Role of the deletion of polymorphism of the angiotensin converting enzyme gene in the progression and therapeutic responsiveness of IgA nephropathy.

Studies conducted over the last decade demonstrated variable therapeutic efficacy of angiotensin converting enzyme (ACE) inhibitor on the progression of glomerular diseases, including IgA nephropathy. In this study, among patients with biopsy-proven IgA nephropathy, 53 patients in whom creatinine clearance had been monitored over 5 yr were recruited for study. These patients were classified into two groups according to whether or not renal function had declined as determined by the slope of creatinine clearance against time: group 1 had stable renal function; group 2 had declining renal function (average: -6.7 +/- 1.3 ml/min/yr). 21 of 53 patients were treated with ACE inhibitor and followed for 48 wk. Gene polymorphism consisting of insertion (I) or deletion (D) of a 287-bp DNA fragment (presumed to be a silencer element) of the ACE gene was determined by PCR. 46 age-matched individuals without history of proteinuria were analyzed as controls. The DD genotype was significantly more frequent in group 2 (43%) than in controls (7%) or group 1 patients with stable renal function (16%). 48 wk after ACE inhibitor administration, proteinuria significantly decreased in patients with DD genotype but not in those with ID or II genotypes. The results indicate that deletion polymorphism in the ACE gene, particularly the homozygote DD, is a risk factor for progression to chronic renal failure in IgA nephropathy. Moreover, this deletion polymorphism predicts the therapeutic efficacy of ACE inhibition on proteinuria and, potentially, on progressive deterioration of renal function.

The gene encoding mouse lymphocyte antigen Ly-49: structural analysis and the 5'-flanking sequence.

Genomic clones encoding the mouse cell-surface antigen, Ly-49, were isolated, and the gene organization was analyzed. The gene spanned approximately 19 kb, and contained seven exons and six introns. The lengths of introns ranged from 1.3 to 8 kb. A 1067-bp sequence in the 5'-flanking region was determined. Primer extension analysis and S1 nuclease mapping revealed a cap site at 158 bp upstream from the ATG coding the N-terminal Met of Ly-49. The 5'-flanking sequence contained a possible promoter sequence, a potential binding site for the T cell-specific transcription factor (TCF-1 alpha/LEF-1), and three sites for the basic helix-loop-helix-binding basic proteins (bHLH). However, no CAAT box-like sequence was present. These results provide important clues for understanding the mechanism of gene expression of lymphocyte antigens.

Adrenomedullin amidation enzyme activities in hypertensive patients.

Adrenomedullin (AM) is a potent vasodilating peptide secreted from the vasculature of various organs. It is biologically active when its C-terminus is amidated. Recently, an RIA method was developed for measurement of the active form of AM, or mature AM. We here employed this method to investigate the significance of amidation of AM in controlling cardiovascular function. Thirty-six patients under hemodialysis were recruited and divided into hypertensive (n = 25; 157/86 mmHg) and normotensive (n= 11; 116/66 mmHg) groups. Mature AM, immature AM and blood pressure were monitored during hemodialysis in all patients. There was a significant reduction in blood pressure during hemodialysis in both groups, although after hemodialysis blood pressure was still higher in hypertensives than in normotensives (139 +/-14.8/76 +/- 2.5 mmHg vs. 110 +/- 5.1/66.7 +/- 3.1 mmHg). Mature AM before hemodialysis were lower in hypertensives than normotensives and it decreased in both groups. Although mature AM decreased more in normotensives than in hypertensives (-27 +/- 8% vs. -17 +/- 5%), at the end point, its level was still higher in normotensives. The ratio of mature AM/immature AM decreased only in normotensives (-11.4 8.7%), whereas it remained stable in hypertensives (0.2 +/- 5.6%). Both groups showed similar changes in ANP, endothelin, catecholamines, cGMP, and NOx. The low level in mature AM level in hypertensives may have contributed to the higher blood pressure in this group. The attenuation of AM amidation in normotensives indicates that an unspecified amidative enzyme of AM was regulated in order to normalize blood pressure.

Massive uncomplicated vascular immune complex deposits in the kidney of a patient with systemic lupus erythematosus.

