bluuebunny/crossref_metadata_2025 huggingface dataset:
Effect of Intrauterine Growth Retardation on the Clinical Course and Prognosis of IgA Glomerulonephritis in Children
Authors: Zidar Nina , Čavić Mojca Avguštin , Kenda Rajko B. , Koselj Mira , Ferluga Dušan
Published: April 2003

Intrauterine growth retardation (IUGR) resulting in a reduced number of nephrons is one of the nonimmune mechanisms that have been recently proposed as contributing to the progression of renal diseases. The purpose of our study was to determine whether IUGR has any effect on the clinical course and prognosis of IgA glomerulonephritis (IgA GN) in children. Fifty children with biopsy-proven IgA GN, who were followed for at least 3 years, were included. Six of the 50 children (12%) had signs of IUGR at birth, defined as birth weight below the 10th percentile for gestational age. There were no significant differences in initial clinical presentation between children with IUGR and those without IUGR. However, in kidney biopsy specimens, we found a significantly higher mean percentage of sclerotic glomeruli in children with IUGR than in those without IUGR (33 vs. 13%, p < 0.015). At the end of the follow-up period, we observed a significantly higher incidence of arterial hypertension in children with IUGR than in those without IUGR (50 vs. 11%, p < 0.05). Other differences between the two groups of children were not statistically significant. In conclusion, our study demonstrated an increased risk of the development of arterial hypertension and glomerulosclerosis in children with IgA GN who had suffered from IUGR with a birth weight below the 10th percentile for gestational age. IUGR may therefore help to identify early in the course of IgA GN those children who are at higher risk of an unfavorable course.
End-Stage Renal Disease following Polycythemia vera: In vitro and in vivo Response of Erythroid Progenitors to Erythropoietin and Effects of Sera on Normal Erythropoiesis
Authors: Shih Lee-Yung , Huang Jeng-Yi
Published: April 2003

We investigated the in vitro erythroid progenitor growth and the effects of sera on normal-marrow CFU-E (colony-forming units – erythroid) growth in 2 patients with renal failure on regular hemodialysis following a prior history of polycythemia vera (PV). PV was diagnosed 3 and 11 years, respectively, before the development of terminal renal failure. One of the patients had entered a spent phase of PV as characterized by diffuse extensive myelofibrosis and anemia; the other also had mild myelofibrosis. The serum erythropoietin (EPO) levels were low or normal on serial measurements by radioimmunoassay. There was no correlation between the hematocrit values and serum EPO levels. EPO-independent erythroid colonies were present in the cultures of bone marrow and peripheral blood cells from both patients after renal failure in the anemic state. With the addition of various concentrations of EPO, the number of erythroid colonies increased as the concentrations of EPO increased which was in accordance with the clinical observation that 1 patient with postpolycythemic myeloid metaplasia partially responded to recombinant human EPO therapy. In the EPO-dependent CFU-E assay, normal-marrow CFU-E numbers supported by 10% of the patient sera were less than those by normal sera. In the absence of EPO in cultures, no erythropoietic activity was found in the patients’ sera. Our study on uremic patients with underlying PV showed that the biologic characteristics of autonomous erythroid progenitor growth for PV persisted during the spent phase and after the development of terminal renal failure with anemia. The erythroid progenitors responded to EPO both in vitro and in vivo. Their sera exhibited an inhibiting effect on the growth of normal-marrow erythroid progenitors.
Correction of Uremic Iron Deficiency Anemia in Hemodialyzed Patients: A Prospective Study
Authors: Fudin Roberto , Jaichenko Jose , Shostak Avshalom , Bennett Michael , Gotloib Lazaro
Published: April 2003

This prospective study was designed to evaluate the eventual correction of anemia and iron status in 39 iron-deficient uremics starting hemodialysis. Nine patients (control group) had no iron supplementation, 10 had oral ferrous iron, and 20 were treated with intravenous iron gluconate. Follow-up periods were 12 months for the control group and 26 months for patients treated with oral or intravenous iron. No patient was treated with erythropoietin. At zero time, all patients were anemic (Hb <78 g/l) and showed signs of severe iron deficiency, diagnosed on the basis of depleted bone marrow iron stores, reduced hemoglobin iron, and transferrin saturation <21%. The hemoglobin levels, observed in patients of the control and the oral iron groups at the end of the follow-up periods, were not significantly different from those detected at zero time. In contradistinction, patients treated with intravenous iron showed after 26 months of follow-up a significant increase of blood hemoglobin values, reaching a mean value of 126 g/l. So far, this evidence supports both the concept that iron absorption is compromised in chronic uremics and that the parenteral way is the more effective route for iron replacement in this specific group of patients.
Tubular Peptide Hypermetabolism and Urinary Ammonia in Chronic Renal Failure in Man: A Maladaptive Response?
Authors: Rustom R. , Maltby P. , Grime J.S. , Hughes A. , Costigan M. , Shenkin A. , Critchley M. , Bone J.M.
Published: April 2003

Excessive renal tubular peptide uptake and degradation reflecting hypercatabolism may be a maladaptive response in chronic renal failure (CRF). It may also offer an explanation for the increased ammoniagenesis, per surviving nephron, observed in CRF but as yet unexplained. Neither has been explored in man. We have shown in patients with normal renal function and heavy (>5.0 g/24 h) proteinuria that tubular catabolism of a technetium-labelled peptide marker, aprotinin, and urinary ammonia were increased compared to others with less proteinuria. We now measure tubular kinetics of aprotinin and urinary ammonia in 16 CRF patients with variable proteinuria. Metabolism and turnover of aprotinin and ammonia excretion were increased, corrected for glomerular filtration rate, to levels found in patients with normal function and heavy proteinuria.
Tissue-Specific Expression of Human Angiotensin II AT1 and AT2 Receptors and Cellular Localization of Subtype mRNAs in Adult Human Renal Cortex Using in situ Hybridization
Authors: Matsubara Hiroaki , Sugaya Takeshi , Murasawa Satoshi , Nozawa Yoshihisa , Mori Yasukiyo , Masaki Hiroya , Maruyama Katsuya , Tsutumi Yoshiaki , Shibasaki Yasunobu , Moriguchi Yasutaka , Tanaka Yohko , Iwasaka Toshiji , Inada Mitsuo
Published: April 2003

