Volume 60, No. 5/2003(November)
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 Clinical Nephrology
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Review
Extracorporeal treatments in sepsis: are there new perspectives?
Abstract
C. Tetta1, V. D’Intini1, R. Bellomo2, M. Bonello1, V.Bordoni1, Z. Ricci1 and C. Ronco1
1Department of Nephrology, Dialysis and Transplantation, St. Bortolo Hospital, Vicenza, Italy, and 2Department of Intensive Care, Austin and Repatriation Medical Center, Melbourne, Australia
Sepsis continues to provide a major challenge to clinicians. Despite vast advancements achieved in the understanding of its pathways and mechanisms, the incidence of sepsis is increasing and the mortality and morbidity rates remain high, generating a considerable burden to health budgets worldwide. Unfortunately, no definitive therapy yet exists that can successfully treat sepsis and its complications. At variance with targeting single mediators, therapeutic intervention aimed at the non-selective removal of pro- and anti-inflammatory mediators seems a rational concept and a possible key to successful extra-corporeal therapies. A further advantage may lie in the continuous nature of such therapy. With such continuous therapy, sequentially appearing peaks of systemic mediator overflow may be attenuated and persistently high plasma levels reduced. This theoretical framework is proposed as the underlying biological rationale for a series of innovative modalities in sepsis. In this editorial, we will review recent animal and human trials which lend support to this concept. We will also review the importance of treatment dose during continuous renal replacement therapy as a major factor affecting survival in critically ill patients with acute renal failure. We will also review novel information related to other blood purification techniques using largo pore membranes or plasma filtration with adsorbent perfusion. Although these approaches are still in the early stages of clinical testing, they are conceptually promising and might represent an important advance.
Originals
The number of CD10-positive glomerular epithelial cells reflects renal prognosis in IgA nephropathy patients
Abstract
A. Sasaoka, K. Nishiya, T. Hosokawa, H. Ito, K. Hashimoto and H. Enzan
1Second Department of Internal Medicine, and 2First Department of Pathology, Kochi Medical School, Kochi, Japan
Background: The glomerular epithelial cells play an important role in glomerular filtration of the kidney. The disruption of these cells contributes to the development of glomerulosclerosis. The present study was performed to elucidate whether loss of the glomerular epithelial cells is associated with renal injury in patients with IgA nephropathy. Patients and methods: Thirty renal biopsy specimens from IgA nephropathy, 12 from minor glomerular abnormalities and 5 from normal controls were observed. The specimens from IgA nephropathy were divided into 2 groups: Group IgA-1, including 11 patients who had received a follow-up renal biopsy because of deterioration of renal function, and Group IgA-2, consisting of the remaining 19 patients without follow-up biopsy. Immunohistochemistry was performed using a monoclonal antibody against CD10 antigen that appears on mature epithelial cells of glomeruli. Results: The average number of CD10-positive glomerular epithelial cells (GECs) was significantly lower in IgA nephropathy than in either minor glomerular abnormalities or the normal controls. In IgA nephropathy, there were significant correlations of the GECs with renal functions. The GECs were reduced along with the progression of histopathological damage. In group IgA-1, the GECs were significantly reduced at the second biopsy compared with the first biopsy, and significantly fewer in group IgA-1 than in group IgA-2 at the first biopsy. The GECs showed a significant correlation with renal prognosis during the follow-up period. Conclusions: The reduction of GECs was associated with renal dysfunction, histopathological damage and renal prognosis. The GECs may be a useful predictor of renal prognosis in IgA nephropathy.
Originals
Is biopsy required prior to cyclophosphamide in steroid-sensitive nephrotic syndrome?
