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.

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.

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.

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.

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.

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.

Hypertension in the African American population: A succinct look at its epidemiology, pathogenesis, and therapy / Hipertensión en la población afroamericana: breve examen de su epidemiología, patogénesis y terapia

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-angiotensinal dosteronesystem. 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 (AU)

La hipertensión arterial es prevalente en la población de raza negra en los EEUU. Presenta una relación directa con el daño cardiovascular y renal. Su patogenia es compleja e incluye la alta incidencia de obesidad, sensibilidad a la sal, y la consecuente activación del sistema de la renina, angiotensina y aldosterona. Eso hace que requiera una combinación terapéutica que incluye cambios dietéticos y regímenes antihipertensivos adecuados. La Sociedad internacional de la hipertensión en pacientes de raza negra recomienda iniciar dietas de control para valores de tensión arterial sistólica/diastólica por encima de los 115/75 mmHg y mantener una tensión arterial por debajo de 135/85 mmHg con el uso de medicación antihipertensiva idónea. El fármaco antihipertensivo adecuado está por determinar en esta población (AU)

Crystal-induced acute kidney injury due to ciprofloxacin.

BACKGROUND: Fluoroquinolones are known to cause acute renal failure due to interstitial nephritis. CASE PRESENTATION: Here we present an elderly woman who developed oliguric acute kidney injury (AKI) after receiving oral and intravenous ciprofloxacin in a 48-hour period. Recently, several case reports have been published in the literature regarding the presence of crystals in the urine sediment of patients treated with ciprofloxacin for different types of systemic infections. Ciprofloxacin crystals precipitate in alkaline urine and provoke renal failure through intra-tubular precipitation. CONCLUSIONS: Conservative measures including intravenous hydration and avoidance of alkalinization of the urine can reverse this condition if applied in time.

Phospholipid makeup of the breast adipose tissue is impacted by obesity and mammary cancer in the mouse: Results of a pilot study.

Obesity, an established risk factor for breast cancer (BC), is associated with systemic inflammation. The breast contains adipose tissue (bAT), yet whether it plays a role in BC progression in obese females is being intensively studied. There is scarce knowledge on the lipid composition of bAT in health and disease. The purpose of this pilot study was: 1) to determine whether obesity and BC are associated with inflammatory changes in bAT 2) to analyze for the first time the lipid profile of bAT in obese and lean mammary tumor-bearing and normal mice. Syngeneic E0771 mammary tumor cells were implanted into the mammary fat pad of lean and diet-induced obese C57BL/6 mice. BATs were analyzed four weeks after tumor cell inoculation by immunohistochemistry and mass spectrometry. Phospholipids were identified and subjected to ratiometric quantification using a TSQ Quantum Access Max triple quadrupole mass spectrometer utilizing precursor ion scan or neutral ion loss scan employing appropriate class specific lipid standards in a two step quantification process. Four main classes of phospholipids were analyzed: phosphatidylcholines phosphatidylserines, phosphatidylethanolamines and phosphatidylinositols. Our results showed that bAT in obese (normal and tumor-bearing) mice contained hypertrophic adipocytes compared with their corresponding samples in lean mice; higher numbers of macrophages and crown-like structures were observed in obese tumor bearers compared to obese normal mice. BAT from normal obese mice revealed higher concentrations of phosphatidylethanolamines. Furthermore, bAT from tumor-bearing mice expressed higher phosphatidylcholines than that from non-tumor bearing mice, suggesting the presence of the tumor is associated with phosphatidylcholines. Conversion of phosphatidylethanolamines to phosphatidylcholines will be investigated in E0771 cells. Additional studies are projected to investigate macrophage activation by these specific classes of phospholipids. Occurrence of triglycerides and free fatty acids will be examined in bAT and similar lipidomic analyses will be carried out visceral adipose tissue, highly inflamed in obesity.

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.

Amyloid A amyloidosis with subcutaneous drug abuse.