All studies analyzing the localization of angiotensin II (Ang II) receptors in the human kidney have been performed at the protein level using 125I-Ang II as a probe. In this study, cellular localizations of Ang II type l (AT1-R) and type 2 (AT2-R) receptor mRNAs in the adult human renal cortex were examined for the first time using in situ hybridization, and their expression patterns determined by RNase protection assay were compared with those in other human tissues. In the human renal cortex obtained from tumor-free portions in renal cell carcinoma, AT1-R mRNA levels were about 8- to 10-fold higher than AT2-R mRNA levels. Human liver and aorta predominantly expressed AT1-R mRNA, while human right atrium contained both AT1-R and AT2-R mRNAs. Ligand-binding assays revealed that the total Ang II receptor number in the human renal cortex was 16.0 ± 3.3 fmol/mg protein, similar to that in liver (17.7 ± 5.8) but significantly higher than in right atrium (11.6 ± 3.2) and aorta (5.6 ± 2.7). Relative distribution ratios of AT1-R and AT2-R numbers in the renal cortex and right atrium were 82/17 and 56/42%, respectively. In situ hybridization study indicated that strongest AT1-R mRNA signals were located in interlobular arteries and tubulointerstitial fibrous regions surrounding interlobular arteries and glomeruli, followed in decreasing order by glomeruli and cortical tubules. Expression of AT2-R mRNA was highly localized in interlobular arteries. Cells present in tubulointerstitial regions were positive for vimentin and collagen type 1, indicating that the majority of the cells present in the regions are fibroblasts. Presence of strong AT1-R mRNA signals in the tubulointerstitial fibrous regions surrounding arteries and glomeruli and the expression of AT2-R mRNA in the interlobular artery were the first evidence, suggesting a pharmacological framework for the differential effects of Ang II receptor subtype mediated renal function in the adult human kidney.
Stimulation of Hepatocyte Growth Factor in Human Acute Renal Failure
Authors: Libetta Carmelo , Rampino Teresa , Esposito Ciro , Fornoni Alessia , Semeraro Luca , Dal Canton Antonio
Published: April 2003

Hepatocyte growth factor (HGF) is a potent mitogen for tubular cells. Experimental injury to the kidney is associated with HGF release both locally and by distant organs stimulated by circulating ‘injurins’. In this study, the serum HGF concentration was measured in patients with acute renal failure (ARF). Normal subjects and chronic renal failure patients either not on dialysis or on regular dialysis treatment served as controls. Human mesangial cells were incubated with sera from ARF patients and controls. The serum HGF concentration was strikingly increased in ARF patients (478 ± 68 ng/dl) and was normal in chronic renal failure patients not on dialysis (20 ± 3 ng/dl) and in those on regular dialysis treatment (25 ± 3 ng/dl). Serum of ARF patients strongly stimulated HGF release from mesangial cells (1,384 ± 55 ng/ml) in comparison with normal serum (67 ± 10 ng/ml). These results indicate that in ARF HGF participates in tubular repair both as an endocrine factor, released in the circulation, and as a paracrine substance, diffusing to the tubules from the mesangium.
Effects of Uremic Plasma on α- and β-Adrenoceptor Subtypes
Authors: Ferchland A. , Rettkowski O. , Pönicke K. , Deuber H.J. , Osten B. , Brodde O.-E.
Published: April 2003

Responsiveness of adrenergic receptors is decreased in patients on maintenance hemodialysis. In this study we investigated whether uremic plasma might affect adrenergic receptors. For this purpose we determined the effects of uremic plasma obtained from 10 patients on hemodialysis treatment (mean age 61 ± 3 years, dialysis frequency 3 × 4 h/week, duration of treatment 3 ± 1 years) before and at the end of the 4-hour dialysis treatment on binding of radioligands to β1- and β2- as well as α1- and α2-adrenoceptors. Plasma from 6 healthy volunteers served as control; the plasmas were studied in three dilutions: undiluted, 1:1 (v/v) and 1:4 (v/v) with saline diluted. Plasma from healthy control did not significantly affect the number of β1- and β2- or α1- and α2-adrenoceptors. On the other hand, uremic plasma significantly decreased the number of β1- and β2-adrenoceptors; this inhibitory effect was also observed when plasma obtained at the end of the 4-hour dialysis treatment was investigated. On the other hand, uremic plasma did not significantly decrease the number of α1- and α2-adrenoceptors. We conclude that in patients on maintenance hemodialysis, the presence of inhibitory substance(s) in uremic plasma could be – at least partly – responsible for the β-adrenoceptor hyporesponsiveness; the mechanism leading ot α-adrenoceptor hyporesponsiveness, however, remains to be elucidated.
Abnormal Increase of Creatine Kinase Plasma Levels following Muscle Exercise in Nephrotic Patients
Authors: Cupisti Adamasco , Chisari Carmelo , Morelli Ester , Meola Mario , Giannini Elena , Rossi Bruno , Barsotti Giuliano
Published: April 2003

