bluuebunny/crossref_metadata_2025 huggingface dataset:
Therapeutic Effects of Ulinastatin on Experimental Crescentic Glomerulonephritis in Rats
Authors: Koizumi Ryuichi , Kanai Hideo , Maezawa Akira , Kanda Tsugiyasu , Nojima Yoshihisa , Naruse Takuji
Published: April 2003

Ulinastatin is a potent protease inhibitor purified from the human urine that has been used clinically to treat acute pancreatitis and circulatory shock. In the current study, we evaluated the therapeutic effects of Ulinastatin in a rat model of crescentic glomerulonephritis (CrGN) and investigated its putative mechanisms. Wistar-Kyoto rats were injected with nephrotoxic serum and received daily intraperitoneal injection of Ulinastatin. Ulinastatin treatment significantly reduced proteinuria and glomerular crescentic formation. Moreover, glomerular infiltration of neutrophils and ED1+ cells (monocytes/macrophages) was significantly suppressed by Ulinastatin. In contrast, the glomerular deposition of heterologous (rabbit) and autologous (rat) antibodies was not changed. Neither serum complement activation nor the anti-rabbit immune response was affected by Ulinastatin administration. Our results suggest that Ulinastatin has preventive effects on rat experimental CrGN, mediated at least in part by inhibiting intraglomerular infiltration of inflammatory cells.
Glomerular Basement Membrane Anionic Sites in Adriamycin Nephropathy: Effect of Saline Loading and Nitric Oxide Modulation
Authors: Hertzan-Levy Shlomit , Fish Roman , Skutelsky Ehud , Wollman Yoram , Chernichovsky Tamara , Polak-Charcon Sylvie , Schwartz Doron , Blum Miriam , Cabili Shaltiel , Iaina Adrian
Published: April 2003

Background: In previous studies we found that experimental Adriamycin (ADR) nephropathy is associated with the loss of glomerular basement membrane (GBM) anionic sites provided by heparan sulfate proteoglycans. Chronic saline loading in normal rats resulted in a similar effect on the GBM anionic sites. The L-arginine-nitric oxide synthase-nitric oxide system is involved in the pathogenesis of experimental chronic renal failure. The present study was performed to determine the combined effect of nitric oxide (NO) modulation and chronic saline loading in ADR nephropathy. The modulation of NO was done by chronic administration of L-arginine (NO donor) or Nw-nitro-L-arginine, a known nitric oxide synthase inhibitor. Methods: Systolic blood pressure was measured in awake rats by a tail-cuff method. Renal function was assessed by creatinine clearance, FeNa%, and daily protein excretion. The change of mean GBM widths and anionic sites distribution were assessed by electron microscopy. The localization of anionic sites was carried out by cationic colloidal gold. Plasma and urinary nitrates (NOx) were measured by nitrite (NO2) + nitrate (NO3), stable metabolites of NO. Results: Two weeks after the ADR administration (3.5 mg/kg BW iv) the rats had severe renal failure (creatinine clearance 134 ± 31 µl/min/100 g BW vs. initial values 670 ± 29 µl/min/ 100 g BW, p < 0.001), high FeNa%, severe proteinuria, increased GBM width, significant reduction of GBM anionic sites and low urinary NOx excretion. The saline loading resulted in further reduction of GBM anionic sites count and blood pressure elevation. The inhibition of NO did not change the course of ADR nephropathy. The main finding of the present study is that chronic administration of L-arginine significantly alleviates the renal failure in the ADR (+/– saline loading) nephropathy. The L-arginine-treated rat had higher creatinine clearance, lower FeNa% and protein excretion and complete normalization of GBM anionic sites distribution. Conclusions: Sodium loading has a deleterious effect on GBM permselectivity. L-Arginine prevents the reduction of GBM anionic sites, decreases proteinuria and alleviates the renal insufficiency in ADR nephropathy.
Nephrotic Syndrome: Molecular and Genetic Basis
Authors: Fogo Agnes
Published: April 2003

Nephrotic syndrome results from varying injuries to the capillary wall of the glomerulus. The components of the capillary wall, including the endothelial cell, glomerular basement membrane and glomerular visceral epithelial cell all may be targets of injury and contribute to proteinuria. These mechanisms of injury include immune complexes, cytotoxins, abnormal protein deposition, metabolic abnormalities, reactive oxygen species, growth factors, hemodynamic stress, and genetic abnormalities. We review mechanisms of glomerular permselectivity, with focus on emerging new understanding of the functions of the glomerular visceral epithelial cell. The significance and consequences of proteinuria and possible pathogenic mechanisms and the effect of interventions in clinical renal disease on these factors are considered.
Vitamin-D Receptor Genotype and Renal Disorder in Japanese Patients with Systemic Lupus erythematosus
Authors: Ozaki Yoshio , Nomura Shosaku , Nagahama Minori , Yoshimura Chie , Kagawa Hideo , Fukuhara Shirou
Published: April 2003

