Pannatier, J. G.

Pascual, M.

Schiffferli, J. A.

Wauters, J. P.

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Nephrol Dial Transplant (1993) 8: 1305-1311LettersNephrologyDialysisTransplantationRemoval of complement factor D by adsorption onpolymethylmethacrylate dialysis membranesSir,Factor D is the rate-limiting enzyme of the alternativepathway of complement activation [1]. Similarly to manyother small-molecular-weight proteins, factor D accumulatesin renal failure. The mean concentration of factor D is1.8ug/ml in normal individuals and approximately 10-foldhigher in patients with end-stage renal failure undergoinghaemodialysis [2]. This increased level of functionally activefactor D is responsible for enhanced activation of the altern-ative pathway in the plasma of patients with end-stage renalfailure [3]. This situation is particularly unfavourable if oneconsiders that the blood of such patients is repeatedlyexposed to artificial membranes. Indeed, most dialysis mem-branes trigger complement activation by the alternative path-way. Because of its size (24 kDa), factor D is unlikely to becleared efficiently during haemodialysis even by highly per-meable filters. Some dialysis membranes have, however, thecapacity to adsorb proteins. For example, /?2-microglobulin(12 kDa) is cleared from plasma by adsorption to dialysisfilters made of polyacrylonitrile or polymethylmethacrylate(PMMA) membranes [4,5].We investigated whether factor D is adsorbed on PMMA,in vitro and in vivo. In vitro, normal human serum wasexposed to various quantities of PMMA-BK-P® (pores of6-8 nm), PMMA-B2® (pores of 1.5-2 nm) or cuprophanefibres obtained by cutting small fragments of new hollow-fibre dialysers. Residual haemolytic factor D was measuredafter an incubation of 30 min at 37°C [6]. There was a lossof haemolytic factor D in normal serum exposed to PMMA-BK-P®, whereas no loss was observed with the other fibres.This loss was dose-dependent and reached 81% when 75 (ilof serum were incubated with 40 mg of fibres. Removal offactor D was then monitored in vivo during seven dialysissessions of patients on chronic haemodialysis using PMMA-BK-1.6P® filters.The factor D levels (corrected for haemoconcentration)decreased from 24.1 ±7.4 ng/ml to 12.2±3.5 ug/ml{P<0.005, paired / test) at the end of dialysis (Figure 1),whereas only a small decrease (from 25.1 ±3.1 ug/ml to22.7 ±2.6 (j.g/ml, P<0.05) was observed during five dialysissessions with cellulose acetate filters (controls, not shown).The decrease of factor D levels was progressive duringdialysis, and in the same range as that of /!2-microglobulin(respectively 49.4 ±6.6% and 41.2 + 6.7%). The total amountof factor D removed per dialysis was calculated to beapproximately 60 mg [6]. Some loss of factor D occurred bymass transfer of the protein to the dialysate, since 9±2 mgwere recovered in the dialysate from three patients. A similarmass transfer of factor D was observed when cellulose acetatefilters were used. Thus, most of factor D removal by PMMA-BK-P® was due to adsorption. This adsorption seems to bemaximal at the beginning of the dialysis session, since samplesof dialysis fluid taken 5 min after the start of dialysis con-tained no factor D, whereas those taken at 30 min werepositive.Because of its short half-life, factor D levels in plasma arerapidly reconstituted after the end of dialysis. The transientBefore AfterFig. 