Nephrotic syndrome is a protein-wasting disorder affecting total body protein metabolism, often leading to reduction of lean body mass and changes of muscle cell composition. The aim of this study was to investigate the susceptibility to muscle cell damage in nephrotic patients following submaximal physical exercise, by detection of the creatine kinase (CK) plasma level changes. Fourteen patients affected by primary nephrotic syndrome, without chronic renal failure, underwent an exercise test on a cycle ergometer for 20 min at a constant speed (60 rpm). In each subject, the work rate (expressed as watts) was established as 70% of the maximum power theoretically calculated on a sex, age, weight and height basis. CK plasma levels (U/l) were determined before and 1, 3, 6 and 24 h after the exercise. Following exercise, CK plasma levels became higher in nephrotics than in normal controls. That is, the amount of CK increments was greater in nephrotics than in controls from the first hour after the end of exertion. These changes, both as absolute values and as percentage of the basal values, correlate positively to daily urinary protein losses; moreover, an inverse relationship was detected with albumin serum levels. However, no correlation was observed between the amount of plasma CK increases and age, body weight, plasma creatinine, plasma cholesterol or hemoglobin levels. These results demonstrate that a greater than normal increase of CK plasma levels occurs in nephrotics following physical exercise, and that this increment correlates with the severity of urinary protein wasting. This suggests an increased susceptibility to muscle injury in nephrotic patients probably related to protein depletion and/or to modifications of muscle cell metabolism. Further studies are needed to define the pathogenesis of our findings.
Enalapril Increases Antioxidant Enzyme Activity in Renal Cortical Tissue of Five-Sixths- Nephrectomized Rats
Authors: Verbeelen Dierik L. , De Craemer Dirk , Peeters Patrick , Vanden Houte Katherina , van den Branden Christiane
Published: April 2003

In rats with five-sixths nephrectomy (remnant kidney), blood pressure, glomerulosclerosis, and proteinuria are significantly reduced by administration of the angiotensin-converting enzyme inhibitor enalapril, during 16 weeks after reduction of the nephron number. The activity of catalase in remnant-kidney cortex homogenate is not influenced by enalapril treatment; the activities of superoxide dismutase and glutathione peroxidase are significantly increased. Elevated lipid peroxidation in cortex homogenates, evaluated by malondialdehyde and 4-hydroxynonenal concentrations, is not changed by treatment. Supplementation of dietary vitamin E to enalapril treatment does not alter antioxidant enzyme activities when compared to enalapril monotherapy. These results show that enalapril improves the balance between reactive oxygen intermediates and antioxidant enzymes in the remnant-kidney cortex of the rat. This finding may in part explain the protective effect of angiotensin-converting enzyme inhibitors on the progression of glomerulosclerosis.
Renal Ischemia – Reperfusion Injury: Contribution of Nitric Oxide and Renal Blood Flow
Authors: Mashiach Elisheva , Sela Shifra , Winaver Josi , Shasha Shaul M. , Kristal Batya
Published: April 2003

The contributions of nitric oxide (NO) and renal blood flow (RBF) were examined in ischemia-reperfusion injury in the rat kidney. The function of both kidneys was assessed by glomerular filtration rate (GFR), and fractional excretion of sodium (FENa), calculated before, during unilateral renal artery clamping (45 min), and following reperfusion (90 min). RBF was measured in the same model by ultrasonic flowmetry. Intrarenal NO levels were modulated by administration of S-nitroso-N-acetylpenicillamine (SNAP), L-arginine, acetylcholine, and the NO synthase inhibitor NG-nitro-L-arginine methyl ester (L-NAME). SNAP increased GFR from 0.20 ± 0.04 ml/min in control ischemic kidney to 0.38 ± 0.06 ml/min and reduced FENa from 19.3 ± 3.4 to 9.5 ± 1.8%. Similar results were observed when L-arginine was administered. Acetylcholine had no effect on GFR or FENa. RBF was fully restored within 60 min following reperfusion, with no change in the rate of recovery by L-arginine. L-NAME aggravated the ischemia-reperfusion injury, preventing full restoration of RBF, further reducing GFR and worsening FENa. In conclusion, ischemia-reperfusion injury ends in low intrarenal levels of NO. We propose that this low NO level results from damage to the endothelial receptor signal transduction process and is not due to impaired NO synthase activity or to changes in RBF.
Differential Effect of Nephrectomy on Renal Expressions of IGF-I and IGFBPs mRNA in Selective Growth Hormone-Deficient Rats
Authors: Kobayashi Shuzo , Ishida Aki , Moriya Hidekazu , Nogami Haruo
Published: April 2003

It is known that growth hormone (GH) contributes to glomerulosclerosis and that this probably occurs via insulin-like growth factor-I (IGF-I). However, the manner by which GH and nephrectomy (Nx) alter IGF-binding protein (IGFBP) mRNA in the kidney has not been fully explained. The effects of GH on renal IGF-I and IGFBP-1, 2, 3, 4, and 5 following Nx were examined in spontaneous dwarf rats (SDRs) which have a complete and specific lack of GH among pituitary hormones. In normal Sprague-Dawley rats (SDs), Nx resulted in significant decreases in levels of IGFBP-1 mRNA and IGFBP-5 mRNA to 62.7 ± 4.9 and 56.5 ± 5.0% those of sham-operated kidneys, respectively. Nx did not alter the IGF-I mRNA level in SDs. The levels of IGFBP-2, IGFBP-3, and IGFBP-4 mRNAs were likewise unchanged following nephrectomy. In SDRs, Nx significantly decreased the levels of IGFBP-1, IGFBP-4, and IGFBP-5 mRNA, to 57 ± 2.6, 46 ± 12, and 64 ± 8.1% of sham-operated animals. However, Nx did not alter the levels of IGF-I, IGFBP-2, and IGFBP-3 mRNA. GH injections of nephrectomized SDRs fully normalized the decreased IGFBP-4 mRNA levels, whereas levels of IGFBP-1 and IGFBP-5 mRNA were not reversed. The altered expression of IGFBP-4 mRNA following Nx of SDRs compared to that of SDs appears highly significant since it is known that, unlike SDs, glomerulosclerosis does not fully develop in SDRs following renal ablation. The change in the IGFBP-4 mRNA level might be related to the development of glomerulosclerosis in SDs.
Lacidipine Protects against Cyclosporine-Induced Nephrotoxicity in Rats
Authors: Naidu M.U.R. , Kumar K.Vijay , Shifow Anwar Ahmed , Prayag A. , Ratnakar K.S.
Published: April 2003