Background/Aims: It is known that allelic variants of the gene encoding the vitamin-D receptor (VDR) detected by BsmI increase the risk of some advanced malignant tumors, suggesting that such variants may cause functional differences in 1,25(OH)2 vitamin D3. We examined the VDR genes of Japanese systemic lupus erythematosus (SLE) patients, to determine whether different genotypes are correlated with SLE or its criteria. Methods: VDR genotyping of 58 unrelated Japanese SLE patients was performed based on polymerase chain reaction-restriction fragment length polymorphism (RFLP). Following amplification, products were digested with BsmI. The RFLPs were coded as Bb, where the uppercase letter signifies the absence of the digested site and the lowercase letter signifies the presence of the site. Results: The frequency of the VDR BB genotype was significantly higher in SLE patients (15.5%, n = 9/58, p < 0.0001) than in controls (5.7%, n = 5/87). Furthermore, a larger proportion of bb individuals was observed among patients with nephrotic syndrome (61.5%, n = 8/13) than among SLE patients without renal dysfunction (35.7%, n = 10/28). There was a significant tendency for the population of patients with the bb genotype to be correlated with that of patients with renal dysfunction (p = 0.0304). Conclusion: These findings suggest that the BB genotype might trigger the development of SLE, and that the bb genotype is associated with lupus nephritis.
Association of Polymorphic Alleles of the Calcium-Sensing Receptor Gene with Parathyroid Hormone Secretion in Hemodialysis Patients
Authors: Yano Shozo , Sugimoto Toshitsugu , Kanzawa Michiko , Tsukamoto Tatsuo , Hattori Tetsuya , Hattori Saburo , Chihara Kazuo
Published: April 2003

The present study was performed to investigate the association of calcium-sensing receptor (CaSR) genotypes with parathyroid hormone (PTH) secretion in hemodialysis patients. Subjects were 122 Japanese hemodialysis patients, including 39 patients with diabetes mellitus (DM). The CaSR polymorphisms tested were codon 990 in intracellular domain (A/A, A/G, and G/G groups) as well as T to C base change of intron 4 (T/T, T/C, and C/C groups). Statistical analysis of these polymorphisms revealed that the serum PTH level was significantly higher in the A/A group than in the G/G group in the former. In addition, the serum PTH level was also significantly higher in patients displaying C allele, as compared with the T/T group in the latter. This association of two polymorphisms with the serum PTH level was observed only in non-DM patients. Although two polymorphisms affected the PTH level independently, patients who possessed both genotypes (AAC+) had a markedly high level of PTH not only in the non-DM group but also in the DM group. The present findings indicate the possibility of the prediction for the extensive progression of secondary hyperparathyroidism through analyzing the CaSR polymorphisms in chronic hemodialysis patients.
Aspects of Cardiovascular Burden in Pre-Dialysis Patients
Authors: Drüeke Tilman B.
Published: April 2003

Background: Cardiovascular disease (CVD) is a major cause of death in patients with chronic renal failure (CRF). It is well recognised that dialysis patients have a high burden of factors that predispose to CVD. What is less clear is the extent of this problem in the pre-dialysis patient. This is the subject of this review. Methods: The role of potentially correctable cardiovascular risk factors in pre-dialysis patients has been examined using published data. Results: Anaemia is a major cardiovascular risk factor in patients with CRF. Partial correction of renal anaemia with recombinant human erythropoietin leads to improvements in cardiac dysfunction in such patients, such as alleviation of left ventricular hypertrophy. Secondly, malnutrition and inflammation have also been recently identified as potentially correctable cardiovascular risk factors in these patients. Conclusions: Patients continue to enter dialysis with a considerable cardiovascular burden, many having already suffered a stroke or myocardial infarction. Many risk factors, including malnutrition and inflammation, account for the increased incidence of cardiovascular events. Anaemia is common in pre-dialysis patients, and early corrective treatment may help to reduce the incidence of CVD and hence improve long-term outcome.
Potassium-Sparing Renal Effects of Trimethoprim and Structural Analogues
Authors: Gabriëls Gert , Stockem Esther , Greven Joachim
Published: April 2003

Background/Aims: The antibiotic antagonists of folic acid trimethoprim, tetroxoprim, pyrimethamine and their antineoplastic analogue methotrexate have structural characteristics in common with the potassium-sparing diuretic triamterene. They may, therefore, share with triamterne potassium-sparing renal effects. Methods: Clearance studies were performed on anesthetized male Sprague-Dawley rats, and the drug effects on glomerular filtration rate and on urinary excretion of sodium, chloride, and potassium were studied. Results: Trimethoprim and tetroxoprim, injected intravenously at doses ranging from 0.3 to 30 mg/kg, induced dose-dependent natriuretic and antikaliuretic renal effects, whereas pyrimethamine at doses ranging from 1 to 10 mg/kg and methotrexate at doses ranging from 10 to 50 mg/kg did not affect urinary sodium and potassium excretion. An antikaliuretic effect was also observed after application of the structurally related antiprotozoal compound pentamidine at doses ranging from 3 to 10 mg/kg. In contrast to trimethoprim and tetroxoprim, the antikaliuresis was accompanied by a marked decrease of urinary sodium and chloride excretion at all of the doses tested. At 10 mg/kg, pentamidine induced a pronounced fall of the glomerular filtration rate (by 43.5%). Conclusions: Trimethoprim and tetroxoprim share with potassium-sparing diuretics natriuretic and antikaliuretic renal effects which may be caused by similar mechanisms in the distal nephron, whereas pyrimthamine and methotrexate do not. A depression of renal hemodynamics is an important factor involved in the antikaliuretic effect of pentamidine.
Angiotensin-Converting Enzyme Insertion/Deletion Polymorphism and Prognosis of IgA Nephropathy
Authors: Syrjänen Jaana , Huang Xiao-Hong , Mustonen Jukka , Koivula Timo , Lehtimäki Terho , Pasternack Amos
Published: April 2003