Abstract
M.B. Stadermann1, M.R. Lilien1, N.C.A.J. van de Kar2, L.A.H. Monnens2 and C.H. Schröder1
1Department of Pediatric Nephrology, Wilhelmina Children’s Hospital, Utrecht, and 2Department of Pediatric Nephrology, University Hospital, Nijmegen, The Netherlands
Aim: The present study was designed to retrospectively evaluate the use of renal biopsies prior to cyclophosphamide therapy. The aim of the study was to determine in how many cases histological outcome of the biopsies had subsequently changed the decision to treat or refrain from treatment. Patients and methods: Between January 1980 and September 2001, 85 children with steroid-sensitive nephrotic syndrome (SSNS) underwent a renal biopsy in the University Hospitals of Utrecht and Nijmegen before the start of an 8-week cyclophosphamide treatment. MCNS was suspected in all children because of the following criteria: edema, proteinuria, hypoalbuminemia, absence of macroscopic hematuria and in rare cases microscopic hematuria, no permanent hypertension, normal C3 serum level, a normal glomerular filtration rate as determined by creatinine clearance and age > 1 year. Cyclophosphamide therapy was indicated because of a frequently relapsing (FR) course of illness in 8 children, because of steroid dependence (SD) in 22 children and because of combined FR and SD in 55 children. Steroid-resistant children were excluded from this study. Results: Histology confirmed the diagnosis MCNS in 84 out of 85 children. In addition to MCNS, IgA deposits were observed in renal specimens of 2 children. In 1 SD child, the initial diagnosis MCNS was changed 3 years later when a repeated biopsy showed progression into focal segmental glomerulosclerosis (FSGS). Conclusion: In summary, no renal biopsy is required prior to cytotoxic therapy in children with uncomplicated steroid-sensitive nephrotic syndrome.
Originals
The effects of dual blockade of the renin- angiotensin system on urinary protein and transforming growth factor-b excretion in 2 groups of patients with IgA and diabetic nephropathy
Abstract
J.H. Song, S.W. Lee, J.H. Suh, E.S. Kim, S.B. Hong, K.A. Kim and M.-J. Kim
1Division of Nephrology and Hypertension, and 2Division of Endocrinology and Metabolism, Inha University College of Medicine, Inchon City, Korea
Aims: The therapeutic benefits of dual blockade of the renin-angiotensin system (RAS) have been inconsistent on renal function and proteinuria. To know the contribution of the heterogeneity of study subjects to such inconsistency, we evaluated the effects of dual blockade of RAS in 2 groups of selected renal diseases, IgA and diabetic nephropathy. To avoid confounding by the blood pressure-reducing effects, angiotensin II receptor antagonists (ATRAs) were added on the patients with long-term, optimally controlled blood pressure taking ACE inhibitors. Twenty-four-hour urinary protein excretion rate and urinary TGF-b1 level were measured as surrogate markers of renal injury. Methods: We conducted a prospective crossover trial with 14 IgA and 18 type-2-diabetic nephropathy patients showing moderate degree of proteinuria (³ 1.0 g/day) and renal dysfunction (creatinine clearance 25 – 75/ml/min). Four to 8 mg once-daily dose of candesartan and placebo were alternatively added on ramipril dose of 5 – 7.5 mg/day for 16 weeks. Results: All baseline data except for the age factor were statistically the same between the 2 disease groups. Twenty-four-hour mean arterial blood pressures were 91.2 ± 1.6 and 92.3 ± 1.8 mmHg in IgA and diabetic nephropathy patients respectively at baseline (p = NS). Mean arterial pressure did not change by the addition of candesartan or placebo in both groups. The addition of candesartan (combination) reduced 24-hour urinary protein excretion rate in IgA nephropathy patients with a mean change of – 12.3 ± 4.5%, which is significantly greater compared to a mean change of –0.1 ± 3.3% after the addition of placebo (placebo) (mean difference 12.4 ± 5.0, 95% CI 1.2 – 23.5; p < 0.05). Urinary TGF-b1 level was reduced considerably by the combination therapy, with a –28.9 ± 6.0% decrease, which was significantly different to that by the placebo, with +4.3 ± 12.4% (33.3 ± 13.5, 3.2 – 63.3; p < 0.05). In diabetic nephropathy patients, the addition of candesartan did not reduce 24-hour urinary protein excretion rate. Mean changes of 24-hour urinary protein excretion rate were –0.8 ± 4.7% by the combination therapy and +0.5 ± 6.1% by placebo (mean difference 1.3 ± 4.7, 95% CI –6.8 – 13.5; p < NS). The level of urinary TGF-b1 was reduced by the combination therapy, with –14.3 ± 9.5% decrease, but it did not reach statistical significance compared to placebo of +0.7 ± 15.5% (15.0 ± 13.5, –14.4 – 44.5; p < NS). The changes in 24-hour urinary protein excretion rate and urinary TGF-b1 level were neither correlated with each other, nor with the change in mean arterial pressure. Significant changes in the renal function were not detected during the study period. Conclusion: Definite beneficial effects of dual blockade of RAS on proteinuria and TGF-b1 excretion were found in IgA nephropathy patients, which was independent of blood pressure-reducing effect. With our 16-week trial, such benefits were not observed in type 2 diabetic nephropathy. The reduction in urinary TGF-b1 level suggests that the combination therapy may provide additional renoprotection through the antisclerosing effects. Based on our results, for a proper interpretation the therapeutic effects of the combination therapy should be evaluated separately according to the underlying renal disease.
