Volume 69, No. 2/2008(February)
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 Clinical Nephrology
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Analysis and Survey
Interpreting regulatory authority guidance on immunosuppressive therapy for renal transplantation: a response to the UK’s National Institute for Clinical Excellence (NICE)
Abstract
A.N. Warrens, K. Baboolal, L. Buist, C. Dudley, G. Koffman, G. Lipkin, N. Parrott, S.H. Powis, P. Sweny and M. Raftery
1Department of Immunology and Renal Medicine, Imperial College London and Hammersmith Hospitals NHS Trust, 2Department of Nephrology and Transplantation, University Hospital of Wales, Cardiff, 3Department of Renal Transplantation, Western Infirmary, Glasgow, 4Renal Unit, Southmead Hospital, Westbury-on-Trym, Bristol, 5Renal and Transplant Unit, Guys and St. Thomas Hospital NHS Trust, Guy’s Hospital, London, 6Department of Renal Medicine, University Hospital Birmingham, Queen Elizabeth Hospital, Queen Elizabeth Medical Centre, Birmingham, 7Renal Transplant Unit, Manchester Royal Infirmary, Manchester, 8Centre of Nephrology, Royal Free and University College Medical School, London, 9Department of Renal Medicine and Transplantation, Royal London Hospital, Whitechapel, London, UK
Aims: A group of UK consultant transplant physicians and surgeons (the Consensus Group) met to consider the implications and interpretation of the National Institute for Clinical Excellence’s (NICE) Technology Appraisal No. 85 on the use of immunosuppressive therapy for renal transplantation in adults. Methods: This group considered what the implications of these guidelines might be for clinical practice and consensus was developed on those areas which were potentially open to different interpretations. A wider survey of nephrologists and transplant surgeons throughout the UK was also performed to gauge the impact of the NICE recommendations. Results and conclusions: The outcome of the discussions of the Consensus Group are presented with particular reference to the recommendations of how to respond to calcineurin inhibitor (CNI) intolerance. The survey suggested that the publication of this NICE guidance has resulted in relatively few changes in prescribing practice: UK transplant centers continue to use a wide range of locally developed protocols for immunosuppressive therapy. These include the use of agents such as mycophenolate mofetil (MMF) and sirolimus, despite the fact that both drugs appeared to receive only conditional acceptance in the NICE Guidelines.Correspondence to:
Dr. A.N. Warrens, Department of Immunology, Imperial College London, Hammersmith Campus, Ducane Road, London W12 0HS, UK
Email: a.warrens@imperial.ac.uk
Review
Early and late fistula failure
Abstract
C. Mercado, L. Salman, G. Krishnamurthy, K. Choi, S. Artikov, I. Thomas, D. Merrill and A. Asif
Division of Nephrology Section of Interventional Nephrology, University of Miami Miller School of Medicine, Miami, FL, USA
While an arteriovenous fistula is the best available form of hemodialysis access, a significant number of fistulae never mature to support dialysis (early failure) or fail after successful use (late failure). Venous stenosis and the presence of accessory veins are the two main causes of early failure. Recent data have demonstrated that a great majority of such AVFs can be successfully salvaged by percutaneous interventions and become available for dialysis. In addition to early failure, a great majority of thrombosed fistulae can also be successfully declotted using simple endovascular techniques. Fistula thrombosis has clear differences from graft clotting. First of all, cannulation of a clotted fistula is more challenging. Secondly, thrombus volume present in a clotted fistula can be quite variable. A fistula might thrombose with minimal or no thrombus. At other times, there is moderate-to-severe thrombus burden that accompanies fistula clotting. While percutaneous balloon angioplasty to correct the underlying stenosis might be all that is needed to declot a fistula with no thrombus, thromboaspiration is required to successfully declot a fistula with moderate thrombus. Salvage of early and late fistula failure is critical to minimize catheter use and is supported by the National Kidney Foundation Dialysis Outcomes Quality Initiative. Additionally, it is a powerful strategy to maximize AVF use in hemodialysis patients.Correspondence to:
A. Asif, MD, Associate Professor of Medicine, Director Interventional Nephrology, University of Miami Miller School of Medicine, Miami, FL 33136, USA
Email: Aasif@med.miami.edu
Originals
Is single-daily low-dose cyclosporine therapy really effective in children with idiopathic frequent-relapsing nephrotic syndrome?