Background/Aim: Well-known factors for a poor prognosis in IgA nephropathy (IgAN) are hypertension, proteinuria, and renal insufficiency at the time of diagnosis. Also hypertriglyceridemia and hyperuricemia seem to play a role in the progression of IgAN. Angiotensin-converting enzyme (ACE) gene I/D polymorphism has been associated with cardiovascular diseases and with progression of IgAN. We, therefore, investigated the contribution of ACE gene I/D polymorphism in the prognosis of IgAN and its association with the other risk factors affecting the prognosis. Methods: A total of 168 patients with IgAN were followed up for 6–17 (median 11) years from renal biopsy with respect to progression of renal disease defined as elevation of serum creatinine above 125 µM (1.4 mg/dl) in men or 105 µM (1.2 mg/dl) in women and over 20% from the baseline level. In addition to serum creatinine, the urinary protein excretion was evaluated at the time of renal biopsy and at the assessment visit at the end of the follow-up period. Results: During the follow-up period, 26 (15%) patients showed progression of renal disease. Patients with ACE genotype II had a more favorable course than those with genotypes ID or DD. Although there were no significant differences among the ACE genotypes with respect to proteinuria ≧1 g/24 h at the time of renal biopsy, proteinuria ≧1 g/24 h was more frequent in patients with genotypes ID or DD than in those with genotype II at the end of the follow-up period. No associations were found between hypertension, serum lipids or serum urate, and ACE genotypes. Conclusions: Our results show that patients with ACE genotype II have a more favorable prognosis than those with genotypes ID/DD. Secondly, proteinuria (≧1 g/24 h) found in patients with genotype II at diagnosis may improve, while in patients with genotypes ID/DD it is a more constant feature.
Comparative CD43 Behavior on Monocytes and Lymphocytes in Kidney Transplants
Authors: Jégo Sophie , Sabri Siham , Soler Mireille , Farnarier Catherine , Lucioni Aline , Dussol Bertrand , Bongrand Pierre , Berland Yvon , Foa Colette
Published: April 2003

In human cultured monocytic cells stimulated by cytokines, CD43 was demonstrated to exhibit a modification of sialylated epitopes (dys-sialylation) [Soler et al: Leukoc Biol 1997;61:609–618]. Therefore, we chose to investigate CD43 behavior on patients who present pathological status implicating monocytes after renal graft (KTR). We performed flow cytometry after immune staining using monoclonal antibodies to CD43 sialic acid-dependent (L60) and -independent (L10) epitopes. Compared to normal controls, mean fluorescence intensity was never altered on lymphocytes. Conversely, on monocytes, we found different profiles with L60: 26% of patients having normal CD43 expression, 54% displayed decreased values and 20% had a double population of monocytes, the major one being normal and the minor one with a very low staining. Decreased values were more frequent among KTR during the first 3 months following transplantation. L10 immunostaining was not altered on monocytes in patients with low values of CD43 staining by L60, confirming that the mechanism involved was a CD43 dys-sialylation. We investigated a possible role of cyclosporin (CsA) on human monocytic (THP-1) and lymphoid (Jurkat) cell lines. CsA decreases CD43 expression in monocytic and not in lymphoid cell lines and could be responsible for the specific dys-sialylation of KTR monocytes. Whatever, CD43 dys-sialylation might lead to functional abnormalities of monocytes in KTR, possibly involving the adhesion process.
Low Molecular Weight Heparin in Hemodialysis Patients with a Bleeding Tendency
Authors: Leu Jyh-Gang , Chiang Shou-Shan , Lin Shu-May , Pai Jung-Kuei , Jiang Wey-Wen
Published: April 2003

Efficacy and safety of a low-molecular-weight heparin (LMWH) were studied in 33 stable maintenance hemodialysis patients who had a bleeding tendency on unfractionated heparin. The optimal dose of LMWH for each patient was titrated before the study; the mean total LMWH dosage was 1,152 ± 574 IU. No major bleeding or clot formation was noted in a total of 2,470 hemodialysis sessions during 6 months of LMWH administration. The mean value of plasma anti-factor Xa (anti-Xa) activity increased from 0.05 ± 0.03 IU/ml before dialysis to 0.34 ± 0.28 IU/ml after 2 h of dialysis and returned to 0.15 ± 0.09 IU/ml after 4 h of dialysis; the mean activated partial thromboplastin time was 26.1 ± 4.4 s before dialysis, 30.7 ± 9.5 s (an 18% increase) after 2 h of dialysis, and 26.2 ± 4.4 s after 4 h of dialysis. No significant change in serum antithrombin levels was noted throughout the whole study period. We conclude that a low dosage of LMWH is safe and effective in hemodialysis patients who have a risk of bleeding with unfractionated heparin. Serum anti-Xa activity is better than activated partial thromboplastin time and antithrombin in assessing the optimal dose of LMWH. A plasma anti-Xa activity of 0.37 IU/ml after 2 h of hemodialysis may represent an optimal dosage of LMWH for most patients.
Transforming Growth Factor-β1 Inhibits Vascular Permeability Factor Release by T Cells in Normal Subjects and in Patients with Minimal-Change Nephrotic Syndrome
Authors: Matsumoto Koichi , Kanmatsuse Katsuo
Published: April 2003

Background/Aim: A lymphokine, the vascular permeability factor (VPF), which increases vascular permeability, has been characterized in minimal-change nephrotic syndrome (MCNS). Transforming growth factor-β (TGF-β) is an immunosuppressive cytokine that inhibits proliferation, cytokine production, and cytotoxic activity of T cells and natural killer cells. We, therefore, investigated the effects of TGF-β1 on the release of VPF by peripheral blood T cells from MCNS patients. The aim of our study was to determine the in vitro immunosuppressive capacity of TGF-β1 in patients with MCNS. Methods: To further test the effect of TGF-β1 on concanavalin A (Con A)-induced VPF release, normal and MCNS T cells were stimulated with 5 µg/ml of Con A in the presence or absence of TGF-β1, and the culture supernatants were tested for the presence of VPF by the method of Lagrue et al. The disease controls included 16 patients with IgA nephropathy. Results: Significantly increased spontaneous and Con A-stimulated secretion of VPF was detected in T-cell cultures of MCNS patients with the nephrotic syndrome as compared with those of normal controls. Addition of TGF-β1 to these cultures inhibited the release of VPF in a dose-dependent manner. The effect of TGF-β1 on the release of VPF was specific, since a reversion was obtained with a neutralizing monoclonal antibody to human TGF-β1. Conclusion: Together, our data demonstrate that TGF-β1 antagonizes the ability of T cells to release VPF, and suggest a role of TGF-β1 in the pathophysiology of VPF in vitro.
Lupus Nephritis in Children: Prognostic Significance of Clinicopathological Findings
Authors: Emre Sevinc , Bilge Ilmay , Sirin Aydan , Kılıcaslan Isın , Nayır Ahmet , Oktem Faruk , Uysal Veli
Published: April 2003

