poor prognosis. There is no standard chemotherapy for this disease. Two recent consecutive patients who had AFP-producing gastric carcinoma were treated with a novel chemotherapy regimen: irinotecan hydrochloride (100 mg/body over 90 min) plus low-dose cisplatin (10 mg/body) by intravenous infusion. Treatment was done weekly during admission and once every 2 weeks on an outpatient basis. Both patients had multiple liver metastases with high serum levels of AFP, and one demonstrated resistance to 5-fluorouracil. In both patients, liver metastases showed a dramatic complete response to chemotherapy, and the serum AFP levels returned to normal. No significant toxicities were observed. These preliminary results suggest that the present regimen may cause fewer side effects while retaining its synergistic antitumor activity. This regimen may therefore be worth trying as first-line chemotherapy for patients with metastatic AFP-producing gastric carcinoma. Received: October 10, 2001 / Accepted: May 7, 2002 Acknowledgment. This work was supported in part by Grants-in-Aid (Nos. 11671254 and 12877194) for Scientific Research from the Japanese Ministry of Education. Reprint requests to: M. Ogawa     

Absence of α6(IV) collagen in kidney and skin of X-linked Alport syndrome patients

Ab stract. To identify the abnormalities of the type IV collagen α6 chain, α6(IV), in Alport syndrome, we examined renal and skin tissue using rat monoclonal antibodies against non-consensus amino acid sequences of α6(IV). Immunofluorescence of normal human kidney and skin tissue revealed linear α6(IV) staining in the basement membrane (BM) of Bowman’s capsule, in some tubules, and also in the epidermal BM. Renal specimens from five male patients of four families with X-linked Alport syndrome showed no reactivity for α6(IV) in Bowman’s capsules and tubules. In these patients, α1(IV) and α2(IV) were normal, whereas α3(IV), α4(IV), and α5(IV) were absent from the BMs of the kidney. In skin tissue of male patients, neither α5(IV) nor α6(IV) were detected. The epidermal BM of female heterozygotes with X-linked Alport syndrome showed a mosaic staining for α5(IV) and α6(IV). These findings indicate that, in addition to a disturbed α3(IV)-α4(IV)-α5(IV) network, patients with X-linked Alport syndrome have abnormalities in α6(IV) of the renal and epidermal BMs at the protein level. Received October 6, 1995; received in revised form April 25, 1996; accepted April 29, 1996