The case of a patient with systemic lupus erythematosus (SLE) is reported which was accompanied by renal dysfunction and massive vascular immune deposits in the kidney without active glomerular lesions. The renal biopsy showed arterioles and small arteries with circumferential periodic acid-Schiff (PAS) and Masson trichrome-positive homogenous material in the subendothelial area in the absence of thrombotic, necrotizing or inflammatory lesions. Immunofluorescence and electron microscopy examination demonstrated immune deposits in the vascular walls. Glomeruli showed only minor abnormalities with a trend to collapse. There was no improvement in renal dysfunction over a 4-year period until the patient's death, despite steroid therapy producing a decrease in disease activity. The autopsy showed similar vascular changes to those seen in the biopsy, however; glomeruli were either sclerotic or showed a trend to collapse. Massive uncomplicated vascular immune complex deposition without active glomerular lesions is rare. The present case indicates that this type of lupus vasculopathy may be a prognostic factor for the loss of renal function in SLE mediated by hemodynamic glomerular injury.

Eradication of Helicobacter pylori restores elevation of serum gastrin concentrations in patients with end-stage renal disease.

In order to explore the role of Helicobacter pylori (H. pylori) infection in hypergastrinemia in patients on dialysis, the changes in serum gastrin concentration were examined before and after eradication treatment for H. pylori. Twenty-seven patients on dialysis were treated for the eradication of H. pylori. Fasting serum gastrin concentrations were measured by a radioimmunoassay which detects gastrin 17. Ammonia and pH levels of the gastric juice were also measured. The serum gastrin concentrations were significantly decreased following eradication of H. pylori, and the mean value reached the normal range. The restoration of hypergastrinemia was associated with marked reductions of gastric juice ammonia and pH levels. In contrast, patients in whom H. pylori was not eradicated showed no changes in these parameters. In conclusion, the elevation of the fasting serum gastrin 17 concentration seen in dialysis patients appeared to be attributable to H. pylori infection in the stomach.

A case of congenital dyserythropoietic anemia type II associated with hemochromatosis.

A 54-year-old woman with anemia, diabetes mellitus and liver dysfunction was admitted to our hospital. Numerous binucleated erythroblasts in the bone marrow, a positive serum acidified test, and the presence of anti I and anti i antigens on the surface of her erythrocytes indicated that she had congenital dyserythropoietic anemia (CDA) Type II. Hemochromatosis was confirmed by a liver biopsy. This case is a sibling of a patient with CDA Type II reported by Omine et al in 1981 (Acta Haematol Jpn 44:1). They report that no physical or hematological abnormalities were found when she was examined at the age of 29 years. Twenty-five years later, she developed CDA Type II and hemochromatosis. This case indicates that long-term observation of the family members of a patient with CDA Type II is necessary.

An autopsy case of light chain deposition disease.

This report describes a case of light chain deposition disease (LCDD) with unusual findings of fibrillar structures in the deposits and marked calcification in several organs. A forty-year-old man was initially diagnosed with LCDD in 1987, and died of sepsis three and one-half-years later. Histological examination of autopsy specimens demonstrated eosinophilic amorphous materials, which differed from amyloid, in vessel walls or around parenchymal cells in almost every organ examined. Ultrastructurally, in addition to granular deposits, fibrillar structures were also seen in the deposits. Marked calcification was present in the myocardium, skeletal muscles, adrenal glands and arteries.

Hyperhomocysteinemia as a possible role for atherosclerosis in CAPD patients.

It has been shown that hyperhomocysteinemia is a risk factor for atherosclerotic vascular disease. In this study, we measured total plasma homocysteine in continuous ambulatory peritoneal dialysis (CAPD) patients and evaluated its correlation with atherosclerosis. Subjects consisted of healthy volunteers, and hemodialysis (HD) and CAPD patients. Fluoro-HPLC was employed to estimate plasma levels of total homocysteine (Hcy). Plasma levels of total Hcy were significantly higher in the CAPD patients compared with the HD patients and controls. Atherosclerotic score (ASS) was calculated, and the correspondence with plasma levels of total Hcy was analyzed. There was a significant correlation between plasma levels of total Hcy and ASS in CAPD patients. However, plasma levels of total Hcy did not correlate with age, plasma vitamin B6 level, residual renal function, protein catabolic rate (PCR), or KT/V. Our present study suggests that elevated concentrations of total plasma Hcy might play a role in the development of atherosclerosis in CAPD patients.