Background: We aimed to review our experience with childhood lupus nephritis (LN) in respect to the analysis of the clinical and histopathological presentation of LN and prognostic factors affecting the kidney and patient outcomes. Method: Forty-three children (39 girls, 4 boys) with biopsy-proven LN were included in the study. The mean age of the children was 12.0 ± 2.8 years. Based on the renal histopathology and clinical presentation, patients were treated with oral prednisone, intravenous pulses of methylprednisolone or intravenous cyclophosphamide. The final clinical status was classified as follows: (1) renal and extrarenal remission; (2) clinically active renal disease, or (3) adverse outcome, i.e., end-stage renal failure (ESRF) or death. Results: The mean duration of follow-up was 7.2 ± 2.8 years (1 month to 14.2 years). All 43 children had hematuria and 53.5% had proteinuria at admission. Fourteen children were in nephrotic status at the onset of disease. Class IV (diffuse proliferative) nephritis was observed in 29 patients as the most frequent histopathology (67.4%). The patients with class IV nephritis had a tendency to develop nephrotic syndrome, heavy proteinuria, increased Cr levels and persistent hypertension at initial evaluation. Thirty-two of 43 children (74.4%) were in renal remission at the last visit. Five-year kidney and patient survival rates from the time of diagnosis to the endpoints of ESRF or death were 83.7 and 90.7% respectively in the whole group while it was 75.9 and 86.2% respectively in the class IV group. Adverse outcome was significantly associated with the persistent hypertension, anemia, high serum Cr level, heavy proteinuria, nephrotic syndrome and class IV nephritis at presentation. Conclusion: We can conclude that the prognosis of LN in children is primarily dependent on the histopathological lesions. Severity of the clinical renal disease at admission and presence of persistent hypertension are the main poor prognostic factors rather than age, gender, low C3 and C4 levels, ANA positivity and the treatment modalities in Turkish children.
Significance of Salivary Epidermal Growth Factor in Peptic Ulcer Diseasein Hemodialysis Patients
Authors: Guh Jinn-Yuh , Chen Hung-Chun , Chuang Lea-Yea , Yang Chi-Yuan , Tsai Juei-Hsiung , Lai Yung-Hsiung
Published: April 2003

Background/Aims: Hemodialysis (HD) patients are prone to developing peptic ulcers. However, of all the risk factors associated with peptic ulcers, none have been shown to be more prevalent in HD patients than in the general population. However, salivary epidermal growth factor (EGF) may play a role in peptic ulcer diseases. Methods: Salivary EGF levels and bioactivities were assayed in 47 maintenance HD patients and 30 normal controls, and the molecular weights of EGF were assessed using high-performance liquid chromatography (HPLC). Results: Salivary EGF levels were not different between both groups of subjects (4.2 ± 0.34 vs. 5 ± 0.54 ng/mg protein, NS), and HPLC revealed that salivary EGF in both groups had similar molecular weights. However, salivary EGF bioactivity was significantly depressed in the HD patients as compared to the normal controls (0.59 ± 0.08 vs. 1.55 ± 0.15 ng/mg protein, p < 0.01). Stepwise multiple regression showed that the low salivary EGF levels were associated with female gender (p < 0.05), while low salivary EGF bioactivity was associated with HD per se (p < 0.05). In the 22 HD patients who underwent gastric endoscopy, salivary EGF bioactivity was significantly lower in those with peptic ulcers than in those without (0.38 ± 0.08 vs. 0.69 ± 0.08 ng/mg protein, p < 0.05). Conclusion: Decreased salivary EGF bioactivity may contribute to peptic ulcer disease among maintenance HD patients.
Low Molecular Weight Heparin Reduces Proteinuria and Modulates Glomerular TNF-α Production in the Early Phase of Adriamycin Nephropathy
Authors: Benchetrit S. , Golan E. , Podjarny E. , Green J. , Rashid G. , Bernheim J. , Hershkovitz R.
Published: April 2003

