Posttransplant antidonor lymphocytotoxic antibody production in relation to graft outcome.

Serial serum samples from 266 recipients of primary renal allografts were monitored posttransplant for the presence of panel reactive lymphocytotoxic antibodies (PRA). The minimum posttransplant follow-up period was 18 months. Patients were classified according to whether or not they produced PRA before and/or after transplantation. The groups were as follows: PRA negative before and after transplant, -/-, 171; PRA positive before and negative after transplant, +/-, 5; PRA positive before and positive after transplant, +/+, 27; PRA negative before and positive after transplant, -/+, 63. Actuarial graft survival at 1 year for each group was 81.3%, 100%, 70.4%, 47.6%, respectively. Fifty-five of the 63 -/+ recipients were retrospectively crossmatched with posttransplant sera against stored donor lymphocytes. Of these, 50 (91%) were posttransplant cross match positive, and 37 (67%) have lost their grafts. In 23 of the 26 cases where an anti-HLA specificity was defined, the antibody was directed against antigens present in the donor but not in the recipient. These results clearly indicate that the production of PRA in recipients of renal transplants is associated with antidonor reactivity and poor graft outcome. The fact that these PRA were often directed against donor HLA antigens emphasizes one of the hazards of mismatching for HLA at transplantation.

Allograft immunity to histocompatibility and organ-specific antigens.

An experimental model has been developed in the dog in which a renal allograft was placed in the neck, leaving one of the dog's own kidney in situ. Five nonimmunosuppressed pairs of dogs have been studied by using the leucocyte migration test (LMT) as an in vitro measure of cell-mediated immunity. Antigen preparations from leucocytes, kidney, liver, and skeletal muscle from both the kidney donor and the recipient were used in the LMT in order to study responses against transplantation and organ-specific antigens. Inhibition of migration with donor-specific leucocyte and kidney antigens was detectable prior to clinical evidence of rejection, which was confirmed histologically. Concurrently, inhibition was also observed with autologous kidney antigen and histological damage was noted in the recipient's own nontransplanted kidney, accompanied by increasing proteinuria. Autologous serum withdrawn daily and added to the test culture medium abolished the inhibition of migration, thus suggesting the development of blocking factor.

Evidence that matching for HLA antigens significantly increases transplant survival in 1001 renal transplants performed in the northwest region of England.

In the 20-year period from March 1968 to March 1988, 860 patients received 1001 renal transplants in the Northwestern Regional Renal Transplant Unit at Manchester Royal Infirmary. Through a continuing policy of avoiding mismatches for HLA antigens and lymphocytotoxic antibody crossmatching, transplant survival rates were found to correlate with the degree of HLA-A and B antigen mismatching from 1968 to 1978 and with HLA-B and DR antigen mismatching from 1979 to 1988. Mismatching for HLA-B and DR antigens was also found to correlate with transplant survival in highly sensitized patients and in patients transplanted since 1981, the "cyclosporine era." Recipients who were HLA-DR1 positive were found to have the highest graft survival compared to recipients negative for this antigen. In contrast, HLA-DR3 positive recipients had the poorest outcome. Transplants from HLA-DRw6 positive donors showed higher transplant survival rates than donor kidneys positive for any other HLA-DR antigen. A correlation of transplant survival with HLA-B and DR mismatching was seen whether kidneys were collected within our region or received through the UK Transplant Service. We conclude that avoidance of mismatching for HLA-B and DR antigens confers high transplant survival rates (91.1% at 5 years for 0 HLA-B and DR mismatches), and in order to achieve this rate for most recipients exchange of donor kidneys between transplant centers will be essential.

Matching for properdin factor B (Bf) in renal transplantation.

Forty-five donor and recipient primary cadaveric kidney transplant pairs were phenotyped for the properdin factor B (Bf) polymorphism. Graft survival was analyzed on the basis of Bf matching between donor and recipient. Patients receiving a Bf-identical kidney had significantly better graft survival than those receiving a Bf-incompatible kidney (P = 0.045). It is postulated that Bf, which maps in the major histocompatibility system, is a marker for genes of importance in kidney transplant survival.

Successful renal transplantation of patients sensitized following deliberate unrelated blood transfusions.