The effect of lacidipine (LA), a new calcium channel blocker with an antioxidant effect, has been studied on cyclosporine (CsA)-induced nephrotoxicity in male Wistar rats. Lacidipine (1 mg/kg BW) was administered orally 3 days before and 14 days concurrently with CsA (50 mg/kg BW orally). Urine volume, Na+, K+, Li+ and creatinine in urine, and blood urea, serum creatinine, lithium, plasma malondialdehyde (MDA) and CsA levels were estimated in blood after 14 days CsA treatment. Kidneys were examined using histological techniques. Blood urea and serum creatinine were increased by 305 and 211%, respectively, with CsA when compared to the saline-treated animals. Creatinine clearance (Ccr) and lithium clearance (Licr) were decreased and proximal tubule fractional reabsorption 1-(Licr/Ccr) was significantly increased with CsA. Lacidipine protected rats from CsA-induced nephrotoxicity. Changes in blood urea, serum creatinine, Ccr, Licr and proximal tubule fractional reabsorption induced by CsA were significantly prevented by LA. There was a 160% rise in MDA levels with CsA, which was significantly reduced equal to control with LA. Histomorphology showed microcalcification with CsA, while it was normal with LA. In rats treated with LA, CsA did not show any microcalcification. Our data suggest that supplementation of LA may be helpful to reduce CsA nephrotoxicity.
Effects of Oral Supplementation with Evening Primrose Oil for Six Weeks on Plasma Essential Fatty Acids and Uremic Skin Symptoms in Hemodialysis Patients
Authors: Yoshimoto-Furuie Keiko , Yoshimoto Kazuo , Tanaka Takaomi , Saima Shigeki , Kikuchi Yuka , Shay Janet , Horrobin DavidF. , Echizen Hirotoshi
Published: April 2003

Abnormalities in plasma composition of essential fatty acids (EFAs) may be associated with the etiology of pruritus and other skin problems in patients undergoing hemodialysis. To study whether an oral supplementation with ω–6 (n–6) EFAs would restore deranged plasma EFAs and ameliorate skin symptoms, 9 and 7 dialysis patients were randomly assigned to receive either γ-linolenic acid (GLA)-rich evening primrose oil (EPO) or linoleic acid (LA) (2 g/day each) for 6 weeks. Plasma concentrations of EFA were analyzed by gas chromatography and uremic skin symptoms were assessed for dryness, pruritus and erythema by questionnaire and visual inspection in a double-blind manner. The patients given EPO exhibited a significant (p < 0.05) increase in plasma dihomo-γ-linolenic acid (a precursor of anti-inflammatory prostaglandin E1) with no concomitant change in plasma arachidonic acid (a precursor of pro-inflammatory prostaglandin E2 and leukotriene B4). In contrast, those given LA exhibited a significant (p < 0.05) increase in LA but not in any other n–6 EFAs, whereas they exhibited a significant (p < 0.05) decrease in plasma docosahexaenoic acid. The patients given EPO showed a significant (p < 0.05) improvement in the skin scores for the three different uremic skin symptoms over the baseline values and a trend toward a greater improvement (0.05 < p < 0.1) in pruritus scores than those given LA. Results indicate that GLA-rich EPO would be a more favorable supplemental source than LA in terms of shifting eicosanoid metabolism toward a less inflammation status through modifying plasma concentrations of their precursor n–6 EFAs. Further studies are required to confirm the efficacy and safety of EPO therapy for the treatment of uremic pruritus.
Plasma and Urine Levels of Uroguanylin, a New Natriuretic Peptide, in Nephrotic Syndrome
Authors: Kinoshita Hiroshi , Fujimoto Shouichi , Fukae Hiroko , Yokota Naoto , Hisanaga Shuichi , Nakazato Masamitsu , Eto Tanenao
Published: April 2003

Uroguanylin, a new natriuretic peptide originally isolated from urine, stimulates the membrane guanylate cyclase C receptor. No information, however, is available on the plasma and urine levels of uroguanylin in nephrotic syndrome (NS), the state associated with sodium and water retention. Using a sensitive radioimmunoassay, we measured the plasma and urine concentrations of immunoreactive (ir-)uroguanylin in NS patients and compared them with those of patients with non-nephrotic glomerulonephritis. Plasma ir-uroguanylin, blood pressure and the cardiothoracic ratio were higher, and urine excretion of ir-uroguanylin was lower in the NS patients. Plasma ir-uroguanylin in the NS patients significantly decreased during remission as compared with findings on admission. There was a significant inverse correlation between the concentration of plasma ir-uroguanylin and that of serum total protein or albumin. Moreover, fluid retention in the NS patients was correlated with the changes in plasma ir-uroguanylin between admission and remission, indicative that the plasma concentration increases with the severity of the nephrotic state. Taking into account its potent natriuretic effect, these findings suggest that uroguanylin may function in the pathophysiological mechanism in NS.
VCAM-1, ICAM-1, and E-Selectin in IgA Nephropathy and Schönlein-Henoch Syndrome: Differences between Tissue Expression and Serum Concentration
Authors: Mrowka Christian , Heintz Bernhard , Sieberth Heinz-Günter
Published: April 2003

