Endothelial Dysfunction: The Secret Agent Driving Kidney Disease.

Endothelial dysfunction can be considered the heart of many kidney and metabolic diseases, including primary hypertension, diabetic nephropathy, and CKD. However, perhaps the conditions most associated with dysfunction or injury of the endothelium are thrombotic microangiopathies (TMAs), such as hemolytic uremic syndrome (HUS) and thrombotic thrombocytopenic purpura (TTP). Specific types of these diseases have been associated with alterations in factors that alter angiogenesis, coagulation, and platelet activation and complement function. Although emphasis has tended to focus on one factor as causing one type of TMA, more recent studies suggest that TMAs often result from the synergism of multiple factors driving endothelial dysfunction. This emphasizes that general measures to improve endothelial health are likely the key for preventing and/or lessening the severity of many kidney and metabolic diseases.TMAs are diseases characterized by thrombocytopenia, microangiopathic hemolytic anemia, and renal injury, in which a common denominator seems to be endothelial dysfunction. Although the disease is generally dominated by renal manifestations in HUS, the dominantmanifestation ismore neurologic in TTP. Pregnancy-associated TMAs may manifest as a hemolysis, elevated liver enzymes, and low platelet count syndrome or preeclampsia. Other related conditions that are often separated from TMAs but in which intravascular blood coagulation also occurs include antiphospholipid syndrome, heparin-induced thrombocytopenia, and disseminated intravascular coagulation. Over the last several decades, a series of breakthroughs has been reported for the various TMAs. These include the discoveries of the role of circulating antiangiogenic factors, such as soluble fms–like tyrosine kinase 1 (sFLT-1) and soluble endoglin, in preeclampsia1,2; the role of Shiga-1 toxin from enterotoxigenic Escherichia coli in epidemic HUS3; the role of deficiency in complement regulatory proteins, such as factor H, in atypical HUS4; and the functional absence of a disintegrin and metalloprotease with thrombospondin type 1 motif 13 (ADAMTS13) caused by genetic absence (in hereditary TTP or Upshaw–Schulman syndrome) or autoantibodies (in acquired TTP).5 The identification of specific etiologies associatedwith specific diseases feeds our natural inclination and that of medical school teaching to think that each disease has a specific cause and a specific treatment. Although it is convenient to link a specific factor with a disease, it is becoming apparent that these factors are often not enough to cause the disease by themselves in the absence of other factors. For example, many subjects with a lack of factorHor a lackofADAMTS13 are asymptomaticuntil some illness occurs that triggers the TMA. As another example, only a small fraction of subjects infected with Shiga toxin– expressing E. coli develop HUS. This suggests that, for TMA to manifest, sufficient endothelial injury must be present, and this may require the presence of other factors that synergize together. In this issue of JASN, Erpenbeck et al.6 investigate the role of ADAMTS13 deficiency as a synergistic factor with sFLT-1 in inducing a preeclampsia-like lesion. sFLT-1 is a circulating inhibitor for vascular endothelial growth factor and placental growth factor that is expressed at high levels in the circulation and placenta of subjects with preeclampsia. It is a prime candidate for causing preeclampsia on the basis of previous studies suggesting that a lack of vascular endothelial growth factor in glomeruli can lead to TMA7; also, administration of sFLT-1 to pregnant rats can induce hypertension and proteinuria with a renal lesion of glomerular endotheliosis, similar to what is observed in preeclampsia.1 Although sFLT-1 is almost certainly one of the key factors driving preeclampsia, there are also reports that ADAMTS13 activity is commonly reduced in patients with preeclampsia.8,9 ADAMTS13 is a protease that cleaves large vWf multimers that are released from activated endothelial cells, thereby blocking local platelet aggregation and thrombosis. Erpenbeck et al.6 show that overexpression of sFLT-1 in control mice induced mild manifestations of TMAs, which has been previously reported, whereas a lack of ADAMTS13 resulted in nomanifestations of TMAs. However, the combination resulted in a lesion that greatly resembled preeclampsia, with thrombocytopenia, hemolytic anemia, glomerular endotheliosis, and marked proteinuria and hypertension. Furthermore, the administration of recombinant ADAMTS13 could largely block the development of these lesions. Published online ahead of print. Publication date available at www.jasn.org.