One of the most powerful influences on cadaveric renal graft survival is the enhancing effect of blood transfusions from unrelated individuals (1, 2). However, the optimum number of transfusions required to achieve this effect remains controversial. Enhanced graft survival following only one or two transfusions has been observed (3), although graft survival has also been found to be better for multitransfused recipients (4). Extrapolating from their studies on mice, Wood et al. (5) suggested that only a very small volume of blood may induce the transfusion effect in humans. As the number of transfusions increases so does the risk of sensitizing the patient to produce lymphocytotoxic antibodies that may impair the chances of the patient receiving a crossmatch-negative kidney graft (6, 7). Thus the problem is to minimize the chance of sensitization while still maintaining the beneficial effect of blood transfusion.

Comparison of serologic and biochemical definitions of HLA class I polymorphisms in cadaver renal transplantation.

The role of biochemical variants in matching renal donors with recipients was investigated in a population of 26 donor recipient pairs from the period 1979-85. Serologic typing was compared with a biochemical analysis of HLA-A and -B antigens in a group in which there had been no mismatches for HLA-A and -B antigens by serology. HLA-A and -B serology was updated using stored material for 92.2% of the renal recipients and donors (n = 51), and HLA-A, -B, and -DR serology was updated for 84.3%. No inconsistencies were found with the HLA-A and -B antigens assigned at the time of transplant. HLA-A and -B antigens of 70% of the renal recipients and donors were analyzed by immunoprecipitation from lymphocytes and serum and analyzed after isoelectric focusing by autoradiography and Western blotting. No biochemical differences between recipient and donor were found for any one pair when HLA-A and -B antigens were serologically the same. This biochemical analysis was useful in providing results where there was doubt over the presence or absence of an antigen serologically. In a well-matched situation, HLA-A and -B serologic types were concordant with results obtained biochemically. However, in a poorly matched situation this could be different.

Immune potential in human uraemia. 1. Relationship of glomerular filtration rate to depression of immune potential.

Aspects of immune potential in uraemic subjects, categorized by glomerular filtration rate, were intercompared and compared with results obtained from a group of normal volunteers. Evidence is presented to show that depression of both cellular and humoral immune potential occurs with progressive reduction of glomerular filtration rate. Lymphocyte transformation testing to the non-specific mitogen PHA revealed a significant elevation of blastogenic response in uraemia after 96 hours of incubation.

Immune potential in human uraemia. 2. Changes after regular haemodialysis therapy.

Parameters of both humoral and cellular immune potential were measured in a group of patients with severe renal failure before and after three months' regular haemodialysis therapy. Evidence is presented of improvement in cellular immune potential and of a tendency of the response of lymphocytes to PHA to return to normal. No improvement in humoral responsiveness was demonstrable, and it is suggested that uraemic patients on regular haemodialysis may have an impaired capacity to establish new immunological memory.

IgM associated primary diffuse mesangial proliferative glomerulonephritis.

Twenty-three cases of IgM associated primary diffuse mesangial proliferative glomerulonephritis are presented. In 18, IgM was the sole localising host immunoglobulin, and it was the predominant globulin in five; C3 was also present in 18. Light microscopy revealed variable diffuse and global mesangial proliferation in all cases, with additional focal global sclerosis in 16, focal segmental sclerosis in 15, and small capsular crescents in seven. Material for electron microscopy was available from 19 patients; in 13, occasional intramesangial electron dense deposits were identified, and in 18 there were irregular, rather ill defined areas of increased electron density in mesangial regions. Clinically, 14 patients presented with the nephrotic syndrome, and nine had asymptomatic proteinuria. During follow-up, only 10 patients showed no change in renal function or improved; the remainder showed increasing hypertension and/or renal function deterioration and four developed end stage renal failure. It is suggested that IgM associated mesangial proliferative glomerulonephritis should be considered as a distinct clinicoimmunopathological entity.

A prospective study of cytomegalovirus and herpes simplex virus disease in renal transplant recipients.

A prospective study of 84 renal graft recipients demonstrated cytomegalovirus (CMV) disease after transplantation in 37% of patients. Reactivation infection was found in 20 of 44 patients (46%) who were seropositive for CMV prior to transplant and primary CMV disease occurred in 11 of 40 (28%) initially seronegative patients. Nearly all cases of primary disease (91%) were associated with symptoms and in these cases CMV was probably acquired via the donated kidneys. Only 35% of the reactivation infections were associated with clinical symptoms. Actuarial life tables indicated that CMV disease did not reduce the length of graft survival. Herpes simplex virus (HSV) infections were diagnosed in 44 (52%) of the patients and included a fatal case of disseminated disease associated with hepatitis.

