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Four patients presented with nephrotic syndrome associated with hypothyroidism; none had thyroid antibodies. Hypothyroidism resolved on remission of nephrotic syndrome in two patients; thyroxine (T4) replacement was ineffective during periods of gross proteinuria in another, and the fourth had had normal thyroid function a year before presentation. Urinary T4 excretion was measured in ten further patients with proteinuria. It was detectable in the urine in five, who had significantly lower serum free T4 (8.5 [95% confidence interval 5.8-11.2] vs 13.9 [11.1-16.7] pmol/l; p less than 0.01) and free triiodothyronine (3.1 [2.2-4.0] vs 4.9 [3.8-6.0] pmol/l; p less than 0.01) concentrations than the five patients without detectable urinary T4.

Renal transplant patients (n = 116) attending an outpatients clinic were screened for hypomagnesaemia. No azathioprine-treated patients (n = 46) but 24% (17 of 70) of the cyclosporin treated patients were hypomagnesaemic. The hypomagnesaemia in all cases was associated with a renal magnesium leak. This leak did not correlate with plasma bicarbonate, urate, calcium, cyclosporin or creatinine concentrations, nor did it correlate with the use of loop diuretics or duration of the transplant. A renal magnesium leak is common in renal transplant patients treated with cyclosporin and it is independent of other markers of nephrotoxicity.

SDZ CHI 621 is a murine-human chimeric monoclonal antibody (mAb) to the interleukin-2 (IL-2) receptor (CD25) intended for prophylactic immunosuppression against acute rejection in the first several weeks following kidney transplantation. A multicentre, prospective, dose-finding study was conducted in 37 primary, mismatched cadaver kidney transplant patients to assess its tolerability, pharmacokinetics and immunodynamics. Successive cohorts of patients were stratified to receive total doses of 20, 30, 40 or 60 mg (n = 4, 4, 14, 15, respectively) administered as 15- or 20-mg intravenous infusions with the first dose given preoperatively and subsequent doses within the first 10 days posttransplant. Daily mAb serum concentrations were analysed by a radioimmunoassay method and the percentage of peripheral T-lymphocytes expressing CD25 from serial blood samples was determined by FACScan. Intravenous administrations were well tolerated. mAb concentration profiles exhibited a biphasic decline with an initial t1/2 of 14.4 ± 14.2 h, terminal t1/2 of 13.4 ± 6.0 days, distribution volume (Vss) of 6.9 ± 3.31 and clearance of 17.4 ± 7.8 ml/h. The concentration-effect (mAb-CD25) relationship indicated that mAb concentrations exceeding a threshold of about 0.7.µg/ml corresponded to complete suppression of CD25 (≤ 3% CD25+ T-cells). The threshold mAb concentration was exceeded at all dose levels, whereas the duration above the threshold (and thus of CD25 suppression) rose with increasing dose: 20 mg, 20 ± 7 days; 30 mg, 32 ± 6 days; 40 mg, 37 ± 10 days; and 60 mg, 53 ± 17 days. As mAb concentrations declined below the threshold following the last dose, CD25 expression returned to baseline (18–44% CD25+ T-cells) within a few days.

Fifteen episodes of encephalopathy have been studied in 13 renal transplant recipients. All episodes of encephalopathy occurred during an acute rejection crisis. Clinical and biochemical features were recorded during rejection crises associated with encephalopathy and in an equal number of uncomplicated rejection episodes in the same patients. Encephalopathy was related to the severity of the rejection crisis and not to other features such as blood pressure, fever, steroid therapy or plasma electrolytes. The definition of the syndrome of rejection encephalopathy and its relation to the severity of the rejection has important therapeutic implications. Steroid therapy should not be withdrawn or reduced because of acute neurological features. Control of hypertension, fluid overload and electrolyte imbalance, in addition to treatment of the rejection episode, are necessary to reverse the encephalopathy. The prognosis of this syndrome is excellent with no long-term sequelae.