Abstract
S. Fujinaga, Y. Ohtomo, T. Someya, T. Shimizu, Y. Yamashiro and K. Kaneko
1Division of Nephrology, Saitama Children’s Medical Center, Saitama,
2Department of Pediatrics, Juntendo Nerima Hospital, Tokyo,
3Department of Pediatrics, Juntendo University School of Medicine, Tokyo and 4Departme
Background: A recent study on renal transplant patients has shown that a single dose of cyclosporine (CsA) has added the advantage of decreasing dosages and adverse effects, while maintaining graft function. However, the efficacy of this regimen in children with idiopathic frequent-relapsing nephrotic syndrome (NS) remains controversial. Methods: 20 children with steroid-dependent NS or CsA-dependent NS (18 with minimal change disease, MCD and 2 with focal segmental glomerulosclerosis, FSGS) were enrolled in this prospective study. CsA was commenced at 1.5 – 2 mg/kg, given as a single daily dose before breakfast, and the dose was adjusted to reach 2 hours post-dose CsA levels (C2) of 600 – 800 ng/ml. Results: In 9 out of 18 patients with MCD, treatment with single-daily CsA for a median of 13 months (range 7 – 21) resulted in a reduction of mean minimum prednisolone (PSL) dose from 1.1 ± 0.55 to 0.04 ± 0.09 mg/kg on alternate days (p < 0.01), and the median relapse rate from 1.3 (1.1 – 2.5) to 0 (0 – 0.2) episodes/6 months (p < 0.01). Of them, PSL could be weaned off in 7 patients (4 of 6 with steroid-dependent NS, only 3 of 14 with CsA-dependent NS) without relapse of NS while on this therapy. However, 11 out of 20 were considered to have treatment failure: 1 with steroid-dependent NS and 10 with CsA-dependent NS. In 2 patients having FSGS, this method showed no beneficial effects. In 18 patients with MCD, relapse free ratio on single-daily CsA therapy was significantly higher in patients whose average C2 levels were greater than 700 ng/ml (p < 0.05). Conclusions: Our experience demonstrates that single-daily low-dose CsA therapy maintaining C2 levels greater than 700 ng/ml may be effective in children with steroid-dependent NS or MCD, with no relapse. In contrast, the usefulness of this regimen in children with CsA-dependent NS appears to be limited.Correspondence to:
S. Fujinaga, MD, PhD, Division of Nephrology, Saitama Children’s Medical Center, 2100 Magome, Iwatsuki-ward, Saitama-city Saitama 339 8551, Japan
Email: f_shuich@d2.dion.ne.jp
Originals
Treatment of lupus nephritis and primary glomerulonephritis with enteric-coated mycophenolate sodium
Abstract
C. Kitiyakara, V. Ophascharoensuk, S. Changsirikulchai, A. Ingsathit, P. Tankee, A. Sangpanich and V. Sumethkul
1Department of Medicine, Ramathibodi Hospital, Mahidol University, Bangkok, 2Department of Medicine, Faculty of Medicine, Chiang Mai University, Chiang Mai, 3Department of Medicine, Faculty of Medicine, Srinakharinwirot University, Bangkok, Thailand
Aims: Mycophenolate mofetil is an effective therapy for lupus nephritis (LN) and other glomerulonephritis (GN). However, gastrointestinal (GI) complications can limit its use. Enteric-coated mycophenolate sodium (EC-MPS) has been designed to reduce GI adverse events, but it has not been fully investigated in the treatment of GN. Methods: Patients with LN and primary GN who had received EC-MPS were studied for effects on renal function. Results: 30 subjects (17 LN, 13 primary GN) were studied. EC-MPS decreased proteinuria in both LN and GN. In LN, 16 patients had EC-MPS as induction therapy. Of these, 8 patients achieved complete remission (CR), 4 had partial remission (PR) and 1 improved renal function. In primary GN, CR was achieved in 4 out of 5 with minimal change disease, but only 1 did not relapse. PR was achieved in 1 of 4 patients with membranous glomerulopathy, 2 out of 2 patients with focal segmental glomerulosclerosis and 1 out of 2 patients with IgA nephropathy. Infections, anemia and alopecia were observed, but no patient had GI side effects. Conclusions: EC-MPS is effective in LN, but not as effective in primary GN. The risk of GI side effects appears to be low, but other side effects can still occur.Correspondence to:
C. Kitiyakara, MB BS MRCP, Department of Medicine Ramathibodi Hospital, Mahidol University, Bangkok 10400, Thailand
Email: kitiyakc@yahoo.com
Originals
Darbepoetin-alfa in renal-transplant patients: an observational monocentric study
Abstract
D. Ribes, N. Kamar, J. Guitard, L. Esposito and L. Rostaing
Nephrology and Kidney Transplantation Department, CHU Rangueil, Toulouse University Hospital, France
Background: Anemia, frequent in post-transplant patients, has been associated with cardiovascular outcomes. Although recombinant human erythropoietin (rHuEPO) is used in post-transplant anemic patients, little information is available concerning the use of darbepoetin-alfa (DA) in this population. Methods: Eligible patients had been recipients of a kidney graft for > 3 months, had anemia and chronic renal failure, but no iron deficiency. 38 patients, not previously treated by rHuEPO (Group 1), were given DA, and 35 rHuEPO-treated patients (Group 2) were switched to DA according to European Summary of Product Characteristics. Only the subcutaneous route was used. Dose adjustments were done to maintain Hb at 11 – 13 g/dl. Hb levels and DA dosage were assessed at baseline, and at Months 3 and 6. Results: Mean age (± SD) of patients was 47.7 (± 13.4) years (53% male). Mean duration of transplantation was 8.5 (± 5.5) years and mean creatinine clearance was 42.5 (± 19.8) ml/min. In Group 1, mean Hb became increased by +1.27 g/dl (95% CI 0.61, 1.94) and mean DA dose was decreased by 44% between baseline and M6. In Group 2, mean Hb and DA dose remained stable between baseline and M6. Hb response to DA appeared faster in patients who had received a transplant for less than 3 years, and lower in patients who had received a transplant more than 12 years previously. Conclusions: DA effectively corrected anemia in renal-transplant patients, in previously treated patients and in EPO-naive patients. DA was also found to be well-tolerated.Correspondence to:
Prof. L. Rostaing, Department of Nephrology and Multiorgan Transplantation, CHU Rangueil, 31059 Toulouse, France
Email: rostaing.l@chu-toulouse.fr
Originals
Reversible primary hypothyroidism in Japanese patients undergoing maintenance hemodialysis
Abstract
T. Sanai, T. Inoue, K. Okamura, K. Sato, K. Yamamoto, T. Abe, K. Node, K. Tsuruya and M. Iida
1Department of Cardiovascular and Renal Medicine, Saga University Faculty of Medicine, Saga, 2Department of Nephrology, Abe Clinic, 3Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, 4Department of Internal Medicine, Saiseikai Yahata Hospital, Fukuoka, Japan
Background/Methods: The presence or absence of hypothyroidism was assessed in 152 consecutive Japanese patients with end-stage renal disease on hemodialysis. Eight patients who had undergone treatment for thyroid disease before starting hemodialysis therapy, and 3 patients with amyloidosis due to rheumatoid arthritis were excluded. Results: Of the remaining 141 hemodialysis patients, 14 (9.9%) (9 males and 5 females, aged 69.1 ± 8.8 years with a mean duration of hemodialysis of 69 ± 51 months) were in a hypothyroid state, defined as a thyroid-stimulating hormone (TSH) level > 5 mU/l. Antithyroid peroxidase antibodies were positive in only 1 of the 14 patients, while antithyroglobulin antibodies were negative in all of these patients. After iodide restriction, the serum TSH level decreased in all the patients from a mean of 16.49 ± 22.80 to 4.44 ± 3.35 mU/l after 1 month, 4.25 ± 2.24 mU/l after 2 months and 3.97 ± 2.22 mU/l after 3 months. The 3 months of iodide restriction were also associated with decreases in systolic blood pressure (142 ± 19 to 125 ± 16 mmHg, p < 0.05), diastolic blood pressure (79 ± 13 to 72 ± 9 mmHg, p < 0.05) and thyroid gland volume estimated by ultrasonography (13.7 ± 6.3 to 11.6 ± 5.2 ml, p < 0.05). Conclusion: A high prevalence of reversible primary hypothyroidism was found in end-stage renal disease patients on hemodialysis. Retention of excess iodide may be the mechanism responsible for reversible hypothyroidism rather than immunological perturbations. It is, therefore, recommended to attempt iodide restriction before starting l-thyroxine replacement therapy.Correspondence to:
T. Sanai, MD, The Department of Cardiovascular and Renal Medicine, Saga University Faculty of Medicine, 5-1-1 Nabeshima, Saga 849-8501, Saga, Japan
Email: sunny@cc.saga-u.ac.jp
Originals
Chronic hypotension in hemodialysis patients: role of functional vascular changes and vasodilator agents
Abstract
E. Coll, M. Larrousse, A. de la Sierra, S. Collado, W. Jiménez and A. Cases
1Nephrology, 2Hypertension Units, 3Centre de Diagnostic Biomedic, Hospital Clínic, Universitat de Barcelona, Catalonia, Spain
Aims: The aim of this study was to evaluate the hemodynamic pattern, vascular compliance, as well as the levels of vasoregulatory hormones and markers of inflammation and oxidative stress in a group of chronic hypotensive (CH) patients undergoing hemodialysis (HD) and to compare them with a group of normotensive HD patients. Material and methods: 14 normotensive and 10 CH hemodialysis patients were included in the study. Hemodynamic characteristics were evaluated by means of the pulse waveform analysis. Plasma levels of nitrites, interleukin-6 (IL-6), malondialdehyde (MDA), PTH-related peptide (PTHrp), catecholamines, angiotensin II and endothelin were measured. Results: Blood pressure (BP) and peripheral vascular resistances (PVR) were lower in the hypotensive group (p < 0.001 and p = 0.005, respectively), whereas cardiac output was similar in both groups. Large (C1) (p = 0.001) and small (C2) (p = 0.022) artery elasticity indices were higher in hypotensive patients. In the whole group, C1 and C2 inversely correlated with mean BP (MBP). Plasma levels of nitrites (p = 0.011) were higher in hypotensive patients and inversely correlated with MBP (r = –0.516, p = 0.012). Time on HD correlated with plasma nitrites (r = 0.478, p = 0.024) and inversely with MBP (r = –0.598, p = 0.003). Conclusions: CH in HD patients is characterized by decreased PVR, a preserved cardiac output and greater vascular compliance. CH is associated with longer time on HD and higher plasma levels of nitrites/nitrates, suggesting that an enhanced production of nitric oxide induced by long-term HD, could be involved in CH. These findings suggest that functional vascular changes, likely related to an enhanced production of vasodilator agents, are responsible for CH in HD patients.Correspondence to:
A. Cases, MD, Nephrology Unit, Hospital Clínic, Villarroel 170, 08036 Barcelona, Spain
Email: acases@clinic.ub.es
Originals
Serum β2 microglobulin (β2MG) level is a potential predictor for encapsulating peritoneal sclerosis (EPS) in peritoneal dialysis patients
Abstract
K. Yokoyama, H. Yoshida, N. Matsuo, Y. Maruyama, Y. Kawamura, R. Yamamoto, K. Hanaoka, M. Ikeda, H. Yamamoto, M. Nakayama, Y. Kawaguchi and T. Hosoya
1Division of Kidney and Hypertension, Department of Internal Medicine,
Jikei University School of Medicine, Tokyo and 2Research Division of Dialysis and Chronic Kidney Disease, Tohoku University Graduate School of Medicine, Sendai Miyagi, Japan
Background: Encapsulating peritoneal sclerosis (EPS) is a serious complication in patients undergoing continuous ambulatory peritoneal dialysis (CAPD) or automated peritoneal dialysis (APD). The aim of this study was to find a predictor for EPS. Methods: Patients with EPS who were detected by a historical cohort study using clinical data of 219 CAPD patients at our hospital. We recruited 25 patients with EPS who were compared with the patients without EPS who were matched for age and dialysis period as controls. Differences between the two groups (non-EPS group and EPS group) with respect to age, gender, primary disease, dialysis period, serum urea nitrogen, serum creatinine, β2MG, CRP and PET (peritoneal equilibration test) category (determined by the peritoneal