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Abstract

V. Wirta¹, P. Saransaari⁴, O. Wirta², V. Rantalaiho², S.S. Oja³, A. Pasternack², T. Koivula¹ and T. Lehtimäki¹

¹Laboratory of Atherosclerosis Genetics, Department of Clinical Chemistry, Centre for Laboratory Medicine, ²Department of Internal Medicine, ³Department of Clinical Physiology, Tampere University Hospital, and ⁴Medical School, University of Tampere, Finland
Background: Methylenetetrahydrofolate reductase (MTHFR) gene polymorphism may cause hyperhomocysteinemia, which affects the vascular endothelium and may induce occlusive vascular disease (OVD). Hypertension thickens small-sized arterial walls and attenuates intramural blood flow. Such OVD can be studied in retinal angiograms as a decrease in the arterio-venous ratio (AVR). Diabetes, by altering microvascular structure and function, in many ways modifies this AVR. Objective: To assess whether MTHFR gene polymorphism (C677T) by causing hyperhomocysteinemia affects the retinal AVR in type 2 diabetic and non-diabetic subjects. Methods: Eighty-four recently diagnosed (< 1 year) type 2 diabetic and 115 non-diabetic subjects were included in the study. Retinal fluoresceine angiograms were recorded and the mean AVR was calculated by measuring transverse vessel diameters at 6 locations. The mean AVR was used as a marker of OVD. The MTHFR VV, VA and AA genotypes were determined by PCR and plasma homocysteine by high-pressure liquid chromatography. Results: In the diabetic subjects with the VV, VA and AA genotypes, the plasma homocysteine levels were 16.5 ± 7, 12.5 ± 4.6 and 11.3 ± 4.9 mM, respectively (p = 0.008, ANCOVA). The corresponding values in controls were 14.6 ± 3.8, 13.7 ± 5.7 and 11.6 ± 4.4 (p = 0.08). Correspondingly, in the diabetic subjects, the AVR values were 0.71 ± 0.07, 0.75 ± 0.07 and 0.73 ± 0.1 (p = NS, ANOVA) and in the control subjects they were 0.8 ± 0.14, 0.81 ± 0.12 and 0.76 ± 0.09 (p = NS, ANOVA). Multiple linear regression analysis (best model c2 = 18.2, R2 = 0.10, p < 0.001) showed that AVR was related to diastolic blood pressure (t = –3.7, p < 0.001) and GFR (t = –2.2, p = 0.03). There was no relation between the AVR and plasma homocysteine levels. Conclusion: In the present study of recently diagnosed type 2 diabetic and non-diabetic subjects, MTHFR gene polymorphism (C677T mutation) slightly affected the plasma homocysteine level but did not alter the arterio-venous ratio.

Abstract

M. Andrassy¹,³, A. Bierhaus¹,³, M. Hong¹,³, J. Sis², S. Schiekofer¹,³, P.M. Humpert¹,³, J. Chen¹,³, M. Haap³, W. Renn³, E. Schleicher³, H.-U. Häring³, K. Andrassy² and P.P. Nawroth¹,³

¹Department of Medicine IV, University of Tübingen, ²Department of Nephrology, and ³Department of Medicine I, University of Heidelberg, Germany
The aim of this study was to determine the effect of rh-EPO on the redox-sensitive transcription factor (NF-kB) in vivo and in vitro. Ten patients (7 female, 3 male), mean age 69.2 ± 11 years, with end-stage renal failure and anemia prior to initiation of regular hemodialysis were enrolled and divided into 2 groups (group A “good responder”, 7 patients and group B “poor responder”, 3 patients) in accordance to the response to rh-EPO therapy. Nuclear binding activity of NF-kB was determined in ex vivo isolated mononuclear cells before, 4 and 8 weeks after onset of regular hemodialysis and rh-EPO therapy by electrophoretic mobility shift assays (EMSA). In group A, a reduction of NF-kB binding activity from 100% to 56 ± 6% was observed within the first four weeks of rh-EPO treatment, while mean hemoglobin rose from 8.2 ± 0.4 g/dl to 11.1 ± 0.2 g/dl. However, this effect was abrogated after another 4 weeks of treatment when NF-kB signal increased back to 85.2 ± 10.6% despite consistent mean hemoglobin level of 11.3 ± 0.4 g/dl. Group B demonstrated a slight increase of NF-kB signal from 100% to 129 ± 18.5%, while mean hemoglobin only moderately rose from 7.6 ± 0.3 g/dl to 8.3 ± 0.1 g/dl within the first 4 weeks, and it further rose to 180 ± 45% after 8 weeks of treatment, while mean hemoglobin (9.5 ± 0.1 g/dl) remained low. The NF-kB binding activity differed significantly when comparing both groups (p = 0.007). Binding activity of Oct-1, serving as control, did not change notably in either group (p = 0.34). In vitro studies showed that rh-EPO did not directly affect NF-kB binding activity in THP-1 cells. However, coincubation of THP-1 cells with erythrocytes led to a reduction of NF-kB binding activity only in THP-1 cells with a hemoglobin level adjusted to 11 g/dl compared to 8 g/dl in the presence of rh-EPO. In vivo and in vitro data implicate a complex interaction between rh-EPO, stimulated RBC and the redox-sensitive transcription factor NF-kB in mononuclear cells.