Originals
Interleukin-18, interleukin-18 binding protein and impaired production of interferon-g in chronic renal failure
Abstract
G. Lonnemann, D. Novick, M. Rubinstein and C.A. Dinarello
1Gemeinschaftspraxis Nephrologie/Dialyse, Langenhagen, Germany,
2Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel, and 3Department of Medicine, University of Colorado Health Science Center, Denver, CO, USA
Uremia is associated with suppressed cellular immune responses, manifested, in part, by impaired interferon-g (IFNg) production. We investigated the influence of kidney function on plasma levels of interleukin-18 binding protein (IL-18BP), the naturally occurring inhibitor of IL-18. Methods: Plasma levels of IL-18, IL-18BP and IFNg were measured by specific immunoassays in patients with normal kidney function (NKF, n = 29), in patients with chronic renal insufficiency (CRI, n = 29), and in patients on hemodialysis (HD, n = 40). In addition, Staphylococcus epidermidis-induced production of IFNg and IL-18 in whole blood cultures was determined in 12 patients on HD and compared to production in 9 controls with NKF. Results: Plasma IL-18 (mean ± SEM) in NKF was 17.9 ± 3.6 pg/ml, in CRI 42.6 ± 7.0 pg/ml (p < 0.01), and in HD 93.5 ± 13.6 pg/ml (p < 0.001). The level of IL-18BP in NKF was 3.4 ± 0.4 ng/ml, in CRI 7.5 ± 0.7 ng/ml (p < 0.001), and in HD 13.1 ± 0.8 ng/ml (p < 0.001). Plasma IL-18BP was inversely correlated with creatinine clearance (correlation coefficient: –0.7479). The level of free IL-18 was calculated in NKF to be 13.8 ± 3.3 pg/ml, in CRI 23.6 ± 3.9 pg/ml (not significant), and in HD 39.6 ± 5.9 pg/ml (p < 0.001). Stimulated whole blood production of IFNg in NKF was 185 ± 74 pg/106 mononuclear cells (PBMC), but suppressed in HD to 27.3 ± 16 pg/106 PBMC (p < 0.05). Conclusion: In uremia, retention of IL-18BP does not suffice to neutralize most of the concomitantly raised levels of total IL-18 resulting in elevated levels of free IL-18. Nevertheless, IFNg production in whole blood is reduced in patients on HD. Therefore, suppression of IFNg production in uremia may be due to inhibitors of IFNg production other than IL-18BP.
Originals
Targeting higher ferritin concentrations with intravenous iron dextran lowers erythropoietin requirement in hemodialysis patients
Abstract
M.V. DeVita, D. Frumkin, S. Mittal, A. Kamran, S. Fishbane and M.F. Michelis
1Division of Nephrology, Department of Medicine, Lenox Hill Hospital, New York, and 2Section of Nephrology, Department of Medicine, Winthrop University Hospital, Mineola, NY, USA
Introduction: Although clinical use of recombinant human erythropoietin (rHuEPO) since 1989 has improved anemia in most end-stage renal disease patients, there are still many hemodialysis patients unable to maintain an adequate hematocrit (HCT) without large doses of rHuEPO. This suggests that anemia is not solely a consequence of rHuEPO deficiency, but may be due to other factors including functional iron deficiency. Since the optimal prescription for iron replacement is not yet known, we evaluated the effect of intravenous iron dextran (IVFe) infusion on serum ferritin (SFer) concentration and rHuEPO dose. Our objective was to raise and maintain serum ferritin concentrations to 2 different levels above the National Kidney Foundation Dialysis Outcome Quality Initiative standard of 100 ng/ml to determine whether, and by what degree rHuEPO dose could be lowered. Methods: HD patients on i.v. rHuEPO with a SFer concentration ³ 70 ng/ml and an HCT of £ 33% were enrolled. Subjects were divided as follows: Group 1: target SFer of 200 ng/ml, Group 2: target SFer of 400 ng/ml. Each subject below the target level received IVFe in up to 10 divided doses during consecutive dialysis sessions as needed to reach the target. HCT was maintained between 32.5% and 36% by adjusting rHuEPO dosage. Results: Mean SFer concentration at the study conclusion in Group 1: 261 ng/ml; Group 2: 387 ng/ml. The mean decrease in rHuEPO dose for Group 1 was 31 U/kg body weight/week (250 – 219 U/kg bw/wk) while in Group 2 it was 154 U/kg body weight/week (312 – 158 U/kg bw/wk) (p < 0.001). There was no difference in HCT between groups. Our results suggest that higher target serum ferritin concentrations can be well tolerated and lower rHuEPO requirements.
