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Abstract

K. Masutani, M. Tokumoto, H. Nakashima, K. Tsuruya, M. Kashiwagi, Y. Kudoh, K. Fukuda, H. Kanai, M. Akahoshi, T. Otsuka, H. Hirakata and M. Iida

¹Department of Medicine and Clinical Science, ²Department of Medicine and Biosystemic Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, and ³Otsuka Tokyo Assay Laboratories, Tokyo, Japan
Aim: Human immune response can be classified into 2 different subsets of T helper cells (Th1 and Th2) based on the pattern of cytokine production. In modern immunology, Th1/Th2 paradigm helps to explain the different inflammatory effector pathways and outcomes in human diseases. The present study was designed to determine the type of immunological response that influences anti-neutrophil cytoplasmic antibody- (ANCA) associated glomerulonephritis (GN) using cytokine analysis of peripheral T cells and diseased kidney tissues. Patients and methods: We analyzed peripheral blood Th1/Th2 ratio in 91 patients with primary GN, including 10 cases of ANCA-associated GN. Tissues were immunostained with markers of T cells and macrophages and osteopontin (OPN). Intrarenal expression of IFN-g and IL-4 mRNAs was evaluated by reverse transcriptase (RT)-PCR. Results: Peripheral Th1/Th2 ratio was significantly higher in ANCA-associated GN (19.4 ± 9.4, mean ± SD, n = 10), than those in healthy controls (7.6 ± 4.1, n = 27), IgA nephropathy (9.6 ± 5.6, n = 45), membranous nephropathy (7.1 ± 4.4, n = 13), minimal-change nephrotic syndrome (8.2 ± 4.5, n = 13) and focal segmental glomerulosclerosis (8.3 ± 3.9, n = 10) (p < 0.01, each). In 7 of 10 cases of ANCA-associated GN, Th1/Th2 ratio decreased significantly after treatment with corticosteroid from 21.0 ± 12.0 to 9.0 ± 6.6 (p < 0.05). Immunohistochemical staining showed numerous infiltrating T cells, macrophages and OPN-positive cells in both glomerular tuft and cellular crescent; OPN-positive cell distribution was similar to that of macrophages. Intrarenal expression of IFN-g mRNA was strongly enhanced whereas a weak expression of IL-4 mRNA was observed especially in advanced cases showing tubulointerstitial injury. Conclusion: Both peripheral and renal immune responses are strongly polarized toward Th1 type immune response in ANCA-associated GN. Peripheral Th1/Th2 ratio may reflect the immune responses in renal injury of ANCA-associated GN.

Abstract

T. Onoe, T. Konoshita, K. Miyagi, K. Yamada, H. Mutoh, I. Koni and H. Nomura

¹Second Department of Internal Medicine, Kanazawa University School of Medicine, and ²Department of General Medicine, Kanazawa University Hospital, Kanazawa, Ishikawa, Japan
Background: Autosomal dominant polycystic kidney disease (ADPKD) is one of the most common inherited renal disorders in the world. Mutations in PKD1 are responsible for 80 – 95% of all autosomal dominant polycystic kidney disease (ADPKD). Although the need for linkage analysis of ADPKD is decreasing after the success of mutation detection at whole exons of PKD1, linkage analysis still has some advantages in detecting non-PKD1 families, thereby avoiding hopeless mutation analysis. Methods: We evaluated ten microsatellite markers beside or inside PKD1 on chromosome 16p. Allele frequency and heterozygosity of each marker were calculated based on the 100 genotypes obtained from 50 normal Japanese. Automated microsatellite genotyping using ABI Prism 377 and GeneScan software was applied. Markers were mapped using radiation hybrid mapping. Finally, this strategy was applied in the linkage analysis of 6 independent Japanese ADPKD families. Results: D16S3024, D16S3082, D16S3027 and D16S423 showed high heterozygosity (> 0.80) in a normal Japanese population and sufficient proximity to the PKD1 gene for linkage analysis. We could successfully analyze 144 genotypes within 7 hours. This strategy produced theoretically near-maximum LOD scores in 4 independent Japanese families inheriting ADPKD. Conclusions: Automated genotyping using microsatellite markers, D16S3024, D16S3082, D16S3027 and D16S423 are very useful in the linkage analysis of ADPKD.

