Volume 66, No. 3/2006(September)
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 Clinical Nephrology
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Editorial
Production and applications of recombinant proteinase 3, Wegener’s autoantigen: problems and perspectives*
Abstract
D.E. Jenne and A. Kuhl
Department of Neuroimmunology, Max Planck Institute of Neurobiology, Martinsried, Germany
Antineutrophil cytoplasmic antibodies (cANCA) against conformational epitopes of proteinase 3 (PR3) are regarded as an important pathogenic marker in Wegener’s granulomatosis (WG). Hence, PR3-based antibody binding assays are widely used for diagnosis and monitoring of the disease. Purification of the native catalytically active serine protease from granulocytes, however, is relatively inefficient, time-consuming and technically demanding. Conformational changes, partial aggregation, denaturation during purification and contaminations with inhibitors or other proteins from plasma and granulocytes, can affect the quality and comparability of PR3-based cANCA determinations. Alternative production of the human PR3 autoantigen by recombinant technologies offers several advantages over the natural antigen, but the complexity and operating expense of these procedures have, so far, delayed the development of new clinical tests. Correct posttranslational processing, conformational identity and antigen stability can be achieved by the expression of PR3 in Sf9 insect cells and in mammalian hosts, HEK293 and HMC-1. Subsequent purification and immobilization of the recombinant antigen is furthermore simplified by the attachment of short carboxyterminal peptide tags. In contrast to conventional capture techniques with murine monoclonal antibodies, tag-based immobilization of the recombinant antigen does not mask portions of the PR3 surface and improves the efficacy of antigen coating. Moreover, recombinant PR3 variants will have a great potential to study individual anti-PR3 responses and will advance the development of new epitope-based therapeutics.
*Presented at the 12th International Vasculitis and ANCA Workshop (June 15 – 18, 2005 Heidelberg, Germany)Correspondence to:
Dr. D.E. Jenne
Department of Neuroimmunology
Max Planck Institute of Neurobiology
Am Klopferspitz 18
82152 Martinsried, Germany
Email: djenne@neuro.mpg.de
Originals
Glomerulonephritis in children with mixed connective tissue disease
Abstract
S. Ito, T. Nakamura, R. Kurosawa, T. Miyamae, T. Imagawa, M. Mori, Y. Aihara and S. Yokota
1Department of Pediatrics, Yokohama City University Medical Center, 2Department of Pediatrics, Yokohama City University, School of Medicine, Yokohama, Japan
Aims: Mixed connective tissue disease (MCTD) has overlapping clinical features with systemic lupus erythematosus (SLE). Renal biopsy is necessary for all children with SLE to evaluate the prognosis, because they are at a quite high risk of developing renal complications. Furthermore, lupus nephritis and hypocomplementemia usually precede the appearance of clinical manifestations. Immune complex-mediated nephritis is one of the major complications of MCTD. Juvenile MCTD is known to be associated with a higher risk of nephritis than adult MCTD. However, it is uncertain whether all children with MCTD should be subjected to a renal biopsy, and whether most of those with hypocomplementemia present nephropathy, as in patients with SLE. We examined the histopathological characteristics of juvenile MCTD nephritis, the importance of renal biopsy and the implications of hypocomplementemia in our patients and reported cases of MCTD. Material and methods: We performed renal biopsy in 11 children with MCTD and found 6 patients with glomerulonephritis. In addition, we studied the frequency and the characteristics of glomerulonephritis in 71 cases of juvenile MCTD (our 11 patients and 60 reported cases). We also analyzed the relationship between hypocomplementemia and pathological features in 41 cases of MCTD nephritis (23 adults, 18 children). Results: 6 of our 11 patients had glomerulonephritis, but of them four had no abnormality in urinalysis at the time of biopsy. In 5 patients renal biopsy showed normal findings. Review of 71 cases of juvenile MCTD showed that of them 28% presented latent asymptomatic nephritis at the time of biopsy. Membranous nephropathy (MN) and mesangial proliferative glomerulonephritis (MPG) were common in MCTD. Interestingly, hypocomplementemia was more frequently observed in patients with MN or mixed form of MN and MPG (MPG/MN) than simple MPG based on our review of 41 cases (p < 0.01). Conclusion: A more aggressive indication of renal biopsy should be considered in children with MCTD because of the high incidence of non-clinical nephritis. The hypocomplementemia observed in patients with MCTD suggests the high frequency of glomerulonephritis, including membranous lesions.Correspondence to:
S. Ito, MD, PhD
Department of Pediatrics
Yokohama City University Medical Center
Yokohama, Urafunecho 4-57, Minamiku
Yokohama, Kanagawa, 232-0024 Japan
Email: hi5-si@urahp.yokohama-cu.ac.jp
Originals
Clinical study of influenza-associated rhabdomyolysis with acute renal failure
Abstract
M. Abe, T. Higuchi, K. Okada, K. Kaizu and K. Matsumoto
1Division of Nephrology and Endocrinology, Department of Medicine, Nihon University School of Medicine, Tokyo, 2Department of Nephrology and Blood Purification, Yokohama Social Insurance Central Hospital, Yokohama, Japan
Aims: Influenza-associated rhabdomyolysis induces renal failure with a fatal outcome. The aim of this study is to evaluate the clinical features, diagnosis, and treatment efficacy of influenza-associated rhabdomyolysis patients with acute renal failure (ARF). Materials and methods: The subjects included 6 patients who had presented with rhabdomyolysis and ARF due to influenza infection on admission to our university hospital and its 2 affiliated hospitals between January 2002 and February 2004. We retrospectively examined the cases. Results: All the patients (n = 6) were males, and none of them had received an influenza vaccine. The viruses were identified as influenza A (n = 5) and B (n = 1). Muscular weakness was observed in many cases (n = 5), whereas pain or tenderness was observed in only 1 case (n = 1). For anuric or oliguric patients (n = 4), blood purification therapy was performed, while for patients in whom the urine volume was normal (n = 2), conservative therapy was administered. Conclusion: Careful medical attention is necessary when patients have muscle pain and weakness. Early recognition of rhabdomyolysis allows prompt institution of an appropriate therapy that includes blood purification and may minimize the renal dysfunction associated with this disorder.Correspondence to:
M. Abe, MD; Division of Nephrology and Endocrinology, Department of Medicine, Nihon University School of Medicine, 30-1, Oyaguchi-Kamimachi, Itabashi-ku, Tokyo, 173-0032, Japan
Email: m_nori@yahoo.co.jp
Originals
Safety of paracentesis in inpatients
Abstract
P. Duggal, K.F. Farah, G. Anghel, R.J. Marcus, A.R. Lupetin, M.M. Babich, S.E. Sandroni and R.L. McGill
1Division of Gastroenterology, 2Division of Nephrology and Hypertension, and 3Division of Diagnostic Radiology, West Penn Allegheny Health System, Allegheny General Hospital, Pittsburgh, PA, USA
Introduction: Prior research has suggested that paracentesis is free from complications such as acute renal failure (ARF) providing albumin is administered. Actual safety of paracentesis > 1,000 ml was assessed at a tertiary care hospital. Methods: 300 inpatient paracenteses performed between 12/99 and 4/04 were identified by coding records, of which 40 procedures were excluded due to lack of pre- or post-procedure lab values. Charts were reviewed for serum creatinine (Scr) before and after procedures, ascites volume, and clinical outcomes. Results: 44 deaths occurred after 260 paracenteses (16.9%). Among 33 patients with ARF, 13 (39.4%) died. Only 31/227 patients without ARF (13.7%) died (p < 0.001). Serum creatinine (Scr) > 1.6 mg/dl prior to paracentesis predicted a 22.5% rate of ARF, compared to 8% for Scr < 1.0 (p = 0.002). ARF increased as volume increased (9.9%, 12.4%, and 14.9%, for volumes of < 2,300, 2,300 – 3,200, and > 3,200 ml) but this trend did not have statistical significance (p = 0.426). ARF occurred in 11/69 (15.9%) of patients receiving albumin, compared to 22/191 (11.5%) of patients who did not (p = 0.462). Conclusions: Paracentesis in inpatients has significant rates of ARF and death. Scr > 1.6 prior to paracentesis predicts an increased rate of ARF. Development of ARF is associated with an increased rate of death. No advantage was demonstrated with administration of albumin. Pre- and post-paracentesis labwork should be routine in inpatients.Correspondence to:
R. L. McGill, MD; 320 East North Avenue, Pittsburgh, PA 15212-4774, USA
Email: rmcgill@wpahs.org
Originals
C-reactive protein induced activation of MAP-K and RANTES in human renal distal tubular epithelial cells in vitro
Abstract
P.C. Baer, S. Gauer, B. Wegner, R. Schubert and H. Geiger