Originals
Quality of life in patients treated with hemodialysis or peritoneal dialysis: What are the important determinants?
Abstract
B. Manns, J.A. Johnson, K. Taub, G. Mortis, W.A. Ghali and C. Donaldson
1Department of Medicine, Foothills Medical Center, University of Calgary, 2Faculty of Public Health Sciences, University of Alberta, Edmonton, 3Department of Medicine, Division of General Internal Medicine, Foothills Medical Center, University of Calgary,
Background: Patients with end-stage renal disease (ESRD) have significant impairments in health-related quality of life (HRQOL). In part, this is due to the intrusiveness of the treatment (hemodialysis or peritoneal dialysis) that is required. It is unclear whether hemodialysis or peritoneal dialysis is associated with a higher HRQOL. Methods: 192 prevalent patients who self-selected treatment with hemodialysis (either in-center, satellite or home/self-care hemodialysis) or peritoneal dialysis were studied to determine whether treatment with hemodialysis or peritoneal dialysis is associated with a higher HRQOL. Demographic, laboratory and clinical information (including the presence of comorbid conditions using the Charlson comorbidity index) was assessed at baseline. The outcome of interest was HRQOL, which was measured using the Kidney Disease Quality of Life-Short Form (KDQOL-SF), the Short-Form 36 (SF-36) and the EuroQol EQ-5D at baseline and after 6 and 12 months of follow-up. Results: There was no significant difference in HRQOL scores for the SF-36, the EQ-5D and for 9 of 11 KDQOL dimensions for patients treated with hemodialysis or peritoneal dialysis at baseline. As expected, HRQOL was significantly lower for patients who had more comorbid disease, required assistance with their daily care, and for patients with less than a grade 12 education. After controlling for the effect of other important variables, HRQOL (as measured by the EQ-5D visual analog or index scores) did not differ between hemodialysis and peritoneal dialysis patients. HRQOL was stable over time, both for patients who started on hemodialysis or peritoneal dialysis. Conclusions: There is no significant difference in HRQOL for prevalent ESRD patients treated with hemodialysis or peritoneal dialysis. It will be important to determine if this finding holds true for incident patients treated with hemodialysis or peritoneal dialysis.
Originals
The epidemic of aging in renal replacement therapy: an update on elderly patients and their outcomes
Abstract
K.J. Jager, P.C.W. van Dijk, F.W. Dekker, B. Stengel, K. Simpson and J.D. Briggs
1ERA-EDTA Registry, Department of Medical Informatics, Academic Medical Center, University of Amsterdam, Amsterdam, 2Department of Clinical Epidemiology, Leiden University Medical Centre, Leiden, The Netherlands, 3Recherche Epidémiologique et Statistique sur l’Environnement et la Santé, INSERM Unité 170, Villejuif cedex, France, and 4Scottish Renal Registry, Glasgow Royal Infirmary, Glasgow, Scotland, UK on behalf of the ERA-EDTA Registry Committee
Background: In the past 2 decades, a rapid growth has occurred in the number of patients over 65 years of age accepted for renal replacement therapy (RRT) with an increasing need for dialysis resources as a consequence. The aim of this study is to describe the trends in incidence, treatment and outcome of RRT of these elderly patients included in the new ERA-EDTA Registry database. Methods: Data from 6 national renal registries have been included for the period 1985 – 1999, comprising data of 18,920 elderly patients starting RRT. We used Cox-proportional hazards regression to predict patient and technique survival. Results: The incidence and prevalence of RRT showed a 4- to 5-fold increase over the period, resulting in 48% of the new patients being older than 65 years in 1999. However, the rates varied considerably between countries. The 2-year patient survival was 51% in dialysis patients. Mortality due to social causes increased with age. Multivariate analysis showed no change with time in patient survival on dialysis, but the risk of death following a first renal allograft between 1995 and 1999 was reduced by 31%, compared with the 1985 – 1989 time period (RR 0.69; 95% CI: 0.54 – 0.90). The relative risk of peritoneal dialysis technique failure was more than doubled in the 1995 – 1999 cohort compared to the 1985 – 1989 cohort (RR 2.38; 95% CI: 1.89 – 3.01), with the highest technique failure rate in the first 2 years of the 1995 – 1999 cohort. Conclusions: The number of elderly patients receiving RRT is rising rapidly. Patient survival on dialysis has been stable over the last 15 years, whereas transplant outcome has improved. The increased peritoneal dialysis technique failure and the high mortality due to social causes in the elderly age groups require further investigation. The challenge of the years ahead is to provide this life-prolonging therapy to all patients who need it in such a way that it improves quality of life and at a cost that a society can afford.
