Atypical Hemolytic-Uremic Syndrome: A Clinical Review.

Atypical hemolytic-uremic syndrome (HUS) is a rare life-threatening disorder characterized by microangiopathic hemolytic anemia, thrombocytopenia, and ischemic injury to organs, especially the kidneys. Microvascular injury and thrombosis are the dominant histologic findings. Complement activation through the alternative pathway plays a critical role in the pathogenesis of atypical HUS. Genetic abnormalities involving complement regulatory proteins and complement components form the molecular basis for complement activation. Endothelial cell dysfunction, probably because of the effects of complement activation, is an intermediate stage in the pathophysiologic cascade. Atypical HUS has a grave prognosis. Although mortality approaches 25% during the acute phase, end-stage renal disease develops in nearly half of patients within a year. Atypical HUS has a high recurrence rate after renal transplantation, and recurrent disease often leads to graft loss. Plasma therapy in the form of plasma exchange or infusion has remained the standard treatment for atypical HUS. However, many patients do not respond to plasma therapy and some require prolonged treatment. Approved by the Food and Drug Administration in the treatment of atypical HUS, eculizumab is a humanized monoclonal antibody that blocks cleavage of complement C5 into biologically active mediators of inflammation and cytolysis. Although case reports have shown the efficacy of eculizumab, randomized clinical trials are lacking. Therapeutic strategies targeting endothelial cells have demonstrated promising results in experimental settings. Therefore, inhibitors of angiotensin-converting enzyme, HMG-CoA reductase, and xanthine oxidase as well as antioxidants, such as ascorbic acid, may have salutary effects in patients with atypical HUS.

Use of Extracorporeal Techniques in the Removal of Dabigatran.

Dabigatran is a novel direct thrombin inhibitor that has proven effective in the prevention of vascular events in patients with nonvalvular atrial fibrillation. Not much is known about the clearance capability with extracorporeal techniques of dabigatran. This review showcases the pharmacokinetics and a perusal of the current literature regarding cases that involved the clearance of the drug in patients with normal renal function and end-stage renal disease. Renal replacement therapy represents a therapeutic option to eliminate dabigatran and decreased the risk of bleeding in patients undergoing emergent surgical procedures on dabigatran.

Contrast-induced nephropathy: pathogenesis and new therapeutic options for prevention.

Contrast-induced nephropathy is a common cause of inpatient and outpatient acute renal failure. The pathogenesis is complex adding difficulty to its management. Several preventive measures that involved the use of intravenous fluids and oral agents have been implemented in human studies with heterogeneous results because of the disparity in defining changes in glomerular filtration rate after renal injury. New preventive techniques based on the pathogenesis of contrast-induced nephropathy are being applied to human subjects with preliminary good outcomes. Future randomized trials will give us the opportunity to elucidate its benefits.

Anti-GBM disease and ANCA during dengue infection.

Anti-glomerular basement membrane (GBM) disease is a severe inflammatory renal disorder due to pathogenic autoantibodies directed mainly against the α3 chain of type IV collagen. In ~1/4 of patients with anti-GBM disease, antineutrophil cytoplasmic antibodies (ANCA) predominantly with myeloperoxidase (MPO) specificity can be detected. Although the inciting stimuli leading to the development of an immune response against the type IV collagen and neutrophils are unknown, evidence indicates that both genetic and environmental factors play a role. Of note, molecular mimicry between self-antigens and nonself-antigens such as antigenic determinants of microorganisms has been implicated in the pathogenesis of anti-GBM disease and ANCA-associated vasculitis. A mosquito-borne viral illness highly prevalent in the tropics and subtropics, dengue can be complicated by acute renal failure, proteinuria, hematuria and glomerulonephritis. We present a 66-year-old woman who was diagnosed with dengue infection and rapidly progressive glomerulonephritis during an outbreak of dengue in Honduras in the summer of 2013. Renal biopsy revealed severe crescentic glomerulonephritis. Immunofluorescence examination demonstrated strong linear IgG deposition along glomerular capillary walls. Serologic tests demonstrated antibodies against GBM, MPO and platelet glycoproteins. The patient was diagnosed with anti-GBM disease associated with p-ANCA with MPO specificity. Despite heavy immunosuppression and plasmapheresis, IgG titers against dengue virus continued to rise confirming the diagnosis of acute dengue infection. We present the first reported case of anti-GBM disease associated with p-ANCA with MPO specificity during dengue infection. This report calls for a heightened awareness of autoimmunity leading to crescentic glomerulonephritis in patients with dengue infection.

