[The place of mycophenolate mofetil in glomerular diseases]. / Place du mycophénolate mofétil dans les glomérulopathies.

VARIOUS EFFECTS: Mycophenolate mofetil (MMF) is a specific inosine monophosphate dehydrogenase inhibitor implied in the de novo synthesis of purine bases; it selectively decreases lymphocyte proliferation and is used for the prevention of acute organ rejection. It also decreases the expression of certain adhesion molecules and slows down the functional renal progression in many experimental models of glomerular nephritis. THE GLOMERULAR PATHOLOGY: To date there has been very few studies on the efficacy of MMF in human glomerular diseases and these have been sporadic clinical observations or series of cases with around ten patients. In general, these reports were of cases in which conventional treatment had failed. IN THE FUTURE: The experimental studies and clinical observations available suggest that MMF will eventually complete the therapeutic arsenal in the management of certain forms of glomerular nephritis.

Efficacy of mycophenolate mofetil on recurrent glomerulonephritis after renal transplantation.

Recurrent glomerulonephritis in transplanted kidneys is not rare despite classical immunosuppressive drugs and depends on the etiology of nephropathy. Treatment of recurrence of renal disease on graft remains controversial. We report 6 cases of patients with recurrent glomerulonephritis after renal transplantation treated with mycophenolate mofetil (MMF). The glomerular diseases were Wegener's granulomatosis (n = 1), membranoproliferative glomerulonephritis type I (n = 1), focal and segmental glomerular sclerosis (n = 1), membranous glomerulonephritis (idiopathic membranous nephropathy (n = 1) and systemic lupus erythematous) (n = 1)) and immunoglobulin A nephropathy (n = 1). MMF was introduced because of intolerance of classical immunosuppressive treatment in 2 cases and because of its inefficiency in the other cases. MMF was introduced between 3 months and 36 months (13.5 +/- 7 months) after recurrence of the primitive glomerulonephritis. During combined MMF/cyclosporine/prednisone therapy, only 3 patients responded to MMF. MMF was disrupted precociously in 1 out of 3 patients who stabilized renal function because of discovery of lung cancer and in 2 out of the 3 other patients because of gastrointestinal intolerance and severe anemia. We supposed that MMF could represent a new effective alternative therapy of recurrent glomerulonephritis on renal graft in some cases.

Myofibroblast: a prognostic marker and target cell in progressive renal disease.

Myofibroblasts play an important role in many tissue injuries, and particularly in renal disease. The myofibroblast differentiation is an early event in the development of fibrosis. Myofibroblast-like cells express smooth muscle (SM) cytoskeletal markers (alpha-SM actin in particular) and participate actively in the production of extracellular matrix. Identification of early risk factors, particularly histological criteria, could be useful to identify patients at risk of progressive renal failure and needing a treatment. The evaluation of myofibroblast differentiation in renal tissue may reflect the intensity of tissue injury, predict long term outcome of chronic renal disease and help physicians to select therapeutic choices. More than a disease activity indicator. myofibroblasts appear to be a pivotal target for future therapies in progressive renal disease.

Mycophenolate mofetil reduces myofibroblast infiltration and collagen III deposition in rat remnant kidney.

