Malignant Nephrosclerosis Research Articles

Endothelial-derived complement factor D contributes to endothelial dysfunction in malignant nephrosclerosis via local complement activation

Malignant nephrosclerosis is a thrombotic microangiopathy associated with abnormal local activation of the complement alternative pathway (AP). However, the mechanism underlying local AP activation is not fully understood. We hypothesized that complement factor D (CFD) secreted by endothelial cells triggers vascular dysfunction in malignant nephrosclerosis via local complement activation. We investigated the deposition of CFD in human kidney biopsy tissues and the function of endothelial-derived CFD in endothelial cell cultures. Immunofluorescence microscopy and laser microdissection-targeted mass spectrometry revealed significant deposition of CFD in the kidneys of patients with malignant nephrosclerosis. Conditionally immortalized human glomerular endothelial cells (CiGEnCs) continuously expressed and secreted CFD in vitro. CFD knockdown in CiGEnCs by small interfering RNA reduced local complement activation and attenuated the upregulation of intercellular adhesion molecule-1 (ICAM-1), vascular adhesion molecule-1 (VCAM-1), von Willebrand factor (VWF), and endothelin-1 (ET-1) induced by Ang II. The expression of CFD in CiGEnCs was significantly higher than that in other types of microvascular endothelial cells. Our findings suggest that (i) glomerular endothelial cells are an important source of local renal CFD, (ii) endothelial-derived CFD can activate the local complement system, and (iii) endothelial-derived CFD mediates endothelial dysfunction, which may play a role in the pathogenesis of malignant nephrosclerosis.

PS-R04-9: REVERSIBLE ACUTE RENAL INJURY IN MALIGNANT HYPERTENSION DURING LONG-TERM FOLLOW-UP

Background: Malignant hypertension is a disease characterized by severe hypertension and multi-organ damage. Although mortality and renal prognosis have improved with antihypertensive therapy, progression to end-stage renal disease remains a leading cause of morbidity and mortality. Case presentation: A 37-year-old man with a history of untreated hypertension and proteinuria was referred to our hospital with complaints of right paralysis. He was diagnosed with left putaminal hemorrhage and treated with conservative blood pressure reduction management. He was also complicated with severe hypertension (blood pressure 231/146 mmHg), acute renal failure (BUN 39 mg/dl, serum creatinine 4.01 mg/dl, urinary protein 2.848 g/gCre), and heart failure with preserved ejection fraction (BNP 373 pg/ml). Initial evaluation demonstrated hyperreninemia (32.6 ng/ml/hr) with hyperaldosteronism (125 pg/ml), consistent with malignant hypertension. Secondary hypertension, such as primary aldosteronism, Cushing's syndrome, pheochromocytoma, and renal artery stenosis was excluded by further examination. His renal size was mildly atrophic assessed by CT scan, suggesting a history of chronic kidney disease. At first, we gradually decreased blood pressure with antihypertensive agents except for angiotensin-converting enzyme (ACE) inhibitor and angiotensin receptor blockade (ARB) so as not to induce exacerbation of renal function via glomerular ischemia. In the long-term, he was treated to achieve a tight blood pressure control to systolic blood pressure of 100–110 mmHg with the combination of ACE inhibitor, calcium channel blocker, and alpha/beta blocker. Although his clinical course showed gradual recovery of renal function, our conservative approach successfully induced renal function recovery over six months of follow-up (BUN 27 mg/dl, serum creatinine 2.26 mg/dl, urinary protein 0.154 g/gCre). Discussion: Previous reports suggest that malignant nephrosclerosis may recover slowly if the blood pressure is tightly controlled during the follow-up. From a long-term perspective, tight blood pressure control with inhibition of the renin-angiotensin-aldosterone system, which is a critical factor of the pathogenesis in malignant hypertension, may provide beneficial effects on the renal prognosis of malignant hypertension.