INTRODUCTION: Amyloid A (AA) amyloidosis is a systemic form of amyloidosis secondary to chronic infections and inflammatory disorders. An acute-phase protein produced by the liver, serum amyloid A (SAA) is the precursor of AA amyloid fibrils. AA amyloid deposition occurs predominantly in the kidneys, spleen, adrenal glands, liver and gastrointestinal tract. The manifestations of AA amyloidosis involving the kidneys include proteinuria, tubular dysfunction and progressive loss of renal function. CASE: We report a 47-year-old drug addict who developed AA amyloidosis as a result of recurrent suppurative skin infections secondary to subcutaneous drug injection. Elevated C-reactive protein concentrations attested to the presence of a chronic systemic inflammatory state. He suffered from the nephrotic syndrome and insidious loss of renal function. Isosthenuria and glycosuria were indicative of renal tubular dysfunction. Renal biopsy demonstrated AA amyloidosis involving the glomeruli, tubular basement membranes and blood vessel walls. CONCLUSION: Superimposed acute tubular necrosis due to concomitant endocarditis and cocaine use accelerated his renal disease. CASE presentation is followed by a brief discussion of clinical features, natural history and outcome of AA amyloidosis with a particular emphasis on AA amyloidosis as a complication of subcutaneous drug abuse.

Necrotizing crescentic glomerulonephritis in a patient with positive serologies for lupus and antineutrophil cytoplasmic antibodies

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Comparison of mortality of ESRD patients with lupus by initial dialysis modality.

BACKGROUND AND OBJECTIVES: Little is known regarding whether mortality among ESRD patients with SLE differs between those initiating with peritoneal dialysis (PD) versus hemodialysis (HD). This study compared the mortality risk of ESRD patients with SLE initiating with PD versus HD after matching their baseline sociodemographic and clinical factors. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Of 11,023 ESRD patients with SLE initiating dialysis with PD or HD between 1995 and 2006 with complete records in the US Renal Data System, 1352 pairs were matched on 13 predictors utilizing a predicted probability of group membership into the PD group using propensity score matching. The primary outcome was overall mortality. Secondary outcomes were cardiovascular-related and infection-related mortality. Outcomes were compared between groups with survival statistics. The period of observation ended on December 31, 2009. The median follow-up was 3 years. RESULTS: Matched pairs were predominantly women (86%) with a median age of 39 years. Matched pairs had a balance (P ≥ 0.05) of all baseline factors. Matched pairs had a similar risk of overall mortality (hazard ratio, 0.96 [95% confidence interval, 0.82 to 1.13]; mortality, 21.4% [290 to 1352] versus 22.5% [304 to 1352] for PD versus HD) within the first 3 years of observation. Matched pairs also had similar cardiovascular-related mortality (10.5% versus 9.5% for PD versus HD) and infection-related mortality (3% versus 4.4% for PD versus HD). CONCLUSIONS: In ESRD patients with SLE, the mortality was similar among those initiating with PD versus HD after predictors were matched between groups.

Tubulointerstitial nephritis accompanying gamma-heavy chain deposition and gamma-heavy chain restricted plasma cells in the kidney.

Monoclonal immunoglobulin heavy chain (HC) diseases are rare proliferative disorders of B lymphocytes or plasma cells characterized by the presence of monoclonal α-, µ-, or γ-HC without associated light chains in the blood, urine, or both. We report a 59-year-old woman with a history of Hodgkin disease who developed hypercalcemia, proteinuria, and impaired kidney function. Protein electrophoresis and immunofixation displayed γ-HC without associated light chains in the serum and urine. Pathologic examination demonstrated severe tubulointerstitial nephritis associated with diffuse and strong linear staining of the glomerular and tubular basement membranes as well as Bowman capsules for γ-HC, but not for κ- or λ-light chains. Immunohistochemical examination of the kidney and bone marrow demonstrated numerous CD138+ plasma cells immunoreactive for γ-HC, but not for κ- or λ-light chains. This is the first report of tubulointerstitial nephritis associated with γ-HC deposition and γ-HC restricted plasma cells in the kidney. This report heightens awareness about tubulointerstitial nephritis as a possible manifestation of γ-HC deposition in the kidney.