Dyslipidemia, malnutrition, inflammation, cardiovascular disease and mortality in chronic kidney disease.

PURPOSE OF REVIEW: Dyslipidemia, malnutrition and inflammation are common in patients with chronic kidney disease (CKD) and are strongly associated with cardiovascular disease (CVD) and increased mortality. The epidemiology of dyslipidemia and its interactions with malnutrition and inflammation in CKD patients have been the subject of much interest in the past decade. Recent clinical trials have explored the effects of statins on CVD specifically in CKD patients. RECENT FINDINGS: Whereas the risk relationship between total cholesterol level and CVD morbidity and mortality is direct, strong and progressive in CKD patients without malnutrition and inflammation, it is inconsistent and often paradoxical in those with malnutrition and inflammation. Accumulating evidence demonstrates that statins reduce significantly the risk of CVD in CKD patients before the initiation of dialysis. However, the beneficial effect of statins in CKD patients on dialysis is uncertain. In CKD patients on dialysis, malnutrition and inflammation pose a higher risk for CVD than dyslipidemia. SUMMARY: In CKD patients, the risk of CVD associated to dyslipidemia is complex and is modified by malnutrition and inflammation.

Balloon cinch deformity during angioplasty procedures: an indication for impending rupture.

Percutaneous transluminal balloon angioplasty (PTA) is a commonly performed procedure for hemodialysis vascular access dysfunction including thrombosis. While PTA is generally safe, balloon rupture during the procedure is a potential complication. Because such a rupture can cause damage to the blood vessel, indication of an imminent balloon rupture might help avoid such a complication. This analysis reports on six PTA procedures that were complicated by balloon rupture. All cases demonstrated terminal (caudal/cranial) cinch deformation. There was a loss of sharp terminal tapering and its replacement with banana silhouette before the balloon rupture. Importantly, the contour deformation and balloon rupture occurred at a pressure that was lower than the rated burst pressure. The cinch deformity can be used as an indication for impending balloon rupture. We suggest deflation of balloons that demonstrate shape deformations to avoid vascular injury.

Renal artery stenosis: to intervene, or not to intervene, "that is the question".

Renal artery stenosis (RAS) due to atherosclerosis continues to be a major cause of secondary hypertension. It can also lead to renal dysfunction due to ischemic nephropathy. While major clinical trials have emphasized that medical management should be preferred over angioplasty and stenting for the treatment of renal artery stenosis, clinical scenarios continue to raise doubts about the optimal management strategy. Herein, we present two cases that were admitted with hypertensive emergency and renal function deterioration. Medical therapy failed to control the blood pressure and in one patient, renal failure progressed to a point where renal replacement therapy was required. Both patients underwent angioplasty (for >90% stenosis) and stent insertion with successful resolution of stenosis by interventional radiology. Postoperatively, blood pressure gradually decreased with improvement in serum creatinine. Dialysis therapy was discontinued. At 4- and 8-month follow-up, both patients continue to do well with blood pressure readings in the 132-145/70-90 mmHg range. This article highlights the importance of percutaneous interventions in the management of atherosclerotic RAS and calls for heightened awareness and careful identification of candidates who would benefit from angioplasty and stent insertion.

Radial artery harvest: a potential cause of arteriovenous access-associated hand ischemia.

