Preexisting human anti-murine immunoglobulin reactivity due to polyclonal rheumatoid factors.

We report that sera from healthy controls, patients with ovarian or lung cancer, and patients with rheumatoid arthritis all contain IgM polyclonal rheumatoid factors which recognize antigenic determinants on murine and to a greater extent human immunoglobulin IgG. The major part of this reactivity is directed against conserved, shared antigenic determinants present on both human and murine IgG. Such antigenicity resides in the protein and not the carbohydrate moiety of IgG, since deglycosylation of the target murine monoclonal antibody did not result in any loss of antibody binding. Studies comparing the binding of polyclonal and monoclonal rheumatoid factors (from patients with rheumatoid arthritis and mixed essential cryoglobulinaemia, respectively) to murine and human IgG show that the antigenic determinants recognized by polyclonal rheumatoid factors are present on both whereas the antigenic determinant recognized by the monoclonal rheumatoid factors is present only on human IgG. Furthermore, patients with rheumatoid arthritis display an elevated human IgM anti-murine immunoglobulin response similar to that seen in cancer patients who have received murine monoclonal antibody therapy. We therefore conclude that, where possible, F(ab')2 fragments of murine monoclonal antibodies should be used for in vivo tumor localization studies to avoid possible immune complex formation, and that patients with rheumatoid arthritis should be considered to be possibly at higher risk of developing immune complex disease, were these rheumatoid factors to bind to the administered murine antibodies in vivo.

Effect of azathioprine and prednisolone on passive enhancement of rat renal allografts.

Passive enhancement provides only partial suppression of rejection in the (DA X Lewis)F1 to Lewis renal allograft model. Suboptimal (8 mg/kg/day) and supraoptimal (30 mg/kg/day) doses of azathioprine administered with enhancing serum failed to suppress the rejection reaction in enhanced animals. Similarly, suboptimal (4 mg/kg/day) and optimal (16 mg/kg/day) doses of methylprednisolone were ineffective. However, the onset of rejection in enhanced animals was delayed by the use of both azathioprine (30 mg/kg/day) and methylprednisolone (16 mg/kg/day). The survival times of enhanced animals treated with azathioprine were significantly shorter than those of animals treated with enhancing serum alone, suggesting that this agent may prevent the development of autoenhancement. Although suboptimal doses of antilymphocyte serum suppress rejection in this enhancement model, the dose requirements of conventional immunosuppressive agents appear to be maximal rather than minimal.

A quantitative comparison of whole antibody and F(ab')2 in kidney allograft enhancement.

Whole antiserum, IgG, and a greater than 99% pure F(ab')2 preparation were compared for their ability to enhance Lewis renal allografts in DA recipients. Despite having unimpaired antigen-binding capacity, the DA anti-Lewis F(ab')2 was virtually ineffective at the highest dose tested, and was calculated to be a minimum of 100 times less effective than whole antibody. The administration of a 10-fold excess of F(ab')2 before an effective dose of IgG did not block the enhancing effect of the latter.

Vein allografts for arterial replacement in rats: an immunological and histological study.

Vein allografts were studied in the rat using the major histocompatibility complex-incompatible DA and Lewis inbred strains. Allografts were performed in the Lewis to DA and DA to Lewis combinations, with Lewis to Lewis isografts serving as controls. Vein grafts were performed by interposing a 1 cm length of fresh iliolumbar vein into a defect of the iliac artery, using microsurgical techniques. The grafts were under observation for 18 weeks for (1) patency, (2) gross structural changes, (3) histological changes, and (4) antibody responses. No immunosuppression was used. All grafts remained patient throughout the period of observation, although aneurysm formation was noted in some allografts toward the end of the observation period. Histologically, allografts and isografts were indistinguishable. In the first 2 weeks, they showed patchy areas of necrosis in the vein walls, with subsequent intimal hyperplasia and medial fibrosis. In both strain combinations a lymphocytotoxin response was induced in most animals, the response being particularly strong in the DA to Lewis combination. All cytotoxic activity could be absorbed out using red blood cells, suggesting that the specificity of the antibody was mainly or entirely directed against SD antigens.

