Volume 65, No. 5/2006(May)
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 Clinical Nephrology
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Originals
Prednisolone and azathioprine in membranous nephropathy: a 10-year follow-up study
Abstract
D.S. Goumenos, M. Ahuja, P. Davlouros, A.M. El Nahas and C.B. Brown
1Nephrology, Internal Medicine, University Hospital, Patras, Greece, 2Sheffield Kidney Institute, Sheffield Teaching Hospitals, Northern General Campus, Sheffield, UK, 3Cardiology, Internal Medicine, University Hospital, Patras, Greece
Background: Idiopathic membranous nephropathy (IMN) is the most common cause of nephrotic syndrome in adults. Although its clinical course is usually benign, some patients develop chronic renal failure. Combination of corticosteroids with cytotoxic drugs and cyclosporin have been used in the treatment of the disease. Conflicting results are reported with the use of prednisolone and azathioprine. In this study, the effect of treatment with prednisolone and azathioprine and the parameters related to a poor outcome over a follow-up period of 10 years is estimated. Methods: 50 patients were included in this study; 33 were treated with prednisolone (initially 60 mg/day) and azathioprine (initially 2 mg/kg body weight/day) in gradually reduced doses for 26 ± 9 months, whereas 17 patients received no immunosuppressive drugs. The clinical course was estimated using the end-points of doubling of baseline serum creatinine and/or end-stage renal failure (ESRF). The contribution of clinical and histological parameters in the clinical outcome was examined by univariate and multivariate analyses. Results: Doubling of baseline serum creatinine was observed in 20 of 50 patients (40%), 14 from treated and 6 from the untreated group (42% vs. 35%, p = NS). ESRF developed in 10 of 50 patients (20%), 7 from treated and 3 from the untreated group (21% vs. 18%, p = NS). Most patients from both groups who reached the end-points had impaired renal function at presentation and persistent nephrotic syndrome during the follow-up period. Both parameters were identified as independent risk factors related to an unfavorable clinical outcome. No difference in the remission rate of nephrotic syndrome was observed between treated and untreated patients (51% vs. 58%, p = NS). Conclusion: Treatment with prednisolone and azathioprine seems to be of no long-term benefit in ameliorating the clinical course of nephrotic patients with membranous nephropathy. Thus, other therapeutic regimens including cyclophosphamide, chlorambucil or cyclosporin should be used in nephrotic IMN patients with poor prognostic features. Correspondence to:
D.S. Goumenos, MD
Department of Internal Medicine, Nephrology
University Hospital
26 500 Patras, Greece
Email: dgoumenos@med.upatras.gr
Originals
Apoptosis, proliferation and inflammatory infiltration in ANCA-positive glomerulonephritis
Abstract
R. Kettritz, S. Wilke, S. von Vietinghoff, F. Luft and W. Schneider
HELIOS-Klinikum Berlin, Franz Volhard Clinic and Department of Pathology, Medical Faculty of the Charité, Humboldt University, Berlin, Germany
Aims: Antineutrophil cytoplasmic antibodies (ANCA) are detected in most patients with crescentic glomerulonephritis and necrotizing small vessel vasculitis. ANCA cause renal inflammation and proliferation. Apoptosis is necessary for resolution of inflammation. We studied apoptosis, apoptosis-regulating proteins, proliferation and infiltration with ANCA target antigen containing neutrophils and monocytes in renal biopsies from ANCA patients and disease controls. Methods: Skin biopsies from patients with leukocytoclastic vasculitis (n = 6) and renal biopsies from patients with ANCA vasculitis (n = 10), ANCA-negative crescentic glomerulonephritis (CGN, n = 7), mesangioproliferative GN (n = 6), post-streptococcal GN (PSGN, n = 4), diabetic nephropathy (n = 6) and minimal change nephropathy (MCNP, n = 6) were evaluated by immunohistochemistry. Biopsies were stained for apoptosis (TdT-mediated UTP nick-end labeling, TUNEL), proliferation (Ki-67), neutrophils (NP 57), and monocytes (KP 1). We also evaluated Fas and Bcl-2 expression. Results: Apoptosis was common in leukocytoclastic vasculitis skin biopsies, but was rare in renal biopsies. ANCA-positive NCGN showed the lowest apoptosis rate, similar to MCNP and diabetic nephropathy. The highest apoptosis rate was seen in PSGN. The highest glomerular Bcl-2 expression was present in ANCA-positive biopsies. The Bcl-2/TUNEL ratio was significantly increased in ANCA-positive necrotizing crescentic glomerulonephritis (NCGN) compared to ANCA-negative CGN and PSGN. When proliferation (Ki-67) and apoptosis were expressed as a ratio, we observed the highest index in biopsies from patients with ANCA-positive NCGN because of their low apoptosis rates. Finally, the glomerular inflammatory infiltrate in ANCA-positive NCGN showed a high percentage of neutrophils. Conclusions: These preliminary results suggest an imbalance between apoptosis and proliferation, favoring proliferation, in renal biopsies from ANCA-positive NCGN patients.Correspondence to:
Prof. Dr. R. Kettritz
Charité Campus Buch
Franz Volhard Klinik
Wiltbergstraße 50
13125 Berlin, Germany
Email: kettritz@fvk-berlin.de
Originals
No indication for activation of exogenous retroviruses in patients with renal allograft rejection
Abstract
C.A. Seemayer1, J. Böni2, J. Steiger3, J. Schüpbach2 and M.J. Mihatsch1
1Institute for Pathology, University Hospital Basle, 2Swiss National Center for Retroviruses, University of Zurich, 3Department of Nephrology, University Hospital Basle, Switzerland
Aim: Reactivation of latent BK virus in kidney-transplanted patients results in severe graft dysfunction. The role of retroviruses infecting also latently target cells is not investigated so far in this setting. We determined the presence or induction of retroviruses in sera of immunosuppressed patients with renal allografts at the timepoint of organ rejection or ongoing polyomavirus nephropathy. Patients and methods: Sera of patients with acute kidney rejection or polyomavirus nephropathy (n = 25) and controls (n = 8) were tested for reverse transcriptase activity by the ultrasensitive product enhanced reverse transcriptase (PERT) assay. In parallel, kidney biopsies were investigated for histological signs of kidney rejection or polyomavirus nephropathy confirmed by either immunofluorescence or immunohistochemistry. Results: None of the investigated sera, specifically those of patients with ongoing BK virus nephropathy, indicated reverse transcriptase activity. Conclusion: Our results do not support the idea of the induction of known or unknown retroviruses in patients with kidney transplantation, even under highly immunosuppressive therapies.Correspondence to:
Prof. Dr. M.J. Mihatsch
Institute for Pathology
Cantonal Hospital
University of Basle
Schönbeinstraße 40
CH-4003 Basel, Switzerland
Email: mjmihatsch@uhbs.ch
Originals
Changes in total parathyroid hormone (PTH), PTH-(1-84) and large C-PTH fragments in different stages of chronic kidney disease
Abstract
J. Herberth, A. Fahrleitner-Pammer, B. Obermayer-Pietsch, P. Krisper, H. Holzer, H.H. Malluche and H. Dobnig
1Division of Nephrology, Bone and Mineral Metabolism, University of Kentucky, Lexington, KY, USA, 2Division of Endocrinology and Nuclear Medicine, Department of Internal Medicine, Medical University, Graz, Austria and 3Division of Nephrology, Department of Internal Medicine, Medical University, Graz, Austria
Introduction: Loss of renal function is accompanied by progressive increase in serum levels of intact parathyroid hormone (iPTH) in patients with end-stage renal disease (ESRD). There is a paucity of data regarding levels of PTH-(1-84) and its large carboxyl-terminal fragments (large C-PTH fragments) and progressive loss of kidney function in patients with chronic kidney disease (CKD). The current study was undertaken to describe the glomerular filtration rate (GFR)-dependent plasma concentrations of PTH-(1-84) and related large C-PTH fragments in adult patients with CKD by using different commercially available PTH assays. Methods: We studied 80 Caucasian patients with CKD stages 1 – 5 without renal replacement therapy. Creatinine clearance was calculated by the Modification of Diet in Renal Disease (MDRD) formula. Levels of iPTH were determined by second-generation assays (iPTH Elecsys® system, Roche Diagnostics; DUO total iPTH, Scantibodies Laboratory, Inc.; iPTH, Nichols Institute Diagnostics). Third-generation assays were used to measure PTH-(1-84) (CAP (cyclase activating PTH), Scantibodies; Bio-Intact PTH, Nichols). Levels of large C-PTH fragments and ratios of PTH-(1-84)/large C-PTH fragments were calculated and statistical analyses performed. Results: Levels of iPTH and PTH-(1-84) showed CKD stage-dependent increases. Variations among the assays increased with progressive loss of kidney function. The assay from Scantibodies showed a GFR-dependent decrease of the ratio 1-84 PTH / large C-PTH fragment that was not observed with the Nichols assay. Conclusion: Increasing variations among the assays with progression of CKD emphasize the fact that the interpretation of measurements must take into consideration the specific assay. We found evidence for a possible preferential increase of the level of large C-PTH fragments over 1-84 PTH in a CKD stage-dependent manner (Scantibodies). The clinical implications of this finding have to be further evaluated by bone biopsy studies.