PS-BPR03-8: MALIGNANT HYPERTENSION WITH ACUTE KIDNEY INJURY AND THROMBOTIC MICROANGIOPATHY SUCCESSFULLY TREATED WITH ANGIOTENSIN RECEPTOR NEPRILYSIN INHIBITOR

Background: Malignant hypertension is a disease characterized by severe hypertension and multi-organ damage. Sacubitril/valsartan, a first-in-class angiotensin receptor neprilysin inhibitor (ARNi), has already demonstrated the superiority of reducing blood pressure versus olmesartan in patients with hypertension. ARNi has also been shown to improve cardiac biomarkers, cardiac remodeling, and prognosis in patients with heart failure, and a new AHA/ACC/HFSA guideline (2022) redefined to recommend ARNi as first-line renin-angiotensin-system inhibitors (class 1a) in patients with HFrEF (heart failure with reduced ejection fraction). However, the evidence about the efficacy and safety of ARNi in end-stage renal disease (ESRD) patients undergoing hemodialysis has been limited. Presentation: A 23-year-old man with no prior medical history was admitted to the previous hospital with severe hypertension (blood pressure 224/159 mmHg) associated with acute kidney injury (BUN 228.5 mg/dl, serum creatinine 25.50 mg/dl) and was referred to our hospital with the initiation of hemodialysis. He was also complicated with hypertensive heart failure with a preserved ejection fraction (NT-proBNP 172113 pg/ml). Blood test results also revealed thrombocytopenia (platelet 11.9 x 103/μL), hemolytic anemia (hemoglobin 7.4 g/dl, LDH 1076 U/L, haptoglobin < 10 mg/dl), and schistocyte on the blood smear, which was suggestive of thrombotic microangiopathy. His blood cell counts and serum LDH levels improved after antihypertensive treatment. Secondary hypertension, such as primary aldosteronism, Cushing's syndrome, pheochromocytoma, and renal artery stenosis, was deniable by further examination. The elevated levels of renin (65.5 ng/ml/hr) and aldosterone (685 pg/ml) were consistent with malignant hypertension. Serum antibody tests for screening of autoimmune disease were all negative. Renal biopsy revealed findings of malignant nephrosclerosis: glomerular collapse, glomerulosclerosis, endothelial swelling, and media thickening of the arteries. Oliguria recovered during the clinical course; however, his renal function did not fully recover. An arterio-venous fistula was created, and maintenance hemodialysis two times per week was continued during hospitalization. Even though his dry weight was adjusted to normal by repeated dialysis, his blood pressure was poorly controlled to systolic blood pressure of 160–170 mmHg by calcium channel blockers, angiotensin II receptor blocker (ARB), and alpha/beta-blockers. After switching from ARB to ARNi by increasing the dose to a maximum of 400 mg, his systolic blood pressure improved to 130–140 mmHg and was stable throughout the day, assessed by ambulatory blood pressure monitoring. Conclusion: Through our experience, it is conceivable that ARNi may be helpful in the settings of resistant hypertension in ESRD patients undergoing hemodialysis.