BACKGROUND: Myofibroblasts have been shown to play a pivotal role in the synthesis of extracellular matrix components in several animal models of renal fibrosis. The purpose of the present study was to investigate whether mycophenolate mofetil (MMF) reduces interstitial myofibroblast infiltration and collagen III deposition in 5/6 nephrectomized rats. METHODS: Forty-five Wistar rats underwent 5/6 renal ablation and received by daily oral gavage either vehicle (N = 20) or MMF (N = 25) during the 60 days following surgery. Groups of five treated and five untreated rats were killed at two, four, and eight weeks after subtotal nephrectomy. Four untreated and three treated rats were killed at week 12, one month after treatment withdrawal. At the time of sacrifice, proteinuria, plasma, and urine creatinine were determined. Immunohistochemistry was performed on renal tissue for alpha-smooth muscle actin (alpha-SMA), a cytoskeletal marker of myofibroblasts, for type III collagen, and for proliferating cell nuclear antigen (PCNA). Moreover, in order to study the in vitro effects of MMF on fibroblast proliferation, rat fibroblasts were cultured in the presence or absence of mycophenolic acid (MPA). RESULTS: At all periods studied, MMF treatment improved renal functional parameters and progressively decreased remnant kidney hypertrophy and glomerular volume increment. Proliferating cells in renal tubules, interstitium, and glomeruli, as well as interstitial myofibroblast infiltration and interstitial type III collagen deposition, were also significantly reduced by MMF treatment. In addition, MPA exhibited a dose-dependent inhibitory effect on in vitro proliferation of rat fibroblasts. CONCLUSION: Reduction of interstitial myofibroblast infiltration may be an important event by which MMF significantly prevents renal injury following subtotal renal ablation. Thus, our results suggest that MMF could be useful to limit the progression of chronic renal disease toward end-stage renal failure.

Role of myofibroblasts during normal tissue repair and excessive scarring: interest of their assessment in nephropathies.

Following injury, tissue repair process takes place involving inflammation, granulation tissue formation and scar constitution. Granulation tissue develops from the connective tissue surrounding the damaged area and contains vessels, inflammatory cells, fibroblasts and myofibroblasts. Myofibroblasts play an important role in many tissue injuries and fibrocontractive diseases. The process of normal wound repair after tissue injury follows a closely regulated sequence including the activation and the proliferation of fibroblastic cells. In pathological situations, the normal resolution stages are abrogated and the proliferation of myofibroblasts continues, inducing excessive accumulation of extracellular matrix. The differentiation of fibroblastic cells into myofibroblasts is an early event in the development of tissue fibrosis. Myofibroblastic cells express smooth muscle cytoskeletal markers (alpha-smooth muscle actin in particular) and participate actively in the production of extracellular matrix. The evaluation of myofibroblast differentiation in renal biopsies would be useful for histopathologists to appreciate the intensity of tissue injury and particularly to predict the long term outcome of some nephropathies. Immunohistochemical studies for alpha-smooth muscle actin should be made systematically in renal tissue biopsies. Myofibroblastic differentiation appears to play a significant role in the progression of renal failure and seems to be a useful marker of progressive disease.

Long-term administration of interferon-alpha in non-responder patients with chronic hepatitis C: follow-up of liver fibrosis over 5 years.

In chronic hepatitis C, previous data have shown that short-term treatment with interferon-alpha (IFN-alpha) can reduce collagen deposition in the liver independently of the viral response. The aim of this work was to determine, in non-responder patients, the long-term effect of IFN-alpha on liver fibrosis according to the total administered dose and the fibrotic stage. Fibrosis was investigated on liver biopsies from 24 non-responder patients with chronic hepatitis C retreated with successive courses of IFN-alpha. The degree of liver fibrosis was assessed on three successive biopsies, performed before IFN-alpha treatment and 1 and 5 years later, in 13 and 11 patients, respectively, treated for less (mean: 7.5 months, 313 MU) and more (mean: 21.8 months, 791 MU) than 1 year. For each biopsy, fibrosis was assessed using a histological semiquantitative fibrosis scoring system and by morphometry after picrosirius red staining. Regardless of the dose and duration of IFN-alpha therapy, a slight decrease of fibrosis was observed in patients 5 years after starting treatment. In cirrhotic patients, a short treatment induced an improvement followed by a relapse of fibrosis in 57%, and only 43% of patients showed constant collagen regression over the 5 years of follow-up. On the contrary, after prolonged therapy, a progressive and significant decrease occurred throughout the follow-up period in all patients (P = 0.045). Long-term treatment with IFN-alpha is therefore associated with regression of liver fibrosis, particularly in cirrhotic patients. These promising results need to be confirmed in a larger series of patients.