Hand ischemia has multiple causes. In this article, we report an additional factor that can induce hand ischemia in hemodialysis patients. A 64-year-old white man with coronary artery disease underwent a coronary artery bypass graft procedure using the left radial artery as the bypass graft. Several months later, a left extremity Gracz fistula was created for arteriovenous access. Ever since dialysis was performed via the fistula the patient has experienced a cold hand and pain during dialysis that was somewhat relieved by wearing a woolen glove while on dialysis. Absence of the radial artery in the context of an ipsilateral arteriovenous access was highlighted as a possible etiology. A complete arteriography to determine the presence of stenoses, distal arteriopathy, and true steal was recommended, but the patient refused to undergo any investigation or procedure and instead decided to continue wearing the glove during the treatment. A plan for close follow-up and possible interventions in the event of worsening pain/ulceration was agreed upon. Radial artery harvest can result in hand ischemia if an ipsilateral arteriovenous access is created. We suggest that the contralateral extremity should be considered if an arteriovenous access is required to minimize this risk of this phenomenon.

Blood pressure recordings during hemodialysis access interventions: implications for acute management.

A retrospective study evaluating the pattern of blood pressure and its related complications before, during, and after percutaneous hemodialysis interventions was performed in patients presenting with asymptomatic hypertension. Hemodialysis patients undergoing percutaneous interventions including tunneled hemodialysis catheter insertion, percutaneous balloon angioplasty and thrombectomy procedure, and stage II hypertension (systolic blood pressure ≥160 mmHg) were included in this analysis. Blood pressure medications were not used while midazolam and fentanyl were routinely administered. Patients were followed for up to 4 weeks to monitor any complications. The mean blood pressure before, during, and after the procedures were 185 ± 18/96 ± 14, 172 ± 22/92 ± 15, and 153 ± 25/87 ± 14, respectively. There was a statistically significant difference between the blood pressure readings before and after the procedure (before = 185 ± 18/96 ± 14, after = 153 ± 25/87 ± 14; p = 0.001). None of the patients had a stroke, myocardial infarction, or acute pulmonary edema before, during, or after the procedure or during the 4-week follow-up period. A significant reduction in blood pressure was observed after the procedure without the administration of any antihypertensive medication. These results suggest that the reduction in blood pressure observed after percutaneous dialysis access interventions (particularly in the presence of midazolam and fentanyl) may make it unnecessary to treat asymptomatic hypertension prior to these procedures.

Inflammation and adipose tissue macrophages in lipodystrophic mice.

Lipodystrophy and obesity are opposites in terms of a deficiency versus excess of adipose tissue mass, yet these conditions are accompanied by similar metabolic consequences, including insulin resistance, dyslipidemia, hepatic steatosis, and increased risk for diabetes and atherosclerosis. Hepatic and myocellular steatosis likely contribute to metabolic dysregulation in both states. Inflammation and macrophage infiltration into adipose tissue also appear to participate in the pathogenesis of obesity-induced insulin resistance, but their contributions to lipodystrophy-induced insulin resistance have not been evaluated. We used aP2-nSREBP-1c transgenic (Tg) mice, an established model of lipodystrophy, to ask this question. Circulating cytokine elevations suggested systemic inflammation but even more dramatic was the number of infiltrating macrophages in all white and brown adipose tissue depots of the Tg mice; in contrast, there was no evidence of inflammatory infiltrates or responses in any other tissue including liver. Despite there being overt evidence of adipose tissue inflammation, antiinflammatory strategies including salicylate treatment and genetic suppression of myeloid NF-kappaB signaling that correct insulin resistance in obesity were ineffective in the lipodystrophic mice. We further showed that adipose tissue macrophages (ATMs) in lipodystrophy and obesity are very different in terms of activation state, gene expression patterns, and response to lipopolysaccharide. Although ATMs are even more abundant in lipodystrophy than in obesity, they have distinct phenotypes and likely roles in tissue remodeling, but do not appear to be involved in the pathogenesis of insulin resistance.

Leptin deficiency-induced obesity affects the density of mast cells in abdominal fat depots and lymph nodes in mice.