Background/Aim: Heparin has been shown to be renoprotective in a number of experimental nephropathies. The inflammatory component in the early phase of Adriamycin (ADR) induced nephropathy has been established. A microdose of low molecular weight heparin (Fragmin; F) has been noted to exert immunomodulatory effects independent of its anticoagulant activity. We assessed the effects of microdoses of F on daily proteinuria and glomerular production of tumor necrosis factor alpha (TNF-α) and prostaglandins 8 and 15 days after induction of ADR nephropathy. Methods: Following intravenous injection of ADR (7 mg/kg) to Wistar rats weighing 200 ± 20 g, F 20 µg/day/rat s.c. was administered for 8 and 15 days (groups F8 and F15). The respective control groups (C8 and C15) received normal saline subcutaneously. Proteinuria, serum albumin, and creatinine clearance were evaluated on days 8 and 15. The production of TNF-α and prostaglandins from glomerular supernatants was measured by radioimmunoassay on days 8 and 15. Results: F significantly reduced proteinuria (mg/day) on day 8: 13.6 ± 1.2 in F8 versus 40.3 ± 2.7 in C8 (p = 0.008). The glomerular production of TNF-α (pi/ml) was significantly lower on day 8 in rats treated with F: 356 ± 33 in F8 versus 764 ± 81 in C8 (p = 0.006). A decrease in the prostaglandin E2/thromboxane B2 ratio was noted in the F group between 8 and 15 days (1.1 in F8 vs. 0.9 in F15, p = 0.005) which principally reflects an increase of thromboxane B2. The antiproteinuric effect of F shown after 8 days was no longer present after 15 days (354 ± 91 mg/day in F15 vs. 499 ± 69 mg/day in C15, p = 0.33). The same trend was seen for the glomerular production of TNF-α. Light microscopy and immunohistochemistry for interstitial and glomerular macrophages were negative. Conclusion: The lowering effect of microdoses of F on the proteinuria seen during the early phase of ADR nephropathy may be mediated by a decreased production of glomerular TNF-α, supporting the anti-inflammatory action of low molecular weight heparin.
Apoptosis of Renal Tubular Cells in Shiga-Toxin-Mediated Hemolytic Uremic Syndrome
Authors: Kaneko Kazunari , Kiyokawa Nobutaka , Ohtomo Yoshiyuki , Nagaoka Rieko , Yamashiro Yuichiro , Taguchi Tomoko , Mori Tetsuya , Fujimoto Junichiro , Takeda Tae
Published: April 2003

In order to clarify the mechanism of unusual renal tubular dysfunction seen in a child with Shiga toxin (Stx)-mediated hemolytic uremic syndrome (HUS), we studied the renal biopsy specimens for Stx binding and apoptosis of renal tubular cells. A 7-year-old boy with Stx-2-mediated HUS demonstrated extensive renal tubular damage characterized by nonoliguric acute renal failure, increased urinary tubular enzymes and defective urine-concentrating capacity. His renal biopsy specimens were analyzed for Stx binding and apoptotic cell death. Seven kidney tissue specimens obtained from patients without HUS served as controls. Detection of Stx binding to renal sections and apoptotic cells were performed using mouse monoclonal anti-Stx 2 antibody and the TUNEL method, respectively. Positive staining was observed predominantly in renal tubular cells, while the 7 kidney tissue specimens from control patients did not show positive staining. To the best of our knowledge, this is the first case to show Stx binding and apoptotic cell death in renal tubules on biopsy specimens obtained from a child with Stx-mediated HUS. In conclusion, this case suggests that vascular endothelial cells are not the sole nor the consistent target for Stx-mediated cell injury and that significant renal tubular damage other than glomerular damage might occur in some children with Stx-mediated HUS.
Transforming Growth Factor-β1 and Myofibroblasts: A Potential Pathway towards Renal Scarring in Human Glomerular Disease
Authors: Goumenos Dimitrios S. , Tsamandas Athanassios C. , Oldroyd Simon , Sotsiou Florentia , Tsakas Sotiris , Petropoulou Chrisanthi , Bonikos Dionysios , El Nahas Abdel Meguid , Vlachojannis John G.
Published: April 2003

Background/Aims: The cellular and humoral factors involved in the development and progression of renal scarring have not been fully investigated. Transforming growth factor-β (TGF-β1) is considered to be the main fibrogenic growth factor and it is implicated in the pathogenesis of renal fibrosis in experimental and clinical nephropathies. On the other hand, collagen III is an important component of the extracellular matrix. In this study we attempted to identify any possible links between TGF-β1 and collagen III synthesis and expression with the expression of myofibroblasts in the evolution of renal scarring in human glomerular diseases. Methods: We studied retrospectively 40 patients with various types of primary and secondary glomerulonephritis (GN), with either proliferative or nonproliferative pattern, with emphasis on the renal synthesis of TGF-β1 and collagen III (detected by in situ hybridization) and their expression (detected by immunohistochemistry) as well as myofibroblast expression. The possible links of TGF-β1 expression with myofibroblast distribution (α-smooth muscle actin, α-SMA(+) cells) and with conventional histopathology and renal function was also examined. Results: TGF-β1 protein and mRNA were detected in the renal tubular epithelial cells and interstitium and to a lesser extent within glomeruli of patients with GN. Collagen III was mainly detected in the interstitium (peritubular and periglomerular areas) and to a lesser extent in the glomeruli. Messenger RNA for collagen III followed a similar peritubular and periglomerular distribution to that of TGF-β1 and α-SMA(+) interstitial cells. The intensity of interstitial TGF-β1 protein expression was significantly related to the degree of interstitial fibrosis (r = 0.628, p < 0.01), tubular atrophy (r = 0.612, p < 0.01), interstitial collagen III expression (r = 0.478, p < 0.05), and serum creatinine values (r = 0.722, p < 0.001). Also there was a close positive correlation between the severity of interstitial myofibroblast expression and interstitial TGF-β1 (r = 0.412, p < 0.05), as well as collagen III (r = 0.409, p < 0.05). In addition, a significant correlation was found between glomerular TGF-β1 expression and severity of glomerulosclerosis (r = 0.620, p < 0.01). Conclusion:  The results of this study suggest that TGF-β1 plays an important role in the pathogenesis of fibrosis developing in human kidney, during the evolution of glomerular disease. Interstitial myofibroblasts may contribute to interstitial fibrosis through the synthesis and release of both TGF-β1 and collagen III.
Inhibitory Effects of Nicorandil on Rat Mesangial Cell Proliferation via the Protein Kinase G Pathway
Authors: Segawa Kayoko , Minami Kouichiro , Shiga Yousuke , Shiraishi Munehiro , Sata Takeyoshi , Nakashima Yasuhide , Shigematsu Akio
Published: April 2003