Passive enhancement and hyperacute rejection of renal allografts in the rat.

Attempts to induce passive enhancement of renal allografts with donor-specific cytotoxic antibody can result in antibody-mediated damage to the grafted organ. Hyperacute renal allograft rejection occurred in the homozygous DA to Lewis strain combination when Lewis anti-DA serum was administered with guinea pig complement. Hyperacute rejection was prevented in four of five rats when Lewis anti-DA F(ab')2 was injected before the administration of Lewis anti-DA serum and complement and these grafts had enhanced survival. Red blood cell absorption of the Lewis anti-DA serum to produce an anti-Ia-like serum, also removed its ability to produce hyperacute rejection without removing its ability to enhance. With appropriate modifications both of these techniques would be applicable to human transplantation.

Use of cyclophosphamide and enhancing serum to suppress renal allograft rejection in the rat.

Cyclophosphamide was tested for its interaction with passive enhancement in suppressing the rejection of kidney allografts in the (DA x Lewis)F1 to Lewis rat strain. Dose response studies with cyclophosphamide showed that 10 mg/kg/day for 14 days was necessary for complete suppression of rejection and indefinite graft survival. Doses of 5 and 3.5 mg/kg/day had only a marginal effect on graft function and survival, although the lymphocytotoxin response to the graft was completely or very substantially suppressed by these smaller doses. The use of passive enhancement with cyclophosphamide at the 5- and 3.5-mg/kg/day doses resulted in a favourable interaction with improved graft function and survival. Interestingly, passive enhancement in combination with 5 mg/kg/day of cyclophosphamide resulted in indefinite graft survival only if cyclophosphamide was given for 28 days. If cyclophosphamide was given for 14 days, rejection was suppressed only during the period of cyclophosphamide treatment.

Interstitial nephritis.

The clinical and pathological findings are reviewed in ten cases where renal biopsy showed abnormalities predominantly within the interstitium. In six the nephritis was considered to be drug-induced; in two the aetiology was slightly obscure but the most likely diagnosis was considered to be sarcoidosis. Of the remaining two cases one was chronic pyelonephritis and the other polyarteritis nodosa. The diagnosis and pathogenesis of the renal lesions are discussed and attention is drawn to the importance of distinguishing primary interstitial changes from those found in association with glomerular disease.

Serum C-reactive protein concentration in the management of infection in patients treated by continuous ambulatory peritoneal dialysis.

In a prospective study over 21 months, serum C-reactive protein (CRP) concentration was measured serially in 39 consecutive patients undergoing continuous ambulatory peritoneal dialysis. All patients with peritonitis mounted a CRP response, and the height of the response correlated well with the severity and extent of the peritoneal damage. Patients who recovered uneventfully after antimicrobial treatment showed a prompt fall in CRP from its peak value towards normal. In contrast, each patient in whom the serum CRP value remained raised after antimicrobial treatment had a complicated course. During routine outpatient follow up the serum CRP value remained within the normal range in the absence of intercurrent complications. These results, together with the commercial availability of rapid and precise assays for CRP, indicate that serial CRP measurements may be useful in monitoring the efficacy of antimicrobial treatment during episodes of peritonitis and in the recognition of intercurrent complications in patients undergoing continuous ambulatory peritoneal dialysis.

Presentation and survival of patients with severe renal failure and myeloma.