Disseminated herpes simplex virus infection with hepatitis in an adult renal transplant recipient.

A rare occurrence of disseminated herpes simplex virus infection with hepatitis in an adult renal transplant recipient is described.

Diseases and histological normality of the renal glomerulus: a clinicopathological study.

Thirty-seven percutaneous renal biopsies showing no significant abnormalities on light microscopy were studied electron optically and by immunofluorescence when available. Assessment of the pathological material was followed by analysis of the patients' clinical notes, and a clinicopathological correlation was carried out. Twenty-three patients fulfilled the clinical criteria of minimal change disease; 10 did not behave clinically as minimal change and showed immune complex deposition; two had benign recurrent haematuria; and two had myelomatosis. Our study shows that if diagnosis is based solely on the light microscope appearances of renal biopsy, diseases other than minimal change are likely to be overlooked. Accuracy of diagnosis in structural terms requires additional immunofluorescence and electron microscopic study; final clinical diagnosis also requires careful follow-up, and repeat biopsy may be necessary.

IgA localisation in glomerular diseases.

The structural changes found on light and electron microscopy study of 25 renal biopsy specimens that showed significant glomerular IgA deposition on immunofluorescence were correlated with relevant clinical data. The morphology of a wide range of glomerulopathies seeen included mesangial proliferative (60%), membranous (12%), rapidly progressive proliferative (8%), mesangio-capillary (8%), and no light microscope change (8%). Four of the 15 cases (60%) of mesangial proliferative glomerulonephritis were associated with focal segmental sclerosis and 10 with focal segmental and focal global sclerosis. In addition, 7 of the 15 cases showed capsular crescents. The clinicopathological correlations indicated that the prognosis in this group is unfavourable when focal global sclerosis and capsular crescents are present, particularly when both occur in the same biopsy specimen.

The need and demand for renal replacement therapy in ethnic minorities in England.

STUDY OBJECTIVE: The study aimed to determine the relative risk of being accepted for renal replacement treatment of black and Asian populations compared with whites in relation to age, sex, and underlying cause. The implications for population need for renal replacement therapy in these populations and for the development of renal services were also considered. DESIGN/SETTING: This was a cross sectional retrospective survey of all patients accepted for renal replacement treatment in renal units in England in 1991 and 1992. PATIENTS: These comprised all 5901 patients resident in England with end-stage renal failure who had been accepted for renal replacement therapy in renal units in England and whose ethnic category was available from the units. Patients were categorised as white, Asian, black, or other. Population denominators for the ethnic populations were taken from the 1991 census. The census categories Indian, Pakistani, and Bangladeshi were aggregated to form the denominator for Asian patients, and black Caribbeans, black Africans, and black others were aggregated to form the denominator for black patients. MAIN RESULT: Altogether 7.7% of patients accepted were Asian and 4.7% were black; crude relative acceptance rates compared with whites were 3.5 and 3.2 respectively. Age sex specific relative acceptance ratios increased with age in both ethnic populations and were greater in females. Age standardised acceptance ratios were increased 4.2 and 3.7 times in Asian and black people respectively. The most common underlaying cause in both these populations was diabetes; relative rates of acceptance for diabetic end-stage renal failure were 5.8 and 6.5 respectively. The European Dialysis and Transplant Association coding system was inaccurate for disaggregating non-insulin and insulin dependent forms. "Unknown causes" were an important category in Asians with a relative acceptance of rate 5.7. The relative rates were reduced only slightly when the comparison was confined to the district health authorities with large ethnic minority populations, suggesting that geographical access was not a major factor in the high rates for ethnic minorities. CONCLUSION: Acceptance rates for renal replacement treatment are increased significantly in Asian and black populations. Although data inaccuracies and access factors may contribute to these findings, the main reason is probably the higher incidence of end-stage renal failure. This in turn is due to the greater prevalence of underlying diseases such as non-insulin dependent diabetes but possibly also increased susceptibility of developing nethropathy. The main implication is that these populations age demand for renal replacement treatment will increase. This will have an impact nationally but will be particularly apparent in areas with large ethnic minority populations. Future planning must take these factors into account and should include strategies for preventing chronic renal failure, especially that due to non-insulin dependent diabetes and hypertension. The data could not determine the extent to which population need was being met; further studies are required to estimate the incidence of end-stage renal failure in ethnic minority populations.