Abstract

T.A. Ikizler, J.D. Morrow, L.J. Roberts, J.A. Evanson, B. Becker, R.M. Hakim, Y. Shyr, J. Himmelfarb

¹Department of Medicine, Division of Nephrology, Vanderbilt University Medical Center, Nashville, Tennessee, USA, ²Department of Medicine, Division of Clinical Pharmacology, Vanderbilt University Medical Center, Nashville, Tennessee, USA, ³Department of Medicine, Division of Nephrology, University of Wisconsin Medical School, Madison, Wisconsin, USA, ⁴Department of Preventative Medicine, Division of Biostatistics, Vanderbilt University Medical Center, Nashville, Tennessee, USA, and ⁵Department of Medicine, Division of Nephrology, Maine Medical Center, Portland, Maine, USA
Aims: Cardiovascular mortality has been reported to be 10- to 20-fold higher in chronic dialysis patients than in the age-matched general population. It has been suggested that increased oxidant stress and resulting vascular wall injury due to uremia and the hemodialysis procedure may be one of the mechanisms predisposing to these cardiovascular complications. Further, hemodialysis membrane bioincompatibility can contribute to increased oxidative stress and prevalence of inflammation. Materials: We studied 18 chronic hemodialysis (CHD) patients (age 62.8 ± 14.7 years, 39% male, 61% African-American, 44% insulin-dependent diabetic, 61% smokers, 61% with documented coronary artery disease) during hemodialysis with 2 membranes with different flux and complement activating properties. Methods: We have measured free and phospholipid-bound F2-isoprostane (F2-IsoP) levels, a sensitive marker of oxidative stress, in CHD patients and compared them to levels in healthy subjects. We have also examined the acute effects of the hemodialysis procedure using both biocompatible and bioincompatible membranes on F2-IsoP levels. Results: The results indicated that, compared to controls, both free (96.2 ± 48.8 pg/ml versus 37.6 ± 17.2 pg/ml) and bound F2-IsoP (220.4 ± 154.8 pg/ml versus 146.8 ± 58.4 pg/ml) levels were significantly higher (p < 0.05 for both). There was a statistically significant decrease in free F2-IsoP concentrations at 15 and 30 minutes of HD, which rebounded to baseline levels at the completion of the procedure. There were no significant differences in F2-IsoP concentrations between the 2 study dialyzers at any time point. Age, smoking status, diabetes mellitus and presence of cardiovascular disease were also not correlated with F2-IsoP levels in this patient population. There was a significant association between predialysis F2-IsoP and C-reactive protein concentrations. Conclusion: Using a sensitive and specific assay for the measurement of F2-IsoP, we demonstrated that CHD patients are under increased oxidative stress. During a single hemodialysis treatment, the hemodialysis membrane appears to have no discernable effect on oxidative stress status. Measurement of F2-isoprostanes may be a useful biomarker of oxidative stress status as well as in developing new therapeutic strategies to ameliorate inflammatory and oxidative injury in this patient population.

