Late low-dose steroid withdrawal in renal transplant recipients increases bone formation and bone mineral density.

Corticosteroids have been the most widely used immunosuppressive agents since the first clinical transplantation in the 1950s. There are few studies of late steroid withdrawal in renal transplantation and none have prospectively assessed bone mineral density (BMD). The study aim was to assess the impact of corticosteroid withdrawal, in stable renal transplant recipients, on BMD and bone turnover. BMD, osteocalcin (OC) and cross-linked telopeptide of type I collagen (CTx) were measured in 92 patients randomized into a trial of steroid withdrawal. Patients with functioning renal transplants for more than 1 year with a serum creatinine below 200 micromol/L entered the trial. All patients were on triple immunosuppression (Cyclosporin microemulsion, Azathioprine and prednisolone), corticosteroids were withdrawn at 1 mg/month. BMD was measured twice annually with serum CTx and OC. One year following withdrawal of glucocorticoids there was no significant difference in creatinine. BMD increased in the withdrawal group (2.54% per year L1-L4, p < 0.01), there was a slight reduction in the control group. Mean OC increased from 5.3 to 12.2 ng/mL (p < 0.05) in the withdrawal group, but was unchanged in the controls. No change was seen in CTx. Corticosteroid withdrawal in renal transplant recipients results in an increase in BMD with a corresponding increase in serum OC.

Reduction of proteinuria with mycophenolate mofetil in predominantly membranous lupus nephropathy.

INTRODUCTION: Lupus membranous nephropathy (LMN) presents a difficult clinical problem as no particular treatment has been proven to be effective. Studies have shown good results with mycophenolate mofetil (MMF) in proliferative lupus nephropathy (LN) (WHO class III and IV disease). OBJECTIVES: To study whether MMF treatment was effective in membranous predominant LN in patients resistant to or intolerant of other immunosuppressive agents. PATIENTS AND METHODS: We retrospectively studied 10 patients with systemic lupus erythematosus who had biopsy-proven predominant LMN (six Vc patients and four Va or Vb patients). Previous treatments included cyclophosphamide, azathioprine, ciclosporin and corticosteroids. The following parameters were recorded at baseline and follow-up: blood pressure, ECLAM, proteinuria, serum albumin and creatinine, routine haematology and immunology. RESULTS: The study included eight women and two men, mean age 38.4 +/- 7.1 yr (range 30-49 yr). The racial distribution was as follows: five Caucasian, and five Black patients. The mean treatment time with MMF was 18.8 +/- 15.4 months (range 3-52 months). Twenty-four-hour urinary protein excretion was reduced from median 2.26 g (range 0-7.92 g) to median 0.66 g (range 0.08-3.85 g) at follow-up (P = 0.0039). Serum albumin increased significantly after treatment from median 29.5 g/l (range 14.0-42.0 g/l) to 33.5 g/l (range 23.0-40.0 g/l) at follow-up (P = 0.04). There were no significant changes in serum creatinine (P = 0.55). CONCLUSION: MMF is a potentially useful immunosuppressive agent in reducing the proteinuria associated with membranous predominant LN.

Mycophenolate mofetil in nonlupus glomerulonephropathy.

Mycophenolate mofetil (MMF) initially found widespread use in the immunoprophylaxis of rejection in organ transplantation. It has subsequently been used in lupus glomerulonephritis, where early studies have shown it to be effective in induction and maintenance therapy. The randomized studies have mostly studied small groups of patients and their conclusions do need to be confirmed in larger studies. MMF has also been used in small numbers of patients in a variety of nonlupus glomerulopathies, which have different underlying immunopathology as well as clinical course, including IgA nephropathy, membranous nephropathy, focal segmental glomerulosclerosis, membranoproliferative glomerulonephritis, hepatitis-C-associated glomerulonephritis and even Goodpasture's syndrome. In this article, we discuss its use in such nonlupus glomerular diseases.

Renal artery stenosis in hypertensive patients with antiphospholipid (Hughes) syndrome: outcome following anticoagulation.

OBJECTIVE: We have demonstrated a point prevalence of 26% renal artery stenosis in patients with antiphospholipid syndrome (APS) and uncontrolled hypertension. We describe the effect of anticoagulation on blood pressure control and renal function. METHODS: We studied 23 patients retrospectively with renal artery stenosis (RAS). Fourteen received oral anticoagulation for more than 1 yr (target International Normalized Ratio (INR) of 3.0-4.5). Five patients had primary APS. Patients were divided into two groups based on their INR (< 3.0 and > or = 3.0). Nine patients had repeat magnetic resonance angiography (MRA) or an angiogram of the renal arteries after 2 yr. RESULTS: Only 8/14 patients managed to maintain their INR > or = 3.0 (median INR 3.1, range 2.8-3.7) while six had a INR < 3.0 (median INR 1.9, range 1.2-2.4). Patients with a median INR < 3.0 had poorly controlled blood pressure and there was significant deterioration in mean serum creatinine values (Wilcoxon's test, P < 0.03). Nine patients underwent follow-up renal artery imaging. Three of nine patients with an INR < 3.0 (median INR 1.9) had re-stenosis and a fourth developed bilateral renal artery stenosis. Five patients with INR > or = 3.0 (median INR 3.1) did not show re-stenosis of the renal arteries; their renal function was stable and blood pressure was well controlled. One other patient with secondary APS (mixed connective tissue disorder) with INR > 3.0 showed recanalization of the stenosed renal artery. CONCLUSION: Anticoagulation with INR maintained > or = 3.0 helped to control the blood pressure and prevent the progression of renal disease.