Case reports
HCV and renal disease: not always associated with mixed cryoglobulinemia
Abstract
M. Garozzo, P. Finocchiaro, C. Martorano and C. Zoccali
Case reports
Crescentic fibrillary glomerulonephritis associated with hepatitis C viral infection
Abstract
G. Guerra, G. Narayan, H.G. Rennke and B.L. Jaber
Division of Nephrology, 1St. Elizabeth’s Medical Center and
2Tufts-New England Medical Center, 3Department of Pathology, Brigham and Women’s Hospital, Boston, Massachusetts, USA
Fibrillary glomerulonephritis (FGN) is a pathological diagnosis that is rarely associated with systemic disorders. In this case report, we describe a woman who presented with FGN of the crescentic type in association with hepatitis C viral infection. The existing literature on the association between these 2 disorders is reviewed, and postulated therapy is presented.
Case reports
Development of hungry bone syndrome after rapid lowering of PTH with intravenous maxacalcitol therapy in a patient with non-uremic secondary hyperparathyroidism
Abstract
J.J. Kazama, K. Suzuki, A. Yokoseki, A. Oyanagi, S. Goto, H. Shimada, H. Maruyama, I. Narita and F. Gejyo
1Division of Clinical Nephrology and Rheumatology, Niigata University Graduate School of Medical and Dental Sciences, 2Division of Intensive Care Medicine, Niigata University Medical Hospital, and 3Division of Endocrinology, Niigata University Graduate Sc
A 41 year-old woman complained of general bone pain and polyuria. She did not have Albright hereditary osteodystrophy. Laboratory examination revealed hypokalemia, hypocalcemia, and an elevation of serum intact PTH concentration. The patient was polyuric and relatively hypercalciuric, though her glomerular filtration rate (GFR) was normal. Neither urinary Pi nor cAMP excretion was remarkably promoted by an exogenous PTH load. An iliac bone biopsy revealed osteopenia, active osteoclastic bone resorption, fibrous transformation in bone marrow tissue, and severely disturbed calcification. Although the oral administration of alfacalcidol showed no effects, 3 weeks of intermittent intravenous injection of maxacalcitol therapy decreased the serum intact PTH concentration from 597 pg/ml to 40 pg/ml, and the bone pain was greatly relieved. However, plasma Ca concentration also decreased and symptoms of tetany appeared. Pseudohypoparathyroidism type Ib was the most likely diagnosis in this patient. In conclusion, maxacalcitol therapy satisfactorily suppressed parathyroid function in a patient with secondary hyperparathyroidism without uremia. Appropriate Ca supplementation was required to perform it safely.
Letters to the Editor
Reply to Kisters
(Clin. Nephrol 58: 461-462)
Letters to the Editor
Reply to Mandal
(Clin. Nephrol 60: 372)
Abstract
K. Kisters, F. Tokmak, M. Kosch and M. Hausberg
Letters to the Editor
Peritoneal dialysis in a nursing home: limited survival expectations
Abstract
T. Wang, S. Izatt, C. Dalglish, J. Bargman, S. Jassal, S. Vas and D. Oreopoulos