BACKGROUND: Mast cells are implicated in the pathogenesis of obesity and insulin resistance. Here, we explored the effects of leptin deficiency-induced obesity on the density of mast cells in metabolic (abdominal fat depots, skeletal muscle, and liver) and lymphatic (abdominal lymph nodes, spleen, and thymus) organs. Fourteen-week-old male leptin-deficient ob/ob mice and their controls fed a standard chow were studied. Tissue sections were stained with toluidine blue to determine the density of mast cells. CD117/c-kit protein expression analysis was also carried out. Furthermore, mast cells containing immunoreactive tumor necrosis factor-α (TNF-α), a proinflammatory cytokine involved in obesity-linked insulin resistance, were identified by immunostaining. RESULTS: ob/ob mice demonstrated adiposity and insulin resistance. In abdominal fat depots, mast cells were distributed differentially. While most prevalent in subcutaneous fat in controls, mast cells were most abundant in epididymal fat in ob/ob mice. Leptin deficiency-induced obesity was accompanied by a 20-fold increase in the density of mast cells in epididymal fat, but a 13-fold decrease in subcutaneous fat. This finding was confirmed by CD117/c-kit protein expression analysis. Furthermore, we found that a subset of mast cells in epididymal and subcutaneous fat were immunoreactive for TNF-α. The proportion of mast cells immunoreactive for TNF-α was higher in epididymal than in subcutaneous fat in both ob/ob and control mice. Mast cells were also distributed differentially in retroperitoneal, mesenteric, and inguinal lymph nodes. In both ob/ob mice and lean controls, mast cells were more prevalent in retroperitoneal than in mesenteric and inguinal lymph nodes. Leptin deficiency-induced obesity was accompanied by increased mast cell density in all lymph node stations examined. No significant difference in the density of mast cells in skeletal muscle, liver, spleen, and thymus was noted between ob/ob and control mice. CONCLUSIONS: This study demonstrates that leptin deficiency-induced obesity is accompanied by alterations in the density of mast cells in abdominal fat depots. The divergent distribution of mast cells in subcutaneous versus visceral fat might partially account for their differential biological behavior. Mast cells might also play a role in adaptive immune response occurring in regional lymph nodes in obesity.

Mast cells, macrophages, and crown-like structures distinguish subcutaneous from visceral fat in mice.

Obesity is accompanied by adipocyte death and accumulation of macrophages and mast cells in expanding adipose tissues. Considering the differences in biological behavior of fat found in different anatomical locations, we explored the distribution of mast cells, solitary macrophages, and crown-like structures (CLS), the surrogates for dead adipocytes, in subcutaneous and abdominal visceral fat of lean and diet-induced obese C57BL/6 mice. In fat depots of lean mice, mast cells were far less prevalent than solitary macrophages. Subcutaneous fat contained more mast cells, but fewer solitary macrophages and CLS, than visceral fat. Whereas no significant change in mast cell density of subcutaneous fat was observed, obesity was accompanied by a substantial increase in mast cells in visceral fat. CLS became prevalent in visceral fat of obese mice, and the distribution paralleled mast cells. Adipose tissue mast cells contained and released preformed TNF-α, the cytokine implicated in the pathogenesis of obesity-linked insulin resistance. In summary, subcutaneous fat differed from visceral fat by immune cell composition and a lower prevalence of CLS both in lean and obese mice. The increase in mast cells in visceral fat of obese mice suggests their role in the pathogenesis of obesity and insulin resistance.

Apoptosis, mastocytosis, and diminished adipocytokine gene expression accompany reduced epididymal fat mass in long-standing diet-induced obese mice.

BACKGROUND: Obesity is characterized by increased cell death and inflammatory reactions in the adipose tissue. Here, we explored pathophysiological alterations taking place in the adipose tissue in long-standing obesity. In the epididymal fat of C57BL/6 mice fed a high-fat diet for 20 weeks, the prevalence and distribution of dead adipocytes (crown-like structures), mast cells (toluidine blue, mMCP6), macrophages (F4/80), and apoptotic cells (cleaved caspase-3) were measured. Moreover, gene and/or protein expression of several adipocytokines (leptin, adiponectin, TNF-α, IL-10, IL-6, MCP-1), F4/80, mMCP6, cleaved caspase-3 were determined. RESULTS: We observed that the epididymal fat mass was lower in obese than in lean mice. In obese mice, the epididymal fat mass correlated inversely with body weight and liver mass. Dead adipocytes, mast cells, macrophages, and apoptotic cells were abundant in the epididymal fat of obese mice, especially in the rostral vs. caudal zone. Accordingly, mMCP6, F4/80, and cleaved caspase-3 gene and/or protein expression was increased. Conversely, adiponectin, leptin, IL-6, and MCP-1 gene expression levels were lower in the epididymal fat of obese than lean mice. Although TNF-α and IL-10 gene expression was higher in the epididymal fat of obese mice, their expression relative to F4/80 and mMCP6 expression were lower in the heavily infiltrated rostral than caudal zone. CONCLUSIONS: This study demonstrates that in mice with long-standing obesity diminished gene expression of several adipocytokines accompany apoptosis and reduced mass of the epididymal fat. Our findings suggest that this is due to both increased prevalence of dead adipocytes and altered immune cell activity. Differential distribution of metabolically challenged adipocytes is indicative of the presence of biologically diverse zones within the epididymal fat.