PS-R05-6: A CASE OF ACUTE KIDNEY INJURY WITH THROMBOTIC MICROANGIOPATHY CAUSED BY MALIGNANT HYPERTENSION

A 31-year-old man was transferred to our hospital because of severe hypertension, acute kidney injury (AKI) and thrombotic microangiopathy (TMA). A month earlier, the patient sought medical attention for epigastric pain. Upper gastrointestinal endoscopy revealed hemorrhagic gastric ulcer, and hemostasis was performed. At that time, his was found to have severe high blood pressure (200/140 mmHg), together with low levels of hemoglobin (Hb) (10.5 g/dL) and platelet (Plt) count (107 x 109/L). One week later, gastric ulcer tended to improve, but the blood pressure was still high (192/122 mmHg), along with severe abnormalities in creatinine (Cr) (10.7 mg/dL), Hb (6.6 g/dL) and Plt levels (139 x 109/L). On the following day, the serum Cr level increased to 13.7 mg/dL, while Hb and Plt levels decreased to 6.3 g/dL and 111 x 109/L, respectively. He was referred and admitted to a local affiliated hospital. Because the patient was considered as AKI due to dehydration and anemia, fluid replacement and blood transfusion were performed. However, his renal function was worsened further and pulmonary congestion appeared, which required initiation of hemodialysis therapy. Because low platelet counts, high LDH levels and schistocytes in peripheral blood were observed, he was diagnosed with TMA and transferred to our hospital. Laboratory data on admission revealed as follows: the plasma renin activity (PRA), 7.8 ng/ml/h, plasma aldosterone concentration (PAC), 443 pg/mL, plasma adrenaline, 12 pg/mL, noradrenaline, 172 pg/ml, ACTH, 17.3 pg/mL, cortisol, 6.9 g/dL, and TSH, 1.71 IU/mL. Renal artery stenosis was not observed by renal artery ultrasound. Echocardiography showed hypertrophy of the left ventricle. Funduscopic examination showed retinal hemorrhages. Renal biopsy revealed a large number of collapsed glomeruli, onion skin lesions in the arterioles and interlobular arteries, luminal narrowing due to thrombosis, and fibrin accumulation on the blood vessel walls, which lead to histological diagnosis of malignant nephrosclerosis and TMA. Intensive treatment with a calcium channel blocker, an ACE inhibitor, and other antihypertensive agents resulted in improved hypertension, and normalized platelet count and LDH levels, together with reduced PRA (3.2 ng/ml/h) and PAC (208 pg/mL). However, withdrawal from hemodialysis was not achieved. We consider that in this case TMA was caused by malignant hypertension due to essential hypertension. We conclude that early detection and intervention for hypertension are mandatory to prevent the progression of malignant hypertension and related organ damages.

PS-R04-5: A CASE OF SEVERE RENAL FAILURE WITH HYPERTENSIVE EMERGENCY WHO SUCCEEDED IN HEMODIALYSIS WITHDRAWAL BY STRICT CONTROL OF BLOOD PRESSURE

Introduction: Hypertensive emergency is a condition in which progressive and irreversible organ damages occur as a result of extremely elevated blood pressure. Although the prognosis for renal outcomes has been improved by advances in antihypertensive therapy, the cases who result in maintenance dialysis are still not uncommon. We herein report a case of hypertensive emergency who was successfully withdrawn from hemodialysis by intensive treatment. Case presentation: A 55-year-old woman, whose systolic blood pressure was 150–160 mmHg constantly for at least 2 years, was seen by her primary care physician due to nocturnal cough and respiratory distress. She exhibited marked hypertension (diastolic blood pressure, 120–130 mmHg) and renal dysfunction (serum creatinine (sCr), 2.76 mg/dL, baseline 0.5 mg/dL). She was diagnosed as hypertensive emergency and was treated with antihypertensive agents immediately. Despite the treatment, her renal function did not improve, so that she was transferred to our hospital for further examination and intensive treatment. While imaging examination revealed a right adrenal tumor, for which primary aldosteronism was suspected, endocrinological examinations showed high plasma aldosterone concentration with high plasma renin activity; therefore it was assumed that the hormonal changes were secondary to hypertensive emergency. Although funduscopic findings were relatively mild (KW-IIb), the condition was considered as accelerated-malignant hypertension caused by essential hypertension. A renal biopsy revealed extensive interstitial damage with onion skin-like lesions, which led to a diagnosis of malignant nephrosclerosis. While continuing strict antihypertensive management including the renin-angiotensin system blockade, hemodialysis was started on day 17 due to progressive renal dysfunction (sCr 9.27 mg/dL). Continuous intensive treatment gradually alleviated renal dysfunction, and hemodialysis was finally withdrawn on day 38. There was no further deterioration seen, and the patient was discharged on day 55. After discharge, her renal function was kept improved and her sCr was 2.5 mg/dL 6 months after the discharge. Discussion and Conclusion: Hypertensive emergency may cause irreversible kidney damage without appropriate antihypertensive therapy. In particular, acute tubular damages have been suggested to correlate with both systolic and diastolic blood pressures. Controlling blood pressure appropriately is crucial to protect kidneys against disease progression and even reverse kidney damage upon acute renal failure with hypertensive emergency.

