Immunosuppression for diabetic glomerular disease?

Abstract

In this issue of Kidney International, Utimura et al1Utimura R. Fujihara C.K. Mattar A.L. et al.Mycopheonlate mofetil prevents the development of glomerular injury in experimental diabetes.Kidney Int. 2003; 63: 209-216Abstract Full Text Full Text PDF PubMed Scopus (171) Google Scholar report that mycophenolate mofetil (MMF) prevents glomerular injury in diabetic rats. Because treatment for diabetic glomerular injury is imperfect, their report is exciting. Those of us trained to classify renal diseases as “immune” or “non-immune” will also find it surprising. How can a drug introduced into nephrology to prevent graft rejection limit glomerular injury caused by lack of insulin? It should be noted that MMF has previously been shown by the same group2Fujihara C.K. Malheiros D.M.A.C. Zatz R. Noronha I.D.L. Mycophenolate mofetil attenuates renal injury in the rat remnant kidney.Kidney Int. 1998; 54: 1510-1519Abstract Full Text Full Text PDF PubMed Scopus (150) Google Scholar and others3Romero F. Rodriguez-Iturbe B. Parra G. et al.Mycophenolate mofetil prevents the progressive renal failure induced by 5/6 renal ablation in rats.Kidney Int. 1999; 55: 945-955Abstract Full Text Full Text PDF PubMed Scopus (186) Google Scholar to limit glomerular sclerosis in rats subjected to renal ablation. It appears that the same cellular mechanisms participate in “immune” and “non-immune” injury, and that refined “immunosuppressive” drugs could ultimately be used to treat a broad spectrum of renal diseases. The main findings of Utimura et al1Utimura R. Fujihara C.K. Mattar A.L. et al.Mycopheonlate mofetil prevents the development of glomerular injury in experimental diabetes.Kidney Int. 2003; 63: 209-216Abstract Full Text Full Text PDF PubMed Scopus (171) Google Scholar can be simply stated. Rats were subjected to uninephrectomy and maintained diabetic for 8 months. MMF largely prevented the development of albuminuria and segmental glomerular injury seen in untreated animals. The beneficial effect of MMF could not be attributed to reduction of glomerular pressure or improvement of glycemic control. Drug levels were not measured, but previous studies have shown that the dose used by Utimura et al yields levels similar to those observed in humans taking MMF. It should be emphasized that MMF was effective early in the disease course when visible injury was confined to the glomerulus. Untreated rats did not exhibit the interstitial infiltrate that is regularly associated with sustained heavy proteinuria. Thus, in the current study, MMF did not prevent injury by interrupting the common pathway of interstitial inflammation and fibrosis, which is thought to accelerate nephron loss in proteinuric glomerular diseases. Why did MMF protect the glomerulus? One possibility is that diabetic glomerular disease has an inflammatory component, represented by glomerular accumulation of macrophages. As Utimura et al point out in their careful discussion, evidence that macrophages participate in glomerular injury has been steadily growing. Macrophages are found in normal glomeruli and their number increases in disease4Van Goor H. Ding G. Kees-Folts D. et al.Macrophages and renal disease.Lab Invest. 1994; 71: 456-464PubMed Google Scholar. Macrophage number increases when nephrosis is induced by toxins, indicating that immune complex deposition is not necessary for macrophage accumulation. Several studies have shown that glomerular macrophage number increases even before proteinuria appears in diabetic rats5Young B.A. Johnson R.J. Alpers C.E. et al.Cellular events in the evolution of experimental diabetic nephropathy.Kidney Int. 1995; 47: 935-944Abstract Full Text PDF PubMed Scopus (305) Google Scholar,6Sassy-Prigent C. Hendes D. Mandet C. et al.Early glomerular macrophage recruitment in streptozotocin induced diabetic rats.Diabetes. 2000; 49: 466-475Crossref PubMed Scopus (274) Google Scholar. This finding was confirmed by Utimura et al. They found that 2 months of diabetes increased the average number of ED-1-positive cells per glomerular profile from 1.4 ± 0.1 to 2.6 ± 0.3 and that this increase was prevented by MMF. The finding of an extra macrophage in glomerular profiles that otherwise appear normal would, at first glance, seem to be a small matter. But diabetic glomerular injury is a slow process in rats as well as in humans. Utimura et al waited 8 months for uninephrectomized diabetic rats to develop injury manifested by modest albuminuria and segmental lesions in approximately 15% of glomerular profiles. Comparison of experimental diabetes and other disease models suggests that glomerular macrophage number increases with the pace of glomerular injury. This raises the question of what brings macrophages to glomeruli. Circulating monocytes, which are the precursors of tissue macrophages, are attracted to sites of cellular injury independent of any expression of foreign antigens. This “innate” immune response is thought to be, in evolutionary terms, older than antigen-dependent immune reactions7Janeway Jr, C.A. Medzhitov R. Innate immune recognition.Annu Rev Immunol. 