We investigated the effects of nicorandil, which is a hybrid between a nitrate and an ATP-sensitive potassium channel (KATP) opener, on cultured rat mesangial cell proliferation. Nicorandil (1 µM to 1 mM inhibited [3H]thymidine incorporation into rat mesangial cells in a concentration-dependent manner. Nicorandil (1 µM to 1 mM) also inhibited the number of cells. Nicorandil increased cyclic guanosine 3′,5′-cyclic monophosphate accumulation in mesangial cells. A protein kinase G inhibitor, KT5823, partially eliminated the inhibition of mesangial cell proliferation by nicorandil. Methylene blue, a guanylate cyclase inhibitor, blocked the inhibitory effect of nicorandil on mesangial cell proliferation. We also examined the effects of KATP mediators. Cromakalim, a KATP activator, and glibenclamide, a KATP inhibitor, had little effect on the proliferation of mesangial cells. These results suggest that the inhibitory effects of nicorandil on mesangial cell proliferation are mediated via the protein kinase G pathway.
Plasticity of Intercalated Cell Polarity: Effect of Metabolic Acidosis
Authors: Schwartz George J.
Published: April 2003

The cortical collecting duct (CCD) is capable of secreting H+ or HCO–3 depending on the acid-base status in vivo. Transport is a function of two types of intercalated cells in the CCD: A-intercalated cells secrete H+ and B-intercalated cells secrete HCO–3. Metabolic acidosis results in a decrease in HCO–3 secretion and an increase in H+ secretion by the respective cells. Using a model of metabolic acidosis in vitro, we have shown that the down-regulation of HCO–3 secretion occurs by endocytosis of apical anion exchangers in B-intercalated cells. The finding of basolateral anion exchangers in some adapted B-intercalated cells is consistent with a reversal of functional epithelial polarity. Plasticity of polarity is also observed in cultured intercalated cells: high-density plating results in converting B- to A-intercalated cells via the deposition of the novel protein hensin in the extracellular matrix. A key problem in renal physiology is to investigate the role of hensin in mediating the adaptation of the CCD to acidosis in vitro and in vivo.
Vitamin B6 Therapy Does Not Improve Hematocrit in Hemodialysis Patients Supplemented with Iron and Erythropoietin
Authors: Weissgarten J. , Modai D. , Oz D. , Chen Levy Z. , Cohn M. , Marcus O. , Dishi V. , Galperin E. , Averbukh Z.
Published: April 2003

Background/Aim: Pyridoxine deficiency may be the cause of failure to respond appropriately to iron and erythropoietin (EPO) administration in hemodialysis patients. Method: We studied 36 patients on chronic hemodialysis amply supplemented with iron and EPO, who failed to raise hematocrit levels >33%. Patients were divided into three equal groups and evaluated for 6 months as follows: Group A – no additional therapy; group B – supplemented with oral pyridoxine 50 mg/day, and group C received 100 mg/day pyridoxine orally. Results: In all our patients, erythrocyte pyridoxine levels were initially within reference range for a healthy population and did not vary significantly during the study period. Likewise, ferritin levels and iron saturation values remained normal and constant. Hemoglobin and/or hematocrit levels remained practically unchanged in all three groups. Conclusions: The results indicate that in hemodialysis patients with normal pyridoxine status who, despite appropriate supplementation of iron and EPO, fail to reach optimal hematocrit levels, additional pyridoxine treatment does not produce any hematocrit elevation.
Enhanced Expression of Plasminogen Activator Inhibitor 1 in Patients with Nephrotic Syndrome
Authors: Yoshida Yukiko , Shiiki Hideo , Iwano Masayuki , Uyama Hideto , Hamano Kazumasa , Nishino Toshihiko , Dohi Kazuhiro
Published: April 2003

Hypercoagulability is present in patients with nephrotic syndrome. However, alterations in coagulation and fibrinolysis reflected in the glomeruli and urine are not fully understood. We examined plasma and urine concentrations of tissue-type plasminogen activator (tPA) and type 1 plasminogen activator inhibitor (PAI-1) in 33 patients with nephrotic syndrome (nephrotic group). We compared these concentrations with the concentrations in 30 nonnephrotic patients with chronic glomerulonephritis (nonnephrotic group) and with the concentrations in 30 healthy volunteers (control group). We also examined fibrin/fibrinogen degradation products in serum and urine and plasma D-dimers. The expression of tPA and PAI-1 was examined in isolated glomeruli using RT-PCR methods. Deposition of fibrinogen/fibrin-related antigen was observed by direct immunofluorescence. The incidence of fibrinogen/fibrin-related antigen deposition in the nephrotic group was significantly higher than that in the nonnephrotic group. The concentrations of fibrin/fibrinogen degradation products in serum and urine and of plasma D-dimers were significantly elevated in the nephrotic group as compared with the nonnephrotic and control groups. The plasma concentrations of tPA in the nephrotic group were significantly higher than those in the control group. The urinary excretion of tPA in the nephrotic group was also significantly higher than in the nonnephrotic and control groups. The urinary excretion of PAI-1 in the nephrotic group was higher than that in the control group. The ratio of PAI-1 mRNA to tPA mRNA in glomeruli was increased in the nephrotic group as compared with the nonnephrotic group. These results indicate that the fibrinolytic activity is increased in patients with nephrotic syndrome despite urinary losses of tPA. However, a relatively enhanced expression of PAI-1 may be involved in the intraglomerular fibrinogen/fibrin-related antigen deposition seen in nephrotic syndrome.
Role of Radio-Guided Surgery in Recurrent Secondary Hyperparathyroidism
Authors: Navarra G. , Feggi L. , Ascanelli S. , Turini A. , Carcoforo P. , De Paoli E. , Pozza E.
Published: April 2003