Correspondence to:
J. Herberth, MD
Division of Nephrology, Bone and Mineral Metabolism
Albert B. Chandler Medical Center
University of Kentucky
800 Rose Street, MN-564
Lexington, KY 40536, USA
Email: jherb2@uky.edu
Originals
Differential effects of very high doses of doxercalciferol and paricalcitol on serum phosphorus in hemodialysis patients
Abstract
H.E. Joist, S.N. Ahya, K. Giles, K. Norwood, E. Slatopolsky and D.W. Coyne
1Renal Division, Department of Internal Medicine, and the Chromalloy American Kidney Center at Washington University School of Medicine, St. Louis, MO, and 2Northwestern Memorial Hospital, Chicago, IL, USA
Background: Treatment of secondary hyperparathyroidism (SHPT) includes use of calcitriol (1,25D3) to suppress parathyroid hormone (PTH), but dosing of 1,25D3 is limited by the development of hypercalcemia and a high calcium × phosphorus (Ca × P) product due to gut absorption of calcium and phosphorus as well as enhanced bone resorption. The vitamin D analog 19-Nor-1,25(OH)2-vitamin D2 (paricalcitol) and the prohormone 1a-OH-vitamin D2 (doxercalciferol) have been proposed as alternatives which may cause less hypercalcemia and elevated Ca × P, while still suppressing PTH. Methods: We performed a prospective study to assess the acute bone mobilization effects of very high doses of paricalcitol and doxercalciferol. 13 hemodialysis patients received 160 mcg of paricalcitol and 120 mcg of doxercalciferol on 2 separate occasions in a research center while on a low calcium, low phosphorus diet, and sevelamer alone as a phosphorus binder. Changes in Ca, PO4, and PTH were measured over 36 h. Results: Serum phosphorus rose faster, and peaked significantly higher at 36 h following doxercalciferol (2.12 ± 0.11 mmol/l) than paricalcitol (1.85 ± 0.07 mmol/l; p = 0.025). Ca × P product also rose more following doxercalciferol than paricalcitol, and peaked higher at 36 h (5.02 ± 0.26 vs. 4.54 ± 0.21 mmol/l; p = 0.061). In contrast, suppression of PTH at 36 h was comparable (63% after paricalcitol and 65% with doxercalciferol). Conclusion: Consistent with animal studies, paricalcitol provides profound PTH suppression, while stimulating bone resorption and/or intestinal absorption less than doxercalciferol, resulting in less elevation of serum phosphorus and Ca × P.Correspondence to:
D.W. Coyne, MD
Washington University School of Medicine
660 S. Euclid Ave.
Campus Box 8129
St. Louis, MO 63110, USA
Email: dcoyne@im.wustl.edu
Originals
Effect of ethanol/trisodium citrate lock on the mechanical properties of carbothane hemodialysis catheters
Abstract
A.L. Bell, R. Jayaraman and L.M. Vercaigne
1Faculty of Pharmacy, University of Manitoba, 2Mechanical and Manufacturing Engineering Department, University of Manitoba, Faculty of Engineering and 3Manitoba Renal Program, Health Sciences Center, Winnipeg, Manitoba, Canada
Aims: The objective of this study was to investigate the effect of three locking solutions on the mechanical properties of carbothane hemodialysis catheters. Methods: Catheters were exposed in vitro to one of three locking solutions (heparin 5000 U/ml; 4% trisodium citrate (TSC) or 30% ethanol/4% TSC). Each solution was locked in six catheters and bathed at 37 ºC for 9 weeks. Changes in the mechanical properties namely, force at break, elongation at break and elastic modulus of the catheters were determined by tensile testing. Results: The ethanol/TSC lock has an effect on the properties of carbothane hemodialysis catheters. The force at break was significantly lower in the ethanol/TSC group compared to the heparin and TSC groups (113.26 N, 191.97 N and 229.72 N, respectively, p < 0.01). Similarly, elongation at break was lower in the ethanol/TSC group, compared to the heparin and TSC groups (stretched 21.97, 38.29, and 42.42 times original length respectively, p < 0.01). The elastic modulus was not significantly different. Conclusions: The effect of the ethanol/TSC lock on the catheters is unlikely to prohibit clinical use. After 9 weeks of exposure to the solution, the catheter segments could still be stretched to 22 times their length and withstand 11.5 kg (113 N) of force. Clinically produced forces during dialysis are many times smaller than the force required to break the catheters examined in this study. Therefore, the ethanol/ TSC lock shows promise as a new catheter locking solution for the treatment of catheter-related infections. Further clinical studies are required.Correspondence to:
L.M. Vercaigne, PharmD
Office 407B
Faculty of Pharmacy
University of Manitoba
50 Sifton Road
Winnipeg, Manitoba R3T 2N2, Canada
Email: lavern_vercaigne@umanitoba.ca
Case Reports
Karyomegalic interstitial nephritis: report of 3 new cases and review of the literature
Abstract
G. Monga, G. Banfi, M. Salvadore, O. Amatruda, C. Bozzola and G. Mazzucco
1Dipartimento di Scienze Mediche, Facoltà di Medicina e Chirurgia, Università del Piemonte, 2Divisione di Nefrologia e Dialisi, Ospedale Maggiore IRCCS, Milano, 3Servizio di Anatomia Patologica, 4Divisione di Nefrologia, Ospedale di Circolo e Fondazione Macchi, Varese, 5Dipartimento di Scienze Biomediche e Oncologia Umana, Facoltà di Medicina e Chirurgia, Università di Torino, Italy
Karyomegalic interstitial nephritis is a rare, but perhaps an “underdiagnosed” condition. Peculiar nuclear changes characterize it, involving mainly tubular cells along with glomeruli and blood vessels. Herein, 3 bioptically proven new cases of patients with chronic renal failure are discussed. The first case had a recently diagnosed karyomegalic nephritis which, to date, still does not require dialysis. The other 2 (brother and sister) required dialysis 4 and 1 years after diagnosis. Karyomegalic changes were found not only in the skin and duodenal biopsies of the male, in skin and liver biopsies of the female and in the urine cells of both patients, but also in several organs (brain, thyroid, lung, esophagus, arteries) as shown at the autopsy of the female. There was a fatal outcome for both patients. The data reported in this study emphasize the usefulness of pathologic investigation of both tissue and urine samples in the identification of this disease. Moreover, as karyomegalic interstitial nephritis is strongly suspected to have a genetic background, its identification may well not only be of clinical relevance, due to its ominous outcome, but may also bear eugenetic value.