Symptomatic cytomegalovirus infection complicating treatment of acute systemic vasculitis.

Cytomegalovirus (CMV) is usually a complication of renal/solid organ or bone marrow transplantation. We describe three cases of severe CMV in the context of vasculitis immunosuppression.

Adult onset Still's disease and collapsing glomerulopathy: successful treatment with intravenous immunoglobulins and mycophenolate mofetil.

In this Grand Round we present a 32-yr-old African man who became severely ill after a 5-month history of weight loss, pyrexia, arthralgia, sweats and rash. He went on to develop pericarditis, pericardial effusion with tamponade, hepatomegaly with abnormal liver function tests, lymphadenopathy, massive proteinuria and required ventilatory, circulatory and renal support. The differential diagnosis was adult onset Still's disease, systemic lupus erythematosus (SLE), infection and lymphoma. Primary infection and lymphoma were excluded and he was treated, with dramatic success, with intravenous immunoglobulins (i.v.IG). Subsequent renal biopsy excluded SLE but confirmed collapsing glomerulopathy. The proteinuria improved dramatically following treatment with mycophenolate mofetil. We discuss some of the difficult diagnostic and management issues raised by this patient and the different uses and mechanisms of action of i.v.IG.

Renal artery stenosis in the antiphospholipid (Hughes) syndrome and hypertension.

BACKGROUND: Hypertension is common in the antiphospholipid (Hughes) syndrome (APS) and its cause is poorly understood. Anecdotal evidence suggests that renal artery stenosis (RAS) may be a relevant and treatable cause of hypertension. OBJECTIVE: To investigate the prevalence of RAS in patients with APS and hypertension. PATIENTS AND METHODS: Three groups of patients were evaluated: (1) 77 patients with positive antiphospholipid antibodies (aPL) (60 secondary APS, 11 primary APS, and 6 with aPL only) and uncontrolled hypertension who were receiving two or more antihypertensive drugs; (2) 91 patients (

Mycophenolate mofetil for systemic lupus erythematosus refractory to other immunosuppressive agents.

BACKGROUND: Mycophenolate mofetil (MMF) is an immunosuppressive drug widely used in solid organ transplantation, and it may play an increasing role in autoimmune disease. MMF has been introduced as a novel immunosuppressive agent in systemic lupus erythematosus (SLE), often in patients intolerant of or resistant to conventional immunosuppressive regimens. METHODS: We studied 21 patients with SLE, most of whom had previously received courses of cyclophosphamide therapy and had also received courses of azathioprine or methotrexate. Indications for treatment included uncontrolled disease activity and worsening renal involvement. RESULTS: MMF treatment resulted in reduced disease activity, as assessed by the SLEDAI (SLE disease activity index) (P=0.0001) and decreased proteinuria (P=0.027) while allowing a significant reduction in oral corticosteroid dose (P=0.0001). Levels of complement factors C3 and C4 and anti-double-stranded DNA antibodies were not significantly affected. CONCLUSION: MMF appears to be a safe and effective alternative immunosuppressant for extra-renal and renal disease in SLE not responding to conventional immunosuppressive treatment.

Hypertension as the presenting feature of the antiphospholipid syndrome.

The antiphospholipid or Hughes syndrome is the association between antiphospholipid antibodies (aPL), venous and arterial thromboses and pregnancy morbidity. Antiphospholipid syndrome (APS) commonly coexists with autoimmune diseases usually systemic lupus erythematosus (SLE), when it is known as secondary APS. When present in isolation it is known as primary APS (PAPS). Although the kidney may be affected in APS, its involvement is perhaps not as well described as that of other organs. Thrombotic microangiopathy (TMA) affecting the kidney has been reported as a manifestation in both primary and secondary APS. This report describes hypertension related to underlying renal TMA as a presenting symptom of APS.

Identification of hepatitis C virus seroconversion resulting from nosocomial transmission on a haemodialysis unit: implications for infection control and laboratory screening.