The tissue expressions of vascular cell adhesion molecule 1 (VCAM-1), intercellular adhesion molecule 1 (ICAM-1) and endothelial leukocyte adhesion molecule 1 (E-selectin-1) were investigated in biopsy specimens from 28 patients with different stages of IgA nephropathy (IgAN) and 20 patients with acute renal failure (ARF) or chronic renal diseases (amyloidosis, Alport’s glomerulopathy) by immunohistochemistry. The results were compared with the serum levels of the three adhesion molecules. VCAM-1 expression was significantly increased on parietal/tubular epithelial cells in IgAN and ARF. Significantly elevated circulating VCAM-1 levels were measured in IgAN and amyloidosis, but did not correlate with renal function (creatinine clearance). Significantly increased glomerular endothelial/epithelial ICAM-1 expression was found in IgAN and ARF. Intense mesangial ICAM-1 expression was found in mild stages of IgAN and in Schönlein-Henoch syndrome. Circulating ICAM-1 was not significantly elevated in IgAN and different renal diseases. VCAM-1 and ICAM-1 expressions of interstitial infiltrating cells were significantly higher in severe than in mild IgAN and associated with an increased infiltration of inflammatory leukocytes. Patients with IgAN and different renal diseases had decreased mesangial and almost absent interstitial E-selectin expression as compared with controls. The circulating E-selectin levels were significantly elevated in ARF. In conclusion, the tissue expression of adhesion molecules in IgAN reflects a continuous inflammatory renal activity. However, only increased circulating VCAM-1 serum levels correlated significantly with the histological state of renal inflammation and could be used as a disease marker.
Differential Changes of Cell Cycle Regulators and Activities in Kidneys during Pre- and Postnatal Development
Authors: Park SungKwang , Kim Won , Lee Hong , Lee DaeYeol , Koh GouYoung
Published: April 2003

The present study was designed to determine the changes of the cyclin/CDK (cyclin dependent kinase)/CKI (CDK inhibitors) system in kidneys during pre- and postnatal development. All protein levels of cyclins (cyclins D1, D3, E, A, B) and protein levels and activities of CDKs (CDK4, CDK2, cdc2) were high in kidneys during the prenatal period and decreased differently during the postnatal period. As the phosphorylated active form of cyclin D1 decreased, the dephosphorylated inactive form of cyclin D1 increased during the early postnatal development. While CDK4 activities decreased markedly, the activities of CDK2 and cdc2 decreased gradually during the early postnatal period. While the p21CIP1 protein was barely detectable during the prenatal period, but was not detectable during the postnatal period, the protein level of p27KIP1 was detectable during pre- and postnatal periods. These results indicate that the cyclin/CDK/CKI system is actively involved in the nephrogenesis during the prenatal period and is closely associated with the withdrawal of the renal cell cycle during the postnatal period.
Abnormal Growth and Clonal Proliferation of Fibroblasts in an Animal Model of Unilateral Ureteral Obstruction
Authors: Sommer Manfred , Schaller Robby , Fünfstück Reinhard , Bohle Adalbert , Böhmer Frank D. , Müller Gerhard A. , Stein Günter
Published: April 2003

The time course for the development of renal interstitial fibrosis (RIF) in rats between days 5 and 25 after unilateral ureteral obstruction (UUO) was studied. In kidneys with UUO under histological examination, an interstitial fibrosis was observed after more than 10 days with progression up to day 25. On day 5, collagen peptidase activity in homogenates of UUO kidneys was about 50% higher than in controls but gradually declined afterwards until reaching the level obtained from contralateral kidneys (CL) on day 25. 10 days after UUO, renal hydroxyproline content was elevated about twofold as compared to CL and sham-operated rats, and increased considerably by day 25 of UUO. In primary cultures of cells obtained from UUO kidneys, fibroblast proliferation increased regardless of the extent of fibrosis. This could be a result of an early inflammatory process. Renal fibroblasts from rats are heterogenous when studied in vitro. When fibroblasts of passage 1 obtained from kidneys 25 days after UUO were plated at low density, the number of mitotic type I clones was elevated 5.5-fold as compared with cultures from CL kidneys. The majority of type I clones in UUO cultures from fibrotic kidneys developed in an unusual fashion with formation of three-dimensional structures. The changes detectable under the unfavorable conditions of clonal culture suggest phenotypical differentiation of a small fraction of fibroblasts from kidneys with RIF. These cells are able to overgrow cell monolayers forming circular growing colonies. Obviously, one needs to distinguish between intensitive proliferation as a consequence of acute inflammation, and the changes in phenotype of a small fraction of renal fibroblasts which are resistant to normal physiologic regulative mechanisms in cell culture. The latter may contribute to matrix disorders and RIF.
Induction of Transient Proteinuria, Hematuria, and Glucosuria by Ethanol Consumption in Japanese Alcoholics
Authors: Ito Satoshi , Ueno Mitsuhiro , Izumi Teiji , Arakawa Masaaki
Published: April 2003

