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Nephrotoxicity of calcineurin inhibitors (CNIs) is an acute, reversible and chronic, irreversible pathology. Histologically, acute nephrotoxicity manifests as hemodynamic modifications caused by vasoconstriction of the essentially afferent arterioles resulting in a drop in the glomerular filtration rate. Chronic nephrotoxicity is characterized by arteriolar hyalinosis resulting in a variety of tubulointerstitial and glomerular lesions with an essentially ischemic mechanism. However, these histological lesions, whether chronic or acute, are not specific of CNI toxicity and can be seen in the course of many pathological circumstances in kidney transplantation. This absence of specificity makes the histological diagnosis of CNI nephrotoxicity difficult. In addition, the individual risk of developing CNI nephrotoxicity, difficult to predict based solely on the pharmacokinetic parameters of systemic CNI exposure, also involves local exposure (CNI concentrations in the graft) modulated by several, notably pharmacogenetic factors. The difficulty of diagnosing CNI nephrotoxicity and the interindividual variability of its risk require development of new diagnostic tools so that the patients at highest risk of developing severe CNI nephrotoxicity lesions, in whom minimization protocols would produce the best risk-benefit ratio, can be identified.

Renal biopsy is an invaluable tool used for the monitoring of grafts and the management of their survival. Since 1993, thanks to research on biopsy tissues that enabled to distinguish the different types of rejection and to find markers of reversible or irreversible rejection, a classification of renal lesions has been established to achieve the regularly updated Banff classification. The last in date (2005) has defined the antibody-mediated chronic rejection, forsaken the term "chronic allograft nephropathy" and described a new class with interstitial fibrosis and tubular atrophy (IF/TA). Systematic or screening biopsies allow revealing infraclinical rejection lesions before any renal function degradation, better understanding of allograft nephropathy pathophysiology, confirming the diagnostic, but also displaying other more specific lesions that could benefit from a treatment. However, the interest of biopsies is limited by interpretation problems and risks for the patient.

Vasculitic lesions are defined by necrosis of the vascular wall with perivascular inflammatory infiltrates. Secondary forms of vasculitis are observed in some systemic diseases, after infections, secondary to drugs or to malignancies. Usually, these secondary forms are characterised by the presence of immunoglobulin and complement deposits and thus probably caused by immune complex deposits. Conversely, necrotizing vasculitis occurring without known causal factor are named primary vasculitis, are not associated with immune deposits. Wegener's granulomatosis, microscopic polyangitis, Churg and Strauss syndrome and the isolated form of necrotizing and crescent glomerulonephritis are closely associated with the anti-neutrophil cytoplasm auto-antibodies (ANCA). The two main auto-antigen targets recognised by ANCA are lysosomal enzymes, proteinase 3 and myeloperoxidase, both contained in azurophilic granules of polymorphonuclear neutrophils and in primary lysosomes of monocytes. It has been demonstrated that ANCA antigens are expressed at the neutrophil (and monocyte) membrane after preactivation and are accessible to antibodies. Thus, ANCA may amplify neutrophils and monocyte activation. However, the causal or induced nature of anti-neutrophil auto-immunity in vasculitis remains unknown.

These antibodies are specific for antigens in the cytoplasm of neutrophils. The main antigenic targets are proteinase 3(PR3) and myeloperoxydase (MPO) but other targets have been described without determinant conclusions for clinical practice. Staining patterns can be distinguished by an indirect immunofluorescence test (IFI), in which ethanol fixed neutrophils from healthy donors are incubated with patient's sera. Two patterns are distinguished: cytoplasmic pattern (c-ANCA) and perinuclear pattern (p-ANCA). When ANCA are detected by IFI, from a practical point of view, anti -MPO and anti-PR3 antibodies are tested. ANCA have been strongly associated with a spectrum of necrotizing small vessel vasculitides that includes Wegener's granulomatosis, microscopic polyangiitis, Churg and Strauss syndrome, pauci-immune focal necrotizing and crescentic glomerulonephritis. ANCA are a diagnosic marker and useful for the follow-up of the patients. ANCA can be observed in other pathologies: rhumatismal autoimmune diseases, inflammatory gut diseases, after drugs (hydralazine, minocycline, propylthiouracil), after silical exposition, infections (cystic fibrosis, endocarditis, HIV infection). The specificity is different and rarely anti-MPO. The ANCA role for the development of vasculitis is not completely elucidated. Some arguments are against a primary role of ANCA in the development of vasculitis. Certainly, amplification role for neutrophil activation is demonstrated but the primary event responsible of neutrophil activation is not yet defined.