2002; 20: 197-216Crossref PubMed Scopus (5713) Google Scholar. Once on the scene, macrophages both facilitate destruction of dangerously damaged cells and stimulate cell proliferation and matrix production for tissue repair. The presence of macrophages thus suggests that diabetic glomerular injury can be divided in two parts. First, endogenous glomerular cells are “stressed” or “injured” by some combination of hemodynamic forces, metabolic changes, and exposure to altered proteins. These stresses do not cause visible structural changes but do lead to secondary expression of cytokines and other factors that attract monocyte/macrophages. The beneficial effect of MMF remains to be explained. Utimura et al incline to the view the MMF limits injury by preventing macrophage accumulation. They suggest that macrophage activation, although undoubtedly advantageous in many settings, causes proteinuria and sclerosis in glomeruli. MMF could certainly help keep macrophages out of injured glomeruli. Mycophenolic acid (MPA), the active metabolite of MMF, was chosen for drug development because it inhibits the inducible isoform of inosine monophosphate dehydrogenase on which lymphocytes and monocytes rely to produce guanine8Allison A.C. Eugui E.M. Mycophenolate mofetil and its mechanisms of action.Immunopharmacology. 2000; 47: 85-118Crossref PubMed Scopus (1004) Google Scholar. The resultant depletion of guanosine nucleotides not only inhibits proliferation but has other important effects. Of particular note, depletion of guanosine nucleotides limits surface expression of adhesion molecules on monocytes8Allison A.C. Eugui E.M. Mycophenolate mofetil and its mechanisms of action.Immunopharmacology. 2000; 47: 85-118Crossref PubMed Scopus (1004) Google Scholar. The resulting impairment of monocyte adhesion at injury sites, which contributes to the efficacy of MMF in preventing graft rejection, could explain the finding that MMF prevents macrophage accumulation in glomeruli of diabetic rats. It should be emphasized that the assumption that macrophages are bad for glomeruli remains unproven. As noted by Utimura et al, the beneficial effect of MMF could be explained by assuming that the drug acts directly on endogenous glomerular cells rather than assuming that it inhibits macrophage action. The identification of MPA as a preferential inhibitor of guanosine synthesis in lymphocytes was a triumph of rationale drug design. But the action of MPA is not completely restricted to immune cells. Other cell types rely on the MPA inhibited isoform of inosine dehydrogenase to varying degrees. Knowledge of MPA action on glomerular cells is incomplete, but two studies have shown that MPA prevents proliferation in mesagnial cells as effectively as it does in lymphocytes9Ziswiler R. Steinmann-Niggli K. Kappeler A. et al.Mycophenolic acid: a new approach to the therapy of experimental mesangial proliferative glomerulonephritis.J Am Soc Nephrol. 1998; 9: 2055-2066PubMed Google Scholar,10Hauser I.A. Renders L. Radeke H.H. et al.Mycophenolate mofetil inhibits rat and human mesangial cell proliferation by guanosine depletion.Nephrol Dial Transplant. 1999; 14: 58-63Crossref PubMed Scopus (120) Google Scholar. Presumably, mycophenolate-induced guanosine depletion could not only prevent mesangial cell proliferation but also block some diabetes-induced change that attracts macrophages. Of note, Utimura et al found that MMF prevented glomerular growth in diabetic rats. These observations raise the tantalizing possibility that a drug that is even more restricted in its action than MMF could act on the glomerulus to prevent diabetic injury without suppressing immune function. At present, we cannot tell whether MMF prevented diabetic glomerular damage in rats by a direct glomerular effect or by limiting an immune response to diabetes-induced glomerular stress. Either way, however, the results of Utimura et al are very hopeful. An obvious practical question is whether diabetic humans suffer the same kind of early glomerular injury that MMF prevented in rats. In this regard, it would be most interesting to know whether glomerular macrophage number increases early in the course of human diabetes. To determine whether MMF limits diabetic glomerular disease in humans requires a larger effort. But the finding that MMF works in rats will certainly motivate new clinical studies.