Urinalysis was carried out in 231 inpatients with alcohol dependence syndrome (215 males and 16 females). Fifty-nine patients (25.5%) showed proteinuria, 97 (42.0%) showed glucosuria, and 62 patients (26.8%) showed hematuria on admission. A total of 135 out of 231 patients (58.4%) showed abnormal urinalysis. Proteinuria was related to high blood pressure, high serum glutamic-oxaloacetic transaminase, glutamic-pyruvic transaminase, lactate dehydrogenase, uric acid, and triglyceride levels, and high urinary amylase concentration. Glucosuria was related to high serum glutamic-oxaloacetic transaminase concentration and a history of gastrectomy. Hematuria was related to high age and high urinary amylase levels. By chi-square test, there was a significant correlation between proteinuria and hematuria (p < 0.001) and between hematuria and glucosuria (p < 0.001), but no correlation was found between proteinuria and glucosuria. The incidence of diabetes mellitus was 10.8% (25 out of 231 patients), but transient hyperglycemia was observed in some patients without diabetes mellitus on admission. Elevated hemoglobin A1, hemoglobin A1c, and fructosamine concentrations were observed in patients with either impaired glucose tolerance or transient hyperglycemia, which suggested the presence of persistent hyperglycemia before admission. On discharge, only 12 out of 198 patients (6.1%) showed abnormal urinalysis. We report that heavy ethanol consumption induces transient abnormal urinalysis results in Japanese alcoholics.
Abnormal Tenascin Expression in Murine Autosomal Recessive Polycystic Kidneys
Authors: Ojeda José L.
Published: April 2003

The mechanisms responsible for renal cyst formation in congenital polycystic kidney disease (PKD) remain unknown. Changes in extracellular matrix (ECM) are regarded as an important pathogenic factor in PKD. Tenascin, an ECM glycoprotein implicated in abnormal growth in adult organs, has not been systematically evaluated in PKD. In this study, tenascin expression was studied by immunohistochemistry in the autosomal recessive polycystic kidneys of C57BL/6J (cpk/cpk) mice. Scanning electron microscopy was performed to determine the cyst types and their temporal evolution, and to establish correlations with the immunohistochemistry observations. Cystic lesions evolved in three main stages. Initially, the cysts appeared as segmental dilatations of both proximal and collecting ducts. In the second stage, the collecting duct cysts (CDCs) underwent rapid growth that led to the destruction of all other kidney elements. In the final stage, the CDCs reached their maximum size and the PKD mice died. Normal differentiated principal cells and three types of intercalated cells were present in the CDC epithelium. In all three stages an intense tenascin expression was detected selectively in the basement membranes of the cysts. In the last stage, an intense tenascin immunoreactivity was also observed in the interstitial fibrotic tissue. The abnormal presence of tenascin in the basement membranes of the cysts suggests that this glycoprotein is implicated in the pathogenesis of the cysts, possibly by stimulating cell proliferation.
Differential Diagnosis between Glomerular and Nonglomerular Hematuria by Automated Urinary Flow Cytometer
Authors: Hyodo Toru , Kumano Kazuo , Sakai Tadasu
Published: April 2003

Objective, fast and easy methods have not been established in the examination of urine sediment to differentiate between glomerular and nonglomerular hematuria. In this study, we used a newly developed automated urinary flow cytometer that can clearly recognize red blood cells (RBC), white blood cells, epithelial cells, bacteria and crystals by their size and fluorescence intensity without sedimentation. 98 urine samples from 31 glomerular and 67 nonglomerular lesions were analyzed by the device, and the criteria to determine the origin of hematuria were established based on the results. Additional 108 cases were tested to evaluate the validity of these criteria. According to the analysis of histograms of urinary RBC size distribution, cases in whom ≥80% of all RBC have forward scatter (FSC) intensities ≦126 and <80% of all RBC have FSC intensities ≥84 were regarded as representing the glomerular type. Cases in whom ≥80% of all RBC have intensities FCS ≥84 and <80% all RBC have FSC intensities ≦126 were regarded as representing the nonglomerular type. Cases in whom <80% of all RBC have FSC intensities ≦126 and <80% of all RBC have FCS intensities ≥84 were regarded as the mixed type. Cases in whom ≥80% of all RBC have FSC intensities ≦126 and ≥80% of all RBC have FSC intensities ≥84 were regarded as the nonglomerular type. The sensitivity for glomerular RBC in the first 98 cases was 90.3% and the specificity 92.5%, and in the second 108 cases the values were 100 and 86.6%, respectively. The automated urinary flow cytometer is useful as a means for routine differential diagnosis of hematuria, and at least it is promising as the screening test for differentiation between glomerular and nonglomerular hematuria, because it can examine numerous samples within a short time and does not necessitate any special skill or knowledge.
Enhanced Hyaluronan Synthesis in the MRL-Faslpr Kidney: Role of Cytokines
Authors: Feusi Ernst , Sun Likang , Sibalic Anita , Beck-Schimmer Beatrice , Oertli Beat , Wüthrich Rudolf P.
Published: April 2003

Background/Aim: Pathological accumulation of the extracellular matrix component hyaluronan (HA) occurs in the kidney cortex in immune-system mediated tissue injury. The purpose of the present study was to examine the pattern of HA deposition and the mechanisms of HA synthesis in the MRL-Faslpr mouse model of lupus nephritis. Methods: Kidneys from normal and autoimmune mice were examined for HA content by immunofluorescence staining. Steady state mRNA levels for key enzymes involved in HA synthesis – uridine diphosphate-glucose dehydrogenase (UDPGDH) and HA synthases (HAS) 1, 2 and 3 – were assessed by reverse-transcriptase polymerase chain reaction (RT-PCR). Using cultured mouse tubular epithelial cells, the regulation of the HA production in vitro in response to tumor necrosis factor alpha and interferon gamma was also examined. Results: By immunofluorescence staining, large amounts of HA were detected in the cortical interstitium of MRL-Faslpr mice with autoimmune renal injury, but not in congenic MRL-++ mice. By RT-PCR the presence of transcripts for several genes involved in the synthesis of HA in normal and autoimmune kidneys could be demonstrated, including mRNA for UDPGDH and HAS1 and HAS2, but not for HAS3. Except for HAS2, steady state mRNA levels for these enzymes did not correlate with disease activity. Analyzing a kidney tubular epithelial cell line in vitro, it was found that tumor necrosis factor alpha and interferon gamma, and particularly the combination of these two cytokines, markedly enhanced the synthesis of HA. The expression of HAS2 mRNA was also enhanced in response to cytokine treatment. Conclusions: HA deposition is prominent in MRL-Faslpr mice with renal disease and could be mediated by local synthesis through HAS1 and HAS2. We hypothesize that the enhanced synthesis of HA could be promoted by proinflammatory cytokines in vivo. The functional significance of HA accumulation in autoimmune renal injury remains to be determined.
Hypoparathyroidism Potentiates Cardiovascular Complications through Disturbed Calcium Metabolism: Possible Risk of Vitamin D3 Analog Administration in Dialysis Patients with End-Stage Renal Disease
Authors: Tsuchihashi Kazufumi , Takizawa Hideki , Torii Taka-aki , Ikeda Rie , Nakahara Norifumi , Yuda Satoshi , Kobayashi Naoko , Nakata Tomoaki , Ura Nobuyuki , Shimamoto Kazuaki
Published: April 2003