Abstract

G. Stoya, A. Klemm, E. Baumann, H. Vogelsang, U. Ott, W. Linss and G. Stein

¹Department of Internal Medicine IV, ²Institute of Anatomy I, and ³Institute of Immunology, Friedrich Schiller University, Jena, Germany
Aim: It is suggested that the red blood cells (RBCs) of uremic patients have increased oxidative damage. The activities of different antioxidant enzymes and the levels of several antioxidants or lipid peroxidation products in RBCs are usually determined to estimate the oxidative stress in uremia. The autofluorescence of RBCs as measured by flow cytometry is caused by the formation of conjugated Schiff base compounds from aldehydes derived from lipid peroxidation and amino groups of phospholipids or cell proteins, and has been proposed as a marker of oxidative stress. The aim of this study was to evaluate if this method is suitable for estimation of oxidative stress in the RBCs of patients with different degrees of renal insufficiency. Patients and methods: To determine the oxidative damage in RBCs in uremia, the autofluorescence of RBCs was measured by flow cytometry in the following 3 groups of patients: group A: 16 patients with chronic renal failure (CRF); group B: 16 hemodialysis (HD) patients; group C: 16 patients with a well-functioning renal allograft. Twenty-four healthy volunteers served as controls. The basal value of RBC autofluorescence and the autofluorescence of RBCs after oxidative damage by treatment with 0.1 mM hydrogen peroxide (H2O2)/0.7 mM sodium azide were determined. Results: In basal RBC autofluorescence values, no differences were found between the 3 groups and the controls. However, there was a significant correlation between the increase of serum creatinine and RBC autofluorescence in the group of patients with CRF (r = 0.521; p = 0.038). After H2O2 treatment, the RBC autofluorescence rose markedly in all individuals. This increase in RBC autofluorescence was significantly higher in the patients with CRF (p = 0.003) and in the HD patients (p = 0.001) compared to the controls. In contrast, there was no difference in RBC autofluorescence between the patients with renal allograft and the controls after H2O2 treatment. Conclusions: In conclusion, flow cytometry is a useful tool for determining oxidative damage in RBCs. The RBCs of uremic patients are more susceptible to oxidative damage induced by H2O2, likely caused by diminished antioxidant defense in the RBC membrane. Successful renal transplantation leads to a normal autofluorescence response in the RBCs after H2O2 treatment.

Abstract

K. Dewitte¹, A. Dhondt², N. Lameire², D. Stöckl¹ and L.M. Thienpont¹

¹Laboratory for Analytical Chemistry, Faculty of Pharmaceutical Sciences, Ghent University, and ²Renal Division, University Hospital, Ghent, Belgium
Aim of the study: Based on data in the literature, it remains unclear whether the ionized fraction of serum total magnesium (Mg) is lower in chronic hemodialysis (HD) patients compared to healthy subjects. Patients and methods: The ionized fraction of serum total Mg was investigated in 49 HD patients, pre- and post-dialysis, and compared to 30 healthy controls. The quality of the analytical performance of the Mg measurements has been emphasized by applying a reference method and/or rigorous internal quality control (IQC). In addition, the ionized fraction of serum total calcium (Ca) was measured in both populations, because the results for Mg should be related to those of Ca. Results: In HD patients, the ionized fraction of serum total Mg was on average 65% (pre-dialysis 64.2% and post-dialysis 66.2%). In healthy controls, the ionized fraction was 64.9%. When the analytical variability was taken into account, no significant differences (p > 0.05) were observed between pre- and post-dialysis samples and controls. For Ca, an ionized fraction of 55.3% was found in HD patients, which was not significantly different from the fraction obtained in the control group (55.7%). Conclusion: The present study demonstrates that, compared to healthy controls, the ionized fraction of serum total Mg is not different in hemodialysis patients.

Abstract

J.A. Vassalotti, A. Falk, E.D. Cohl, J. Uribarri and V. Teodorescu

¹Division of Nephrology, Mount Sinai Medical Center, New York, USA ²Division of Radiology, Mount Sinai Medical Center, New York, USA and ³Division of Surgery, Mount Sinai Medical Center, New York, USA
Aims: The arteriovenous fistula (AVF) is the preferred hemodialysis access. Subset analyses of both the HEMO and DOPPS studies have shown that obese hemodialysis patients have a lower prevalence of functioning AVF. Doppler ultrasound may increase the prevalence of functioning AVF in obese subjects. Patients and methods: The effect of pre-operative vein mapping employed between 10/01/98 and 12/08/00 on the prevalence of functioning AVF in a single university hemodialysis program was studied. Pre-operative ultrasound was performed to study venous and arterial systems on both arms. Results: There were 50 obese patients, defined as body mass index (BMI) ³ 27 kg/m2, and 130 patients with a lower BMI. The groups were similar in mean age and diabetes prevalence. The obese group had statistically significantly more females 34/50 versus 61/130 with p = 0.01. There was no statistically significant difference between the vein mapping parameters studied in the two BMI groups, including mean mid-forearm cephalic vein diameter, distal radial artery peak systolic velocity and subclavian vein patency. No obese patient required venography. There was no significant difference between the number of functioning AVF in both groups (22/50 obese, 48/130 lower BMI, p = 0.24). Conclusions: Pre-operative vein mapping is associated with a similar prevalence of functioning AVF in obese and lower BMI patients. Pre-operative ultrasound screening is a useful tool to promote AVF placement in obese patients.

