Volume 67, No. 3/2007(March)
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 Clinical Nephrology
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Originals
Parathyroid hormone and large related C-terminal fragments increase at different rates with worsening of renal function in chronic kidney disease patients. A possible indicator of bone turnover status?
Abstract
C. Donadio, M. Ardini, A. Lucchesi, E. Donadio and T. Cantor
1Department of Internal Medicine, Nephrology, 2Department of Veterinary Anatomy, Physiology and Biochemistry, University of Pisa, Italy, 3R&D, Scantibodies Laboratory, Santee, CA, USA
Background: The intact parathyroid hormone (PTH) serum value has been the non-invasive biomarker of choice for the early diagnosis of renal bone disease in the chronic kidney disease (CKD) patient population. It has now been known that the intact PTH assay value is the sum of 1-84 PTH (true hypercalcemic PTH) and large C-terminal PTH fragments, mainly 7-84 PTH, a fragment with hypocalcemic hormone actions. Aim: The aim of this study was to investigate the differences among the different functional stages of CKD in the following PTH parameters: intact PTH, 1-84 PTH, 7-84 PTH, and the ratio 1-84 PTH/7-84 PTH. GFR (clearance of 99mTc-DTPA) was measured in 164 (85 males and 79 females) adult CKD patients with different degrees of renal function impairment (serum creatinine 0.50 – 12.1 mg/dl, mean 2.00). Patients and methods: Plasma concentrations of calcium, phosphate, 1-84 PTH and intact PTH were also measured. The value of 7-84 PTH was calculated as the difference between intact PTH and 1-84 PTH. The reduction of GFR was accompanied by an increase of intact PTH, with a prevalent increase of 7-84 PTH over 1-84 PTH, resulting in a decrease of the ratio 1-84 PTH/7-84 PTH. Results: The values of 7-84 PTH showed a discrimination between Stages 1 and 2 (GFR > 60 ml/min ) and Stage 3 (GFR 30 – 60 ml/ min) CKD patient populations. In fact, 7-84 PTH was already significantly increased in patients at CKD Stage 3. The analysis of individual patients indicated that a low value (< 1.4) of the ratio 1-84 PTH/7-84 PTH, suggestive for low bone turnover, was already found in more than 20% of CKD Stage 3 patients. Conclusion: The results of the present study demonstrate that the reduction in GFR is accompanied by a higher increase in 7-84 PTH with respect to 1-84 PTH, which suggests the possibility that bone metabolism and calcemic status are already reduced in patients with moderate renal failure (CKD Stage 3).Correspondence to:
Prof. C. Donadio Department of Internal Medicine, Nephrology University of Pisa 56100 Pisa, Italy
Email: c.donadio@med.unipi.it
Originals
Darbepoetin alfa once every 2 weeks for treatment of anemia in dialysis patients: a combined analysis of eight multicenter trials
Abstract
J. Mann, M. Kessler, G. Villa, A. Martinez-Castelao, B. Feldt-Rasmussen, J. Cruz, W.H. Hörl, C. Mattin, C. Praml and M. Wilkie
1Städtisches Krankenhaus, Munich, Germany, 2Centre Hospitalier Universitaire (CHU) de Nancy-Brabois, France, 3“S. Maugeri” Foundation, IRCCS, Pavia, Italy, 4Hospital de Bellvitge, Hospitalet de Llobregat, Spain, 5Rigshospitalet Nephrology Clinic, Copenhagen, Denmark, 6Fresenius Medical Care, Venda Nova, Portugal, 7Universitätsklinik für Innere Medizin III, Vienna, Austria, 8Amgen Ltd., Cambridge, UK, 9Amgen (Europe) GmbH, Zug, Switzerland, 10Northern General Hospital, Sheffield, UK
Aim: Darbepoetin alfa has a longer half-life than epoetin-(EPO) alfa or beta, allowing administration at less frequent intervals for the treatment of renal anemia. The aim of the present analysis was to evaluate the efficacy and tolerability of an every-2-week (Q2W) schedule of darbepoetin alfa in a large cohort of dialysis patients. Methods: Data were combined from eight similarly designed 24-week phase 3b European studies, in which patients receiving EPO alfa or beta once-weekly were converted to Q2W darbepoetin alfa. Darbepoetin alfa dosage was titrated to maintain hemoglobin (Hb) between 10 and 13 g/dl and efficacy was evaluated during a 4-week evaluation period. Results: In the 1,101 patients assigned to Q2W darbepoetin alfa (i.v., n = 