The beneficial effect of elective transfusion on renal allograft survival must be weighed against the risks of sensitisation. We report a randomised controlled trial in which patients in end-stage renal failure who were non-parous and not previously transplanted or transfused, were entered in a transfusion protocol during which one group received no drugs (controls), one received azathioprine, and one received cyclosporin. Each group was given three identical transfusions of leucocyte-enriched fresh blood at 2-3 week intervals. The transfused blood was of known HLA type and donor/recipient pairs were completely mismatched. Sensitisation rates were assessed by T and B cell cross-matches between donor and recipients and by the screening of all sera against lymphocytes from 40 random donors. Fifty-one patients have completed the protocol, 20 in the control group, 12 in the azathioprine group, and 19 in the cyclosporin group. The sensitisation rate in the control group was 30%, occasionally of high titre, and persistent. In the azathioprine group, 25% developed anti-HLA antibodies and reactivity was of high titre and was broadly specific. Sensitisation in the cyclosporin group was 10%, was narrowly specific, reacting with only 10% of a panel, and was transient. There was no difference in graft survival between the groups. We conclude that cyclosporin therapy concurrent with third-party transfusion reduces the incidence, titre, and duration of sensitisation.

Biopsies of normal kidneys taken at time of transplantation were studied using a variety of immunofluorescent and cytochemical techniques. A heterogeneous population of HLA-DR+ cells was found, mainly confined to the intertubular interstitium. The majority of these cells (80%) were positive when stained with a rabbit anti-factor VIII antiserum suggesting that they were endothelial cells. A minority however (20%) were factor VIII- but were positively stained with FMC17, a monoclonal antibody (McAb) directed against human monocyte/macrophage antigens. Positive staining of this subpopulation was also noted with RFD1, a McAb which reacts with an antigen on human interdigitating cells (ID cells). Cytochemical reactions revealed that these cells contain adenosine triphosphatase (ATPase) and acid phosphatase (ACP) and thus do not conform to the phenotype of tissue histiocytes. The phenotype of this latter population is identical with that of the ID cells found in tonsil, thymus and spleen and it is suggested that they play a major role in initiating the process of renal allograft rejection.

The relative importance of increased lipoprotein synthesis and decreased lipoprotein catabolism is examined in 13 patients with untreated nephrotic syndrome by the use of intravenous fat tolerance tests analysed in relation to other parameters of lipid metabolism. Increased lipoprotein synthesis in nephrotic patients was indicated by the fact that at a given fractional clearance rate of Intralipid (K2), nephrotic patients had higher serum TG concentrations than did control subjects. A defect in lipoprotein catabolism was also suggested by the frequent finding of intermediate density lipoproteins on electrophoresis and the marginally low (p = 0.05) mean K2 in nephrotic patients. A highly significant (p less than 0.001) positive correlation between HDL-cholesterol concentrations and postheparin fractional clearance rates (K'2) of Intralipid led to the speculation that in the severe nephrotic state (albumin less than 20 g/l) the loss of high density lipoproteins may contribute to the hyperlipidaemia.

The urinary excretion of two proteins, B-2-microglobulin (beta 2M) and N-acetyl-B-D-glucosaminidase (NAG) was measured in 25 patients with rheumatoid arthritis (RA) on nonsteroidal anti-inflammatory drugs (NSAID). Although beta 2M excretion was normal NAG excretion was raised. As NAG excretion by a group of osteoarthritis patients receiving similar doses of NSAIDs was normal, it is concluded that rheumatoid disease per se may be associated with mild renal tubular dysfunction. Twelve of the above 25 patients were then given oral triethylphosphine-gold (auranofin) 6 mg daily and urinary beta 2M and NAG were measured after 6 months' treatment. Urinary excretion of beta 2M and NAG was also measured in 13 patients with RA established on intramuscular sodium aurothiomalate (MGST) and NSAIDs. Neither auranofin nor myocrisin were found to further significantly increase beta 2M and NAG excretion. These results suggest that gold compounds are not toxic to renal tubular epithelium.

The value of captopril-enhanced 99mTc DTPA scintigraphy as a screening test for renovascular disease was prospectively studied in 44 hypertensive patients suspected to have renal-artery stenosis. Renal impairment (plasma creatinine greater than 130 mumol/l) was present in 29 patients. At angiography 13 patients had unilateral stenosis, two bilateral stenosis, and 29 patients had no renovascular disease. Captopril induced a fall in split renal function in the kidney ipsilateral to the stenosis in all patients with unilateral disease (mean 52 +/- 23% to 44 +/- 21% of total renal function; P less than 0.001). A positive captopril scintigram (defined as a fall of 5% or more in split renal function) had a sensitivity of 85% and a specificity of 72% in the detection of unilateral renal-artery stenosis. Captopril-enhanced 99mTc DTPA scintigraphy is a promising non-invasive screening test for the detection of renal-artery stenosis.