Correspondence to:
Dr. G. Monga
Dipartimento di Scienze Mediche
Facolta di Medicina e Chirurgia
Via Solaroli 17
28100 Novara, Italy
Email: guido.monga@med.unipmn.it
Case Reports
Microscopic polyangiitis atypically presenting with tubulointerstitial nephritis
Abstract
Y.K. Wen and M.L. Chen
1Department of Medicine, 2Department of Pathology, Division of Nephrology, Changhua Christian Hospital, Changhua, Taiwan
A 65-year-old woman was admitted with a 4-week history of non-specific constitutional symptoms. Microscopic hematuria, proteinuria and mild renal insufficiency together with the presence of serum antineutrophil cytoplasmic antibodies prompted to perform a renal biopsy. The specimen showed tubulointerstitial nephritis without glomerular change. However, she developed purpura on lower limbs and hemoptysis, along with diffuse pulmonary infiltrates on chest radiograph, 2 weeks after admission. Skin and lung biopsies demonstrated leukocytoclastic vasculitis and diffuse alveolar hemorrhage, respectively. Microscopic polyangiitis was diagnosed based on clinical and pathological criteria. Clinical improvement occurred after intensive immunosuppressive therapy was given. This case illustrates an unusual renal presentation of tubulointerstitial nephritis in microscopic polyangiitis. The possible pathogenetic mechanism will be discussed.Correspondence to:
Dr. Y.K. Wen
Division of Nephrology
Department of Medicine
Changhua Christian Hospital
135 Nansiao St.
Changhua, 500, Taiwan
Email: 9965@cch.org.tw
Case Reports
Exanthema and acute anuric renal failure
Abstract
M. Resch1, B. Banas1, D. Endemann1, M. Mack1, G.A.J. Riegger1, H.-J. Gröne2 and B.K. Krämer1
1Klinik und Poliklinik für Innere Medizin II, University of Regensburg, 2Deutsches Krebsforschungszentrum Pathologie, Heidelberg, Germany
A 15-year-old girl with a history of Kawasaki disease was admitted to our nephrological department due to acute renal failure. Despite antibiotic therapy because of fever and the symptoms of a pharyngitis in the last few days, the girl showed persisting fever and developed arthralgias, an exanthema and a rising serum creatinine as well as anuria. A wide variety of differential diagnoses has to be thought of because of the history of the Kawasaki disease (symptoms like fever, pharyngitis, exanthema and arthralgia), i.e. hemolytic-uremic syndrome, vasculitis, ascending infection, postinfection glomerulonephritis. In consideration of etiologically unclear “rapidly progressive renal failure” with anuria and thrombocytopenia an immediate renal biopsy was done and revealed a severe drug induced acute interstitial nephritis. Due to this diagnosis we treated the patient with corticosteroids. Within 4 weeks serum creatinine declined to 1.8 mg/dl but did not normalize.Correspondence to:
Dr. M. Resch
Klinik für Innere Medizin II
Abteilung Nephrologie
Universität Regensburg
93042 Regensburg, Germany
Case Reports
Analysis of the NPHP genes in two Japanese patients with suspected sporadic juvenile or adolescent nephronophthisis
Abstract
A. Komatsuda, R. Masai, H. Wakui, K. Iwamoto, N. Aiba, H. Ohtani, K. Satoh, T. Haseyama, H. Imai, Y. Nakamoto and K. Sawada
1Third Department of Internal Medicine, Akita University School of Medicine, Akita, 2Department of Internal Medicine, Satoh Clinic, Yamagata, 3Department of Internal Medicine, Haseyama Clinic, Akita, 4Department of Nephrology and Rheumatogy, Aichi Medical University, Aichi, 5Department of Internal Medicine, Kichijoji Asahi Hospital, Tokyo, Japan
Background: Mutations in 3 genes (NPHP1, NPHP3 and NPHP4) have been identified in patients with juvenile or adolescent nephronophthisis (NPHP) without extrarenal involvement, mainly in patients from western countries. In this study, we analyzed mutations in the NPHP genes of 2 Japanese patients with suspected sporadic juvenile or adolescent NPHP without extrarenal involvement. Methods: A renal biopsy was performed in the 2 patients. Genomic DNA was prepared from peripheral blood mononuclear cells of the patients and their family members. The above NPHP genes were examined by deletion analysis or direct automated sequencing of polymerase chain reaction-amplified DNA products. Results: Histological findings in the patients were compatible with those of NPHP. In 1 patient, we identified a novel deletion mutation including about half of exons of the NPHP1 gene. In another patient, there was no mutation in the NPHP genes examined. Conclusions: We found a novel NPHP1 deletion in 1 patient. To our knowledge, this is the second Japanese NPHP case in which genetic diagnosis was made.Correspondence to:
A. Komatsuda, MD
Third Department of Internal Medicine
Akita University School of Medicine
1-1-1 Hondo
Akita City, Akita 010-8543, Japan
Email: komatsud@med.akita-u.ac.jp
Case Reports
A case of renal hypouricemia caused by urate transporter 1 gene mutations
Abstract
T. Inazu
Department of Clinical Research, Saigata National Hospital, Niigata, Japan
Hypouricemia is a common disorder in the general population. Herein, renal hypouricemia caused by human urate transporter 1 (hURAT1) gene mutations in a Japanese patient with intellectual disability is reported. She had compound heterozygous mutations in this gene (W258X and IVS2+1G>A), nevertheless, she showed no clinical manifestations such as urolithiasis and exercise-induced acute renal failure. Restriction enzyme analysis with HphI was useful to screen the IVS2+1G>A mutation in hURAT1 gene.Correspondence to:
T. Inazu, MD
Department of Clinical Research
Saigata National Hospital
Ogata, Joetsu, Niigata 949-3193, Japan
Email: tinazu@saigata-nh.go.jp
tapostolou@ath.forthnet.gr
Treatment of severe hypercalcemia due to refractory hyperparathyroidism in renal transplant patients with the calcimimetic agent cinacalcet
Abstract
T. Apostolou, L. Damianou, V. Kotsiev, S. Drakopoulos and V. Hadjiconstantinou
1Nephrology Department, 2Renal Transplant Unit of Evangelismos General Hospital, Athens, Greece
Calcimimetic agents increase the sensitivity of calcium sensing receptors of parathyroid glands and suppress both serum calcium levels and parathyroid hormone. There are still limited data on the treatment of renal transplant patients with severe hypercalcemia and hyperparathyroidism with calcimimetics (cinacalcet). We describe two such renal transplant patients with chronic kidney disease Stage 3 who presented with persistent hypercalcemia (serum calcium 11.5-12 mg/dl) and refractory hyperparathyroidism (iPTH 194-547 pg/ml). Control of hypercalcemia with cinacalcet (serum calcium < 10 mg/dl) resulted also in an improvement of hyperparathyroidism, but with a slower rate than that of the lowering of serum calcium. Addition of a vitamin D analog together with the calcimimetic agent resulted in faster control of the resistant hyperparathyroidism in both patients (iPTH <145 pg/ml) with clinical improvement and without any side effect. It seems that this new agent will improve our clinical approach of renal bone disease permitting a more integrated and successful treatment of hyperparathyroidism and its consequences on patients with chronic kidney disease.Correspondence to:
T. Apostoulou, MD
108A Sofokli Venizelou Street
Athens, Greece
Email: tapostolou@ath.forthnet.gr
Case Reports
A cloudy bag and genital ulcers
Abstract
J. Liesker, A.-M. van Elsacker-Niele, R. Blanken and C. Halma
Department of Internal Medicine, Medical Center Leeuwarden, 2Department of Medical Microbiology, Public Health Laboratory, 3Department of Dermatology, Medical Center Leeuwarden, The Netherlands
A 30-year-old patient treated with CCPD presented with genital ulcers and a culture-negative peritonitis. Herpes simplex virus type 2 (HSV-2) was cultured from the effluent and the genital lesions. Primary HSV-2 infection was diagnosed by serology. This is the first documented case of PD peritonitis caused by HSV-2. We speculate that cases of culture-negative PD peritonitis may be due to recurrences of genital herpes.Correspondence to:
C. Halma MD, PhD
PO Box 888
8901 BR Leeuwarden, The Netherlands
Email: C.halma@znb.nl
Letter to the Editor
Hepatitis B infection as a possible cause of focal segmental glomerulosclerosis (FSGS)
Abstract
J. Herberth, Z. Herberth, S.R. Abul-Ezz, J. Kumar and N. Gokden