PS-R04-6: A CASE OF MALIGNANT NEPHROSCLEROSIS WITHDREW FROM TEMPORARY HEMODIALYS

In the Case of AKI (acute renal injury) due to malignant hypertension, appropriate BP (Blood Pressure) management is important and sometimes requires hemodialysis. Here we report a 49-year-old female patient with malignant hypertension, AKI and acute pulmonary edema. She presented with severe hypertension (BP213/150 mmHg), high serum creatinine level (Cr12.74 mg/dL), congestive heart in chest radiographic findings and nerve head edema (Scheie: H4S3). There were no findings associated with renal artery stenosis. She was diagnosed as AKI due to malignant hypertension. Nicardipine continuous intravenous infusion was carried out for BP control and temporary hemodialysis had begun almost simultaneously. On Day 5 of admission, she had received oral Ca blocker and low dose of ACE inhibitor (temocapril). BP level remained stable thereafter. Nevertheless, oliguric renal failure lasted for several weeks. On Day 10 of admission, we performed renal biopsy and confirmed onion-skin-like intimal thickening and luminal narrowing findings. These were corresponded to malignant nephrosclerosis, not to chronic nephritic syndrome. We continued 2 times per week hemodialysis using the indwelling catheter after discharge. Her daily urinary output increased substantially day by day (over 1000 ml/day) and her serum creatinine level became less and less around Cr 4.0 mg/dL. This case withdrew temporary hemodialysis over a period of five months conclusively. In some cases, renal dysfunction is improved slowly in the long-term course by appropriate BP management. Accordingly, it is necessary to evaluate the possibility whether or not withdrawing from hemodialysis in the cases of AKI due to malignant hypertension.

MO043: Role of the I416L variant of complement factor I in the occurrence of thrombotic microangiopathy among patients of African ancestry

Abstract BACKGROUND AND AIMS Complement dependent hemolytic and uremic syndrome (c-HUS) predisposes to hypertensive crisis and chronic hypertension. Reciprocally, hypertensive crisis may precipitate thrombotic microangiopathy (TMA) via endothelial shear stress. Patients of African ancestry have long been recognized for their predisposition to both chronic hypertension and chronic kidney disease (CKD). Yet, despite growing evidence meant to bridge the divide between the complement alternative pathway and hypertensive crisis [1] (i) c-HUS is only known to account for a small fraction of the cases of malignant HTA (5%) [2] or TMA (4%) [3] (ii) complement genetic investigations in the population of African ancestry are sparse. Recently, the I416L CFI variant, which is specific to patients of African ancestry, has been classified as likely pathogenic (https://databases.lovd.nl/shared/variants/0000521158#00005040). By running a query through the BIOMNIS genetic databank, we sought to identify and provide a phenotypic description of the patients carrying the I416L CFI variant. METHOD All samples were sequenced at the BIOMNIS center (Lyon, France) using the Illumina platform and subsequently processed via the in-center bioinformatics pipeline. The BIOMNIS genetic databank compiles a total of 2886 whole exome sequencing (WES) nationwide (single unrelated patients) for renal (n = 1200) and non-renal indications (n = 1686). Once patients were recognized to carry the I416 variant, deidentified clinical data was provided by the attending nephrologist. RESULTS Among 1686 WES performed for non-renal indications, three unrelated patients harbored the I416L variant. Out of the 1200 WES performed for renal indications, we identified eight unrelated patients carrying the I416L CFI variant. All patients were of African Ancestry and were heterozygous for the variant, including five males with median age of 38.5 years. They all shared a common history remarkable for hypertension of early onset at median of 33 years [21–38]. None of these patients were acknowledged to have c-HUS prior to WES. In six cases, the kidney disease was undetermined. Four patients experienced TMA: three during bouts of malignant hypertension with concurrent biological TMA. One of them exhibited signs of TMA on biopsy with superimposed signs of malignant nephrosclerosis and another on a kidney transplant. Three patients disclosed genetic risk factor for kidney disease including Apol1 pathogenic variants (G1 and/or G2) (n = 2) and URAT1-related pathogenic variant (n = 1). Five patients had at least one additional risk factor for renal disease. All but one patient progressed to CKD including end-stage CKD on four instances with a median follow-up of 6.5 years. One patient presented with TMA following kidney transplantation. Only one patient whose hypertensive crisis manifested as preeclampsia and HELLP was free of CKD on last follow-up. CONCLUSION C-HUS may go unrecognized or mimic vascular nephropathy. These results make a case for a streamlined genotyping of patients, especially patients of African ancestry with a history of hypertension of early onset. Additional triggers acting as second ‘hits’ such as hypertension, pregnancy or genetic and non-genetic renal risk factors may aggravate the course of kidney disease. Yet, further investigations are warranted to appreciate the true clinical significance of this variant as it entails momentous therapeutic and medico-economic implications, most notably the use of anti-C5 therapy.