function testing) were analyzed. Results: According to multiple regression analysis, a high β2MG level was an independent risk factor for EPS (odds ratio 1.162, 95% confidence interval 1.026 – 1.317, p = 0.018). Other clinical markers did not show positive significance. A ROC (receiver operating characteristic) curve was prepared to evaluate the suitability of β2MG measurement as a screening test. The sensitivity was 64% and the specificity was 80% when a β2MG level of 37.0 mg/dl was taken as the cut-off value. The odds ratio for occurrence of EPS was 8.8 when β2MG level was in the range of 35 – 40 mg/dl, 13.5 when β2MG level was > 40 mg/dl and 1 when β2MG level was < 30 mg/dl. Conclusion: These findings suggest that β2MG is useful as a screening test for the onset of EPS, and that β2MG and accumulation of middle-molecular uremic substances may be related to the pathophysiology of EPS.Correspondence to:
K. Yokoyama, MD, Division of Kidney and Hypertension, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo, Japan
Email: keitaro@jikei.ac.jp
Case Reports
Pacemaker infection with propionibacterium and a nephritic sediment
Abstract
M. Kimmel, U. Kuhlmann and D.M. Alscher
Department of General Internal Medicine and Nephrology, Robert Bosch Hospital, Stuttgart, Germany
Like any other implanted foreign body, the different parts of pacemakers (pulse generator pocket, epicardial or transvenous leads) can become infected. Staphylococcus aureus and coagulase-negative staphylococci are the causative organisms in most of the cases (65 – 75%), propionibacterium is described to be involved in only 1% of cases. This report describes a case of nephritic sediment in a young female patient with a pacemaker implantation 9 years ago because of a third degree atrioventricular block, in which a battery exchange was necessary 2.5 years ago. This young patient was referred from a nephrologist for renal biopsy because of a nephritic sediment and diffuse complaints including low-grade fever with a suspected underlying autoimmune disease. The laboratory examinations were all negative with the exception of a diminished C3 complement level. Blood cultures were positive for propionibacterium, but the microbiologists were considering it as a contamination. 11 more blood cultures collected thereafter were all positive and a transesophageal ultrasound revealed a small vegetation at 1 of the transvenous electrodes of the pacemaker. Because of a penicillin allergy she was treated with clindamycin, and the blood cultures were negative after a few days. After a full course (7 weeks) of antibiotic treatment the C3 complement level normalized and a series of 10 blood cultures remained negative 10 – 15 days after discontinuation of antibiotic therapy. Discussing all the differential diagnoses of a nephritic sediment combined with hypocomplementemia, positive blood cultures and a vegetation on a pacemaker electrode in the transesophageal ultrasound, the diagnosis of an immune complex glomerulonephritis due to a propionibacterium pacemaker infection needs no confirmation by renal biopsy.Correspondence to:
Dr. M. Kimmel, Robert-Bosch-Hospital, Auerbachstraße 110, 70376 Stuttgart, Germany
Email: vm.kimmel@t-online.de
Case Reports
Type B insulin resistance syndrome induced by increased activity of systemic lupus erythematosus in a hemodialysis patient
Abstract
Y. Nagayama, H. Morita, D. Komukai, S. Watanabe and A. Yoshimura
Department of Medicine, Division of Nephrology, Showa University Fujigaoka Hospital, Yokohama, Japan