Background: The aim of this paper is to state the role of radio-guided surgery (RGS) in case of recurrent secondary hyperparathyroidism. Methods: Two cases of recurrent secondary hyperparathyroidism were treated using RGS. After a preoperative assessment, which included ultrasonography (US), MRI and 99mTc-radiolabelled sestamibi scan, a radio-guided neck re-exploration was planned. On the day of surgery the patients underwent a radionuclide injection. After 90 min, surgery began. Results: Dissection was guided by placing the probe in the wound to localize any increased concentration of radioactivity. In the first case the probe identified the gland located deeply in the right tracheo-esophageal groove; in the other case the probe detected a site of increased uptake in the upper mediastinum. Both lesions were dissected and excised; a frozen section confirmed they were parathyroid glands with diffuse hyperplasia. The operative time was less than 60 min in both cases. The patients were discharged on the first postoperative day. A decrease in serum calcium and PTH was observed subsequently. A minimum follow-up of 6 months did not show any recurrence. Conclusion: RGS can help in detecting the parathyroid tissue in selected cases of renal hyperparathyroidism and makes operation much easier and more predictable.
Hereditary Hypophosphatemic Rickets with Hypercalciuria: Report of a New Kindred
Authors: Sermet-Gaudelus Isabelle , Garabédian Michèle , Dechaux Michèle , Lenoir Gérard , Rey Jean , Tieder Martin
Published: April 2003

We report a new kindred of hereditary hypophosphatemic rickets with hypercalciuria. The symptomatic child and several relatives had increased renal phosphate clearance leading to hypophosphatemia, hyperabsorptive hypercalciuria, low PTH and increased 1,25-(OH)2D serum level. However, association with vitamin D deficiency and normal urinary excretion of cyclic AMP might suggest another tubular defect in phosphate transport.
The Polymorphonuclear Leukocyte – A New Target for Erythropoietin
Authors: Sela S. , Shurtz-Swirski R. , Sharon R. , Manaster J. , Chezar J. , Shkolnik G. , Shapiro G. , Shasha S.M. , Merchav S. , Kristal B.
Published: April 2003

A previous study from our laboratory has shown that erythropoietin (EPO), beside its traditional role in erythropoiesis, acts as an alleviator of oxidative stress and inflammation in chronic hemodialysis (HD) patients, conferred in part by activated polymorphonuclear leukocytes (PMNLs). To substantiate this phenomenon, the existence of EPO receptors (EPO-Rs) on PMNL membrane was examined at the transcriptional and translational levels. mRNA for EPO-R was detected in PMNLs using specific primers directed towards the extracellular region of human EPO-R cDNA. The predicted 300-bp fragment was amplified by reverse transcriptase-polymerase chain reaction. Subcloning and sequence analysis revealed 100% homology of this fragment with human EPO-R. The receptor protein was detected on the surface of intact PMNLs using 125I-EPO. The protein was further demonstrated by flow cytometric analysis using a fluorescent monoclonal anti-EPO-R. The percentage of PMNLs expressing EPO-R showed a strong correlation with the level of EPO in the serum, suggesting an upregulation of the receptor by the hormone. Taken together with our recent findings that EPO attenuates the oxidative stress and inflammation contributed by PMNLs in HD patients, the detection of functional EPO-R expression in PMNLs places these cells among the nonerythroid, EPO-responsive target populations.
Effect of L-Carnitine Supplementation in Hemodialysis Patients
Authors: Veselá E. , Racek J. , Trefil L. , Jankovy’ch V. , Pojer M.
Published: April 2003

Background/Aim:L-Carnitine is important in β-oxidation of fatty acids. A lack of carnitine in hemodialysis patients is caused by insufficient carnitine synthesis and especially by its loss during dialysis. The aim of our study was to test the influence of carnitine supplementation on plasma lipids, red blood cell count, and metabolism of free radicals. Methods: Twelve regularly dialyzed patients (average age 55.5 years, average dialysis treatment period 22.5 months) were given 15 mg/kg L-carnitine intravenously three times weekly (after each hemodialysis session) for 6 months. Laboratory markers of oxidative stress, lipid metabolism, and red blood cell count were measured before the supplementation and then controlled during two 3-month intervals. Nine patients were retested 3 months after the supplementation had ended. Results: All supplemented patients showed increased plasma free carnitine in comparison with the pretreatment values (113.3 ± 11.2 vs. 62.3 ± 16.7 µmol/l, p < 0.001). The proportion of decreased L-carnitine values after hemodialysis was reduced from 79 to 22%. Plasma total cholesterol (4.66 ± 0.30 mmol/l after treatment vs. 5.65 ± 1.53 mmol/l before treatment, p < 0.05) and LDL cholesterol (1.74 ± 0.86 vs. 2.81 ± 1.43 mmol/l, p < 0.05) decreased. The albumin concentration significantly increased from 34.8 ± 7.3 to 46.0 ±5.4 g/l (p < 0.05). Intraerythrocyte reduced glutathione increased from 1.65 ± 0.25 to 2.23 ± 0.16 mmol/l (p < 0.001), and the plasma antioxidant capacity increased from 1.65 ± 0.09 to 2.06 ± 0.17 mmol/l (p < 0.001). At the same time, plasma malondialdehyde decreased from 4.18 ± 0.72 to 3.07 ± 0.35 µmol/l (p < 0.001). The erythropoietin dose could be reduced from an average value of 5,500 to 3,500 U/week. No significant changes in the above-mentioned parameters were observed in a control group of dialyzed patients without L-carnitine supplementation. Conclusion: Regular carnitine supplementation of hemodialysis patients can improve their lipid metabolism, protein nutrition, red blood cell count, and antioxidant status.
Combined Treatment with Low-Dose Pravastatin and Fish Oil in Post-Renal Transplantation Dislipidemia
Authors: Grekas D. , Kassimatis E. , Makedou A. , Bacharaki D. , Bamichas G. , Tourkantonis A.
Published: April 2003