Potential Involvement of Complement Activation in Kidney Vascular Lesions of Arterionephrosclerosis.

BackgroundComplement dysregulation has been implicated in the pathogenesis of malignant nephrosclerosis with typical pathological manifestation as thrombotic microangiopathy (TMA) in recent studies. The aim of the present study was to evaluate the potential role of complement activation in arterionephrosclerosis, the major pathological change in benign hypertensive nephrosclerosis.MethodsPatients with biopsy-proven arterionephrosclerosis from 2010 to 2018 in our center were retrospectively enrolled in the present study. The clinical data were retrieved from the medical chart record. The pathological changes of renal biopsy were semiquantitatively evaluated. The ratio of inner-/outer-luminal diameter of the arterioles was calculated to evaluate the degree of arteriosclerosis. Immunohistochemical staining of CD34 and CD68 was adopted to evaluate peritubular capillary (PTC) density and macrophage infiltration, respectively. Complement components, including C3d, C4d, C1q, and C5b-9, were detected by immunohistochemical staining in paraffin-embedded sections. IgM and albumin were detected by immunofluorescence staining in frozen renal tissues.ResultsFifty-two patients were enrolled. The mean age was 45.0 ± 12.7 years, with 39 (75%) males. The median duration of hypertension was 66 months (IQR: 24–138 months). A total of 950 arterioles were evaluated, with a mean ratio of the inner/outer luminal diameter of 0.43 ± 0.05. The ratio of the inner-/outer-luminal diameter correlated with eGFR (r = 0.341, p = 0.013), sclerotic/ischemic glomerular lesions (r = –0.364, p = 0.008) and PTC density (r = 0.426, p = 0.002). Seventy-four percent (703/950) of the evaluated arterioles had C3d deposition with various patterns and intensities. The percentage of C3d-positive arterioles ranged from 63.6 to 100.0% in each specimen. The ratio of the inner/outer luminal diameter of arterioles correlated with the intensity of C3d deposition (r = –0.174, p = 0.001). Infiltration of macrophages was observed around C3d-positive arterioles. The percentage of C3d-positive arterioles was correlated with macrophage infiltration in each specimen (r = 0.330, p = 0.018). Occasional C4d-positive staining on arterioles was observed with no deposition of C1q or C5b-9 in arterionephrosclerosis specimens.ConclusionOur findings provide evidence for potential complement activation in the pathogenesis of vascular lesions in arterionephrosclerosis.

On the question of benign and malignant nephrosclerosis

Analyzing the topic at hand, K. Rosenthal

POS-404 POTENTIAL ROLE OF COMPLEMENT IN VASCULAR LESIONS OF ARTERIONEPHROSCLEROSIS

Renal damage from hypertension is categorized as benign nephrosclerosis (bN) and malignant nephrosclerosis (mN). Complement dysregulation has been found as a major causative factor in the pathogenesis of mN lesions in previous studies. The aim of the present study was to evaluate the potential role of complement in bN.

Association between thrombotic microangiopathy and activated alternative complement pathway in malignant nephrosclerosis.

