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Genetic testing of complement and coagulation pathways in patients with severe hypertension and renal microangiopathy.

ABSTRACT: A diagnosis of thrombotic microangiopathy on kidney biopsy in a patient presenting with hypertensive emergency has historically elicited the diagnosis of malignant hypertension-associated thrombotic microangiopathy. Recent studies, however, have raised awareness that a number of these patients may actually represent atypical hemolytic uremic syndrome. To further investigate this premise, we performed next-generation sequencing to interrogate the coding regions of 29 complement and coagulation cascade genes associated with atypical hemolytic uremic syndrome in 100 non-elderly patients presenting with severe hypertension, renal failure and a kidney biopsy showing microangiopathic changes limited to the classic accelerated hypertension-associated lesion of arterial intimal edema ('mucoid intimal hyperplasia') in isolation and without accompanying glomerular microthrombi. No pathogenic or likely pathogenic variants were identified in any of the genes analyzed, although 13 patients had rare variants of uncertain significance predicted to be deleterious by all in-silico prediction methods utilized. Accordingly, this large patient cohort showed no definitive burden of disease secondary to genetic variants involving complement or coagulation pathways, which contrasts sharply with the high frequency of similar mutational events reported for atypical hemolytic uremic syndrome. Our results also inform recent data by suggesting that patients who present with severe or malignant hypertension and renal thrombotic microangiopathy may be at higher risk for atypical hemolytic uremic syndrome only if the biopsy shows more active disease that includes glomerular fibrin thrombi.

SUBMITTER: Larsen CP

PROVIDER: S-EPMC5843820 | biostudies-literature | 2018 Mar

REPOSITORIES: biostudies-literature

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Genetic testing of complement and coagulation pathways in patients with severe hypertension and renal microangiopathy.

Larsen Christopher P CP Wilson Jon D JD Best-Rocha Alejandro A Beggs Marjorie L ML Hennigar Randolph A RA

Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc 20171117 3

A diagnosis of thrombotic microangiopathy on kidney biopsy in a patient presenting with hypertensive emergency has historically elicited the diagnosis of malignant hypertension-associated thrombotic microangiopathy. Recent studies, however, have raised awareness that a number of these patients may actually represent atypical hemolytic uremic syndrome. To further investigate this premise, we performed next-generation sequencing to interrogate the coding regions of 29 complement and coagulation ca ...[more]

PMID: 29148534

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Project description:Early identification and treatment significantly improve clinical outcomes of psychotic disorders. Recent studies identified protein components of the complement and coagulation systems as key pathways implicated in psychosis. These specific protein alterations are integral to the inflammatory response and can begin years before the onset of clinical symptoms of psychotic disorder. Critically, they have recently been shown to predict the transition from clinical high risk to first-episode psychosis, enabling stratification of individuals who are most likely to transition to psychotic disorder from those who are not. This reinforces the concept that the psychosis spectrum is likely a central nervous system manifestation of systemic changes and highlights the need to investigate plasma proteins as diagnostic or prognostic biomarkers and pathophysiological mediators. In this review, we integrate evidence of alterations in proteins belonging to the complement and coagulation protein systems, including the coagulation, anticoagulation, and fibrinolytic pathways and their dysregulation in psychosis, into a consolidated mechanism that could be integral to the progression and manifestation of psychosis. We consolidate the findings of altered blood proteins relevant for progression to psychotic disorders, using data from longitudinal studies of the general population in addition to clinical high-risk (CHR) individuals transitioning to psychotic disorder. These are compared to markers identified from first-episode psychosis and schizophrenia as well as other psychosis spectrum disorders. We propose the novel hypothesis that altered complement and coagulation plasma levels enhance their pathways' activating capacities, while low levels observed in key regulatory components contribute to excessive activation observed in patients. This hypothesis will require future testing through a range of experimental paradigms, and if upheld, complement and coagulation pathways or specific proteins could be useful diagnostic or prognostic tools and targets for early intervention and preventive strategies.

Dataset Information

Genetic testing of complement and coagulation pathways in patients with severe hypertension and renal microangiopathy.

Publications

Genetic testing of complement and coagulation pathways in patients with severe hypertension and renal microangiopathy.

Similar Datasets

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