Background: The most common cause of post-transplant dyslipidemia is the use of corticosteroids and cyclosporin-A (CyA). The HMG-CoA reductase inhibitors have emerged as the agents of first choice in the treatment of post-transplant hyperlipidemia in combination with low fat diet. The objective of this study was to evaluate the efficacy of combined treatment with low-dose pravastatin and fish oil in post-renal transplantation dislipidemia. Patients and Methods: Twenty-four renal transplant patients, 15 men and 9 women aged from 30 to 60 years with stable renal function were included in this study. All patients were transplanted from living related donors and were given a stable triple immunosuppressive therapy, with methylprednisolone, azathioprine and CyA. All patients were also given a standard diet containing 1 g/kg BW protein, reducing the daily fat to less than 30%, and maintaining at least a 1:1 ratio of saturated to polyunsaturated (or monounsaturated) fats. A dosage of 20 mg pravastatin (pravachol) and 1 g of fish oil (prolipid) were added to the diet after dinner, according to our protocol. Blood samples were taken after each study period for total cholesterol, LDL-cholesterol, triglycerides, Apo A1, Apo B, Lp(a), creatinine, CPK and fibrinogen determination. Results: At the end of the therapeutic protocol with pravastatin a significant reduction (p < 0.02) of total and LDL-cholesterol was observed, but no significant change in triglycerides, HDL, Lp(a), Apo A1, Apo B and fibrinogen was shown. At the end of the therapeutic protocol with pravastatin and fish oil supplement significant changes were seen in TC (p < 0.02), TG (p < 0.03), LDL-C (p < 0.03), Apo A1 (p < 0.04) and Apo B (p < 0.05) concentrations. There were no significant changes in HDL-C and Lp(a) concentrations. Renal function and cyclosporine levels were not changed during and after the study. CPK was increased only in one case. Conclusions: It is suggested that if the response to the diet is inadequate, the use of combined treatment with low-dose pravastatin and fish oil is a more effective strategy than the pravastatin treatment alone for changing the lipid profile after renal transplantation.
Effect of Methyldopa on Renal Function in Rats with L-NAME-Induced Hypertension in Pregnancy
Authors: Podjarny Eduardo , Benchetrit Sydney , Katz Bernard , Green Janice , Bernheim Jacques
Published: April 2003

Background: Pregnancy-induced hypertension is characterized by an increased sympathetic activity and probably by a decreased synthesis/activity of nitric oxide. The aim of the present study is to evaluate whether the beneficial action of the sympathetic antagonist methyldopa (a first-choice hypotensive agent in the treatment of PIH) may be associated to changes in nitric-oxide synthesis. Methods: Forty pregnant Wistar rats received L-NAME (NO synthase inhibitor, 9–10 mg/kg/day) from mid-pregnancy (day 11) through to term. Some rats were treated with daltroban (TxA receptor antagonist, 60 mg/kg/day), diltiazem (calcium channel blocker, 30 mg/kg/day), methyldopa (central adrenergic antagonist, 400 mg/kg/day) or L-arginine (260 mg/kg/day) from mid-pregnancy. The effect of the different treatments on systolic blood pressure (SBP), creatinine clearance (CCR), urine protein excretion (UP) and urinary nitrate excretion (UNO3, representing urine NO metabolite) were evaluated and the results compared with those found in normal pregnancy. Normal pregnant rats receiving similar treatment were used as controls. Results: In normal pregnant (P) rats, SBP values decreased from 94 ± 2 to 83 ± 3 mm Hg at the end of pregnancy (p < 0.01) and CCR augmented significantly. Drug treatment had no significant effect. In NAME-treated rats, at the same period, the SBP augmented from 92 ± 1 to 129 ± 1.8 mm Hg (p < 0.01). At the end of pregnancy, NAME rats had significantly lower CCR values and higher UP excretion when compared with P rats. UNO3 increased significantly in P and in P rats treated with methyldopa. As expected, in NAME rats UNO3 excretion was significantly reduced. Treatment with methyldopa normalized SBP, improved CCR and proteinuria and was associated with an increase in UNO3. Similar results were obtained with L-arginine treatment. Diltiazem lowered SBP significantly but had no effect on renal function or UNO3 and daltroban had no effect. Conclusion: The increased UNO3 found in NAME rats treated with methyldopa suggests that the vasoconstriction secondary to chronic NO inhibition may be partially related to an increased sympathetic activity. The efficient action of the sympathetic antagonist methyldopa may be due not only to its antihypertensive effects but also by its stimulating effect on NO synthesis leading also to an improvement of renal function.
Relationship between Insulin Resistance and Uremic Toxins in the Gastrointestinal Tract
Authors: Okada Kazuyoshi , Takahashi Yoshiko , Okawa Erina , Onishi Yoshihiko , Hagi Chihiro , Aoki Kyoko , Shibahara Hiroshi , Higuchi Terumi , Nagura Yuji , Kanmatsuse Katsuo , Takahashi Susumu
Published: April 2003

The relationship between insulin resistance and local uremic toxins was examined using an oral adsorbent. Fourteen rats demonstrating a diabetic state underwent two-thirds, nephrectomy and were divided into two groups. The control group was fed standard rat chow, and the test group was fed standard rat chow containing 5% AST-120. The target level of blood glucose was achieved by controlling the dosage of exogenous insulin. All rats were sacrificed at week 6. Body weight, blood glucose level, and renal function at week 6 were not significantly different between both groups. However, the mean blood glucose level and the mean dose of exogenous insulin in the AST-120-fed group were significantly reduced as compared with the control group. The results of the present study indicate that administration of an oral adsorbent in diabetic nephropathy decreases the doses of exogenous insulin and improves insulin resistance, and that uremic toxins which exist in the gastrointestinal tract play important roles.