1. Plasma levels of complement factor D before and afterdialysis of patients with PMMA-BK-P* filters.decrease of factor D might, however, have a favourable effectby decreasing alternative pathway activation during haemo-dialysis. Furthermore, a sustained reduction in factor Dlevels might be obtained during continuous haemofiltrationas performed in patients with acute renal failure due to sepsisor other causes. Under such circumstances, a partial decreasein the activation of the alternative pathway might favourablyaffect the outcome of the patient [7]. Other biomaterialsadsorb factor D [8,9]. It appears certainly worthwhile todevelop new biomaterials that down-regulate complementactivation during dialysis.Laboratory of Immunonephrology, M. PascualCentre Medical Universitaire, Geneva, J. A. SchifferliSwitzerland J. G. PannatierDivision of Nephrology, CHUV, J. P. WautersLausanne, Switzerland1. Lesavre PH, MOller-Eberhard HJ. Mechanism of action offactor D of the alternative complement pathway. J Exp Med1978; 148: 1498-15092. Volanakis JE, Barnum SR, Giddens M, Galla JH. Renal nitrationand catabolism of complement protein D. N Engl J Med 1985;312: 395-3993. Pascual M, Paccaud JP, Macon K, Volanakis JE, Schifferli JA.Complement activation by the alternative pathway is modified inrenal failure: the role of factor D. Clin Nephrol 1989; 32: 185-1934. Goldman M, Dhaene M, Vanherweghem JL. Removal of j}2-microglobulin by adsorption on dialysis membranes. Nephrol DialTransplant 1987; 2: 576-5775. Mineshima M, Hoshino T, Era K et al. Difference inbeta-2-microglobulin removal between cellulosic and syntheticpolymer membrane dialyzers. ASA/O Trans 1990; 36: M643-6466. Pascual M, Steiger G, Estreicher J, Macon K, Volanakis JE,© 1993 European Dialysis and Transplant Association-European Renal Association1306Schifferli JA. Metabolism of complement factor D in renal failure.Kidney Int 1988; 34: 529-5367. Hakim RM, Wingard RL, Lawrence P, Parker A, Schulman G.Use of biocompatible membranes improves outcome and recoveryfrom acute renal failure. JASN 1992; 3: 3678. Pascual M, Schifferli JA. Adsorption of complement factor D bypolyacrylonitrile dialysis membranes. Kidney Int 1993; 903—9119. Pascual M, Piastre O, Montdargent B, Labarre D, Schifferli JA.Specific interactions of polystyrene biomaterials with factor D ofhuman complement. Biomaterials 1993; 14: 665-670OKT3: a therapeutic alternative in recurrence of focalglomerulosclerosis in the transplanted kidney?Sir,The longer survival in renal transplants due to betterimmunosuppression has increased interest in recurrence ofprimary nephropathies in the graft. In childhood the incid-ence of post-transplant recurrence of focal segmental glom-erulosclerosis ranges from 15 to 40%, according to the series[1,2]. Once the recurrence is diagnosed the deterioration ofthe graft is usually rapid, resulting in graft loss. We report agirl with steroid-resistant nephrotic syndrome due to focalsegmental glomerulosclerosis and its outcome after threeconsecutive renal transplants.A female, 2 years 5 months, who presented with a nephroticsyndrome resistant to 8 weeks of standard treatment withprednisone and to one cyclophosphamide course of 8 weeksis described. The renal biopsy showed a focal segmentalglomerulosclerosis with mesangial proliferation. The condi-tion progressed to end-stage renal disease 20 months afteronset of the disease. In June 1983 she received a renal graftfrom a live related donor, and a bilateral nephrectomy wasperformed at the same time. Conventional immunosuppres-sion with prednisone, beginning with 3 mg/kg per day andtapering to 0.2 mg/kg per day by 6 months post-transplantation, and azathioprine (2 mg/kg per day) wasfollowed. She showed an immediate recurrence with pro-teinuria >40mg/m2 per hour and hypoalbuminaemia of2.2 g/dl. A biopsy of the allograft carried out 6 months latershowed focal segmental glomerulosclerosis with mesangialproliferation, as in the native kidney. Nephrotic syndromestatus was maintained during the entire post-transplantfollow-up, until the reinstitution of dialysis therapy after11 months.In April 1985 the patient received a second renal graftfrom a cadaver donor. The immunosuppression scheduleincluded prednisone and cyclosporin (5-7 mg/kg per day)from the first day. After the fifth transplant day, a massiveproteinuria >40mg/m2 per hour and hypoalbuminaemia<2.5g/dl appeared. The hypoalbuminaemia was correctedafter 5 months, keeping the proteinuria between 60 and80 mg/m2 per hour. This time the progressive reduction ofallograft function was slower and led to