Abstract

N. Kimata, K. Nitta, T. Akiba,K. Tominaga, K. Suzuki, Y. Watanabe, T. Haga, A. Kawashima, N. Miwa, E. Nishida, T. Aoki and H. Nihei

¹Department of Medicine and ²Division of Blood Purification, Kidney Center, Tokyo Women’s Medical University, Tokyo, and ³Dialysis Center, Takeda General Hospital, Fukushima, Japan
Objective: Intraluminal thrombosis of the catheter was thought to be a major cause of catheter dysfunction. We evaluated if thrombi appear in the luminal side or outside of the catheters placed in the femoral vein in 21 hemodialysis patients. Methods: 23 double-lumen catheter (25 cm long and 4 mm diameter polyurethane) strippings were consecutively performed. Mean catheter dwell time was 17.9 ± 11.2 days (2 – 45 days). The femoral vein was observed with ultrasound echography, and thrombo-venous ratio (thrombus diameter/vein diameter) was calculated. X-rays were also taken to clearly visualize the thrombi followed by contrast medium injection through the catheter. Results: Tube-shaped thrombi were echographically detected in 22 of 23 catheters (95.7%) when the catheter was stripped. Ten catheters (43.5%) were stripped due to the reduced blood flow, and tube-shaped thrombi were observed in the femoral vein, whereas no thrombus was found in the intraluminal side of the catheter. In 7 of 23 patients (30.4%) with leg edema on the same side of the catheter, the thrombo-venous ratio was 78.9 ± 7.4%, which was higher than that in the patients without leg edema (52.1 ± 11.1%). Conclusion: The tube-shaped thrombi, formed around the double-lumen catheter, may cause catheter dysfunction and reduced venous return of the lower legs. The catheter should be removed as soon as thrombosis is diagnosed, especially when accompanied by leg edema.

Abstract

N. Yanai-Berar, O. Ben-Itzhak, J. Green and F. Nakhoul

Departments of ¹Nephrology and ²Pathology, Rambam Medical Center, Haifa, and ³Israel and Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel
Influenza vaccination is a widely accepted practice, particularly among the elderly and high-risk individuals. Minor and transitory side effects following the vaccination are common, while systemic complications are infrequently reported. We describe here a case of a patient who presented to the emergency room with arthralgia, myalgias and purpura, following influenza vaccination. Necrotizing vasculitis associated with pauci-immune glomerulonephritis was observed on kidney biopsy. With increasing use of influenza vaccination, attention should be drawn to the possible expression of systemic adverse effects such as vasculitis and glomerulonephritis.

Abstract

K. Masutani, T. Mizumasa, T. Iwanaga, M. Shinozaki, T. Yanagida, M. Kashiwagi, K. Fukuda, H. Kanai, R. Katafuchi and H. Hirakata

¹Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, and ²Kidney Unit, Fukuoka Red Cross Hospital, Fukuoka, Japan
A 23-year-old man was admitted with macrohematuria and systemic edema appearing after an acute upper respiratory tract infection. He had been diagnosed 6 years earlier with IgA nephropathy (IgA-N). On admission, hypertension, nephrotic syndrome and hypocomplementemia were evident together with a high titer of anti-streptokinase (ASK). Renal biopsy showed severe glomerular mesangial proliferation, segmental endocapillary proliferation and crescent formation. Immunofluorescence microscopy (IF) showed strong deposition of C3 and reduced deposition of IgA. Electron microscopy showed a so-called ?hump? on the epithelial side of the glomerular basement membrane.These features were consistent with post-streptococcal acute glomerulonephritis (PSAGN) superimposed on IgA-N. Following 2 weeks of observation, blood pressure, C3 level and ASK titer returned to normal ranges, although nephrotic syndrome was still evident, which necessitated oral prednisolone (30 mg/day) therapy. Another biopsy taken 2 months later demonstrated regression of endocapillary proliferation and IF showed decreased deposition of C3. Immunohistochemical staining of the specimen taken on admission revealed the presence of numerous T cells and macrophages in the interstitium. Macrophages were also seen in the glomerular tuft. Many interstitial infiltrating cells were positive for interferon-g, but their number diminished after treatment. Our findings suggest that PSAGN complicating pre-existing IgA-N activates cellular immunity and augments renal tissue injury.