1Department of Internal Medicine III, Division of Nephrology, J.W. Goethe University, Frankfurt/Main, Germany, 2Department of Medicine, Division of Nephrology and Immunology, University of Alberta, Edmonton, Canada, 3Department of Pediatrics, J.W. Goethe-University, Frankfurt/Main, Germany
Aims: C-reactive protein (CRP) is a component of the acute-phase reaction to inflammation, severe tissue injury, and infection. Investigations have shown that CRP concentration is highly increased in the urine during acute renal graft dysfunction and, therefore, may affect tubular cell metabolism. Nevertheless, no data about the effects of CRP on human renal tubular epithelial cells are available. Methods: Human renal distal tubular cells (DTC) were isolated immunomagnetically and cultured. Cells were stimulated with affinity chromatography pure native CRP from human ascites (10 – 0.001 mg/ml). Phosphorylation of MAP-K was assessed by Westernblot analysis. Release of RANTES and interleukin-6 was evaluated with an enzyme immunoassay. Cytotoxic effects of CRP were determined by a commercially available Live/Dead assay and MTT assay. Effects on cell proliferation were analyzed by a fluorimetric assay. Results: Westernblot analysis clearly showed that CRP activates the MAP-K pathway of DTC. CRP upregulated RANTES expression of DTC in a significant and dose-dependent manner. CRP (10 mg/ml) induced a 12.3-fold upregulation, CRP 1 or 0.1 mg/ml induced a 6.3-/2.8-fold RANTES upregulation, respectively. Interleukin-6 synthesis was not influenced. Cytotoxic, proliferative or apoptotic effects were not observed at the concentrations used. Conclusions: We demonstrated an activating effect of CRP on DTC in vitro. In vivo, this effect of CRP might be part of the immune activation cascade during episodes of renal graft rejection or bacterial infections. Correspondence to:
Dr. P.C. Baer
Johann Wolfgang Goethe University
Department of Internal Medicine III
Division of Nephrology
Theodor-Stern-Kai 7
60590 Frankfurt/Main, Germany
Email: P.Baer@em.uni-frankfurt.de
Originals
Uremic pruritus is associated with higher Kt/V and serum calcium concentration
Abstract
M.I. Duque, S. Thevarajah, Y.H. Chan, A.B. Tuttle, B.I. Freedman and G. Yosipovitch
1Departments of Dermatology, Wake Forest University School of Medicine, Winston-Salem, NC, USA, 2Biostatistics Unit, Faculty of Medicine, National University of Singapore, Singapore, 3Internal Medicine/Nephrology, Wake Forest University School of Medicine, Winston-Salem, NC, USA
Background: The prevalence and characteristics of uremic pruritus have not recently been investigated in a US dialysis cohort. This study examined uremic pruritus and associated risk factors in hemodialysis patients treated in the year 2005. Methods: The prevalence and characteristics of pruritus (short version McGill pain questionnaire), severity (10 cm visual analogue scale), and effect on quality of life (Skindex-16) were determined in thrice weekly hemodialysis patients. Daugirdas single-pool Kt/V, clinical and laboratory data were recorded. Results: 105 of 307 screened hemodialysis patients met inclusion criteria and were evaluated, 49% (151) were excluded due to advanced age, 3% (9) other skin diseases, and 14% (42) refused. Participants were 55% male (58/105) and 65% African-American (68) with a mean ± SD age of 48 ± 11 years. The overall prevalence of pruritus was 57% (60/105, 95% CI 47 – 67%) and a positive correlation was observed between the presence of uremic itch and serum calcium concentration (p = 0.04). Intact PTH and serum phosphorus concentration were not associated with either the presence or intensity of itch. Intensity of pruritus was positively correlated with increasing months on dialysis (64 ± 63 vs. 51 ± 46 months for itch and non-itch, respectively; p = 0.02), higher Kt/V (1.82 ± 0.7 vs. 1.70 ± 0.56 for itch and non-itch, respectively; p = 0.01) and skin dryness (p = 0.01). Patients receiving statins were significantly less likely to report pruritus (p = 0.02) and uremic itch adversely impacted several aspects of quality of life. Conclusions: Pruritus remains a common and significant symptom in adequately hemodialyzed patients. Higher serum calcium concentrations, longer durations of ESRD and higher Kt/V appear to be important factors associated with uremic pruritus.Correspondence to:
B.I. Freedman, MD
Department of Internal Medicine
Section on Nephrology
Wake Forest University School of Medicine
Medical Center Boulevard
Winston-Salem, NC 27157-1053, USA
Email: bfreedma@wfubmc.edu
Originals
Does loss of residual renal function lead to malnutrition in peritoneal dialysis patients?
