Marianne Haag-Weber

Low-GDP fluid (Gambrosol trio®) attenuates decline of residual renal function in PD patients: a prospective randomized study

BACKGROUND Residual renal function (RRF) impacts outcome of peritoneal dialysis (PD) patients. Some PD fluids contain glucose degradation products (GDPs) which have been shown to affect cell systems and tissues. They may also act as precursors of advanced glycosylation endproducts (AGEs) both locally and systemically, potentially inflicting damage to the kidney as the major organ for AGE elimination. We conducted a clinical study in PD patients to see if the content of GDP in the PD fluid has any influence on the decline of the residual renal function. METHODS In a multicentre approach, 80 patients (GFF > or = 3 mL/min/1.732 or creatinine clearance > or =3 mL/min/1.73 m(2)) were randomized to treatment with a PD fluid containing low levels of GDP or standard PD fluid for 18 months. RRF was assessed every 4-6 weeks. Fluid balance, mesothelial cell mass marker CA125, peritoneal membrane characteristics, C-reactive protein (CRP), total protein, albumin, electrolytes and phosphate were measured repeatedly. RESULTS Data from 69 patients revealed a significant difference in monthly RRF change: -1.5% (95% CI = -3.07% to +0.03%) with low GDP (43 patients) vs -4.3% (95% CI = -6.8% to -2.06%) with standard fluids (26 patients) (P = 0.0437), independent of angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker medication. Twenty-four-hour urine volume declined more slowly with low-GDP fluid compared to standard fluids (12 vs 38 mL/month, P = 0.0241), and monthly change of phosphate level was smaller (+0.013 vs +0.061 mg/dL, P = 0.0381). CONCLUSIONS Our prospective study demonstrates for the first time a significant benefit concerning preservation of RRF and urine volume of using a PD fluid with low GDP levels. These findings suggest that GDPs might affect patient outcome related to RRF.

Safety, immunogenicity and efficacy of subcutaneous biosimilar epoetin-α (HX575) in non-dialysis patients with renal anemia: a multi-center, randomized, double-blind study.

BACKGROUND HX575 is a biosimilar version of epoetin-α that is approved for the treatment of anemia associated with chronic kidney disease (CKD) using the intravenous route of administration. Here we report data from a study of anemic pre-dialysis patients to assess the safety, immunogenicity and efficacy of subcutaneous (s.c.) administration of HX575 vs. Erypo®/Eprex® (Ortho Biotech, Neuss, Germany). METHODS This was a randomized, double-blind study in adult patients (n = 337) with Stage III - V CKD and a hemoglobin (Hb) level of 7.5 - 11.0 g/dl. Eligible patients were randomized to 52 weeks of treatment with HX575 or Erypo®/Eprex® at a starting dose of 25 IU/kg body weight 3 times weekly or 75 IU/kg body weight once weekly during Weeks 1 - 5. This could be adjusted after 5 weeks to maintain Hb levels between 10 and 12 g/dl. The primary objective was to assess the safety and immunogenicity of HX575 compared with Erypo®/Eprex®. Efficacy endpoints were mean absolute change in Hb from baseline to end of Week 13 and mean weekly epoetin dosage in Weeks 11 - 13. RESULTS HX575 was equivalent to Erypo®/Eprex® in terms of maintaining Hb levels and epoetin dose requirements. Two patients in the HX575 group developed neutralizing antibodies (NAbs) to erythropoietin, which resulted in the study being terminated prematurely. Aside from these two events, reported adverse events were as expected for patients with Stage III - V CKD and similar in both treatment groups. CONCLUSIONS This study demonstrated the efficacy and therapeutic equivalence of s.c. HX575 compared with the reference epoetin-α, but 2 patients developed NAbs during treatment with s.c. HX575 in this study. Results of a thorough root-cause analysis reported elsewhere indicate that increased tungsten exposure in pre-filled syringes precipitated immunogenic reactions.

Tidal peritoneal dialysis for home-treated patients: Should it be preferred?

Tidal peritoneal dialysis (TPD) was introduced to increase the efficacy of peritoneal dialysis. We measured peritoneal clearances of small solutes and beta2-microglobulin, peritoneal protein loss, and efficacy of ultrafiltration in 30 patients during TPD and intermittent peritoneal dialysis (IPD) with low-dialysate flow (1.7 L/h) and, in addition, in 17 of these patients using a high-dialysate flow (3 L/h). Using a low-dialysate flow, patients with low/low average peritoneal transport rates showed significantly better peritoneal creatinine and urea nitrogen clearances during IPD compared with TPD, whereas there was no difference between these two treatment modalities in high/high average transporters. With high-dialysate flow, peritoneal clearances of creatinine and urea nitrogen were similar between TPD and IPD independent of peritoneal transport type. Clearances of phosphate and beta2-microglobulin were similar between TPD and IPD independent of dialysate flow or peritoneal transport type. Increasing the dialysate flow rate led to a significant increase in small-solute clearances, but not beta2-microglobulin clearances, in both peritoneal transport types. Total peritoneal protein and albumin losses were similar between TPD and IPD only with low-dialysate flow. However, using a high-dialysate flow, total protein losses tended to increase in both transport types during IPD compared with TPD. In conclusion, up to a dialysate flow of 3 L/h, TPD did not provide better small-solute or middle-molecule clearances compared with IPD. Moreover, using a low-dialysate flow, IPD was superior to TPD in low/low average transporters.