Malignant nephrosclerosis, defined as renal microangiopathy in the setting of severe hypertension, remains a critical renal emergency leading to end-stage renal disease despite aggressive anti-hypertensive treatment. Recently, activation of the complement alternative pathway (AP) has been reported to play a prominent role in the pathogenesis of malignant nephrosclerosis. However, subsequent study failed to recapitulate the findings of genetic complement abnormalities in the disease. This study aimed to determine the presence of AP activation and genetic complement defects and establish their correlations to renal microangiopathy lesions, clinical features and prognosis in patients with malignant nephrosclerosis. Fifty patients with malignant hypertension and concomitant thrombotic microangiopathy (TMA) proven by renal biopsy were investigated; 25 cases of kidney donors who received zero-hour allograft biopsies were used as normal controls. Various renal TMA lesions in patients with malignant nephrosclerosis were reviewed and evaluated using a semi-quantitative scoring system. Deposition of C5b-9, C3a, C5a, C4d and mannose-binding lectin was assessed by immunohistochemistry. Co-localization of C5b-9 and CD34 was detected by confocal microscopy. Complement factor B (FB), factor P (FP; properdin), factor D (FD), factor H (FH), C3a and C5a levels were quantified by enzyme-linked immonosorbent assay in plasma and urine samples of patients with malignant nephrosclerosis and controls. Genetic abnormalities of complement components were analysed by whole-exome sequencing. Renal biopsies of malignant nephrosclerosis showed identical histopathological and ultrastructural features to atypical haemolytic uraemic syndrome. C5b-9, C3a and C5a deposits were found along the walls of arteries/arterioles and glomerular capillaries and localized in the endothelial cells. Elevated plasma and urinary levels of FB, FP, FD, C3a and C5a as well as decreased FH levels were observed in patients with malignant nephrosclerosis compared with normal controls. The urinary levels of complement AP components, but not the plasma levels, were correlated with renal functions, prognosis and active TMA lesions except for arteriolar thrombi. Finally, mutations of the MCP, CFB, CFH and CFHR5 genes were identified in 8 of 20 patients with malignant nephrosclerosis. Aberrant complement AP dysregulation was demonstrated and associated with the activity, severity and renal outcomes of malignant nephrosclerosis. This observation warrants screening for complement defects in patients with malignant nephrosclerosis for the potential use of complement regulators and also highlights the need for further investigation of the precise role of AP in the pathogenesis of the disease.

The role of complement in arterial hypertension and hypertensive end organ damage.

Increasing evidence indicates that hypertension and hypertensive end organ damage are not only mediated by haemodynamic injury but that inflammation also plays an important role. The complement system protects the host from a hostile microbial environment and maintains tissue and cell integrity through the elimination of altered or dead cells. As an important effector arm of innate immunity, it plays also central roles in the regulation of adaptive immunity. Thus, complement activation may drive the pathology of hypertension through its effects on innate and adaptive immune responses, aside from direct effects on the vasculature. Recent experimental data strongly support a role for complement in all stages of arterial hypertension. The remarkably similar clinical and histopathological features of malignant nephrosclerosis and atypical haemolytic uraemic syndrome suggest also a role for complement in the development of malignant nephrosclerosis. Here, we review the role of complement in hypertension and hypertensive end organ damage. LINKED ARTICLES: This article is part of a themed issue on Canonical and non-canonical functions of the complement system in health and disease. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v178.14/issuetoc.

Does established vascular kidney disease exist?

Does established vascular kidney disease exist?

SUN-152 POTENTIAL ROLE OF INTERLEUKIN-11 IN A RAT MODEL OF MALIGNANT NEPHROSCLEROSIS

Malignant hypertensive nephrosclerosis develops in some but not all cases of severe hypertension; the underlying molecular mechanisms are not clear. We compared gene expression in renovascular hypertensive rats which developed malignant hypertensive nephrosclerosis with gene expression in rats which were hypertensive but did not develop malignant nephrosclerosis. Further, we investigated the potential role of one candidate molecule identified from our gene expression screen, Interleukin-11 (IL-11).

Malignant hypertension as a rare cause of thrombotic microangiopathy

Malignant hypertension can occasionally be associated with microangiopathic haemolytic anaemia. A 38-year-old male presented with nausea, vomiting, loss of appetite and oliguria for 2 weeks. He was diagnosed with hypertensive...

A pathogenic role of complement in arterial hypertension and hypertensive end organ damage.