We assessed the nephrotoxicity of ionic and non-ionic radiocontrast material (CM) in two groups of patients in a prospective study. One group of 25 potential live kidney donors was studied following conventional renal angiography, carried out as part of the routine pre-operative assessment. The other group of 49 renal transplant patients with varying degrees of renal impairment was studied following digital vascular imaging carried out for investigation of hypertension. Plasma creatine, urinary N-acetyl-D-glucosaminidase (NAG), urinary microglobulin (B2M) and urinary protein excretion were measured before and after the imaging procedure. There were no significant changes in these parameters following digital vascular imaging, but there were increases in plasma creatinine (p less than 0.005) and urinary NAG creatinine ratio (p less than 0.002) in the conventional angiography group following the procedure. Substantial proteinuria developed in 35% of patients following conventional angiography. The differences in nephrotoxicity of radiocontrast agents during the two procedures could not be accounted for by the dose of material used, but probably reflect the effect of differences in the route of administration on the maximal concentration of the material reaching the kidney. Non-ionic radiocontrast material proved less toxic than ionic and may be preferable in conventional angiography.

Patients on continuous ambulatory peritoneal dialysis (CAPD) were studied for three years. 29 of them who had been on CAPD for six months or more were compared with patients on intermittent peritoneal dialysis (IPD) and on haemodialysis (HD). CAPD patients had significantly higher levels of HDL-cholesterol than HD patients. Urea, potassium, phosphate, and urate levels were significantly lower, and haemoglobin levels significantly higher, than in the IPD and HD groups. 43 CAPD patients studied had a peritonitis rate of 2.22 episodes per patient-year. CAPD offers an alternative form of dialysis to those unsuitable for HD, but until peritonitis rates can be reduced CAPD cannot rival HD as a long-term treatment.

Cyclosporine A enhances platelet aggregation. In view of the reported increase in thromboembolic episodes following cyclosporine A (CyA) therapy, the effect of this drug on platelet aggregation and thromboxane A 2 release was investigated. The addition of CyA, at therapeutic concentrations to platelet rich plasma from normal subjects in vitro was found to increase aggregation in response to adrenaline, collagen and ADP. Ingestion of CyA by healthy volunteers was also associated with enhanced platelet aggregation. The CyA-mediated enhancement of aggregation was further enhanced by the addition in vitro of therapeutic concentrations of heparin. Platelets from renal allograft recipients treated with CyA also showed hyperaggregability and increased thromboxane A 2 release, which were most marked at "peak" plasma CyA concentration and less so at "trough" concentrations. Platelet hyperaggregability in renal allograft patients on long–term CyA therapy tended to revert towards normal following the replacement of CyA with azathioprine. Hypertensive patients with renal allografts on nifedipine therapy had normal platelet function and thromboxane release in spite of CyA therapy. These observations suggest that CyA-mediated platelet activation may contribute to the pathogenesis of the thromboembolic phenomena associated with the use of this drug. The increased release of thromboxane A 2 (a vasoconstrictor) may also play a role in mediating CyA-related nephrotoxicity.

Summary Eight hypertensive renal allograft recipients who had received captopril are presented. Captopril in a maximal daily dose of 250 mg enabled the withdrawal of large doses of beta-blocking agents and vasodilators. Blood pressure was satisfactorily controlled in all except one. No adverse side effects were observed other than the 'first dose' effect which resulted in transient anuria in one patient. Captopril appears to be a useful agent in the management of severe hypertension after renal transplantation.

The association between hyperlipidaemia and kidney disease was first noted in 1827 by Bright who described lactescent serum in patients with the nephrotic syndrome. The advent of dialysis and renal transplantation has allowed more detailed study of lipoprotein metabolism in chronic renal failure and accumulating evidence of accelerated atherosclerosis in these patients has renewed interest in uraemic hyperlipidaemia. This chapter will document the lipid and lipoprotein abnormalities observed in dialysis patients, will outline the possible mechanisms involved in their aetiology and will discuss how such abnormalities may represent risk factors in the pathogenesis of atherosclerosis.