Background/Aim: Progressive cardiovascular calcification in dialysis patients with end-stage renal disease (ESRD) is a serious complication; however, the precise mechanism remains uncertain. We tested whether metabolic calcium abnormalities and hypoparathyroidism might have a correlation with cardiovascular complications in ESRD patients. Methods: A series of 48 ESRD patients with cardiovascular diseases and/or congestive heart failure, aged 36–82 (61 ± 12) years, 23 male and 25 female, were enrolled in this study. Serum total calcium (Ca, mmol/l), inorganic phosphate (mmol/l), and intact parathyroid hormone (iPTH, pg/ml) levels were determined in all cases. Results: Organic heart disease was confirmed in 28 patients (58.3%), including 15 with coronary artery disease: 8 with aortic aneurysm, 8 with stenotic valvular heart disease, 9 with excessive mitral annular calcification, 3 with dialysis cardiomyopathy, and 7 with obstructive arterial disease. Serum iPTH measurement revealed hypoparathyroidism (iPTH <60) in 20 of 48 (41.7%) and hyperthyroidism (iPTH ≧200) in 13 of 48 (27.1%) subjects. The 20 patients with low iPTH had a higher prevalence of valvular heart disease, a higher total Ca level corrected for serum albumin (2.70 ± 0.30 in low iPTH vs. 2.47 ± 0.30 in normal iPTH, 2.35 ± 0.20 in high iPTH, p = 0.003) and a higher tendency of vitamin D3 analog use (65% in low iPTH vs. 33% in normal iPTH and 46% in high iPTH, p = 0.078). Moreover, corrected serum Ca exhibited a negative logarithmic correlation with serum iPTH: corrected Ca = –0.284× log (iPTH) + 3.021 (r = 0.637, p = 0.0001). Multiple logistic regression analysis revealed diabetes and hypoparathyroidism (iPTH <60) as risk factors for cardiovascular complications in ESRD. Conclusion: These results suggest that hypercalcemia and hypoparathyroidism in conjunction with vitamin D3 use might play an important role in cardiovascular complications of chronic dialysis patients.
Renal Clearance of N1-Methylnicotinamide: A Sensitive Marker of the Severity of Liver Dysfunction in Cirrhosis
Authors: Orlando Rocco , Floreani Maura , Napoli Eleonora , Padrini Roberto , Palatini Pietro
Published: April 2003

Background/Aims: Data have appeared suggesting that an impairment of renal tubular secretion is present in liver cirrhosis, even in the absence of a clinically evident renal dysfunction. To address this question, we evaluated the renal clearance of N1-methylnicotinamide (NMN), a marker of the renal secretory function, in healthy subjects and patients with liver cirrhosis of increasing severity, but with a normal glomerular filtration rate. Methods: The renal clearances of endogenous NMN, inulin, and creatinine were measured in 14 normal subjects and in two groups of age-matched cirrhotic patients (10 Child A and 10 Child C). In 6 subjects, 2 per group, the concentration dependence of the NMN clearance was also studied, following an oral nicotinamide load. Results: Contrary to expectations, the renal NMN clearance increased in cirrhotic patients, in relation to the severity of liver disease (r = 0.83 with Pugh’s score; p < 0.001). The NMN-to-inulin clearance ratio increased from a control value of 2.2 ± (SD) 0.4 to 3.1 ± 0.2 and 5.2 ± 0.9 in Child A and Child C cirrhotics, respectively (p < 0.001 for all comparisons), indicating that NMN was completely cleared from plasma in the latter patients. Consistently, the analysis of the concentration dependence of the renal NMN clearance revealed the presence of a carrier-mediated reabsorption which apparently was no longer operating in the decompensated patients. Discriminant analysis showed that renal NMN clearance, and NMN-to-creatinine and NMN-to-inulin clearance ratios could all distinguish between the three study groups, with sensitivities and specificities equal or greater than 90%. Conclusions: Contrary to previous proposals, NMN is not a probe of general validity for renal tubular secretion. In particular, due to an imbalance between secretion and reabsorption, its renal clearance in liver cirrhosis cannot be used to determine the degree of tubular secretion of which an individual is capable. However, renal NMN clearance appears to be a very sensitive marker of the severity of liver dysfunction in cirrhosis. The potentialities of this renal parameter as a diagnostic and prognostic test in liver cirrhosis deserve further study.
Adrenomedullin Gene Transcription Is Decreased in Peripheral Blood Mononuclear Cells of Patients with IgA Nephropathy
Authors: Kubo Atsushi , Nishitani Yoshiharu , Minamino Naoto , Kikumoto Katsuro , Kurioka Hideyuki , Nishino Toshihiko , Iwano Masayuki , Shiiki Hideo , Kangawa Kenji , Dohi Kazuhiro
Published: April 2003