Abstract

H. Burkhardt, T. Hahn and R. Gladisch

Specialty Geriatrics, IV. Medical Department, University of Heidelberg, Klinikum Mannheim, Mannheim, Germany
Background: Autosomal dominant polycystic kidney disease (ADPKD) is one of the most common inherited renal disorders in the world. Mutations in PKD1 are responsible for 80 – 95% of all autosomal dominant polycystic kidney disease (ADPKD). Although the need for linkage analysis of ADPKD is decreasing after the success of mutation detection at whole exons of PKD1, linkage analysis still has some advantages in detecting non-PKD1 families, thereby avoiding hopeless mutation analysis. Methods: We evaluated ten microsatellite markers beside or inside PKD1 on chromosome 16p. Allele frequency and heterozygosity of each marker were calculated based on the 100 genotypes obtained from 50 normal Japanese. Automated microsatellite genotyping using ABI Prism 377 and GeneScan software was applied. Markers were mapped using radiation hybrid mapping. Finally, this strategy was applied in the linkage analysis of 6 independent Japanese ADPKD families. Results: D16S3024, D16S3082, D16S3027 and D16S423 showed high heterozygosity (> 0.80) in a normal Japanese population and sufficient proximity to the PKD1 gene for linkage analysis. We could successfully analyze 144 genotypes within 7 hours. This strategy produced theoretically near-maximum LOD scores in 4 independent Japanese families inheriting ADPKD. Conclusions: Automated genotyping using microsatellite markers, D16S3024, D16S3082, D16S3027 and D16S423 are very useful in the linkage analysis of ADPKD.

Abstract

N. Kishimoto, Y. Mori, T. Nishiue, Y. Shibasaki, O. Iba, A. Nose, Y. Uchiyama-Tanaka, H. Masaki, H. Matsubara and T. Iwasaka

¹Renal Division and ²Cardiovascular Center, Department of Medicine II, Kansai Medical University, Osaka, Japan
Background: An accessible non-invasive method for evaluating renal regional blood flow in real time is highly desirable in the clinical setting. Recent progress in ultrasonography with microbubble contrast has allowed quantification of regional blood flow in animal models. Aims: Goal of this study was to establish a convenient contrast-enhanced harmonic ultrasonography (CEHU) method for evaluating renal cortical blood flow in humans. Methods: We carried out intermittent second harmonic imaging in 9 healthy volunteers. Pulse interval was progressively decreased from 4 s ? 0.2 s during continuous venous infusion of the microbubble contrast agent. Results: Pulse interval versus CEHU-derived acoustic intensity plots provided microbubble velocity (MV) and fractional vascular volume (FVV) during renal cortical perfusion in humans. Low-dose dopamine infusion (2 mg/min/kg) resulted in a significant increase in MV which correlated well with the increase in total renal blood flow (RBF) determined by a conventional study of p-aminohippurate clearance (CPAH) (r = 0.956, p < 0.0001). Although FVV was not significantly increased, alterations in CEHU-derived renal cortical blood flow calculated by the products of MV and FVV were also correlated with alterations in total RBF (r = 0.969, p < 0.0001). Thus, low-dose dopamine infusion increases renal cortical blood flow observed in CEHU, mainly by increasing MV. Conclusions: The present study shows that renal cortical blood flow in humans can be measured non-invasively by CEHU and that CEHU can be used for quantitatively evaluating changes induced by a therapeutic agent such as dopamine in flow velocity and in FVV.