Effects of exercise training on subcutaneous and visceral adipose tissue in normal- and high-fat diet-fed rats.

Regular physical activity improves glucose tolerance and decreases adiposity. Our aim was to investigate the effects of exercise training on subcutaneous (inguinal) and visceral (parametrial) adipose tissue in rats that were fed a chow diet (13% fat) or made insulin resistant by a high-fat diet (60% fat). Sprague-Dawley rats performed 4 wk of voluntary wheel running or were kept as sedentary controls. The training groups fed chow and the high-fat diet achieved similar running distances (8.8 +/- 1.8 and 9.3 +/- 1.9 km/day, respectively). Training improved oral glucose tolerance in chow-fed rats and prevented the glucose intolerance that occurred in sedentary rats fed the high-fat diet. In both subcutaneous and visceral adipose tissue, the high-fat diet-induced increases in fat pad weight (67% and 133%, respectively), adipocyte size (20% and 43%), and cell number (36% and 65%) were completely prevented by exercise training. Cytokine mRNA expression in visceral fat did not change with exercise training. However, in subcutaneous fat, training actually increased mRNA expression of several cytokines [IL-6: 80% (P < 0.05); TNF-alpha: 100% (P < 0.05); IL-1 receptor antagonist (IL-1Ra): 57% (P = 0.08)] with no detectable increases in serum cytokine concentrations. In summary, exercise training can overcome high-fat diet-induced impairments in glucose tolerance and increases in adipocyte size, cell number, and fat pad mass. Improved glucose tolerance was accompanied by an increase in cytokine gene expression in subcutaneous fat. This finding raises the possibility of a specific role of subcutaneous adipose tissue in adaptive responses to exercise training.

The potential role of complements in cocaine-induced thrombotic microangiopathy.

Thrombotic microangiopathy (TMA) is a rare disorder characterized by microvascular injury and occlusion resulting in tissue ischemia and dysfunction. TMA occurs in a variety of settings including cocaine use. Although cocaine is widely used in the United States, cocaine-associated TMA is only rarely reported. Therefore, other factors may predispose cocaine users to the development of TMA. Emerging evidence indicates that cocaine activates complements. Therefore, complement activation may contribute to the development of cocaine-induced TMA. Here, we report a cocaine user who presented with renal failure. Renal biopsy demonstrated TMA. Laboratory tests revealed reduced serum complement C3 and normal complement C4 levels indicative of alternative complement activation. We postulate that complement activation is involved in the pathogenesis of cocaine-induced TMA.

C3 Glomerulopathy and Atypical Hemolytic Uremic Syndrome: Two Important Manifestations of Complement System Dysfunction.

The advances in our understanding of the alternative pathway have emphasized that uncontrolled hyperactivity of this pathway causes 2 distinct disorders that adversely impact the kidney. In the so-called atypical hemolytic uremic syndrome (aHUS), renal dysfunction occurs along with thrombocytopenia, anemia, and target organ injury to multiple organs, most commonly the kidney. On the other hand, in the so-termed C3 glomerulopathy, kidney involvement is not associated with thrombocytopenia, anemia, or other system involvement. In this report, we present 2 cases of alternative pathway dysfunction. The 60-year-old female patient had biopsy-proven C3 glomerulopathy, while the 32-year-old female patient was diagnosed with aHUS based on renal dysfunction, thrombocytopenia, anemia, and normal ADAMTS-13 level. The aHUS patient was successfully treated with the monoclonal antibody (eculizumab) for complement blockade. The patient with C3 glomerulopathy did not receive the monoclonal antibody. In this patient, management focused on blood pressure and proteinuria control with an angiotensin-converting enzyme inhibitor. This article focuses on the clinical differences, pathophysiology, and treatment of aHUS and C3 glomerulopathy.