We reviewed the clinical features and outcome of 56 patients with myeloma and severe renal failure managed in a single institution over a 15-year period. Renal failure was recognized within 2 months of the diagnosis of myeloma in 75% of patients, and was the initial presentation of myeloma in 50%. Patients were staged by the Durie and Salmon classification. Light-chain and IgD myeloma accounted for 46% of cases, and Bence-Jones proteinuria was identified in > 90%. In 43%, a potential precipitant of renal failure was identified, usually hypercalcaemia or a non-steroidal anti-inflammatory agent. A preserved corrected calcium at presentation was characteristic (2.40 +/- 0.15 mmol/l, n = 42), even after excluding those with hypercalcaemia requiring specific intervention (n = 14, 2.76 +/- 0.51; p < 0.01): this finding in patients with unexplained acute renal failure should alert clinicians to the possibility of myeloma. Forty-seven patients (84%) required dialysis. Only seven (15%) ever regained renal function. Median survival (all patients) was 8 months. One-third died within 3 months of referral and one-third survived > 1 year. Hypoalbuminaemia and reduced platelet count at presentation were associated with reduced survival, but hypercalcaemia, infection, dialysis, (urgent or long-term), and dialysis modality were not. Chemotherapy was associated with increased survival, but progression of myeloma and infection were the two most frequent causes of death. Severe renal failure was associated with advanced myeloma stage and light-chain/IgD paraproteinaemia. Survival was related to severity of myeloma and not requirement for dialysis per se.

Renal complications of jejuno-ileal bypass for obesity.

Jejuno-ileal bypass has until recently been an accepted treatment for refractory morbid obesity. Although hyperoxaluria causing renal tract calculi is a well-recognized complication, we describe eight patients who developed significant renal failure attributable to hyperoxaluria resulting from this procedure, three requiring renal replacement therapy. We review the literature, describing 18 other cases with renal failure, the mechanisms of hyperoxaluria and its treatment. Because reversal of the bypass may result in stabilization or partial improvement of renal function, these patients require long-term follow-up of renal function.

High incidence of end-stage renal disease in Indo-Asians in the UK.

In a retrospective survey, we show that the incidence of end-stage renal disease (ESRD) is significantly raised among immigrant Indo-Asians referred to two UK renal units (p < 0.001). In addition to the expected increase in diabetic nephropathy, glomerulonephritis and chronic pyelonephritis are also seen more frequently in Indo-Asians. The most striking finding was a five-fold increase in ESRD of uncertain cause (p < 0.001) presenting with small smooth kidneys, which was strongly associated with active, mostly non-renal tuberculosis. The causes of this generalized increased susceptibility to renal disease are unknown. These findings have important implications both for primary health care screening and for planning the provision of renal replacement therapy.

Outcome following haemodialysis catheter-related Staphylococcus aureus bacteraemia.

Staphylococcus aureus is a frequent cause of haemodialysis access-related bacteraemia. The propensity for this organism to seed from the bloodstream to distant sites is well recognized, but the rate at which this occurs is poorly defined in patients with removable haemodialysis catheters. This retrospective study identified 47 patients with 50 episodes of S. aureus haemodialysis catheter-related bacteraemia between August 1993 and December 1995. Adverse events were recorded until February 1996. Thirty of 50 episodes (60%) were apparently uncomplicated. Bacterial seeding to heart valves or distant sites was documented in eight episodes (16%), of which six occurred during antibiotic therapy. A further 12 patients had persistent bacteraemia in the absence of a defined focus of infection, the last positive blood culture ranging from 2-19 days (mean 6.6, median 5) after removal of the haemodialysis catheter and commencing appropriate antibiotic treatment. The serious nature of this infection confirms the need for prevention, together with effective strategies for investigation and treatment in this patient population.

Recurrence of circulating anti-glomerular basement membrane antibody three years after immunosuppressive treatment and plasma exchange.

A patient with auto-antibody mediated Goodpasture's syndrome was successfully treated with cytotoxic drugs, steroids and plasma exchange. After an absence of three years, circulating anti-glomerular basement membrane antibodies reappeared, and linear IgG staining of the glomeruli was shown by immunofluorescent studies. Renal function did not change and there was no evidence of pulmonary hemorrhage. Antibody levels then fell spontaneously over the succeeding 18 months.

Proliferative glomerulonephritis associated with mantle cell lymphoma--natural history and effect of treatment in 2 cases.