196, s.c., n = 905), mean (SD) Hb levels were 11.53 (0.77) g/dl at baseline and 11.35 (1.04) g/dl at evaluation (mean change in Hb –0.27 g/dl, 95% confidence interval –0.34, –0.20). Hb levels were maintained between 10 and 13 g/dl during evaluation in 85% of patients. Darbepoetin alfa doses were similar at baseline and evaluation, and the i.v. and s.c. routes were associated with similar efficacy and dose requirements. Darbepoetin alfa was well-tolerated. Conclusions: Q2W darbepoetin alfa is effective in maintaining Hb levels in dialysis patients switched from weekly rHuEPO, regardless of the route of administration and with no notable increase in the weekly equivalent dose.Correspondence to:
Prof. Dr. J. Mann Städtisches Krankenhaus München-Schwabing 6. Medizinische Abteilung Kölner Platz 1 80804 München, Germany
Email: johannes.mann@kms.mhn.de
Originals
Anemia in patients with Wegener’s granulomatosis
Abstract
M. Riegersperger, G. Sengoelge, M. Köller, N. Grossmann, T. Benesch and G. Sunder-Plassmann
1Division of Nephrology and Dialysis, 2Division of Rheumatology, Department of Medicine III, Medical University Vienna, 3Division of Nephrology, Department of Medicine VI, Wilhelminenspital and 4Institute of Medical Statistics, Medical University Vienna, Vienna, Austria
Aims: Anemia is commonly observed among patients with chronic kidney disease (CKD). No such information is available for patients with a history of systemic vasculitis. Methods: We examined the prevalence of anemia, the response to therapy with erythropoiesis-stimulating agents (ESA), and the association of anemia with the kidney function in clinically stable patients with Wegener’s granulomatosis in a retrospective, single-center study. Results: The mean hemoglobin concentration of 36 patients (mean age: 58 years; 15 female, 21 male; mean duration of disease: 4.6 years) was 13.0 ± 2.1 g/dl, and the mean estimated glomerular filtration rate (eGFR) was 41 ± 21 ml/min/1.73 m2. 14 of 36 patients (38.8%) presented with anemia (hemoglobin concentration < 12 g/dl in women, < 13 g/dl in men, or ESA therapy). In patients with a CKD Stage 3 or 4, anemia was present about twice as much as compared to the Third National Health and Nutrition Examination Survey (NHANES III) population. The hemoglobin concentration, however, was not associated with a change of kidney function (p = 0.1578). Conclusions: We found a higher prevalence of anemia in patients with Wegener’s granulomatosis, as compared to the NHANES III population. The hemoglobin concentrations showed no association with changes of kidney function.Correspondence to:
M. Riegersperger, MD Division of Nephrology and Dialysis Department of Medicine III Medical University Vienna Währinger Gürtel 18 – 20 1090 Vienna, Austria
Email: markus.riegersperger@meduniwien.ac.at
Originals
Effect of pentoxifylline on graft function of renal transplant recipients complicated with chronic allograft nephropathy
Abstract
K.-H. Shu, M.-J. Wu, C.-H. Chen, C.-H. Cheng, J.-D. Lian and Y.-S. Lu
1Department of Medicine, Division of Nephrology, Taichung Veterans General Hospital, 2Department of Medicine, Division of Nephrology, Chung-Shan Medical University, Taichung, 3Department of Medicine, Division of Nephrology, Nan-Tou General Hospital of the Department of Health of the Executive Yuan, Nan-Tou, Taiwan
Background: Chronic allograft nephropathy (CAN) is characterized by a progressive deterioration of renal function with various degrees of proteinuria. Currently, there is no effective treatment despite the introduction of new generations of immunosuppressants. Pentoxifylline (PTX) is a phosphodiesterase inhibitor that possesses antiproteinuric effect and has been proved to be effective in treating several glomerular diseases. The purpose of the current study was to examine the effect of PTX on renal transplant patients with established CAN. Materials and methods: Renal transplant recipients with biopsy-proven CAN were recruited for the study. All the patients had been on angiotensin-converting enzyme inhibitor or angiotensin receptor blocker for more than 1 year and were on a triple immunosuppressive regimen including corticosteroid, calcineurine