The kidney is affected in a variety of vasculitic syndrome. Vasculitis represent an heterogeneous group of inflammatory disease concerning vessels. They can be considered as secondary in systemic lupus erythematosus, cryoglobulinemia, rheumatoid polyarthritis but also in infectious diseases (Streptococci, hepatitis B) in malignant disease and after drugs. However, in many circumstances, no causes are found. The discovery of autoantibodies directed against components of neutrophil cytoplasm (ANCA) represent a great progress in the understanding of vasculitis. ANCA are autoantibodies directed against neutrophil lysosomial enzymes, preferentially myeloperoxidase and proteinase 3. They are frequently found in patients with idiopathic necrotizing vasculitis, systemic or localized to the kidney (Wegener granulomatosis, microscopic periarteritis, pauci-immune necrotizing glomerulonephritis, Churg and Strauss syndrome and polyarteritis nodosa). Diagnostic and prognostic values are sure, although their presence is unconstant with variable percentage in relation with the type of vasculitis. The increase of ANCA level is not always related with disease relapse. Conversely, a permanent low level means a quiescent disease. At the present time, it is not known if ANCA play a pathogenetic role or if they constitute a marker of the disease.

The specific antigens to antineutrophil cytoplasmic antibodies (ANCA) and their relations with renal diseases begin to be well-known. In patients with systemic vasculitis, two major antigens have been recognized: proteinase 3 and myoloperoxydase. These enzymes are located in the azurophilic granules of neutrophils and migrate to the surface of these cells when they are activated. Other antigens, such as elastase, lactoferrin, CAP57 and cathepsin G, have been identified, but they are less commonly encountered. The presence of ANCA is particularly frequent in Wegener's granulomatosis, microscopic periarteritis, crescentic necrotizing glomerulonephrites without immunoglobulin deposits; it is less frequent in periarteritis nodosa and in Churg-Strauss' syndrome. ANCA can now be considered as markers of vasculitis; they are related to disease activity and can be used to evaluate the effectiveness of treatments.

In a retrospective study of 82 adults with idiopathic membranous nephropathy, we have studied the predictive factors of renal death. Thirty one patients developed renal failure, sixteen of them progressed to end-stage renal failure (ESRF) (13 males and 3 females). Nine patients developed ESRF in the first 5 years following the renal biopsy. The males and the patients with a nephrotic syndrome have a high risk of ESRF. The age is not a predictive factor of poor outcome. Hypertension seems to be more frequent in patients who developed early but slowly progressive renal failure. Extensive renal interstitial lesions are indicative of poor renal prognosis.

The authors have studied 6 cases of systemic AA amyloidosis associated with ankylosing spondylitis. Renal failure occurred in all patients a mean of 19 years after the clinical onset of the rheumatic disease. Three patients progressed rapidly (between 3 months and 3 years) to end-stage renal failure. Such an outcome did not depend upon early onset of the renal impairment, degree of inflammation or treatment with colchicine. All patients were alive 2 to 10 years later, and this confirms a better prognosis than with AL amyloidosis. The utility of combining Wright's permaganate reaction with immunological methods to characterize the amyloid deposits was also confirmed. It is concluded that amyloidosis is a rare complication of ankylosing spondylitis and probably depends on a genetic predisposition. The possibility of amyloidosis should be kept in mind when proteinuria or renal failure appear in the course of ankylosing spondylitis.