The self-amplifying cascade of messenger and effector molecules of the complement system serves as a powerful danger-sensing system that protects the host from a hostile microbial environment, while maintaining proper tissue and organ function through effective clearance of altered or dying cells. As an important effector arm of innate immunity, it also plays important roles in the regulation of adaptive immunity. Innate and adaptive immune responses have been identified as crucial players in the pathogenesis of arterial hypertension and hypertensive end organ damage. In line with this view, complement activation may drive the pathology of hypertension and hypertensive injury through its impact on innate and adaptive immune responses. It is well known that complement activation can cause tissue inflammation and injury and complement-inhibitory drugs are effective treatments for several inflammatory diseases. In addition to these proinflammatory properties, complement cleavage fragments of C3 and C5 can exert anti-inflammatory effects that dampen the inflammatory response to injury. Recent experimental data strongly support a role for complement in arterial hypertension. The remarkably similar clinical and histopathological features of malignant nephrosclerosis and atypical hemolytic uremic syndrome, which is driven by complement activation, suggest a role for complement also in the development of malignant nephrosclerosis. Herein, we will review canonical and noncanonical pathways of complement activation as the framework to understand the multiple roles of complement in arterial hypertension and hypertensive end organ damage.

Clinico-pathological characteristics and outcomes of patients with biopsy-proven hypertensive nephrosclerosis: a retrospective cohort study.

BackgroundThis study aimed to investigate renal outcomes and their predictors in biopsy-proven hypertensive nephrosclerosis (HN) patients and to compare clinico-pathological characteristics and prognoses between benign nephrosclerosis (BN) and malignant nephrosclerosis (MN) patients.MethodsData for biopsy-proven HN patients were retrospectively analyzed. Renal survival rates and relationships between clinico-pathological characteristics and outcomes were assessed.ResultsA total of 194 patients were enrolled; the mean age at biopsy was 43.8 years, and male gender predominated (82.5 %). The median duration of hypertension was 5.0 years, and the mean systolic and diastolic blood pressures were 195 ± 37 and 126 ± 26 mmHg, respectively. The median serum creatinine (Scr) level, estimated glomerular filtration rate (eGFR), and proteinuria level were 1.61 mg/dl, 49.6 ml/min/1.73 m2, and 0.80 g/24 h, respectively. BN and MN were found by renal biopsy in 55.2 % and 44.8 % of patients, respectively. At biopsy, MN patients were younger, and had higher median Scr and proteinuria levels, higher incidences of anemia, hypertensive heart disease and hypertensive retinopathy, and worse renal outcomes than BN patients. During a median follow-up period of 3.0 years, 36 patients (18.6 %) reached end-stage renal disease (ESRD), and the 5- and 10-year cumulative renal survival rates for HN patients were 84.5 % and 48.9 %, respectively. A decreased baseline eGFR, an increased baseline proteinuria level, anemia, increased percentage of global glomerulosclerosis and tubular atrophy and interstitial fibrosis (TAIF) were independent predictors of future ESRD.ConclusionsThe clinico-pathological characteristics and prognoses were significantly different between the MN and BN patients. The renal outcomes of HN patients were independently associated with the baseline eGFR and proteinuria level, anemia, percentage of global glomerulosclerosis and TAIF.Electronic supplementary materialThe online version of this article (doi:10.1186/s12882-016-0254-2) contains supplementary material, which is available to authorized users.

Thrombotic Microangiopathy and Low ADAMTS 13: Case Report and Review of the Literature

Background: Thrombotic Microangiopathy (TMA) is a multi-organ dysfunction syndrome characterized by microvascular thrombosis, thrombocytopenia and hemolytic anemia with diverse etiologies ranging from primary Thrombotic thrombocytopenic purura (TTP) and Hemolytic uremic syndrome (HUS) to secondary phenomena to medications, severe uncontrolled hypertension and autoimmune disorders i.e Scleroderma renal crises, catastrophic antiphospholipid syndrome and pre-eclampsia, prompt diagnosis, identification of potential etiologies and treatment are essential steps for reducing morbidity and mortality. Case Report: We describe a case of a 34-year-old man who presented with features of advanced renal impairment, severe uncontrolled hypertension and thrombotic microangiopathy, overall clinical picture was most consistent with malignant hypertension and hypertensive nephrosclerosis secondary to long standing uncontrolled hypertension, however a serum test ordered measuring the activity of ADAMTS 13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13) resulted one week later was consistent with reduced enzyme activity, challenging the first diagnosis. Conclusions: Clinical correlation and high index of suspicion are essential in the diagnosis and management of thrombotic microangiopathy, The reduction in ADAMTS -13 activity or antigen level has been thought to be a primary cause of thrombotic microangiopathies I.e TTP and HUS, however recent studies have shown a negative correlation between ADAMTS-13 activity and elevated blood pressure (BP) in malignant hypertension.