inhibitor and mycophenolate mofetil. PTX in a dose of 1,200 mg/day was administered for at least 6 months. The following parameters were assessed at baseline, the 3rd and the 6th month post treatment: systolic and diastolic blood pressure, number of anti-hypertension drugs, serum creatinine (sCr), estimated glomerular filtration rate (eGFR), 24-hour urinary protein excretion (U/P), urinary N-acetylglucosaminidase (NAG) and intracytoplasmic Th1/Th2 cytokines production of peripheral blood CD4+ cells. Results: A total of 17 (11 male and 6 female) patients were enrolled in the study. The mean duration of follow-up post transplant was 10.6 ± 4.4 years. The baseline data of sCr, eGFR and U/P were 1.83 ± 0.46 mg/dl, 38 ± 8 ml/min and 2.65 ± 2.15 g/day, respectively. Corresponding values at the 3rd and 6th month post treatment were 1.90 ± 0.43 mg/dl (p = NS), 33 ± 7 ml/min (p = NS), 2.13 ± 1.13 g/day (p < 0.05) and 2.03 ± 0.64 mg/dl (p < 0.05), 32 ± 10 ml/min (p < 0.05), 2.74 ± 0.93 g/day (p = NS), respectively. When individual data were analyzed, five cases (29.4%) showed a U/P significant reduction of more than 50% of baseline value, while in 10 cases (58.8%) the graft function remained either stable (9 cases) or improved (1 case) at the end of treatment. Urinary NAG was elevated at the 3rd month, but stabilized thereafter. The Th1/Th2 intracytoplasmic cytokine pattern of peripheral blood CD4+ cells showed a significant decrease of cells bearing TNF-a (15.0 ± 14.4% vs 14.2 ± 17.0%, p < 0.05) and cells bearing IL-10 (1.60 ± 1.23% vs 0.90 ± 0.66%, p < 0.05) at the 3rd month. Conclusion: In this pilot study, PTX seemed to be temporarily effective in reducing proteinuria. The graft function was stabilized in more than half of patients at the end of follow-up.Correspondence to:
K.-H. Shu, MD Division of Nephrology, Department of Medicine Taichung Veterans General Hospital, No. 160, Sec. 3, Chung-Kang Rd., Taichung, Taiwan
Email: khshu@vghtc.gov.tw
Originals
Reduced-exposure cyclosporine is safe and efficacious in de novo renal transplant recipients treated with enteric-coated mycophenolic acid and basiliximab
Abstract
K. Budde, J.-L. Bosmans, J. Sennesael, M. Zeier, P. Pisarski, M. Schütz, W. Fischer, H.-H. Neumayer and P. Glander
1Department of Nephrology, Campus Charité Mitte Charité, niversitätsmedizin Berlin, Germany, 2Department of Nephrology, University Hospital Antwerp, Edegen/Antwerp, Belgium, 3Renal Unit, Academisch Ziekenhuis, Vrije Universiteit Brussel, Belgium, 4Department of Internal Medicine/Nephrology, University of Heidelberg, Germany, 5University of Freiburg, Germany, and 6Novartis Pharma GmbH, Nürnberg, Germany
Background: The lower limit of exposure to calcineurin inhibitors has not yet been established in de novo renal transplant patients receiving mycophenolic acid therapy with basiliximab. Methods: A 12-month, multicenter, randomized, open-label trial was carried out in which de novo renal transplant patients received enteric-coated mycophenolate sodium, cyclosporine microemulsion, steroids and basiliximab. Patients were randomized to receive standard-exposure (n = 45) or reduced-exposure (n = 44) cyclosporine, based on differing C2 target ranges, after the first month post-transplant. Results: Cyclosporine exposure gradually increased over the first month and was lower than previously recommended. Mean calculated creatinine clearance (primary end-point) was similar in the standard-exposure and reduced-exposure groups at month 6 (55.3 ± 3.2 ml/min and 61.5 ± 3.7 ml/min respectively, n.s.). There were 4 deaths but no death-censored graft losses, resulting in 95.5% patient and graft survival at one year in both groups. At 6 and 12 months, the incidence of biopsy-proven acute rejection was 17.8% and 17.8% in the standard-exposure group, and 13.6% and 15.9% in the reduced-exposure group. Adverse events were similar between treatment groups. Exploratory analyses could not identify a lower limit for the optimal CsA exposure range, but results suggested that high exposure at one year was associated with deteriorating renal function. Conclusions: These results indicate that enteric-coated mycophenolate sodium with reduced-exposure cyclosporine, steroids and basiliximab induction has an excellent therapeutic effect and is safe in de novo kidney transplant recipients. Lower C2 targets than previously recommended, particularly early post-transplant, do not appear to be associated with compromised efficacy.Correspondence to:
Dr. K. Budde Department of Nephrology Campus Charité Mitte Charité Universitätsmedizin Berlin Schumannstrasse 20/21 10117 Berlin, Germany
Email: klemens.budde@charite.de
Case Reports
Chronic myeloid leukemia-associated membranoproliferative glomerulonephritis that responded to imatinib mesylate therapy
Abstract
J.P. Dwyer, K.M. Yates, E.L. Sumner, W.J. Stone, Y. Wang, M.J. Koury, A.B. Fogo and R. Zent
1Division of Nephrology, 2Department of Medicine, 3Department of Pathology, Vanderbilt University Medical Center, 4Department of Medicine, Tennessee Valley Healthcare Veterans Affairs Hospital, Nashville, TN, USA
There is no known clinical association between chronic myelogenous leukemia (CML) and membranoproliferative glomerulonephritis (MPGN). We present a patient who was followed in the renal clinic for proteinuria of unknown etiology (3.2 g/24 h) and normal renal function who was diagnosed with CML as well as MPGN and acute renal failure at the same time. The patient’s renal function and proteinuria improved when his CML was treated with imatinib mesylate, suggesting that CML either caused or exacerbated existing MGPN. To the best of our knowledge, this is the first reported case of MPGN associated with CML that improved with imatinib mesylate therapy.Correspondence to:
R. Zent, MD, PhD Medical Center North, C3210 Vanderbilt University Medical Center Nashville, TN 37232, USA
Email: Roy.Zent@vanderbilt.edu
Case Reports
Renal involvement in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL)
Abstract
T. Kusaba, T. Hatta, T. Kimura, K. Sonomura, S. Tanda, N. Kishimoto, H. Kameyama, M. Okigaki, Y. Mori, N. Ishigami, T. Mizuno, M. Nakagawa and H. Matsubara
1Division of Hypertension and Nephrology, 2Division of Cardiology and Vascular Regenerative Medicine, Department of Medicine, and 3Research Institute for Neurological Diseases and Geriatrics, Department of Neurology and Gerontology, Kyoto Prefectural University of Medicine, Kyoto, Japan
Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a hereditary systemic arteriopathy presenting with migraines, mood disorders, focal neurologic deficits, recurrent ischemic attacks and dementia in young adults. The genesis of this disease relates to missense mutation of the Notch3 gene. We report here a newly identified CADASIL patient and discuss unique vascular lesions observed in the kidney. A 64-year-old female was admitted to our hospital for the investigation of proteinuria, hematuria and progressive neurological abnormalities. Her mother and brother died of cerebral infarction at a relatively young age despite a lack of apparent risk factors for arteriosclerosis. Over the past 4 months before admission, she had suffered from frequent transient ischemic attacks despite appropriate antiplatelet therapy. Blood examination revealed mild renal insufficiency and urinalysis revealed moderate protein excretion and dysmorphic hematuria. Magnetic resonance imaging of the brain revealed multiple infarcts and leukoencephalopathy. Histopathological analysis of the kidney revealed focal segmental mesangial proliferation, the loss and degeneration of arterial medial smooth muscle cells and arterial intimal thickening. Immunofluorescence analysis of glomeruli revealed IgA deposition in the mesangial area. Electron microscope analysis revealed electron-dense deposition also in the mesangial area. In addition, granular osmophilic material (GOM) was observed in the extraglomerular mesangial area and around the vascular smooth muscle cells. Genetic analysis of Notch3 revealed an R141C missense mutation and she was diagnosed with CADASIL complicated with IgA nephropathy. In immunohistological analysis, Notch3 stains were positive in vascular smooth muscle cells of the interlobular arteries and both afferent and efferent arterioles, and weak in the glomerular mesangial area. Antihypertensive treatment using angiotensin II receptor blocker and a low protein diet were initiated, and her urinary protein excretion decreased to 0.2 g/day. However, due to the progression of her neurological abnormalities, she became socially withdrawn. In CADASIL, GOM, abnormal accumulation of Notch3 ectodomain, is thought to induce the degeneration and loss of vascular smooth muscle cells and subsequent intimal thickening. Analysis of our cases provided that these morphological abnormalities were also observed in the CADASIL patient kidney.Correspondence to:
T. Kusaba, MD Division of Nephrology and Hypertensio Department of Internal Medicine Kyoto Prefectural University of Medicine 456 Kajii-cho Kamigyo-ku Kyoto-city, 602-8566, Japan
Email: fwnk5760@mb.infoweb.ne.jp
Case Reports
Successful use of cinacalcet HCl in a patient with end-stage renal failure and refractory secondary hyperparathyroidism due to parathyromatosis
Abstract
R. Unbehaun and W. Lauerwald
Nephrologische Gemeinschaftspraxis, Gera, Germany
We present the case of a 65-year-old male on long-term dialysis for end-stage renal failure, who developed persistent secondary hyperparathyroidism after subtotal parathyroidectomy, which proved refractory to treatment. Parathyromatosis, a rare cause of recurrent hyperparathyroidism, which may develop when tissue seeded into the neck during subtotal or total parathyroidectomy becomes hyperfunctioning [Maxwell and Winearls 1997], was diagnosed. The patient had excessively high levels of circulating parathyroid hormone (PTH), elevated serum calcium and deteriorating cardiovascular status. Repeated surgery and treatment with high-dose vitamin D failed to provide a sustained decrease in serum PTH levels. Administration of cinacalcet HCl, a second generation calcimimetic, at doses of 30 – 180 mg/day provided a gradual and sustained suppression of PTH (> 1,700 – 344 ng/l) without increasing the calcium-phosphate product.Correspondence to:
R. Unbehaun Nephrologische Gemeinschaftspraxis Straße des Friedens 122 07548 Gera, Germany
Email: rolf.wolf@gmx.de
Case Reports
Aborted sudden cardiac death in two patients with Bartter’s/Gitelman’s syndromes
Abstract
R. Scognamiglio, C. Negut and L.A. Calò
Department of Clinical and Experimental Medicine, Matabolic Cardiology, and 2Clinica Medica 4, University of Padova, Italy
Sudden cardiac death (SCD) occurs in patients with Bartter/Gitelman syndromes. Hypokalemia and QTc prolongation are suggested mechanisms. SCD, however, has also been described at normal potassium concentration. This study reports the cases of one Bartter and one Gitelman patient, who experienced an aborted SCD, and evaluates the possible mechanisms of life-threatening arrhythmias and sudden death in these patients in order to contribute to a systematic screening/treatment protocol for them. After the episode of aborted SCD the patients underwent echocardiographic analysis at resting and during isometric exercise, complete electrophysiologic study and coronary angiography. Ventricular arrhythmias were not inducible during the electrophysiologic study, and coronary vessels were normal at angiography. Exercise induced LV dysfunction with reduction of cardiac index, paradoxical QTc prolongation and prolongation of QTc during nocturnal vagal stimulation in addition to hypokalemia might be identified as possible additional triggering factors for aborted SCD in these patients, leading to the conclusion that hypokalemia might not be the only factor capable of precipitating SCD in Bartter’s/Gitelman’s syndromes. The identification and recognition of other possible triggering mechanisms is extremely important in these patients and suggests the need for a systematic cardiac screening/treatment protocol for an effective prevention.
Correspondence to:
L.A. Calò, MD, PhD Department of Clinical and Experimental Medicine Clinica Medica 4, University of Padova Via Giustiniani, 2 35128 Padova, Italy
Email: renzcalo@unipd.it
Letters to the Editor
Reply to Sheth et al. (Clin Nephrol 65, 134-137)
Abstract
Y. Heled and P. Deuster
Letters to the Editor
New pharmacoeconomic option in uremic anemia management
Abstract
V. Savica, L. Mantovani, D. Santoro, B. Ricciardi and G. Bellinghieri