A case of hematophagic histiocytosis associated with acute renal failure.

The present report describes a rare case of hematophagic histiocytosis associated with acute renal failure. A 32-year-old woman was referred to us from a local hospital because of progressive deterioration of renal function, jaundice and a bleeding tendency. The physical findings at admission revealed hyperemic conjunctivae, gingival bleeding, hepatomegaly, and generalized myalgia. Laboratory data indicated a decrease in platelet count, azotemia and hyperbilirubinemia. Marked elevation of serum triglycerides and ferritin was also noted. Histiocyte proliferation with phagocytosis of erythrocytes and platelets was observed in a bone marrow aspirate. A renal biopsy specimen exhibited lesions generally observed in acute tubular necrosis: degeneration and necrosis of tubular epithelial cells; round cell infiltration and edema in the interstitium; and unremarkable glomeruli. The serum titer to coxsackievirus B1 rose from < 4x at admission to 16x after recovery from the illness, suggesting that this virus may have been the causal organism of the accompanying infection. The patient's symptoms improved rapidly with supportive therapy, and complete restoration of renal function was achieved in 20 days. The morphological characteristics of the bone marrow aspirate and the clinical course were compatible with hematophagic histiocytosis.

An adult case of polycystic kidney disease associated with congenital hepatic fibrosis.

Congenital hepatic fibrosis is often associated with infantile, but not with adult polycystic kidney disease. We report the unusual case of an adult patient with polycystic kidney disease complicated by congenital hepatic fibrosis. A 27-year-old women was admitted to our hospital because of gross hematuria due to hemorrhage from renal cysts. She presented hematemesis from ruptured esophageal varices at the age of 14 years. She was diagnosed as having end-stage renal disease due to polycystic kidney disease at the age of 23 years, and maintenance hemodialysis was initiated the following year. Gross hematuria was managed with supportive therapy. However, the patient developed cholangitis and died of sepsis. Postmortem examinations as well as the patient's clinical course suggested that she had an autosomal dominant type of polycystic kidney disease. Histological findings of the liver were compatible with congenital hepatic fibrosis.

[An adult case of glomerulocystic kidney disease].

A 56-year-old female presented with end-stage renal disease. A CT scan of her kidneys demonstrated that the density of the renal parenchyma was quite low as compared with normal kidneys, and that corticomedullary demarcation was obscured. Magnetic resonance imaging (MRI) disclosed low intensity of the kidneys in T1-weighed images, and high intensity in T2-weighed images. In order to elucidate the etiology of her kidney disease, open renal biopsy was performed. The kidney surface was covered with numerous cysts with a diameter of less than 3 mm. Biopsy specimens from the cortical surface showed multiple cystic lesions. Serial sections of more than 200 slices of the biopsy material demonstrated that traces of collapsed glomeruli were present in most of the cysts. On electron microscopy, some epithelial cells lining the cysts were found to be round-shaped and contained a substantial amount of mitochondria, suggesting proximal tubules. These histological findings were compatible with glomerulocystic kidney disease (GCKD). An adult case of GCKD has rarely been reported, but the CT scan as well as MRI of the kidneys appeared to complement the diagnosis of GCKD. Although the cysts of GCKD have been considered to be dilatations of the Bowman's capsules, our observation suggested that part of the cells lining the cysts consisted of proximal tubular epithelium.

Late-onset renal dysfunction in a patient with non-Hodgkin's lymphoma following an autologous bone marrow transplantation.

Various types of glomerulonephropathy have been reported in patients with malignant lymphoma. The present report describes a 21-year-old man with non-Hodgkin's lymphoma who developed renal insufficiency 4 months after undergoing autologous bone marrow transplantation without combined total body irradiation treatment. At the presentation of renal dysfunction, the malignant lymphoma had been in complete remission. A renal biopsy specimen revealed glomerular changes resembling those seen in patients with hemolytic uremic syndrome. However, hematologic examinations exhibited no evidence of thrombocytopenia or thrombotic microangiopathy, such as red cell fragmentations on the peripheral blood smear. Although the etiology of this nephropathy remains unclear, the chemotherapeutic agents administered in conditioning regimens for bone marrow transplantation were suspected of contributing to the renal insufficiency. Methylprednisolone pulse therapy appeared to be effective in arresting progression of the nephropathy. This case indicates that renal function should be monitored carefully in patients with malignant lymphoma after bone marrow transplantation, even if such patients lack the signs or symptoms of thrombotic microangiopathy.