Interstitial alpha-smooth muscle actin: a prognostic marker in membranous nephropathy.

AIM: Membranous nephropathy in adults causes 20% of nephrotic syndromes. Spontaneous outcome of this glomerulopathy is difficult to evaluate from clinical and histological data. Some patients can achieve complete remission, while others develop progressive renal failure. In this study we assessed alpha-smooth muscle actin (alpha-SMA) expression in renal interstitial myofibroblasts as a marker to predict the outcome of membranous nephropathy. PATIENTS AND METHODS: Renal function tests in tandem with alpha-SMA immunolabelling were performed on 25 patients with a mean follow-up of 7.2+/-5.6 years. The intensity of interstitial alpha-SMA (ialpha-SMA) immunostaining was compared to changes in glomerular filtration rate (GFR) evaluated by inulin clearance, between the time of diagnosis (GFR1) and the end of follow-up (GFR2). RESULTS: A significant correlation (r = 0.62, p<0.001) was found, between the intensity of interstitial myofibroblasts, immunolabeling and GFR at the end of follow-up. Moreover, the annual GFR variation and the annual percentage of GFR variation were correlated to interstitial myofibroblast labeling (respectively r = 0.62, p<0.001; r = 0.67, p<0.001). In addition, the importance of proteinuria, initial GFR impairment and fibrosis were confirmed as prognostic criteria. CONCLUSION: This study strongly shows that ialpha-SMA expression is a useful and early prognostic marker in the evolution of membranous nephropathy.

[Non-steroidal anti-inflammatory agent and angiotensin converting enzyme inhibitor: a dangerous combination during postoperative period]. / Anti-inflammatoire non stéroïdien et inhibiteur de l'enzyme de conversion: association dangereuse en période postopératoire.

A 72-year-old man experienced a postoperative acute renal failure (ARF) from a nonsteroidal anti-inflammatory drug (NSAID) and an angiotensin converting enzyme inhibitor (ACEI) intake and promoted by an unrecognized myeloma, peroperative hypotension and hormonal response to surgical stress. This drug combination can result in ARF through a fall of glomerular filtration by combined renal blood flow changes: NSAID inhibit vasodilation by renal prostaglandins, and the vasoconstrictor effect on the efferent arteriole is inhibited by the ACEI. Nephrotoxicity during the simultaneous use of ACEI and NSAID is increased by other risk factors of renal insufficiency such as ageing, preexisting renal disease and hypovolaemia. In these cases, a preventive therapy should be considered.

Apoptosis during wound healing, fibrocontractive diseases and vascular wall injury.

Following injury, tissue repair involves inflammation, granulation tissue formation and scar constitution. Granulation tissue develops from the connective tissue surrounding the damaged or missing area and contains mainly small vessels, inflammatory cells, fibroblasts and myofibroblasts. As the wound closes and evolves into a scar, there is a striking decrease in cellularity, including disappearance of typical myofibroblasts. The question arises as to what process is responsible for granulation tissue cell disappearance. Our results (in cutaneous wounds) and results of other laboratories (particularly in lungs and kidney) suggest that apoptosis is the mechanism responsible for the evolution of granulation tissue into a scar. During excessive scarring (hypertrophic scar or fibrosis), it is conceivable that the process of apoptosis cannot take place. After experimental endothelial injury in an artery, accumulation of smooth muscle cells participates in the formation of intimal thickening. Apoptotic features have been observed in cells of intimal thickening and also within human atherosclerotic plaques. In the case of atherosclerosis, apoptosis could be detrimental: since smooth muscle cells participate in plaque stability, apoptosis could lead to weakening and rupture of the plaque. These results underline the fact that both increased cell survival or excessive cell death can be associated with pathological disorders. Specific therapies devised to enhance or decrease the susceptibility of individual cell types to apoptosis development could modify the evolution of a variety of human diseases.