Abstract

S. Seeliger¹, M. Hausberg², I. Eue², T. Usdin³, K.H. Rahn² and M. Kosch²

¹Department of Paediatrics, ²Department of Internal Medicine D (Nephrology), University Hospital Münster, Germany, and ³Unit of Cell Biology, Laboratory of Genetics, National Institute of Health, Bethesda, Maryland, USA
Background: Parathyroid hormone (PTH) has specific effects on function, migration and proliferation of human leukocytes. These effects may contribute to accelerated atherosclerosis and impaired immune response observed in patients with renal insufficiency. Recently, a new G protein-coupled receptor with substantial implications for vascular function – the PTH2 receptor (PTH2-R) – has been identified, however, expression and distribution in humans and a possible regulation has not yet been studied. We therefore investigated the expression of the PTH2 receptor on human leukocytes in healthy subjects and in patients with hyperparathyroidism. Methods: PTH2 receptor expression was quantified by flow cytometry (FACS) analysis on monocytes, lymphocytes and granulocytes that were isolated from peripheral blood (hypotonic density gradient centrifugation) and by immunohistochemistry using a specific a-PTH2-R antibody produced in rabbit. Results of 22 patients with hyperparathyroidism (12 renal allograft recipients, 10 hemodialysis patients, mean age 43 ± 8 years) were compared to 22 age and sex-matched healthy controls. Results: Mean relative antigen density of the PTH2 receptor and percentage of positive cells in healthy subjects was 19 ± 5 and 90 ± 6% on granulocytes, 5 ± 2 and 55 ± 19% on monocytes, and 24 ± 7 and 21 ± 7% on lymphocytes. In patients with hyperparathyroidism, mean antigen density was significantly lower on granulocytes and monocytes (17 ± 4% and 3 ± 1%, p < 0.01, respectively). The percentage of positive cells and mean expression on lymphocytes was not significantly different. A significant and inverse correlation was found between plasma PTH concentrations and the mean PTH2 receptor expression on granulocytes (r = –0.41, p < 0.05). Conclusions: The PTH2 receptor is expressed on human granulocytes and – to a lesser degree – on monocytes and lymphocytes. In patients with hyperparathyroidism the PTH2 receptor is down-regulated as function of plasma PTH levels.

Abstract

R.D. Poduval and M.S. Hammes

Division of Nephrology, University of Chicago Hospitals, Pritzker School of Medicine, Chicago, IL, USA
Aim: Patients with end-stage renal disease are at increased risk for tuberculosis (TB). The Centers for Disease Control and Prevention (CDC) has recommended annual skin testing for TB, with tuberculin-purified protein derivative (PPD), in patients with chronic renal failure. The aim of this study was to identify the incidence and prevalence of tuberculin positivity and assess the utility of the tuberculin test in an inner city dialysis population. Methods: All patients on chronic hemodialysis at a center affiliated to the University of Chicago, who were tuberculin-tested between 1997 and 2000 or had previously documented PPD positivity precluding retesting, were included. Demographics, comorbidity, and tuberculin and anergy reactivity were recorded. A positive PPD was an induration of > 10 mm in response to 5 tuberculin units of PPD, and anergy an induration of < 2 mm in response to the anergy antigens (Candida and Mumps), at 48 h. PPD-positive patients were compared with PPD-negative patients; Fisher’s exact test and t-test were used, p < 0.05 was considered significant. Results: Of 131 patients at the dialysis center, 118 were studied. The remaining 13 refused consent to PPD testing. 41 (35%) were PPD-positive, 77 (65%) were negative. Of the 77 PPD-negative patients, 62 (81%) were anergic. None of the PPD-positive patients had clinical or radiographic signs of active TB. Only 20 patients received INH prophylaxis, the others refused or had contraindications to therapy. The conversion rate ranged from 3 – 8% per year. Demographics, nutritional parameters, comorbidity and adequacy of dialysis did not help predict PPD positivity. Conclusion: There is a high prevalence of PPD positivity and anergy among dialysis patients. As the diagnostic utility of the time-tested PPD test is unclear in an anergic dialysis population, the need for a high index of suspicion for active tuberculosis and timely diagnostic work up should be reinforced and not replaced by total dependence on the tuberculin test.

Abstract

H. Trimarchi, M.R. Mongitore, P. Baglioni, M. Forrester, E.A.R. Freixas, M. Schropp,H. Pereyra and M. Alonso

Division of Nephrology and Biochemistry Laboratory, Hospital Británico de Buenos Aires, Argentina
Background: Oxidative stress has been implicated in the development of endothelial damage in hemodialysis (HD). We have assessed the effects of N-acetylcysteine (NAC), a compound with antioxidant effects, on malondialdehyde (MDA), a marker of oxidative stress on lipid peroxidation. Methods: A clinical trial was conducted in which 24 chronic HD patients were divided into 2 groups according to gender, age, time on HD and cause of renal failure. The NAC group (n = 12) received 600 mg of NAC twice a day for 30 days. The remaining patients constituted the control group (n = 12). MDA levels were measured pre- and post-dialysis at the beginning of the study (baseline) and on day 30 (30 days). Results: Baseline pre- and post-dialysis MDA levels were not different between both groups and were above normal values. A significant decrease was found in the NAC group when either pre- or post-dialysis MDA levels were compared to the corresponding control group levels on day 30 (pre-dialysis NAC vs control group 3.01 ± 0.6 vs 4.5 ± 0.73 mmol/l, p < 0.0001, post-dialysis NAC vs control group 2.76 ± 0.5 vs 4.39 ± 0.7 mmol/l, p < 0.0001). Only in the NAC group were pre-dialysis MDA 30-day levels different from pre-dialysis baseline levels (3.01 ± 0.6 vs 5.07 ± 1.6 mmol/l, p < 0.002). Post-dialysis MDA 30-day concentrations were significantly lower than post-dialysis MDA baseline levels (2.76 ± 0.5 vs 4.32 ± 0.7 mmol/l, p < 0.002) and pre-dialysis MDA 30-day measurements (2.76 ± 0.5 vs 3.01 ± 0.6 mmol/l, p < 0.011). Conclusions: MDA levels are elevated in chronic HD patients and are not significantly reduced by HD. NAC significantly reduces malondialdehyde levels in chronic HD patients.