Six families including 27 patients with adult nephronophthisis were studied. The diagnosis was based on the evidence of heredofamilial chronic tubulointerstitial renal disease, not related to urologic abnormality, and progressing to renal failure in at least 2 members of each kindred. In two families, the mode of inheritance is compatible with recessive autosomal transmission; retinal heredodegeneration was found in both kindreds; mean age at end-stage renal failure (ESRF) was 22 years. In one additional case, kidney involvement is apparently sporadic, and associated with retinal changes and blindness. In one kindred, the mode of inheritance could not be determined. In the last 3 families, pedigrees are compatible with dominant autosomal transmission; retinal involvement was found in none; ESRF developed at a mean age of 47 years. Renal cysts were detected by ultrasonography in 9 of 12 patients; they were located at the cortico-medullary junction or in the medulla in 5 cases. Renal biopsy showed rather similar changes in the various kindreds. These results are compared with those already reported from 29 families with adult nephronophthisis.

Circulating anticoagulants with antiprothrombinase activity were detected in 14 out of 49 patients (i.e. 29%) presenting with severe forms of systemic lupus erythematosus (SLE) predominantly renal (29) or extrarenal (20). Nine of these 14 patients had thrombopenia and 8 had a falsely positive Wassermann test. The anticoagulants were more frequently encountered in patients with severe extrarenal manifestations (9/20 cases) than in patients with severe proliferative renal lesions (5/29 cases). They were found in 5 out of 10 patients with arterial and/or venous thrombosis. Anticoagulant levels paralleled the course of the disease during treatment. No haemorrhage was observed in 14 percutaneous renal biopsies performed on 11 patients free from outer coagulopathies. This suggests that the presence of antiprothrombinase anticoagulants in the blood of patients without thrombopenia or other coagulation disorders is compatible with surgery or biopsy of the kidney.

We report a case of necrotizing glomerulonephritis with linear fixation along the glomerular basement membrane (GBM) atypical by: 1) the absence of significant renal failure or evidence of pulmonary involvement; 2) no detectable circulating anti GBM antibody by indirect immunofluorescence or radioimmunoassay.

Clinical use of OKT3 for the treatment of ongoing rejection episodes has already been demonstrated as being highly effective. This work shows for the first time that combining azathioprine and OKT3 was able to delay as well as to decrease both the intensity and the quality of the anti-OKT3 immunization, allowing a 1-month prophylactic use of the MoAb. It also proves that OKT3 used prophylactically during one month can lead to 4-year first cadaver graft and patient survival rates better than those ever reported with any other immunosuppressive regimen. These results were obtained with lower doses of steroids and other immunosuppressive agents than in conventionally treated control patients. After the first two injections of OKT3, tolerance was perfect allowing out-hospital administration, and side effects consisted only in an increased number of viral infections instead of the bacterial infections observed in the conventional treatment groups. The prophylactic use of OKT3 should give even better results if it were possible to reach a 1-month administration schedule in all patients by modulating the dose of OKT3 according to the T3+ cell count and the monitoring of serum OKT3 levels.

Out of 55 patients with severe systemic lupus erythematosus (SLE) retrospectively studied from 1962 to 1979, 32 had diffuse proliderative glomerulonephritis and 23 had one or several extrarenal and/or haematological manifestations of the disease. All received corticosteroids in high dosage (0,8 to 1,5 up period was 48 months from the beginning of treatment. The actuarial survival rates for the whole groupe after 1,5 and 10 years were 92,4%, 83,4% and 77,2% respectively. Eight patients died: 5 of SLE and 3 of iatrogenic complications. Four are kept alive by maintenance haemodialysis. At the end of the study period, SLE was quiescent in 37 patients, including 14 who had discontinued corticosteroids for 5 to 72 months. The five-year survival rates were very similar in patients with renal and extrarenal involvement (86,4% and 81,6% respectively). In the latter group myocardial insufficiency, thrombopenia and thromboembolic complications were the main factors of morbidity and mortality. Corticosteroids were administered alone to 25 patients and in combination with cyclophosphamide to the remaining 30. Cyclophosphamide was given initially in 13 cases or subsequently on account of intolerance (7 cases) or resistance (10 cases) to steroids. Similar results were obtained with these two therapeutic regimens, but it must be noted that cyclophosphamide was mainly used in the more severe forms of SLE.