The effect of dietary fish oil supplements on renal failure and lipid abnormalities was studied in 14 adult renal transplant recipients with chronic vascular rejection. The rate of decline of renal function (assessed by studying the slope of reciprocal plasma creatinine plots) slowed significantly during a 6-month period on fish oil supplements compared with the preceding 6-month control period (slope 1/cr during supplementation -3.6 X 10(-5) mumols/l per month compared with -13.5 X 10(-5) before, the difference in slope being -9.8 X 10(-5), 95% confidence interval (CI) -16.2 X 10(-5), -3.5 X 10(-5), P less than 0.05). Total plasma triglyceride concentrations decreased during supplementation (mean change -1.15 mmol/l, 95% CI -1.84, -0.47, P less than 0.003), but there was no change in total plasma cholesterol concentration or urinary protein excretion. Platelet function was studied in nine patients. Platelet aggregation induced by adrenaline and collagen was reduced by fish oils (median change in per cent aggregation), adrenaline 2 mumols/l, -36% (95% CI -68%, -8%, P less than 0.05), collagen 1 mg/1, -13% (95% CI -44%, -2%, P less than 0.05). Platelet thromboxane A2 release in response to these agents was also significantly reduced. These results demonstrate that fish oils preserve residual function in renal graft failure due to chronic vascular rejection.

The effect of cyclosporin on proteinuria was studied in 11 patients with steroid-responsive nephrotic syndrome (10 minimal change nephropathy, one IgM nephropathy) and in four patients with steroid-resistant nephrotic syndrome from focal segmental glomerulosclerosis. Cyclosporin (mean initial dose 7.7 mg/kg per day) produced a complete remission of proteinuria in 15 nephrotic episodes in the ten patients with minimal-change nephropathy after a mean 14.3 days (range 7-23 days) of therapy. All patients remained in remission while receiving cyclosporin (mean duration of follow-up 147 days; range 40-230 days). However, when cyclosporin was discontinued on nine occasions in five patients, all relapsed after a mean 47.8 days (range 7-180 days). Four of the five patients were subsequently rechallenged with cyclosporin and all responded. Maintenance cyclosporin therapy to prevent relapse was not associated with any adverse effects, and there was no significant difference between the creatinine clearance before and after 30 days of therapy (86.9 +/- 19.3 and 81.7 +/- 23.5 ml/min respectively, P greater than 0.1). The patient with steroid-responsive IgM nephrotic syndrome did not respond to cyclosporin, and there was no significant effect of cyclosporin on proteinuria in the four patients with FSGS. Cyclosporin is an effective agent for the treatment of patients with frequently relapsing minimal-change nephropathy who became steroid dependent when cyclophosphamide is contraindicated. However, unlike cyclophosphamide, long-term remissions which persist after treatment is withdrawn are not obtained, and patients may be said to be cyclosporin dependent.