Granulocyte activation during haemodialysis in the absence of complement activation: inhibition by calcium channel blockers

Abstract The effect of the calcium channel blockers nifedipine (9 and 18 μg kg‐1h‐1), diltiazem (100 and 200 μg kg‐1h‐1) and verapamil (19 μg kg‐1h‐1) continuously infused during haemodialysis on granulocyte and complement activation was investigated. Plasma levels of lactoferrin, elastase in complex with α1‐proteinase inhibitor (E‐α1PI) and C3a were measured in patients dialysed with dialysers made of cuprophane, polymethylmethacrylate (PMMA) and polyacrylonitrile (PAN). Calcium channel blockers caused no change of blood pressure during haemodialysis in all patients. There was no effect of nifedipine, diltiazem or verapamil on plasma lactoferrin, E‐α1PI or C3a levels in patients dialysed with cuprophane. However, plasma lactoferrin and E‐α1PI values were significantly reduced by all calcium channel blockers in patients dialysed with PMMA, and also by nifedipine and verapamil in patients dialysed with PAN. Our data indicate that calcium channel blockers inhibit granulocyte activation occurring in dialysers with very little anaphylatoxin formation. These drugs, however, are ineffective in patients dialysed with cuprophane where complement activation takes place. Therefore, granulocyte activation during haemodialysis in the absence of complement activation seems to be mediated by calcium ions.

Prospective multicenter study of HX575 (biosimilar epoetin-α) in patients with chronic kidney disease applying a target hemoglobin of 10--12 g/dl.

HX575 was approved in the European Union in August 2007 as the first-ever biosimilar epoetin-α product. The present study extended the safety database on HX575 by monitoring adverse events (AEs) in clinical practice. Hemoglobin (Hb) levels and HX575 doses were recorded for the assessment of efficacy. This open, 6-month single-arm study was conducted in 10 European countries with a target enrollment of 1,500 patients with anemia due to chronic kidney disease (CKD). HX575 was intravenously (i.v.) administered aiming at an Hb target of 10 - 12 g/dl. Most patients (92.3%) had already received erythropoiesis stimulating agents (ESAs) treatment before enrolment into this study; the recorded treatments mainly comprised i.v. or subcutaneous (s.c.) administration of epoetin-α, epoetin-β or darbepoetin. The study period covered 770 patient years. The observed AE profile was in line with expectations for this patient population. Thrombotic vascular events (TVEs) were reported in 11.9% of patients (0.2612 per patient year). Tumor incidence was 1.4% (0.0299 per patient year). No subject developed anti-epoetin antibodies. Mean Hb levels were effectively maintained between 11.2 and 11.3 g/dl following the conversion from a broad spectrum of pre-study ESA treatments with stable overall mean i.v. HX575 doses. The proportion of patients within the Hb target range increased from 57.5% at baseline to 66.8% at study end.

Influence of the preceding exchange on peritoneal equilibration test results: A prospective study

The standard peritoneal equilibration test (PET) should be performed after a long overnight dwell, which is easily possible in continuous ambulatory peritoneal dialysis patients. However, for such a procedure, patients undergoing automated peritoneal dialysis or daily ambulatory peritoneal dialysis have to change their regimen and, in the case of high peritoneal transport rates, run the risk for fluid absorption. We compared dialysate to plasma ratios (D/P) of creatinine, blood urea nitrogen (BUN), phosphate, sodium, total protein, and albumin measured during PET after an 8- to 11-hour dry period (PET dry), after a preceding exchange with a long dwell time (PET standard), and immediately after tidal peritoneal dialysis (PET tidal). D/P ratios of creatinine, BUN, phosphate, and sodium at 2 and 4 hours were greater during PET dry compared with both PET standard and PET tidal. The quotient of dialysate glucose at 2 hours to dialysate glucose at time point 0 was significantly less in PET dry compared with both PET tidal and PET standard. During the first 2 hours of PET, the increase of D/P curves of creatinine and BUN, as well as phosphate, was significantly steeper in PET dry than PET tidal and PET standard. D/P ratios of albumin and protein were greatest in PET dry and least in PET tidal. There was a significant difference between all three PETs at 0, 2, and 4 hours of dwell time. PET curves were significantly steeper during PET dry compared with PET tidal in case of D/P protein (during the first 2 hours of dwell time) and D/P albumin (during the entire dwell time). Similar differences between the PET curves of protein and albumin were observed between PET dry and PET standard. These data clearly indicate a dry period before PET significantly influences the D/P ratios of small solutes, protein, and albumin measured during the test.

Ultrasonography of the catheter tunnel in peritoneal dialysis patients: what are the indications?