Abstract

R. Schindler, F. Christ-Kohlrausch, U. Frei and S. Shaldon

¹Department of Nephrology and Internal Intensive Care Medicine,
Charité Campus Virchow-Klinikum, Humboldt University, Berlin, Germany and ²Monaco
Aims: The increasing use of high-flux membranes for hemodialysis has raised concerns that patients dialyzed with these membranes may be at higher risk of being exposed to cytokine-inducing bacterial substances in the dialysate than patients dialyzed with low-flux membranes. We investigated the permeability of various high-flux membranes for both purified E. coli lipopolysaccharide (LPS) as well as for LPS derived from Stenotrophomonas (Sten.) maltophilia. Materials and methods: An in vitro dialysis circuit with saline in the blood compartment of 3 dialyzers containing different membranes (polysulfone, helixone and Diapes) was employed. The dialysate was challenged with increasing doses of sterile filtrates derived from Sten. maltophilia cultures or with purified LPS from E. coli. Samples from the blood compartment were tested for cytokine induction (IL-1b, IL-6 and TNF) in mononuclear cells as well as for LPS by limulus amebocyte lysate test (LAL). Results: IL-6 induction above sterile controls (< 0.02 ng/ml IL-6) was observed by samples from the blood side of DIAPES dialyzers (1.2 ± 0.7 ng/ml IL-6) after challenging the dialysate with 4.1 ± 3.6 U/ml E. coli LPS (9.9 ± 4.5 ng/ml IL-6). In contrast, at the same challenge dose no significant IL-6 induction above sterile controls was observed by blood side samples of polysulfone (0.15 ± 0.07 ng/ml) and helixone (0.09 ± 0.05 ng/ml) dialyzers. Increasing the amount of E. coli LPS in the dialysate further augmented IL-6 induction by blood side samples of Diapes but not of polysulfone and helixone dialyzers. Similar results were obtained for IL-1b and TNF. After challenging the dialysate with E. coli LPS as well as with cultures of Sten. maltophilia, significantly more LAL reactivity was observed in the blood compartment of Diapes compared to polysulfone and helixone. Conclusions: There are considerable differences between high-flux membranes regarding their permeability for cytokine-inducing substances from E. coli as well as for LPS derived from E. coli and Sten. maltophilia. Dialyzers that leak CIS under aqueous conditions in vivo should not be used unless the dialysate has passed through an ultrafilter.

Abstract

L. Labriola, M. Jadoul, M. Daudon, Y. Pirson and M. Lambert

Divisions of ¹General Internal Medicine and ²Nephrology, Cliniques Universitaires St. Luc, Université Catholique de Louvain, Brussels, Belgium, and ³Laboratoire de Biochimie, G.H. Necker – Enfants Malades, Paris, France
The authors report the case of a 45-year-old woman admitted for pneumonia who presented anuric acute renal failure after 12 days of intravenous amoxycillin-clavulanate treatment. Acute renal failure resolved rapidly and completely after antibiotic withdrawal. Analysis of the first post-anuric urine specimen showed many crystals. Infrared spectrophotometry revealed that the crystals were composed of trihydrated amoxycillin. The possibility of intrarenal obstruction due to massive drug crystalluria should not be overlooked in the face of abrupt anuria.