Atypical hemolytic uremic syndrome in the setting of complement-amplifying conditions: case reports and a review of the evidence for treatment with eculizumab.

Atypical hemolytic uremic syndrome (aHUS) is a rare, genetic, progressive, life-threatening form of thrombotic microangiopathy (TMA) predominantly caused by dysregulation of the alternative pathway of the complement system. Complement-amplifying conditions (CACs), including pregnancy complications [preeclampsia, HELLP (hemolysis, elevated liver enzymes, low platelet count) syndrome], malignant hypertension, autoimmune diseases, transplantation, and others, are associated with the onset of TMA in up to 69 % of cases of aHUS. CACs activate the alternative pathway of complement and may be comorbid with aHUS or may unmask a previously undiagnosed case. In this review, three case reports are presented illustrating the onset and diagnosis of aHUS in the setting of different CACs (pregnancy complications, malignant hypertension, renal transplantation). The report also reviews the evidence for a variety of CACs, including those mentioned above as well as infections and drug-induced TMA, and the overlap with aHUS. Finally, we introduce an algorithm for diagnosis and treatment of aHUS in the setting of CACs. If TMA persists despite initial management for the specific CAC, aHUS should be considered. The terminal complement inhibitor eculizumab should be initiated for all patients with confirmed diagnosis of aHUS, with or without a comorbid CAC.

IgA-dominant post-infectious glomerulonephritis; making another case in support of renal biopsy in type 2 diabetic nephropathy.

BACKGROUND: Approximately one-third of individuals with type 2 diabetes mellitus will eventually develop diabetic nephropathy (DN). Impaired renal function in type 2 diabetics may also be secondary to non-diabetic renal disease (NDRD). NDRD in type 2 diabetics may occur alone in the absence of DN or may be superimposed on DN. Renal biopsy maybe indicated to establish the correct diagnosis and to ascertain the severity of glomerular and tubulointerstitial pathology. CASE: We report a patient with type 2 diabetes mellitus and chronic renal insufficiency who developed worsening of renal function in the setting of staphylococcal infection and antibiotic use. CONCLUSION: Renal biopsy revealed IgA-dominant post-infectious glomerulonephritis and acute interstitial nephritis superimposed on diabetic glomerulosclerosis. Accumulating evidence indicates that, NDRD accounts for impaired renal function in a significant number of patients with type 2 diabetes mellitus. The presence of clinical, biochemical, and radiological features that suggest NDRD should prompt pathological evaluation of the kidney.

The endothelium as the common denominator in malignant hypertension and thrombotic microangiopathy.

The endothelium plays a pivotal role in vascular biology. The endothelium is the primary site of injury in thrombotic microangiopathies including malignant hypertension. Endothelial injury in thrombotic microangiopathies is the result of increased shear stress, toxins, and/or dysregulated complement activation. Endothelial injury can lead to microvascular thrombosis resulting in ischemia and organ dysfunction, the clinical hallmarks of thrombotic microangiopathies. Currently, available therapies target the underlying mechanisms that lead to endothelial injury in these conditions. Ongoing investigations aim at identifying drugs that protect the endothelium.

Hypertension in the African American population: A succinct look at its epidemiology, pathogenesis, and therapy.

Arterial hypertension is prevalent in the black population in the United States. It is directly related to cardiovascular and kidney damage. Its pathogenesis is complex and includes the high incidence of obesity, salt sensitivity and the activation of the renin-angiotensin-aldosterone system. This complexity requires a therapeutic combination that includes changes in dietary habits and appropriate antihypertensive regimes. The International Society of Hypertension in Blacks recommends initiating dietary intervention for values of systolic/diastolic arterial blood pressure above 115/75 mmHg and maintaining arterial blood pressure below 135/85 mmHg using appropiate antihypertensive medication. The most adequate antihypertensive drug for this population has yet to be determined.