reinstitution ofdialysis therapy after 44 months. No episode of rejection wasdiagnosed. Histological confirmation of recurrence was madeon the allograft nephrectomy.In March 1991 the patient received a third renal graftfrom a cadaver donor. This time the immunosuppressionschedule included OKT3 at 5 mg/day as induction therapy,beginning at the surgery room and maintained until cyclo-sporin addition at the 5th day. Immediate diuresis wasestablished but a similar clinicobiochemical nephrotic syn-drome developed again within the 12-48 h following surgery.A complete remission of the nephrotic syndrome wasachieved after the fourth day of OKT3 therapy. Currently,after 24 months of follow-up, the patient has not had anyNephrol Dial Transplant 1993: Lettersfurther proteinuria, keeping steady creatinine levels of88 umol/1. She remains immunosuppressed with cyclosporinand prednisone.The patient showed all the criteria for poor transplantoutcome because of high risk of recurrence: (1) age less than3 years at the onset of the disease; (2) rapid evolution toend-stage renal disease; (3) mesangial proliferation in therenal biopsy; and (4) steroid-resistant nephrotic syndrome.The immediate evolution in the three consecutive renal graftswas characterized by the rapid reappearance of nephroticsyndrome. The course of the second graft, treated withcyclosporin, was characterized by a partial remission of thenephrotic syndrome and a slower deterioration of the renalfunction. The cyclosporin effect suppressing T lymphocyteresponse through the reduction of lymphokine secretionseems to be the key to its therapeutic action in the nephroticsyndrome [3,4]. The resolution of the nephrotic syndromein the third transplant may be due to a similar effect ofOK.T3 therapy on T lymphocyte function.Paediatric Nephrology UnitHospital Infantil LA FEAv Campanar, 21Valencia, SpainI. ZamoraJ. Simon1. Scnguttuvan P, Cameron JS, Hartley RB et al. Recurrence offocal segmental glomerulosclerosis in transplanted kidney; ana-lysis of incidence and risk factors in 59 allografts. Pediatr Nephrol1990; 4: 21-282. Cameron JS. Recurrent primary disease and de novo nephritisfollowing renal transplantation. Pediatr Nephrol 1991; 5: 412-4213. Striegel JE, Sibley RK, Fryd DS, Mauer SM. Recurrence of focalsegmental sclerosis in children following renal transplantation.Kidney Int 1986; 30: S44-S504. Burke JR, Rigby RJ. Cyclosporin and prednisolone: do theyprevent recurrence of focal segmental glomerulosclerosis? Nephron1986; 43: 236-237Haemorrhagic fever with renal syndromeSir,Haemorrhagic fever with renal syndrome (HFRS) is causedby Hantavirus infection. This virus is thought to be distrib-uted world-wide, primarily in rodent reservoirs. HFRS ischaracterized by fever, hypotension purpura, and interstitialnephritis [1], It has now been identified in many countriesin Europe and in the United States of America, areas notpreviously thought to be endemic for these viruses. Daviesel al. [2] have provided presumptive evidence for the presenceof Hantavirus in Ireland. Although the acute disease appearsto resolve, there is now increasing evidence that residualrenal dysfunction and perhaps progression to chronic renalfailure can ensue. In this regard, 9% (8 of 90) patients onchronic renal dialysis in Northern Ireland and 2.7% (7 of254) of chronic dialysis patients in Baltimore, Maryland,USA were found to have serologic evidence of exposure toHantavirus [3,4].We screened blood samples from 411 renal patients in therepublic of Ireland, of whom 203 were on maintenancehaemodialysis and 207 had a functioning renal transplant.Patients were studied from all the renal units in Ireland andthus had both rural and urban distribution. All sera werescreened at 1 in 100 dilutions for IgG antibodies to protypeHantaan virus by ELISA. Antigen was derived from Vero-E 6infected cell lysates.

Removal of comPlement factor D by adsorption on polymethylmethacrylate dialysis membranes

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