The epithelial cell line LLC-PK1, which expresses many proximal tubular characteristics, was used to investigate the relationship between calcium, the calcium channel blocker verapamil, and cyclosporine toxicity. The LLC-PK1 cells took up cyclosporine when this was added in a concentration of 2 micrograms/ml, and this uptake was maximal at 30 min (112 +/- 3 ng cyclosporine/mg cell protein). At 12 micrograms/ml it inhibited the sodium glucose cotransporter, as assessed by phlorizin-inhibitable 14C-alpha-methyl glucopyranoside (alpha-MG) uptake (control 37.2 +/- 6.3, 12 micrograms/ml 21.2 +/- 1.1 mumol/hr/mg protein). Cyclosporine at 2 micrograms/ml did not affect cell growth after 5 days (control 945 +/- 60 micrograms cell protein per 25 cm2 flask, 2 micrograms/ml cyclosporine/ml 1046 +/- 32 micrograms protein/flask), even in the presence of 7.6 mM ionized calcium (862 +/- 37 micrograms protein/flask). Cyclosporine at 12 micrograms/ml inhibited cell growth (286 +/- 27 micrograms protein/flask), and raising the ambient ionized calcium concentration to 7.6 mM reduced cell growth further (91 +/- 6 micrograms protein/flask). Cyclosporine at concentrations of 2 and 12 micrograms/ml produced increasing cell vacuolation, as seen in vivo. Short-term uptake of 2 micrograms/ml cyclosporine could be inhibited by 1.0 mM and 0.5 mM verapamil (49 +/- 9.5 and 71 +/- 6.4 ng cyclosporine/mg cell protein, respectively, at 30 min). However, in the presence of 2 micrograms/ml cyclosporine 0.1 mM verapamil was toxic to the cells grown over five days (44 +/- 5 micrograms protein/flask). At 0.01 mM verapamil was not toxic to cell growth (921 +/- 29 micrograms protein/flask), but raising the medium calcium to 7.6 mM reduced cell growth (652 +/- 96 micrograms/ml). Inhibition of cyclosporine uptake did not occur with 0.01 mm verapamil (control 145.6 +/- 12.3 vs. 0.01 mM verapamil 150.4 +/- 3.8 ng cyclosporine/mg cell protein). The LLC-PK1 cell line represents a good in vitro model for cyclosporine renal tubular toxicity, as the in vivo observation of glycosuria and proximal tubular cell vacuolation in cyclosporine nephrotoxicity can be reproduced. In vitro this is shown to be associated with inhibition of sodium-dependent glucose cotransport. Verapamil inhibited cyclosporine uptake, but only at concentrations that were toxic to the cells. Verapamil potentiated rather than reduced the increased cyclosporine toxicity produced by increasing the medium calcium concentration. The suggested protective effect of verapamil against cyclosporine nephrotoxicity is therefore unlikely to be due to inhibition of cyclosporine uptake or of calcium entry into proximal tubular cells.

Three mg/kg bodyweight per day of intravenous methylprednisolone for 3 consecutive days is as effective as 15 mg/kg bodyweight per day of methylprednisolone in reversing acute renal allograft rejection (80% vs 68%; 95% confidence intervals of the difference are -8% to 32%). This dose was not associated with an increased incidence of further rejection episodes. It may not be necessary to continue with the common practice of administering high-dose intravenous methylprednisolone for acute renal graft rejection.

The survival from acute renal failure requiring renal replacement therapy was studied in 90 critically-ill patients admitted to an intensive care unit. Mean age (+/- SD) was 51 +/- 14.6 (range 17 to 81) years. Mechanical ventilation was required in 88 patients and 71 patients received total parenteral nutrition. Thirty-three per cent of patients left the intensive care unit alive and 24 per cent survived to leave hospital. Final survival was 20 per cent in medical patients (n = 49), 29 per cent in surgical patients (n = 38) and 100 per cent in obstetric patients (n = 3). Hypotension, requirement for inotropic support, oliguria and sepsis were all associated with a poorer prognosis. The mode of renal replacement therapy did not affect survival, but additional haemodialysis was required in 33 of 65 patients treated by continuous arteriovenous haemofiltration but none of 22 treated with continuous arteriovenous haemodialysis (p less than 0.001). APACHE II score was calculated for 87 patients. Mean APACHE II score was 26.1 +/- 6.9 (range 14 to 44). APACHE II score on admission predicted the likelihood of survival well. No patients with a score of more than 40 survived, compared to 40 per cent of those with scores of 10 to 19. Pre-existing organ insufficiency or immunosuppression meriting a CHE score of 5 was associated with a very poor survival (1 of 30 patients). APACHE II score is a reliable indicator of severity of illness and likelihood of survival in critically-ill patients with acute renal failure. The widespread adoption of APACHE II scoring for patients with acute renal failure requiring intensive care would facilitate medical audit and comparison of studies from various centres.