We measured mRNA levels of adrenomedullin (AM), C-type natriuretic peptide (CNP), vascular endothelial growth factor (VEGF), interleukin 1β (IL-1β) and interleukin 6 (IL-6) in peripheral blood mononuclear cells (PBMC) of patients with IgA nephropathy. To evaluate these mRNA levels, we employed a real-time quantitative PCR method which was performed using a hybridization probe labeled with two fluorescence dyes. This strategy was found to afford the standard curves with a high correlation, suggesting that this method is useful for evaluations of mRNA levels. By this method, levels of AM, CNP, VEGF, IL-1β and IL-6 mRNA in PBMC of 49 IgA nephropathy patients and 35 healthy volunteers were evaluated. Among the mRNAs examined, AM mRNA levels were significantly lower in severe-grade than in mild-grade IgA nephropathy patients. Furthermore, AM mRNA levels correlated with CNP mRNA levels in PBMC of patients with IgA nephropathy, and each peptide generated from these mRNAs has antiproliferative effects on mesangial cells. These data indicate that gene expression of AM in PBMC is regulated according to the pathophysiological states of IgA nephropathy and that decreased AM production may contribute to the progression of IgA nephropathy.
Nonviral and Viral Gene Transfer to the Kidney in the Context of Transplantation
Authors: Benigni Ariela , Tomasoni Susanna , Lutz Jens , Amuchastegui Susana , Capogrossi Maurizio C. , Remuzzi Giuseppe
Published: April 2003

Background/Aims: Local modulation of the immune response through genetic manipulation of the graft is an attractive novel approach to overcome the toxicity of immunosuppressive therapy to prevent acute graft rejection. We have previously reported that the cationic polymer polyethylenimine 25k (PEI 25k) transduced reporter genes when injected into the renal artery, but with a low transfection efficiency. Here we compare the risk/benefit profiles of such a nonviral versus a viral technique of gene transfer to the kidney in the context of renal transplantation. Methods: Donor kidneys from Lewis rats were perfused in a closed circuit with an artificial cell-free medium containing PEI 25k complexed to an expression vector coding for the β-galactosidase (β-gal) gene and subsequently transplanted in a syngeneic animal. In a second set of experiments, donor kidneys were injected or perfused with a replication-deficient adenovirus encoding the β-gal gene (AdCMV.βgal; 1 × 109 plaque-forming units) before transplantation. Results: Perfusion of the kidney with PEI 25k/DNA complexes resulted in large areas of hypoperfusion characterized by injured glomeruli and tubuli, capillary thrombosis and accumulation of C3 in glomerular capillaries. Reperfusion of the kidney was achieved by lowering the PEI 25k/DNA ratio, but no detectable transfection was observed. In animals receiving adenovirus, the β-gal activity increased with time and was localized mainly in proximal and distal tubular cells, as documented by β-gal histochemistry and in situ hybridization. A significantly increased expression of β-gal was achieved by perfusion of the kidney with AdCMV.β-gal before transplantion, β-gal staining mainly localizing in proximal and distal tubular cells. Conclusions: Unlike nonviral methods of gene delivery, adenovirus-mediated gene transfer to the kidney offers exciting perspectives for the development of molecular medicine in the field of organ transplantation.
Effect of Regional Citrate Anticoagulation on Leukopenia, Complement Activation, and Expression of Leukocyte Surface Molecules during Hemodialysis with Unmodified Cellulose Membranes
Authors: Dhondt Annemieke , Vanholder Raymond , Tielemans Christian , Glorieux Griet , Waterloos Marie-Anne , De Smet Rita , Lameire Norbert
Published: April 2003

Background: Dialysis with complement-activating membranes is associated with leukopenia, which is related to an increased expression of adhesion molecules on leukocytes. Citrate chelates calcium and has been claimed to attenuate leukopenia. Methods: In this study, the effects of citrate anticoagulation on leukocyte and granulocyte counts, complement activation, and the expression of CD11b, CD11c, and CD45 on the surface of granulocytes were evaluated during hemodialysis with unmodified cellulose membranes. Standard heparin was compared to citrate in three different schedules: citrate was infused to obtain a concentration of either 7 or 10 mmol/l blood. CaCl2 was administered into the dialyzer outlet at 8.25 mmol Ca2+/h (citrate 10 mmol/l) or at 11 mmol Ca2+/h (citrate 7 and 10 mmol/l) to restitute the calcium levels in the blood returning to the patient. Results: The use of citrate at a high concentration (10 mmol/l) was associated with a blunted upregulation of CD11b, both at the inlet and at the outlet bloodline; for CD11c a reduced upregulation was observed on granulocytes harvested from the inlet bloodline. No effects of citrate were observed on leukopenia, granulocytopenia, or complement activation. A positive correlation between the decrease in systemic ionized Ca2+ concentration and the increase in CD11b and CD11c expression was found. Conclusion: Citrate/CaCl2 administration affects leukocyte adhesion molecule expression in a dose-dependent way; however, no significant effect could be demonstrated on leukopenia and complement activation.
Amlodipine Besylate Induced Acute Interstitial Nephritis
Authors: Ejaz A. Ahsan , Fitzpatrick Peter M. , Haley William E. , Wasiluk Andrzej , Durkin Alan J. , Zachariah Prince K.
Published: April 2003

Adverse effects of amlodipine besylate, a widely used antihypertensive medication, include peripheral edema, flushing, headache, pruritus, and rash. An adverse renal effect attributable to the medication has hitherto not been reported in the literature. We herein report a case of amlodipine besylate induced acute interstitial nephritis.