Influence of Haemodialysis Membranes on {beta}2-Microlobulin Kinetics:In Vivo and In Vitro Studies

Amyloidosis of the ß₂-microglobulin (ß₂M)type is a recently recognised complication of dialysis. We studiedplasma and ultrafiltrate ß₂M in 36 chronic haemodialysispatients. Long-term dialysis with standard cuprophan membranein non-oliguric patients and with the AN69 polyacrylonitrilemembrane in oliguric patients resulted in lower plasma ß₂Mconcentrations (means±SD, 24.4±6.6 and 33.0±8.2µg/ml, respectively) than with cuprophan in oliguric patients(47.0±13.2 µg/ml, P<0.01). In acute studies, plasma ß₂M (corrected for haemoconcentration)increased, although not significantly, during cuprophan dialysis(n=10) from 40.6±12.2 to 44.8±7.6 µg/mland decreased during AN69 dialyis (n=10) from 39.4±18.0to 24.3±7.1 µg/ml (P<0.02). After 15 min ultrafiltration,ß₂M sieving coefficient in vivo was 0.33 for AN69but near zero for cuprophan. Total mass transfer of ß₂Macross the AN69 membrane during a 4-h dialysis was 142 ±45.8 mg(n=7). AN69, but not cuprophan, membrane fragments incubatedin vitro with normal or uraemic plasma exhibited avid [125-I]ß₂M binding (respectively 12.9% vs 0.47% and 6.09%vs 0.06% of total ß₂M bound at 30 mim, n=6, P<0.001for both). No in vitro generation of ß₂M from wholenormal or uraemic blood could be demonstrated during incubationwith either membrane. In conclusion, at least in some patients, standard cuprophandialysis promotes retention and possibly tissue release of ß₂Min vivo, whereas AN69 dialysis leads to ß₂M removaldue to both transmembrane transfer and, to a lesser extent,membrane binding.     

PTH/PTHrP receptor mRNA is down-regulated in epiphyseal cartilage growth plate of uraemic rats

PTH/PTHrP receptor mRNA is down-regulated in epiphyseal cartilagegrowth plate of uraemic rats. Growth retardation, hypocalcaemia,hyperphosphataemia, and skeletal resistance to the action ofPTH are well known features of advanced chronic renal failure(CRF). It has been suggested that the downregulation of renaland skeletal PTH receptors (PTH/PTHrP-R) could play an importantrole in the occurrence of these abnormalities. In the presentstudy, four uraemic (4 weeks after 5/6 nephrectomy) and fourcontrol (sham-operated) rats were analysed for PTH/PTHrP-R mRNAexpression at the proximal femoral and tibial growth platesby in situ hybridization. Uraemic rats had plasma biochemicalabnormalities of advanced CRF including high creatinine, phosphate,and PTH, and low calcium and calcitriol levels. The femoraland tibial bones of uraemic animals were shorter in length thanthose of control rats, and had reduced width and cellularityof the epiphyseal cartilage growth plate. Mean (±SD)tibia growth plate width was 152±30 µm in uraemicrats, compared with 170±35 µm in control rats.The difference was mostly due to a marked reduction of the zoneexpressing PTH/PTHrP-R (mature chondrocytes) which was 30±5µm in tibias from uraemic versus 44±10 µmin tibias from control rats. The hybridization signals of PTH/PTHrP-Rper individual cell were quantified on dark field images usinga computer-assisted image analysis system. The number of grainsin PTH/PTHrP-R positive cells was also decreased in uraemicrats, 103±13 compared with 123±14 arbitrary units(dark pixel density)/cell in control rats (P 0.005). In conclusion,these data indicate that rats with severe CRF and secondaryhyperparathyroidism have reduced epiphyseal cartil age PTH/PTHrP-RmRNA expression. This alteration may be relevant in the pathogenesisof growth retardation in uraemia.     