[Eradication of Helicobacter pylori in patients with end-stage renal disease undergoing dialysis treatment].

The aim of the present study was to examine the efficacy and safety of combination therapy with amoxicillin (AMPC), lansoprazole, and plaunotol for the eradication of H. pylori in dialysis patients. The subjects consisted of 15 dialysis patients (10 men and 5 women, mean age of 56 +/- 2.4 years) in whom H. pylori was found in the stomach. H. pylori status was evaluated by histology, culture and rapid urease test with biopsy specimens of the gastric mucosa. The patients were treated with AMPC 500 mg once a day for 3 weeks, lansoprazole 30 mg once a day for 8 weeks and plaunotol 80 mg three times a day for 24 weeks. In addition, the concentrations of serum gastrin and gastric juice ammonia were measured. Fourteen patients completed the treatment schedule, while one discontinued treatment because of nausea and diarrhea. Among the 14 patients, H. pylori was eradicated in 11 without any side effects (eradication rate 78.6%). Concentrations of gastric juice ammonia and serum gastrin were reduced significantly in patients who became H. pylori-negative. The present study indicates that combination therapy with AMPC, lansoprazole and plaunotol is safe and efficient for the eradication of H. pylori in dialysis patients. The results also suggested that elevated concentrations of gastric juice ammonia and serum gastrin in dialysis patients can be attributed, at least in part, to H. pylori infection.

[Hyperhomocysteinemia in CAPD patients: peritoneal transport of total homocysteine at peritoneal equilibration test and daily elimination of total homocysteine].

Peritoneal equilibration tests (PET) were performed in patients on continuous ambulatory and automated peritoneal dialysis (CAPD, APD) to evaluate the peritoneal transport capabilities for total homocysteine (tHcy) and other amino acids. Forty-five patients (24 males, 21 females, 50.6 +/- 12.8 years old) maintained on PD for 43.4 +/- 30.3 months participated in the study. PET revealed a markedly lower dialysate to plasma (D/P) ratio of tHcy at 4 hours (0.148 +/- 0.047) than those of other amino acids. A significant positive correlation between the D/P ratio of tHcy and the D/P ratio of creatinine was found, as well as between the D/P ratio of tHcy and the D/P ratio of albumin. The most significant positive correlation was found between dialysate and plasma levels of tHcy at 4 hours. There was no difference in the D/P ratio of tHcy between patients with D/P ratios of creatinine higher than the sample median of 0.68 and with D/P ratios of creatinine below 0.68, while the D/P ratios of other amino acids except threonine in the former patients tended to be higher than those of the latter patients. The D/P ratio of tHcy in patients with serum levels of albumin higher than 4.0 g/dl was significantly higher than that in patients with a ratio less than the sample median of 3.9 g/dl, whereas there were no significant differences in the D/P ratios of other amino acids. These observations suggest that the dialysate level of tHcy is primarily affected by the plasma level of tHcy, and that protein-bound Hcy mainly regulates the D/P ratio of tHcy. Daily peritoneal elimination of tHcy in 20 PD patients was 40.6 +/- 28.4 micromol. A significant positive correlation between the elimination of tHcy and plasma level of tHcy was also found. Daily elimination of tHcy in 7 patients with APD tended to be lower than that in 13 patients with CAPD. These findings indicate that the daily peritoneal elimination of tHcy does not compensate for the daily amount of tHcy metabolized in normal kidney, and that other therapies, such as folic acid administration, are required to improve hyperhomocysteinemia in patients on PD.

[Effects of folic acid supplementation on hyperhomocysteinemia in CAPD patients: effects on unsaturated fatty acids].

