Immunoglobulin therapy may be effective in treating severe IgA nephropathy and protecting renal function. However, prospective controlled trials must confirm these preliminary results.

The nephrotic syndrome (NS) carries one of the highest risks of thrombotic complications. Consequently, over the last 15 years, some nephrologists have treated patients at risk (i.e. those with albuminemia < 20 g/l and membranous nephropathy) with anticoagulants: either subcutaneous heparin (Kakkar protocol) or antivitamin K. Low-molecular-weight heparin (LMWH) has a longer plasma half-life and better bioavailability than standard heparin and can thus be administered as a single daily injection. LMWH also carries a lower risk of hemorrhage. We prospectively studied the safety and efficacy of the LMWH Enoxaparin for preventive anticoagulation in NS. In a preliminary study, 10 adult nephrotic patients with biological markers of thrombosis risk (severe hypoalbuminemia and/or anomalies of the fibrinolytic pathway and/or deficiency in coagulation inhibitors) were given 40 mg (4,000 U) of Enoxaparin daily for at least 3 months; 3 patients were treated for 3 months, 1 for 6 months and 6 for 12 months. Patients were assessed for silent thrombosis, using renal vein Doppler ultrasonography, lower leg vein Doppler ultrasonography and lung ventilation-perfusion scintigraphy, before entry to the trial and subsequently at 3-month intervals. As LWMH caused no obvious side effects and no thrombosis was observed during the pilot study, we then placed 55 adult nephrotic patients free of thrombosis on the same treatment. Patients were seen according to the usual calendar required by their individual illnesses. At each examination, patients were assessed for clinical signs and symptoms of thrombosis and side effects; plasma D-dimer and urinary fibrin-fibrinogen degradation products were also measured at each visit. Twenty-five of the 55 patients (minimal-change disease, n=15; membranous nephropathy, n=2; systemic lupus erythematosus, n=2; other forms of glomerulonephritis, n = 6) received LMWH for less than 4 months. No side effects or thrombosis were observed, with the exception of 1 patient who had local intolerance to Enoxaparin but not to Teldeparin. The other 30 patients (membranous nephropathy, n=14; segmental glomerulosclerosis, n = 13; other nephropathies, n=3) received LMWH for at least 6 months (median, 13 months; range, 6-48 months). No side-effects or thrombosis were observed. Enoxaparin caused no changes in bone density in patients at risk of osteoporosis, as determined by absorptiometry. The self-administered LMWH therapy was well accepted by patients, most of whom found it straightforward and painless. The results of this prospective study suggest that the LMWH Enoxaparin given at a dose appropriate for adult NS patients with a high thrombotic risk is safe, effective and easily self-administered. The incidence of bleeding was low. Our findings provide arguments for the adoption of LMWH as first-line preventive anticoagulation in NS.

Following recent experimental data suggesting an aggravating effect of circulating proinflammatory cytokines on the histological lesions of IgAN, we studied changes in serum proinflammatory cytokines and their soluble receptors and antagonists in patients treated with polyvalent immunoglobulins (15 with severe nephropathy who had indicators of poor prognosis: heavy proteinuria, hypertension, altered renal function and Lee's histological grade III or IV; and 14 with moderate forms of IgAN who had permanent albuminuria > 300 mg/day and < 2000 mg/day, Lee's histological grade II and a glomerular filtration rate > 70 ml/min) in comparison with healthy controls (n = 20) and patients with non-IgA nephritides (n = 50). These were measured by means of specific immunometric assays before and after 9 months of immunoglobulin therapy. Total tumour necrosis factor (TNF) serum and IL-6 levels were elevated in IgAN patients before therapy, relative to controls, and normalized after immunoglobulin therapy. Levels of soluble TNF receptor of type I (sR55) and type II (sR75) increased on immunoglobulin therapy. TNF index alpha-55,75 used to assess biologically available TNF-alpha (ratio of total TNF-alpha divided by levels of soluble TNF receptors sR55 and sR75) was elevated before therapy and was below healthy control values after 9 months of immunoglobulin administration. Levels of serum IL-1 receptor antagonist were low prior to immunoglobulin administration in patients with severe forms of IgAN, and normalized on therapy. Serum interferon-gamma was unmodified. The histological activity index correlated with serum total TNF-alpha, TNF index alpha-55,75 and serum IL-6 levels, whereas proteinuria correlated with serum total TNF-alpha and TNF index alpha-55,75 but not with serum IL-6. These data suggest that the overproduction of proinflammatory cytokine is unbalanced by their natural antagonists in IgAN and Henoch-Schönlein syndrome. This process may play a role in the progression of the disease and be one of the targets of immunoglobulin therapy.

Recently, our group has shown that a 3-month course of intravenous immunoglobulin (2 g/kg/monthly) followed by 6 months of intramuscular immunoglobulins (IMIG, 16.5%, 0.35 ml/kg every 15 days) was able to slow or to stop the decline in the glomerular filtration rate, to reduce proteinuria, hematuria, leukocyturia and the histological index of activity on renal biopsy in patients with severe forms of IgA nephropathy (IGAN) and Henoch-Schönlein purpura (HSP). The aim of this open prospective trial was to evaluate the efficacy and safety of low-dose immunoglobulin therapy in moderate IGAN and HSP with permanent proteinuria. Fourteen patients with moderate IGAN [idiopathic IGAN: n= 11; chronic idiopathic HSP: n = 3] and permanent albuminuria were treated with polyvalent IMIG (16.5%) for 9 months (0.35 ml/kg once a week for 1 month, followed by 0.35 ml/kg every 15 days for a further 8 months). Eligibility criteria in the study were Lee histological stage I, II or III, albuminuria between 300 and 2,000 mg/ day and a glomerular filtration rate > 70 ml/min/1.73 m². IMIG were well tolerated and only 1 patient withdrew from the trial. No viral, renal or immunological side effects were observed. IMIG induced a significant decrease in albuminuria as well as in the histological activity index in the 11 cases in which a follow-up biopsy was performed. There was also a decrease in serum IgA, serum β₂-microglobulin and IgA immune complex levels, and an increase in serum IgG₁ levels. Twelve of the 13 evaluable patients improved during treatment. Systemic symptoms disappeared after 2 months of starting IMIG in the 3 HSP patients. IMIG therapy for IGAN only appeared to be suspensive, since its withdrawal was followed by relapse. We conclude that IMIG may be an effective immunomodulatory treatment of IGAN and HSP, although prospective controlled trials are required to confirm these preliminary results.

To study the specificity of gut hyperpermeability in primary glomerulonephritis, we investigated intestinal permeability by means of ⁵¹Cr-EDTA testing in 20 healthy individuals and in 30 patients with Immunoglobulin A nephropathy (IgA GN), 25 with idiopathic nephrotic syndrome (INS) and 20 with immune complex glomerulonephritis (IC-GN; membranous + membranoproliferative glomerulonephritis). Gut permeability was statistically increased in each patient group versus the controls [controls: 2% (0.4-3.9); IgA GN: 3.25% (0.7-17.70); INS: 3.71% (0.82-10); IC-GN: 3.40% (0.30-16); results are median (range); p < 0.005, nonparametric Mann-Whitney test]. An increase in intestinal permeability exceeding the upper limit of control values (95th percentile) was observed in 36% of IgA GN, 60% of INS and 50% of IC-GN patients. We conclude that intestinal permeability is frequently increased in primary glomerulonephritis and may also be increased in types of glomerulonephritis other than IgA GN.