The importance of sonography for the early detection and follow-up of tunnel infections in peritoneal dialysis patients is well documented, whereas other indications are less clear. We investigated indications and outcome of 738 ultrasound examinations of the peritoneal dialysis catheter tunnel. Indications for tunnel sonography included routine screening (27%), exit-site infection without peritonitis (24.1%), follow-up of tunnel infection (29.5%), clarification of questionable results (7.5%), pain in the course of the catheter tunnel (1.8%), peritonitis without (5.3%) and with (2.0%) exit-site infection, search for foci (2.2%), and recurrent peritonitis (0.7%). No positive sonographic results were obtained during routine screening or in patients with fever or elevated C-reactive protein levels showing no clinical signs of exit-site infection. Sonographic examinations were positive in 1 of 13 patients with pain in the course of the catheter tunnel, in 1 of 39 cases of peritonitis not associated with exit-site infection, in 12 of 15 patients with peritonitis and simultaneous exit-site infection, and in 2 of 5 patients with recurrent peritonitis. Questionable results were detected in 15 of 178 patients with exit-site infection, in 15 of 199 routine examinations, in 2 of 16 examinations of patients with elevated C-reactive protein levels or fever, and in 2 of 15 cases of peritonitis and simultaneous exit-site infection. All but two of these questionable results had to be rated as negative during further follow-up. We conclude that tunnel sonography is indicated in patients with exit-site infection (including cases with simultaneous peritonitis), for follow-up of tunnel infections, and for estimating the prognosis of these infections. Furthermore, tunnel sonography should be performed in patients with recurrent peritonitis. Tunnel sonography is not indicated for routine screening, search for foci, in cases of peritonitis without exit-site infection, or in patients with pain in the course of the catheter tunnel showing no other clinical signs of exit-site infection.

The impact of residual renal function on survival

(See related article by A. Parikova et al. Free water transport, small pore transport and the osmotic pressure gradient. Free water transport, small pore transport and the osmotic pressure gradient three-pore model of peritoneal transport. Simonsen O et al. Fluid and electrolyte transport across the peritoneal membrane during CAPD according to the three-pore model. A et al. Aquaporin-1 plays an essential role in water permeability and ultrafiltration during peritoneal dialysis. Mice that lack endothelial nitric oxide synthase are protected against functional and structural modifications induced by acute peritonitis. 11. Rippe B, Venturoli D. Simulations of osmotic ultrafiltration failure in CAPD using a serial three-pore membrane/fiber matrix model. Glomerular endothelial glyco-calyx constitutes a barrier to protein permeability. et al. Mini-peritoneal equili-bration test: a simple and fast method to assess free water and small solute transport across the peritoneal membrane. The standard peri-toneal permeability analysis: a tool for the assessment of peritoneal permeability characteristics in CAPD patients. Dialysis patients have 10–20 higher mortality rates compared to controls. Factors discussed to influence mortality in dialysis patients are hypertension, left ventricular hyper-trophy (LVH), increased pulse pressure, phosphorus, calci-fication, inflammation, malnutrition, fluid and sodium balance , interdialytic weight gain, removal of middle molecule uraemic toxins and residual renal function (RRF) [1]. LVH and hypertension are frequent findings in dialysis patients

Neutrophil Activation During Hemodialysis

Oxidative metabolism of PMNs of uremic patients is enhanced due to unknown serum (plasma) factors which are removed during hemodialysis. Respiratory burst activity is diminished in both PMA-stimulated and unstimulated states compared to healthy controls. Hemodialysis normalizes stimulated and decreases unstimulated hydrogen peroxide production. Several authors found that resting and stimulated chemiluminescence (CL) during hemodialysis correlates with complement activation, whereas other authors describe CL using dialyzer membranes with only mild anaphylatoxin formation. Alterations of PMN carbohydrate metabolism in uremic patients improves during HD with polysulfone. HD with PMMA, however, activates glycogenolysis. These alterations may be responsible for disturbance in phagocytosis. Degranulation during HD also occurs in absence of complement activation. Calcium channel blockers decrease activation of PMNs using dialyzers with only little anaphylatoxin formation.

Neutrophil β2-Microglobulin and lactoferrin content in renal failure patients

Abstract Multiple dysfunctions of polymorphonuclear leukocytes (PMNLs) contribute significantly to the increased morbidity and mortality among patients with end-stage renal disease. In the present study, we measured the PMNL content of β 2 -microglobulin (β 2 m) and lactoferrin in different states of renal insufficiency and after kidney transplantation. PMNLs were lysed ultrasonically and, after centrifugation, both proteins were assayed in the supernatant by enzyme-linked immunosorbent assay technique. Despite marked differences in plasma β 2 m levels, no significant difference in PMNL content of β 2 m and lactoferrin could be shown among the groups analyzed. There was also no correlation between plasma β 2 m level and PMNL β 2 m content. In control subjects, as well as in renal allograft recipients with a well-functioning graft, PMNL β 2 m level correlated positively with PMNL lactoferrin level (pooled data, r = 0.55; P