Hyperhomocysteinemia has been recognized as one of the risk factors for atherosclerosis and premature vascular disease. Patients on dialysis and end-stage renal disease also manifest high plasma concentrations of homocysteine. We performed this study to evaluate the effects of folic acid supplementation on hyperhomocysteinemia in CAPD patients. Twenty-three CAPD patients (8 males, 15 females, 49.1 +/- 14.2-years-old) dialyzed for 22.7 +/- 19.2 months participated in the study. Daily 5-mg doses of folic acid supplementation for 4 weeks significantly reduced plasma concentrations of total homocysteine (p < 0.01) and serine (p < 0.001). This observation suggests that the reduction of plasma concentrations of total homocysteine results from activation of homocysteine remethylation to methionine. On the other hand, folic acid supplementation also revealed significant correlations between changes in serum concentrations of both dihomo-gamma-linolenic acid and arachidonic acid and changes in plasma concentrations of total homocysteine (r = -0.517, p < 0.05, r = -0.451, p < 0.05, respectively). In addition, serum concentrations of both dihomo-gamma-linolenic acid and arachidonic acid in 11 CAPD patients with hyperhomocysteinemia (> or = 35 micromol/litter) were significantly lower than those of 12 CAPD patients with normohomocysteinemia (< 35 micromol/litter) (p < 0.05, p < 0.05, respectively). Serum concentrations of both dihomo-gamma-linolenic acid and arachidonic acid in CAPD patients with hyperhomocysteinemia increased significantly (p < 0.01, p < 0.05, respectively) and reached similar levels of CAPD patients with normohomocysteinemia, while plasma concentrations of total homocysteine decreased after folic acid supplementation. These findings suggest that correction of hyperhomocysteinemia in patients on dialysis produces an increase in unsaturated fatty acids.

[A case of primary amyloidosis associated with giant cell infiltration within a Bowman's capsule].

A 67-year-old man was hospitalized with a diagnosis of nephrotic syndrome. Physical findings at admission were generalized edema and macroglossia. Urinalysis showed massive proteinuria, + +occult blood, and granular and broad casts. Ig A lambda monoclonal gammopathy was noted in the serum. There was no evidence of myeloma in the bone marrow aspirate, scintigram or X-ray of the bone. A biopsy specimen of the kidney showed massive deposits of structureless material in the glomeruli. Marked cell infiltration was also observed in the interstitium. Multinucleated giant cells were occasionally seen in the Bowman's capsules and the interstitium. There were reactive changes in the Bowman's capsule adjacent to the giant cell. The deposits were proved to be amyloid by positive staining with Congo red and apple-green birefringence by polarized light. In addition, microfibrills seen on electron microscopy displayed deposits. Amyloid depositions were observed in other tissues such as gingiva, skin and tongue. Staining of amyloid with Congo red was resistant to potassium permanganate, and amyloid was positively stained with lambda-light chain of immunoglobulin. These findings indicated that the patient had primary amyloidosis. Infiltration of the multinucleated giant cell has been reported only in patients with familial amyloidosis and secondary amyloidosis associated with rheumatoid arthritis. To our knowledge the present case is a first report of the giant cell infiltration in a Bowman's capsule in primary amyloidosis.

[Polymorphism of T cell receptor genes and hyper-production of cytokines: their possible contribution to the pathogenesis of IgA nephropathy in ddY mouse].

The ddY mouse has been used as the spontaneous model animal of human IgA nephropathy (IgAN), because kidney lesion as well as immunological abnormalities resemble that of human IgAN. The intensity of mesangial IgA deposition in neonatally thymectomized ddY mice, in which T cell function was impaired, was less severe, indicating that cytokines from T cells determine the amount of mesangial IgA deposition. Therefore ddY mouse may possess a large amount of cytokines due to hyperactivity of T cells. To elucidate the reason for T cell hyperactivity in ddY mice, genetic polymorphism of T cell receptor genes was examined. Though restriction fragment length polymorphism (RFLP) of alpha and beta chain genes is the same as that of normal mice, the RFLP of the gamma chain is unique. Since T cells bearing gamma chain are observed frequently in the tonsil gland or intestinal intraepithelium, which are indispensable lymphoid tissues for IgA production, an uncommon DNA sequence of the gamma chain could contribute to the pathogenesis of IgAN.