Hemodialysis-associated amyloidosis and beta-2 microglobulin. Clinical and immunohistochemical study

The beta-2 microglobulin type of amyloidosis was identified in articular and para-articular tissues of 14 patients with non-amyloid nephropathies undergoing long-term hemodialysis. Ten patients had carpal tunnel syndrome, 13 had juxta-articular radiolucent cysts (complicated by spontaneous fractures of the femoral neck in three), and six had destructive arthropathies of the large joints of the limbs. Massive amyloid deposits were found in the synovium, capsule, ligaments, articular cartilage, and/or bone. They were characterized by Congo red-induced green birefringence that was sensitive to potassium permanganate treatment. They reacted with anti-beta-2 microglobulin antiserum, whereas they did not react with antibodies directed against AA protein, prealbumin, or immunoglobulins. These data suggest that the potentially disabling arthropathy of hemodialysis is due to amyloid lesions. The persistently elevated plasma beta-2 microglobulin levels may play a role in the pathogenesis of this recently recognized complication, and if so, this complication should be preventable.     

Short-term effect of folic acid supplementation in renal transplant recipients and chronic kidney disease patients with comparable renal function impairment

Recent evidence suggested that the efficacy of folic acid supplementation in reducing plasma total homocysteine (Hcy) concentration might be similar in renal transplant recipients (RTR) and chronic kidney disease (CKD) patients with a comparable degree of reduction of renal function. However, a direct comparison of the response to high dose folic acid supplementation between renal transplant recipients and CKD patients has never been made. Therefore, the goal of this study was to evaluate the response to folic acid (5 mg/day) supplementation in 15 stable renal transplant recipients with evidence of chronic allograft nephropathy, and in 15 CKD (stage 3) patients matched for age, sex and renal function living in the area of Skopje, Macedonia. After 12 weeks of folic acid supplementation, plasma total Hcy concentrations were significantly reduced in the two groups. Percent reduction of plasma total Hcy levels was nearly identical in the two groups (25.7% vs 24.5%, p = NS). These results confirm previous findings regarding the efficacy of folic acid therapy given separately to either renal transplant recipients or CKD patients, and extend them to a direct confirmation of identical efficacy.     

Hyperhomocysteinaemia: a significant risk factor for cardiovascular disease in renal transplant recipients

Moderate hyperhomocysteinaemia has been shown to constitutean independent risk factor for cardiovascular disease (CVD),a frequent cause of morbidity and mortality in renal transplantrecipients (RTR). In these patients few data regarding bothtotal homocysteine levels and their influence on cardiovas cularrisk have been reported. We therefore studied serum homocysteinelevels in deep-frozen sera from 42 kidney transplant recipientswith a follow-up of 11±4.5 years (mean±SD) aftertransplantation. Eighteen patients had one or more ischaemicevents (CVD(+)) and 24 patients had none (CVD(–)). Serumsamples had been drawn 1–6 months prior to the first vascularevent in CVD(+) patients and serum storage time was comparablein both CVD(–) and CVD(+) patients. Serum homocysteinelevels were measured using a radioenzymatic method. Mean homocysteinelevel was significantly higher in 42 RTR males and females (15.5±6.3,13.5±5.5 µM respectively) compared with 35 controlsubjects matched for age and sex (8.7± 1.9, 7.5±l.9µP<0.001). The difference in serum homocysteine levelsbetween CVD(+) and CVD(–) RTR nearly reached statisticalsignificance in male patients (18.6±7.8 versus 13.1 ±3.4µM, P<0.06) but not in female patients (P=NS). In theCVD(+) group 11/18 patients had homocysteine levels > 14µM (the upper limit in healthy controls) versus 7/24 inthe CVD(–) group (P=0.04). In these patients we simultaneouslymeasured in the same serum samples, serum triglycerides, andtotal and HDL cholesterol, and calculated LDL cholesterol. Bystepwise discriminant analysis and by logistic regression analysisin this relatively small patient population, only serum triglyceridesand homocysteine were selected as risk factors associated withCVD. We conclude that signi ficant hyperhomocysteinaemia ispresent in renal transplant recipients and represents a potentialrisk factor for cadiovascular disease in these patients.     

Hypothyroidism and resistance to human recombinant erythropoietin

Sir, Many possible causes of resistance to human recombinant erythropoietin(rh-EPO) have been reported in patients with renal failure [1].However, some factors remain controversial. We     

Increased plasma S-nitrosothiol levels in chronic haemodialysis patients

Nephrol Dial Transplant 2003; 18: 153–157