Abstract
L.-T. Cheng, W. Chen, W. Tang and T. Wang
1Division of Nephrology, Peking University First Hospital, 2Division of Nephrology, Peking University Third Hospital, Beijing, China
Objectives: It is usually believed that loss of residual renal function is associated with anorexia and the development of malnutrition. We conducted a retrospective study in our center to evaluate the effect of declining residual renal function on patients’ nutritional status. Methods: All incident uremic patients (n = 46) who began peritoneal dialysis from January 1, 2003 – June 1, 2003 in our center were closely followed for 1 year with focus on maintaining strict volume control with time on dialysis. Patient’s residual renal function (RRF) was assessed by the average renal urea and creatinine clearances. Those patients who had more than 50% decrease in GFR were selected for the present analysis. Serum albumin (ALB), dietary protein intake (DPI) and subjective global assessment (SGA) were closely followed. Results: There were 16 patients (9 males and 7 females) included in the present analysis, among whom 31.3% were diabetics. Patients’ GFR declined significantly (RRF were 4.32 ± 2.69, 2.99 ± 2.21 and 1.24 ± 0.99 ml/min for Months 1, 6 and 12, respectively, p < 0.05), along with a significant decline in urine volume (985.62 ± 543.29, 698.13 ± 463.59 and 425.63 ± 320.52 ml/d for Months 1, 6 and 12, respectively, p < 0.01). Although weekly peritoneal Kt/V did not increase significantly, peritoneal ultrafiltration increased significantly during this period (428.75 ± 408.96, 534.38 ± 296.39, 844.38 ± 440.35 ml for Months 1, 6 and 12, respectively, p < 0.05). Serum ALB increased significantly (32.34 ± 5.07, 34.74 ± 4.89 and 36.21 ± 3.98 g/l for Months 1, 6 and 12, respectively, p < 0.01). DPI also increased significantly. The prevalence of malnutrition (by SGA) decreased from 62.5% at the start of dialysis to 18.8% at the end of this study (p < 0.05). Conclusions: Our study suggests that rapid decline of residual renal function in PD patients does not necessarily lead to decreased dietary protein intake and deteriorated nutritional status. Focus on incremental peritoneal fluid removal along with the decline in residual renal function and, thus, maintaining volume control may be one of the critical reasons for the success. Correspondence to:
T. Wang, MD, PhD
Division of Nephrology
Third Hospital, Peking University
49 North Garden Rd, Haidian District, Beijing 100083, P.R. China
Email: wangt@bjmu.edu.cn
Case Reports
PR3-ANCA-positive crescentic necrotizing glomerulonephritis accompanied by isolated pulmonic valve infective endocarditis, with reference to previous reports of renal pathology
Abstract
M. Fukuda, M. Motokawa, T. Usami, T. Oikawa, K. Morozumi, A. Yoshida and G. Kimura
1Department of Internal Medicine and Pathophysiology, Nagoya City University Graduate School of Medical Sciences and 2Kidney Center, Nagoya Daini Red Cross Hospital, Nagoya, Japan
Patients with infective endocarditis (IE) often have renal complications which may include infarcts, abscesses and glomerulonephritis (GN). Furthermore, it is generally accepted that there is an association between IE and anti-neutrophil cytoplasmic antibody (ANCA). Here, we report the case of a 24-year-old man who developed rapidly progressive GN in the course of IE due to infection with a-streptococcus. The initial clinical manifestation of the condition was severe sacroiliitis without fever. Sandwich ELISA showed that the patient was positive for PR3-ANCA at low titer, and the classical complement pathway was also activated. Renal biopsy demonstrated several lesions: focal embolic GN, GN with immune deposits and focal and segmental crescentic necrotizing GN. Treatment with antibiotics and steroids led to eradication of the infection, and resolution of the renal disease was accompanied by immediate disappearance of PR3-ANCA and hypocomplementemia. During a 4-year follow-up period, no recurrence was observed. There have only been 7 case reports of GN associated with IE and PR3-ANCA in which the renal pathology has been described, and the current report is the first to document renal pathology in a patient with isolated pulmonic valve IE and PR3-ANCA. Moreover, this report is the first to show a change in renal biopsy findings in response to treatment. A review of the 7 literature cases and that of our patient showed that none involved pauci-immune GN. Hence, further studies are needed to clarify the prevalence of pauci-immune GN in ANCA-positive IE patients.Correspondence to:
M. Fukuda, MD
Department of Internal Medicine and Pathophysiology
Nagoya City University Graduate School of Medical Sciences
Mizuho-ku, Nagoya 467-8601, Japan
Email: momoca@sage.ocn.ne.jp
Case Reports
A blue kidney – chronic renal failure as a consequence of siderosis in paroxysmal nocturnal hemoglobinuria?