Hepatitis C virus (HCV) seroconversion was detected by routine screening in a haemodialysis patient, Patient 1. Serological investigations were undertaken over the following 3 months to determine if further transmission to other patients on the unit had occurred. No additional cases were identified. Twenty-two haemodialysis patients known to have HCV infection were investigated using molecular epidemiological methods to determine if transmission between patients had occurred. HCV viraemia was demonstrated by polymerase chain reaction in 19 of 22 patients (86%). Genotyping showed that eight patients were infected with genotype 1, three with genotype 3 and eight, including Patient 1, with genotype 2. Phylogenetic analysis of viral sequences from the eight patients with genotype 2 revealed three, including Patient 1,with a novel subtype of HCV type 2, and revealed close similarity between viral sequences from patient 1 and those from one other patient, suggesting transmission. This was consistent with haemodialysis histories. Among other patients with genotype 2, there were two with subtype 2a and three others with three separate novel subtypes, as yet undesignated. With the exception of patient 1, all patients infected with novel subtypes were of Afro-Caribbean origin. The HCV prevalence among patients on the haemodialysis unit was high (14%), which may reflect the ethnicity of our haemodialysis population. This case emphasises the risk of nosocomial transmission and the importance of infection control procedures on haemodialysis units, and highlights the usefulness of molecular epidemiological techniques for the investigation of outbreaks of HCV infection.

Scleromyxoedema and thrombotic thrombocytopaenic purpura: two rare conditions both responding to plasma exchange.

We report the case of a 66-year-old female who over an 18-month period developed severe, disabling scleromyxoedema with pulmonary fibrosis. Treatment with oral prednisolone and melphalan had failed to prevent disease progression. Treatment with a 5-day course of plasma exchange, intravenous cyclophosphamide (500 mg) and methyl-prednisolone (1 g on 3 consecutive days) was unfortunately followed by the development of thrombotic thrombocytopaenic purpura (TTP). After 17 extra plasma exchanges, she recovered and there has been a dramatic improvement in her skin signs. We postulate that the extra plasma exchanges which she received as a consequence of developing TTP have contributed to this result. To our knowledge, TTP has never been associated with scleromyxoedema, but it is likely to be a coincidence in this case.

Sparing of first dose effect of monovalent anti-CD3 antibody used in allograft rejection is associated with diminished release of pro-inflammatory cytokines.

The murine monoclonal antibody OKT3 is the best known of the anti-CD3 antibodies used for the prevention and treatment of renal allograft rejection. Use of this antibody is associated with improved graft outcome but it has a number of adverse effects thought to result from the massive release of pro-inflammatory cytokines. It has been postulated that OKT3 causes cytokine release because of cross-linking of CD3 molecules on the cell surface by bivalent anti-CD3 antibodies, such as OKT3, and the simultaneous binding of the Fc regions of these monoclonal antibodies to Fc receptors on other cells resulting in cell activation. Monovalent antibodies directed against the CD3 antigen should not, in theory, cause cell activation and cytokine release by this postulated mechanism. This study details the use of a monovalent anti-CD3 monoclonal antibody in the treatment of allograft rejection in five renal transplant recipients and documents the degree of TNF, IFN-g and IL6 release generated after antibody injection. Monovalent anti-CD3 monoclonal antibody reversed the rejection episode for which it was used and was well tolerated in all patients. TNF, IFN-g and IL6 measurement showed that little pro-inflammatory cytokine release occurred after this drug. It is likely that the relative lack of side-effects of monovalent anti-CD3 reflects the blunted release of pro-inflammatory cytokines. Monovalent anti-CD3 monoclonal antibody may be a useful addition to the reagents available to treat allograft rejection.

Analysis of activated T cell infiltrates in rat renal allografts by gamma camera imaging after injection of 123iodine-interleukin 2.

Activated T cells bearing receptors for interleukin 2 (IL-2) play an important role in immunity and in immunopathological processes such as allograft rejection. In order to investigate the presence of activated T cells in lymphocytic infiltrates in transplanted kidneys, we investigated the uptake and retention of radioactivity after an intravenous injection of radioiodinated IL-2 in experimentally transplanted rats. IL-2 was enzyme radiolabelled with 123iodine using a glucose oxidase/lactoperoxidase method and shown to retain specific binding on an IL-2 receptor positive cell line, C58E6. To examine the kinetics of 123iodine-interleukin 2 (123I-IL-2) uptake in vivo, animals that had been transplanted five days previously with allogeneic or syngeneic grafts were injected with 123I-IL-2 and then imaged using an external gamma camera. Radioactivity was measured at time points up to 240 min after intravenous injection of 123I-IL-2. Four groups of animals were examined: allogeneic grafts (n = 7); syngeneic grafts (n = 6); ischaemic native kidneys (n = 5) all following injection with 123I-IL-2; and allogeneic transplants (n = 5) after injection of 123I-lactalbumin, an irrelevant molecule of similar molecular weight to IL-2. The peak radioactivity after injection was measured and the amount of radioactivity retained in the graft at increasing time intervals after injection was expressed as a function of initial peak radioactivity. At four hours after injection of 123I-IL-2, mean retention of activity by rejecting grafts was 77(+/- 2.68)% of peak activity, compared to 45(+/- 6.38)% in syngeneic controls (p < 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)