No abstract

Thrombotic microangiopathy (TMA) refers to a clinical and pathological syndrome in which endothelial injury results in the manifestations of thrombocytopenia, microangiopathic hemolytic anemia, and renal injury. A host of etiologies may induce endothelial injury and TMA, including enteric bacterial toxins, deficiency or dysfunction of complement regulatory proteins, deficiency or inhibition of von Willebrand factor cleaving proteases, and factors that inhibit endothelial cell proliferation and turnover. This has led specialists to concentrate on these specific inciting factors in terms of designing treatment and management. However, a key and less recognized factor is the underlying level of endothelial health. Indeed, many subjects with hereditary etiologies may remain disease free for years, and may never develop disease. Others with acute inciting events such as E coli O157 enteritis never manifest TMA. Experimental studies document the importance of specific factors such as endothelial nitric oxide levels in helping to protect animals from TMA. This suggests that one might approach the management of TMA not simply with specific treatments aimed at the underlying hereditary cause or inciting event, but rather also at general measures that may improve overall endothelial health. We propose studies to determine if interventions known to improve endothelial health, such as the administration of ACE inhibitors, statins, vitamin C, allopurinol, or nitric oxide-producing drugs may be able to prevent TMA even in subjects with underlying hereditary conditions that would otherwise predispose them to these diseases.

No abstract

Defective control of the alternative pathway of complement is an important risk factor for several renal diseases, including atypical hemolytic uremic syndrome. Infections, drugs, pregnancy, and hemodynamic insults can trigger episodes of atypical hemolytic uremic syndrome in susceptible patients. Although the mechanisms linking these clinical events with disease flares are unknown, recent work has revealed that each of these clinical conditions causes cells to release microparticles. We hypothesized that microparticles released from injured endothelial cells promote intrarenal complement activation. Calcineurin inhibitors cause vascular and renal injury and can trigger hemolytic uremic syndrome. Here, we show that endothelial cells exposed to cyclosporine in vitro and in vivo release microparticles that activate the alternative pathway of complement. Cyclosporine-induced microparticles caused injury to bystander endothelial cells and are associated with complement-mediated injury of the kidneys and vasculature in cyclosporine-treated mice. Cyclosporine-induced microparticles did not bind factor H, an alternative pathway regulatory protein present in plasma, explaining their complement-activating phenotype. Finally, we found that in renal transplant patients, the number of endothelial microparticles in plasma increases 2 weeks after starting tacrolimus, and treatment with tacrolimus associated with increased C3 deposition on endothelial microparticles in the plasma of some patients. These results suggest that injury-associated release of endothelial microparticles is an important mechanism by which systemic insults trigger intravascular complement activation and complement-dependent renal diseases.

Factor H is a regulator of the alternative pathway of complement. Genetic studies have revealed that patients with factor H mutations are at increased risk for several types of renal disease. Pathogenic activation of the alternative pathway in acquired diseases, such as ischemic acute kidney injury, also suggests that non-mutated factor H also has a limited ability to control the alternative pathway in the kidney. In the current study we examined the ability of circulating factor H to control alternative pathway activation on renal tubular epithelial cells. We found that an absolute deficiency of factor H prevented complement activation on the cells after ischemia/reperfusion, likely because of consumption of alternative pathway proteins in the fluid phase. In contrast, when the fluid phase regulation by factor H was retained but the interaction of factor H with cell surfaces was blocked, complement activation after renal ischemia/reperfusion increased. Finally, a recombinant form of factor H that is specifically targeted to sites of C3 deposition was found to reduce complement activation in the tubulointerstitium after I/R. These studies demonstrate that native factor H provides critical regulation of the alternative pathway in the renal tubulointerstitium after injury, but that this protection is incomplete. An inhibitor that targeted recombinant factor H to the tissue surface prevented alternative pathway activation and attenuated renal injury after I/R.