Urinary N-acetyl-beta-D-glucosaminidase as an indicator of tubular damage in multiple myeloma.

In 34 patients with multiple myeloma we have studied urinary N-acetyl-beta-D-glucosaminidase (NAG) as an index of tubular injury and related it to urinary light chain excretion and serum creatinine. Our results confirm the association of light chain proteinuria with both tubular damage and global renal impairment, but show that not all light chains are nephrotoxic. Tubular damage occurs independently of global renal impairment. Clinically, urinary NAG appears to be a useful index of early tubular damage in multiple myeloma.

Epidemiology and natural course of idiopathic nephrotic syndrome.

The term "idiopathic nephrotic syndrome" is poorly defined and is used to refer to a variety of glomerular lesions. This article seeks to clarify the situation by considering the case for treating minimal-change nephropathy, focal and segmental glomerulosclerotic lesions, and mesangioproliferative lesions with predominantly IgM deposition as separate disease entities. In children, nephrotic syndrome has a pattern different from that in adults, in whom a wider pathogenetic spectrum is seen. There is support for the use of prospective clinicopathological data as the basis of identifying those patients with nephrotic syndrome who will progress to end-stage renal failure. Very heavy, persisting proteinuria is one marker of such progression and is also an indicator of metabolic complications, such as cardiovascular disease, which further increase the risks of mortality and morbidity in this group of patients.

Tubular function in multiple myeloma.

In 42 myeloma patients our results confirm the association of light chain proteinuria and renal damage, but suggest that while the amount of light chain excreted is an important factor, only some light chains are nephrotoxic. The excretion of the proximal tubular cell lysosomal enzyme N acetyl B D glucosaminidase was a sensitive index of tubular injury, while the presence of low molecular weight proteinuria (Retinol Binding Protein and Lysozyme) was shown to indicate tubular dysfunction in a kidney sufficiently damaged to produce an impaired GFR. Isolated defects of distal tubular function (acid load response and concentrating ability) were rare. Such changes were seen mainly as part of global renal impairment and were usually associated with such specific pathophysiological conditions as plasma hyperviscosity or tubular crystal deposition. Hypercalcemia had a specific effect on the concentrating ability independent of any impairment of renal acidification.

Acute intravascular hemolysis with minimal renal impairment in Clostridium perfringens infection.

We report here a case of post-abortal clostridium prefringens infection in which there was severe intravascular hemolysis with black urine, but only minor abnormalities of the clotting mechanism and mild renal failure. The patient recovered following supportive therapy only.

Reduction of post-transplant proteinuria due to recurrent mesangial proliferative (IgM) glomerulonephritis following plasma exchange.

A patient developed recurrent IgM proliferative glomerulonephritis and a nephrotic syndrome following HLA-identical living donor renal transplantation. Two intensive five-day courses of plasma exchange were followed by sustained reduction of proteinuria. Renal function has remained normal at all times. Immune complex sizing revealed a high titer of middle range complexes (mol. wt. 1 x 10(6) daltons app.); immune complex clearance following an antigen load was not improved by plasma exchange suggesting no alteration of reticulo-endothelial function. Possible mechanisms of benefit are discussed.

The changing pattern of children's dialysis and transplantation over 20 years.

The changing treatment and outcome for children with chronic renal failure (CRF) requiring renal replacement therapy (RRT) was assessed in children referred to the only paediatric unit in the North West Region of England between 1968 and 1988. There were 108 children. Referrals in consecutive 5-year time periods increased from 9 to 41 over the 20 years with the overall incidence of new referrals less than 15 years old reaching 8.5 per million childhood population in 1983-87, whilst the proportion of children under 5-years increased from 0% to 22%. The survival rate was better in those commencing RRT in the later years: 5-year survival 56% for the 1968-72 cohort vs 88% for 1978-82. The increasing number of referrals particularly among young children, coupled with improved survival rates have considerable implications when determining the provision of care for children with ESRD.