We describe 2 patients with mantle cell lymphoma who presented with dialysis-dependent acute renal failure and in whom the renal biopsies showed proliferative glomerulonephritis. The first patient had lymphadenopathy and the second splenomegaly, but no cause was initially identified in either case. The first patient was treated with immunosuppressive drugs, the second was given no specific therapy; renal function recovered in both. However, more than 1 year later, both again became dialysis-dependent but had also developed generalized lymphadenopathy. A diagnosis of mantle cell non-Hodgkin's lymphoma was made in both cases. The association of active lymphoma and renal disease supports a paraneoplastic mechanism for the occurrence of the glomerulonephritis in these patients. The literature describing the association between non-Hodgkin's lymphoma and glomerulonephritis is reviewed.

Objective monitoring of activity in Wegener's granulomatosis by measurement of serum C-reactive protein concentration.

Serial measurements of the serum concentration of C-reactive protein were made in 38 patients with Wegener's granulomatosis during a period of 6 years. The concentration was always elevated when the disease was active, even in patients receiving immunosuppressive treatment, and fell rapidly in association with clinical remission induced by immunosuppression. During periods of complete remission, in the absence of any intercurrent condition, the value remained within the normal range. The correlation between C-reactive protein level and disease activity was much closer than that between erythrocyte sedimentation rate and disease activity. These results indicate that serial measurement of the serum C-reactive protein fills the urgent need for an objective index of the activity of Wegener's granulomatosis and its response to therapy.

Outcome following staphylococcal peritonitis.

OBJECTIVE: Staphylococcus spp predominate as the causative pathogen of continuous ambulatory peritoneal dialysis (CAPD)-related peritonitis.This study evaluated the difference in morbidity and mortality between peritonitis caused by S. aureus and coagulase-negative staphylococci (CoNS). DESIGN: Prospective observational study. SETTING: A single regional dialysis unit in a teaching hospital. PATIENTS: Thirty-seven patients had S. aureus peritonitis and 65 patients had CoNS peritonitis between July 1990 and November 1995. MAIN OUTCOME MEASURES: Using the first recorded episode of peritonitis, survival analysis was performed for time to (1) death, (2) removal of peritoneal dialysis catheter, and (3) change to hemodialysis. Abdominal complications were recorded for the first and subsequent episodes. RESULTS: No difference in time to death was demonstrated for the two groups (p = 0.79), although two deaths that occurred during therapy for peritonitis were attributable to S. aureus infection. In addition, 5 patients developed serious abdominal complications related to an episode of S. aureus peritonitis. Patients with S. aureus peritonitis had a shorter time to both peritoneal dialysis catheter removal (p = 0.004) and change to hemodialysis (p = 0.014). The change in mode of dialysis was independent of catheter loss. CONCLUSION: This study highlights the serious nature of S. aureus peritonitis and confirms the need for effective preventive measures against infection by this pathogen.

The quality of life of dialysis patients treated with recombinant human erythropoietin.

In June 1986, eight haemodialysis patients, seven male, one female, entered a pilot trial of recombinant human erythropoietin (EPO) at the Churchill Hospital Renal Unit. Six patients completed the Nottingham Health Profile (NHP) before starting EPO therapy, in order to assess quality of life, and were retested when haemoglobin level reached 120 g/l. A further test was given at one year. Statistically significant improvements were seen in the areas of Energy and Emotional Wellbeing. In the subsequent UK trial, involving previously transfusion dependent patients from nine centres, the pre and post treatment NHP scores of a further 18 patients have been assessed. Highly significant improvements were found in Energy, Physical Mobility (p less than 0.005) and in Emotional Wellbeing (p less than 0.002). Improvements which did not reach significance were found in the areas of Sleep, Social Isolation and Pain problems. An increase in appetite, and less sensitivity to cold were noted by over one third of patients. Problems with Employment, Looking after the Home, and Relationships were greatly reduced. We conclude that early findings show EPO treatment to improve not only the haemoglobin levels, but also the quality of life of haemodialysis patients with the anaemia of end stage renal failure.