Abstract

H. Takahashi, S. Muto, E. Nakazawa, S. Yanagiba, Y. Masunaga, Y. Miyata, K. Tamba, E. Kusano, M. Matsuo, T. Matsuo and Y. Asano

¹Department of Nephrology, Jichi Medical School, Tochigi, and ²Department of Central Laboratory and Internal Medicine, Hyogo Prefectural Awaji Hospital, Hyogo, Japan
We report on the management of a 36-year-old hemodialysis patient with heparin-induced thrombocytopenia (HIT, type II) and clot formation in extracorporeal circulation. Platelet aggregation test and measurement of anti-platelet factor 4/heparin complex antibody by enzyme-linked immunosorbent assay revealed to us that our patient had developed HIT. Instead of heparin, we used nafamostat mesilate (NM) as an anticoagulant during hemodialysis, but could not completely prevent HIT-induced thrombocytopenia or clot formation in the extracorporeal circuit. Combined use of NM and aspirin completely inhibited platelet aggregation, decrease in platelet count and clot formation in the extracorporeal circuit.

Abstract

B.R. Don and A.I. Chin

Division of Nephrology, University of California Davis Medical Center, Sacramento, CA, USA
Calcific uremic arteriolopathy (calciphylaxis) is one of the more devastating complications that can develop in patients with chronic renal failure. This disorder is associated with calcium-phosphorus deposition in the subcutaneous arterial vessels and presents as a progressive ischemic necrosis of the skin resulting in large subcutaneous ulcerations with eschar formation. Mortality rates are substantially greater in chronic renal failure patients with calciphylaxis, and the major cause of death is infection and sepsis. We have developed a treatment strategy that employs a combination of therapies, which is based on reducing the known risk factors for the development of calciphylaxis as well as utilization of a number of treatment modalities that have been proven successful in the treatment of this disorder.

Abstract

M.S. Parisi, B. Oliveri, J. Somoza and C. Mautalen

Sección Osteopatías Médicas, Hospital de Clínicas, Universidad de Buenos Aires, Buenos Aires, Argentina
The efficacy and safety of the vitamin D analog, doxercalciferol (1a-hydroxyvitamin D2, 1aD2) in the treatment of secondary hyperparathyroidism in hemodialysis patients has been previously reported. We report thse effect of 16-week 1aD2 treatment on mineral metabolism and bone mineral density (BMD) in a hemodialysis patient with persistent secondary hyperparathyroidism post parathyroidectomy, resistant to previous calcitriol treatment. Levels of iPTH, bone-specific alkaline phosphatase and serum type I collagen C telopeptide were above normal at baseline and were substantially decreased with 1aD2 treatment (–92%, –63% and –53%, respectively). BMD increased in all areas: total skeleton (+6.5%), lumbar spine (+6.9%) and total femur (+4.3%). The patient showed no hypercalcemia, and phosphorus levels remained between 3.3 and 6.2 mg/dl.

Abstract

M. Guglin, C. Dey, G.M. Meny, W. Sultan and L.S. Weisberg

¹Divisions of Cardiology and ²Nephrology, UMDNJ/Robert Wood Johnson Medical School, The Cooper Health System, Camden, New Jersey, and ³The American Red Cross, Penn Jersey Region, Philadelphia, Pennsylvania, USA
Aims: To describe a patient with end-stage renal disease who developed non-cardiogenic pulmonary edema after transfusion of packed red blood cells. Design: Case report and literature review. Results: The patient under consideration is a 60-year-old woman who developed acute pulmonary edema after transfusion of packed red blood cells without concomitant dialysis. The initial diagnosis of fluid overload was managed by isolated ultrafiltration. Minimal fluid removal led to significant hypotension that was resistant to vasopressors. Subsequent pulmonary artery catheter readings were consistent with non-cardiogenic pulmonary edema. The patient improved spontaneously over the next few days with supportive care only. Plasma from the donors was checked for granulocyte antibodies and antibodies to HLA class I antigens. No granulocyte antibodies were detected in donor plasma but of one the HLA antibodies detected in donor plasma had specificity for a recipient HLA-A antigen. These characteristics supported a final diagnosis of transfusion-related acute lung injury (TRALI). Conclusions: Acute pulmonary edema following blood transfusion in a dialysis-dependent patient does not always signify fluid overload and nephrologists should be aware of the alternative diagnosis of TRALI. Proper awareness of TRALI will lead to prompt diagnosis and appropriate management.

Abstract

M. Sato, T. Kogure, N. Yanagisawa, H. Haizuka and Y. Nakashima

Abstract

K.T. Woo and Y.K. Lau

Abstract

I. Tzanakis, A. Papadaki, S. Kagia, N. Karefyllakis, V. Spandidakis, N. Girousis and N.Kallivretakis

Abstract

H. Kamimura, K. Tsuchiya, K. Honda, H. Kobayashi, T. Ogawa, H. Nihei and T. Mochizuki

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Volume 59, No. 6/2003(June)