Abstract
P. Kümpers1, A. Herrmann1, J. Lotz2, M. Mengel3 and A. Schwarz1
1Department of Nephrology, 2Department of Radiology, 3Institute of Pathology, Medical School Hannover, Germany
Acute renal failure is a known complication during hemolytic crisis in paroxysmal nocturnal hemoglobinuria (PNH). However, chronic renal failure is rare despite the well-known spectacular hemosiderosis of the kidneys due to chronic hemolysis. Here, we report about a 74-year-old man with PNH who developed acute on chronic renal failure after an episode of intercurrent urinary tract infection and subsequent hemolytic crisis. Mild chronic hemolysis, well-documented over the past decade, had long been considered the cause of a constantly declining glomerular filtration rate. Accordingly, magnetic resonance imaging during admission demonstrated marked siderosis of both kidneys, supporting the hypothesis that chronic renal failure (CRF) was likewise related to PNH. However, a renal biopsy revealed acute tubular necrosis and distinct renal siderosis, as expected. Additionally, tubulointerstitial injury and global glomerular sclerosis, best classified as arterionephrosclerosis, were present. In retrospect, these findings were explained by a 15-year history of hypertension and a 4-year medication with cyclosporine. Careful diagnostic workup including a renal biopsy is mandatory, given a misleadingly suggestive correlation between chronic hemolysis and CRF. Chronic renal failure in PNH is a diagnosis of exclusion, even if radiologic evidence of heavy siderosis draws off the physician’s attention.Correspondence to:
Dr. P. Kümpers
Department of Nephrology
Medical School Hannover
Carl-Neuberg-Straße 1
30625 Hannover, Germany
Email: pkuempers@htp-tel.de
Case Reports
Candida glabrata fungemia in a diabetic patient with neurogenic bladder: successful treatment with micafungin
Abstract
N. Haruyama, K. Masutani, K. Tsuruya, S. Sugiwaka, J. Toyonaga, T. Yao, K. Goto, M. Tokumoto, H. Hirakata and M. Iida
1Department of Medicine and Clinical Science, 2Department of Urology, Graduate School of Medical Sciences, Kyushu University, 3Kidney Care Unit, Kyushu University Hospital, Fukuoka, Japan
A 69-year-old man was transferred to our hospital because of fever and acute renal failure. 5 weeks prior to admission, he was admitted to another hospital and treated with several antibiotics including vancomycin, but fever did not subside and renal dysfunction showed rapid progression. On admission, laboratory findings revealed pyuria, inflammatory changes, acute renal failure, and disseminated intravascular coagulation (DIC). Computed tomography showed left ureteral stone and hydronephrosis. Gallium scintigraphy showed avid uptake in the left kidney. Serum concentration of vancomycin was 57.4 mg/ml. Candida glabrata was isolated from blood, sputum and urine. Under the diagnosis of fungemia and left pyelonephritis, he was treated with micafungin (150 mg/day), gabexate mesilate and insertion of a double-ended pigtail catheter. The above treatment produced regression of systemic inflammation, DIC and acute renal failure. At the last follow-up 3 weeks after discharge, ureteroscopy showed that the ureter stone had already passed but a soft white-yellowish bezoar was detected in the ureter. In this case, neurogenic bladder, poorly controlled diabetes, and long-term antibiotic treatment probably enhanced the development of C. glabrata infection. Antifungal treatment with micafungin is useful in patients with non-albicans Candida infection.Correspondence to:
H. Hirakata, MD, PhD
Kidney Care Unit
Kyushu University Hospital
Maidashi 3-1-1, Higashi-ku, Fukuoka, 812-8582, Japan
Email: hirakata@kcu.med.kyushu-u.ac.jp
Letters to the Editor
Biomarker for IgM nephropathy variant and therapy
Abstract
N. Futrakul and P. Futrakul
Letters to the Editor
Single-dose daily treatment with cyclosporin A for relapsing nephrotic syndrome: report of a case showing poor response
Abstract
H. Tanaka, K. Tsugawa, K. Tsuruga, J. Shimada, K. Suzuki and E. Ito
Letters to the Editor
A dilemma in treating angiomyolipoma in a horseshoe kidney
Abstract
S. Lee, Y.B. Jang, K.P. Kang, W. Kim, S.-O. Lee, C.Y. Yim, S.K. Kang, Y.M. Han and S.K. Park