A-23-year-old woman with systemic lupus erythematosus (SLE) and on hemodialysis for 5 years was admitted to the hospital because of severe general fatigue. On admission, laboratory findings showed that fasting plasma glucose levels ranged from 25 – 45 mg/dl, a test for antinuclear antibody (ANA) was positive (1 : 320, with a discrete-speckled pattern), serum C3 and C4 complement and CH50 level were remarkably depressed (22.5 mg/dl, < 5.1 mg/dl, < 13 U/ml, respectively), and insulin receptor antibodies were present (89.3% inhibition of 125I-insulin binding to cultured human lymphocytes by a binding inhibition assay). She also showed acanthosis nigricans. The patient was diagnosed to suffer from a Type B insulin resistance syndrome. The patient’s serum insulin and C-peptide levels were markedly elevated during hypoglycemia without insulinoma (2,313.8 µU/ml, 55 ng/ml, respectively). Interestingly, not only postprandial hyperglycemia but also fasting hypoglycemia was observed. Treatment with steroid pulse and subsequent high dose of prednisolone resulted in restoration of euglycemia associated with disappearance of insulin receptor antibodies and improvement of both serum hypocomplementemia and the high titer of ANA. Later, the patient’s course was complicated by hemorrhagic shock due to duodenal ulcer and she died of subsequent pneumocystis carinii pneumonia. The presented patient developed a Type B insulin resistance syndrome induced by increased activity of SLE after she had been treated with hemodialysis for 5 years. This is the first reported case with such a history and constellation. It is recommended that SLE patients on dialysis are carefully followed-up by clinical and serological monitoring. Type B insulin resistance syndrome must be considered in the differential diagnosis of hypoglycemia in SLE patients on dialysis.Correspondence to:
Y. Nagayama, MD, Department of Medicine Division of Nephrology, Showa University Fujigaoka Hospital, 1-30 Fujigaoka, Aoba-ku, Yokohama 227-8501, Japan
Email: ynagayama1147uomo@ybb.ne.jp
Case Reports
Association of INVS (NPHP2) mutation in an adolescent exhibiting nephronophthisis (NPH) and complete situs inversus
Abstract
M. Okada, K. Sugimoto, Y. Shimada, S. Fujita, H. Yanagida, K. Yagi and T. Takemura
Department of Pediatrics, Kinki University School of Medicine, Osaka-Sayama, Japan
Cystic kidney disease has been linked to mutations in the Invs gene in mice with an inversion of embryonic turning (inv/inv) and the INVS (NPHP2) gene in human infantile nephronophthisis (NPH). Infantile NPH shows marked cyst formation in contrast to other forms of NPH and rapidly progresses to end-stage renal failure (ESRD) before 5 years of age. In this report, we describe an adolescent with a mutation in INVS who had preservation of his renal function beyond infancy. The patient showed findings of NPH with mild renal insufficiency together with situs inversus. He also exhibited a series of features consistent with Jeune syndrome involving asphyxiating thoracic dystrophy, heart failure and hypertension prior to advanced renal insufficiency. Based upon these features, our patient is likely to have the combined clinical features of infantile NPH with Jeune syndrome. Genetic analysis for INVS disclosed a heterozygous mutation of TrG at position rs7024375 in the 5’UTR of INVS in the patient and his mother, while no abnormalities were found in any of the 17 exons of INVS or NPHP1, 3 and 4. To our knowledge, this is the first patient possessing a genetic alteration in INVS who had preservation of renal function past childhood. This study suggests that our patient may be a compound heterozygote for infantile NPH and Jeune syndrome, because both these disorders are transmitted mainly as an autosomal-recessive trait.Correspondence to:
T. Takemura, MD, Department on Pediatrics, Kinki University School of Medicine, 377-2 Ohno-higashi, Osaka-Sayama, 589-8511, Japan
Email: tsukasa@med.kindai.ac.jp
Letter to the Editor
Gross hematuria as an unusual manifestation in minimal change nephrotic syndrome
Abstract
H. Matsukura, T. Fuchizawa, O. Higuchi and T. Miyawaki
1Department of Pediatrics, Saiseikai Toyama Hospital, Toyama, 2Department of Pediatrics, Himi City Hospital, Himi city, 3Department of Pediatrics, Faculty of Medicine, University of Toyama, Toyama, Japan
Correspondence to:
Dr. H. Matsukura, Department of Pediatrics Saiseikai Toyama Hospital,
33-1 Kusunoki, Toyama, 931-8533, Japan
Email: matsukura-npr@umin.net