In the DA-to-Lewis renal allograft model, donor whole blood enhanced renal allograft survival (14.5 +/- 7.6 days versus 6.9 +/- 0.6 days in controls [P less than 0.01]). The effect of individual cell components given in numbers equivalent to those present in the enhancing volumes of donor whole blood was studied. Immunization with donor red cells alone produced greater enhancement than that produced by whole blood (36.14 +/- 19.5 days [P less than 0.01]). B lymphocytes also enhanced allograft survival (16.0 +/- 3.9 days [P less than 0.01]). Although slight enhancement was observed with platelets (8.5 +/- 0.6 days) and 10(5) dendritic cells (8.4 +/- 0.5 days), in terms of allograft function dendritic cell immunization produced evidence of dose-dependent accelerated rejection. A similar finding was obtained with donor T cell immunization. Donor plasma had no effect. We conclude that, although donor blood has an overall enhancing effect on renal allograft survival in this model, the sensitizing and enhancing effects can be ascribed to individual types of cells.

Peripheral blood lymphocytes from normal seropositive donors and renal transplant recipients on various immunosuppressive regimens have been tested for their ability to mount a cytotoxic response when cultured with autologous EB virus-infected B cells and thereby to cause regression of proliferating b-cell foci. Cultures from 10 normal seropositive donors all showed the normal pattern of regression. Lymphocytes from patients receiving Cyclosporin A therapy with or without prednisolone completely failed to cause regression, thus allowing B-cell lines to proliferate unchecked. Cells from two of 17 patients treated with azathioprine and prednisone also failed to cause regression. The cells from the remaining 15 individuals showed regression response varying from minimal to normal. These results suggest a mechanism by which EB virus-related tumours may arise in immunosuppressed renal allograft recipients.

Renal transplant recipients with underlying polycystic kidney disease (PKD) may present with recurrent urinary tract infection (UTI). This is often due to persistent infection in one or both of the native polycystic kidneys. It may be necessary to remove the infected kidney in order to remove the source of persistent infection. Gallium-67 scintigraphy was performed in 11 renal transplant recipients with underlying PKD. Positive studies were obtained in four recipients who had recurrent UTI. The scan also localized which of the kidneys (native or transplant) was the site of persistent infection. These four recipients subsequently had nephrectomy of the infected polycystic kidneys as suggested by the scan. Negative scans were obtained in seven recipients who did not have recurrent UTI. Gallium scintigraphy is a useful test for detecting and localizing the site of persistent UTI in renal transplant recipients with underlying PKD who present with recurrent UTI.

Sixty-five renal transplant recipients underwent digital vascular imaging of the graft and simultaneous selective venous sampling for plasma renin activity. Renal artery stenosis was found in seven patients but did not appear to be functionally important. Diffuse intrarenal arterial attenuation was found in seven patients and was associated with impaired graft function and perfusion; it may indicate chronic rejection. Lower pole hypoperfusion was found in nine patients without impaired graft function or perfusion; its clinical relevance is uncertain. Aneurysmal dilatation of the main renal artery was found in two patients. Severe hypertension was common in patients with these three major abnormalities, but a causal association between the abnormality and hypertension could rarely be inferred. It may be the abnormalities on digital vascular imaging, especially diffuse intrarenal arterial attenuation and lower pole hypoperfusion, are secondary to severe hypertension. Digital vascular imaging with simultaneous selective venous sampling for plasma renin activity is useful in evaluating the vascular anatomy of the grafted kidney and in assessing any abnormality found. The combined procedure was well tolerated by all patients with no complications and no incidence of acute tubular dysfunction or proteinuria after the investigation.

Revue de l'evolution chez 12 malades sous hemodialyse soumis a une parathyroidectomie totale. Disparition complete de toute fonction parathyroidienne dans 6 cas. Dans quelques cas cas cependant les concentrations d'hormone sont augmentees apres quelques annees, suggerant une reactivation de quelques vestiges de glandes. Il semble que l'etat uremique favorise cette reactivation

Three patients with myasthenia gravis, in whom a thymoma had been removed during total thymectomy four to 14 years earlier, developed glomerulonephritis presenting as the nephrotic syndrome. All had been treated previously by plasma exchange and were receiving azathioprine. Two were also taking prednisolone. Serum immune complexes containing IgM were present in all three. Renal histology showed either focal segmental glomerulosclerosis, minimal change lesion or focal proliferative glomerulonephritis. No immunoglobulin deposits were seen. Two patients lost their proteinuria on high dose corticosteroid therapy and their renal function improved. Glomerulonephritis occurred in nine per cent of patients with thymoma receiving immunosuppressive treatment with azathioprine for more than two years. We suggest that this treatment may be implicated in its aetiology.