Abstract

T. Suehiro, K. Masutani, T. Suehiro, K. Masutani, K. Tsuruya, K. Fukuda, H. Kanai, R. Katafuchi, Y. Nagatoshi and H. Hirakata

¹Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, ²Kidney Unit, Fukuoka Red Cross Hospital, and ³Division of Pediatrics, National Kyushu Cancer Center, Fukuoka, Japan
A 15-year-old boy developed nephrotic syndrome and acute renal failure 4 years after allogenic bone marrow transplantation (BMT) for lymphoid crisis of chronic myelocytic leukemia. On admission, he presented with clinical features of chronic GVHD including transient exacerbation of cholestatic liver injury. Renal biopsy showed diffuse proliferative glomerulonephritis with cellular crescents. The patient was treated with methylprednisolone pulse therapy (1 g/day, for 3 days) followed by oral prednisolone. Renal function gradually improved but nephrotic state was persistent. A second renal biopsy showed improvement of acute tubular necrosis and endocapillary proliferation and transformation of crescents into a fibrous form. After tapering of oral prednisolone, cyclophosphamide was started, which resulted in a gradual improvement of proteinuria. Several cases of nephrotic syndrome occurring after BMT have already been reported, but most cases had membranous nephropathy. In our case, renal biopsy revealed diffuse proliferative glomerulonephritis with findings of active cellular immunity, and aggressive treatment resulted in attenuation of these findings. Moreover, chronic GVHD-related liver injury was noted at the time of this episode. Our findings suggest that chronic GVHD may be complicated with diffuse proliferative glomerulonephritis through unknown cellular immune mechanism.

Abstract

R. Russell, M.A. Brookshire, M. Zekonis and S.M. Moe

¹Department of Veterans Affairs, Medicine Service, Nephrology Division, ²Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana, USA
Calcific uremic arteriolopathy (CUA; calciphylaxis), is reported in approximately 4% of patients receiving hemodialysis, and is characterized by skin lesions that may include firm plaques or subcutaneous nodules. The syndrome has been associated with the use of calcium-containing phosphate binders, high serum phosphorus levels, and elevated calcium phosphorus (Ca P) product. This report describes a 73-year-old white male with chronic renal failure due to diabetes mellitus and hypertension, who had been on home hemodialysis for 3 years. He developed CUA after an acute elevation in serum phosphorus (8.1 mg/dl) and Ca P product (84.2), with painful skin lesions that rapidly progressed to become circumferentially located around the entire lower left extremity. The patient declined amputation, opting for a treatment approach that included aggressive management of phosphorus and calcium, more frequent dialysis, and rigorous wound care. All calcium-containing phosphate binders were discontinued. The patient was switched from calcitriol to paricalcitol, a less calcemic form of vitamin D replacement therapy, from which he was slowly weaned. Dialysis dose and frequency was also increased to 4 hours, 6 times weekly. The patient was given sevelamer hydrochloride (Renagel®) – a calcium-free phosphate binder – with meals at an initial dose of 6.4 g/day. After 5 months, the dose was increased to 8 g/day, with additional dietary counseling to restrict phosphorus intake. At this point, serum phosphorus decreased to 4.9 mg/dl and calcium levels had fallen to 8.5 mg/dl, compared to 9.5 – 10.4 mg/dl prior to diagnosis of CUA with an overall decline in the Ca × P product. Significant healing of the lesions was noted at 8 months following diagnosis, with near-total healing by 12 months. Our studies support that lowering of elevated serum phosphorus, calcium, and Ca × P product, together with aggressive wound care may contribute to the successful outcome of patients with CUA.

Abstract

S. Pearson, M.A. Jackson and P.B. Rylance

Renal Unit, New Cross Hospital Wolverhampton, United Kingdom
A 47-year-old dialysis patient developed severe sclerosing peritonitis. The patient has been unable to take any nutrition by mouth for 27 months. She has been maintained daily on home parenteral nutrition and hemodialysis 3 times per week. It has been possible for her to have a good quality of life and to maintain good nutritional status.

Abstract

Z. Armaly, E. Khankin, R. Ramadan, O. Ben-Itzhak, L. Guralnik, J. Green and F. Nakhoul

Abstract

A.M. Koorts, C.D. Potgieter and M. Viljoen

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Volume 58, No. 3/2002(September)