Pharmacological manipulation of arachidonic acid-epoxygenase results in divergent effects on renal damage.

Kidney damage is markedly accelerated by high-salt (HS) intake in stroke-prone spontaneously hypertensive rats (SHRSP). Epoxyeicosatrienoic acids (EETs) are epoxygenase products of arachidonic acid which possess vasodepressor, natriuretic, and anti-inflammatory activities. We examined whether up-regulation (clofibrate) or inhibition [N-methylsulfonyl-6-(2-propargyloxyphenyl)hexanamide (MS-PPOH)] of epoxygenase would alter systolic blood pressure (SBP) and/or renal pathology in SHRSP on HS intake (1% NaCl drinking solution). Three weeks of treatment with clofibrate induced renal cortical protein expression of CYP2C23 and increased urinary excretion of EETs compared with vehicle-treated SHRSP. SBP and urinary protein excretion (UPE) were significantly lowered with clofibrate treatment. Kidneys from vehicle-treated SHRSP, which were on HS intake for 3 weeks, demonstrated focal lesions of vascular fibrinoid degeneration, which were markedly attenuated with clofibrate treatment. In contrast, 2 weeks of treatment with the selective epoxygenase inhibitor, MS-PPOH, increased UPE without significantly altering neither urinary EET levels nor SBP. Kidneys from vehicle-treated SHRSP, which were on HS intake for 11 days, demonstrated occasional mild damage whereas kidneys from MS-PPOH-treated rats exhibited widespread malignant nephrosclerosis. These results suggest that pharmacological manipulation of epoxygenase results in divergent effects on renal damage and that interventions to increase EET levels may provide therapeutic strategies for treating salt-sensitive hypertension and renal damage.

Critical blood pressure threshold dependence of hypertensive injury and repair in a malignant nephrosclerosis model.

Most patients with essential hypertension do not exhibit substantial renal damage. Renal autoregulation by preventing glomerular transmission of systemic pressures has been postulated to mediate this resistance. Conversely, malignant nephrosclerosis (MN) has been postulated to develop when severe hypertension exceeds a critical ceiling. If the concept is valid, even modest blood pressure (BP) reductions to below this threshold regardless of antihypertensive class (1) should prevent MN and (2) lead to the healing of the already developed MN lesions. Both predicates were tested using BP radiotelemetry in the stroke-prone spontaneously hypertensive rats receiving 1% NaCl as drinking fluid for 4 weeks. Severe hypertension (final 2 weeks average systolic BP, >200 mm Hg) and MN (histological damage score 36±5; n=27) developed in the untreated stroke-prone spontaneously hypertensive rats but were prevented by all antihypertensive classes (enalapril [n=15], amlodipine [n=13], or a hydralazine/hydrochlorothiazide combination [n=15]) if the final 2-week systolic BP remained <190 mm Hg. More impressively, modest systolic BP reductions to 160 to 180 mm Hg (hydralazine/hydrochlorothiazide regimen) initiated at ≈4 weeks in additional untreated rats after MN had already developed (injury score 35±4 in the right kidney removed before therapy) led to a striking resolution of the vascular and glomerular MN injury over 2 to 3 weeks (post-therapy left kidney injury score 9±2, P<0.0001; n=27). Proteinuria also declined rapidly from 122±9.5 mg/24 hours before therapy to 20.5±3.6 mg 1 week later. These data clearly demonstrate the barotrauma-mediated pathogenesis of MN and the striking capacity for spontaneous and rapid repair of hypertensive kidney damage if new injury is prevented.