C. John Sperati

Fibromuscular Dysplasia: State of the Science and Critical Unanswered Questions A Scientific Statement From the American Heart Association

Fibromuscular dysplasia (FMD) is nonatherosclerotic, noninflammatory vascular disease that may result in arterial stenosis, occlusion, aneurysm, or dissection.1–3 The cause of FMD and its prevalence in the general population are not known.4 FMD has been reported in virtually every arterial bed but most commonly affects the renal and extracranial carotid and vertebral arteries (in ≈65% of cases).5 The clinical manifestations of FMD are determined primarily by the vessels that are involved. When the renal artery is involved, the most frequent finding is hypertension, whereas carotid or vertebral artery FMD may lead to dizziness, pulsatile tinnitus, transient ischemic attack (TIA), or stroke. There is an average delay from the time of the first symptom or sign to diagnosis of FMD of 4 to 9 years.5,6 This is likely because of a multitude of factors: the perception that this is a rare disease and thus FMD is not considered in the differential diagnosis, the reality that FMD is poorly understood by many healthcare providers, and the fact that many of the signs and symptoms of FMD are nonspecific, thus leading the clinician down the wrong diagnostic pathway. A delay in diagnosis can lead to impaired quality of life and poor outcomes such as poorly controlled hypertension and its sequelae, TIA, stroke, dissection, or aneurysm rupture. It should also be noted that FMD may be discovered incidentally while imaging is performed for other reasons or when a bruit is heard in the neck or abdomen in an asymptomatic patient without the classic risk factors for atherosclerosis. The first description of FMD is attributed to Leadbetter and Burkland7 in a 5½-year-old boy with severe hypertension and a renal artery partially occluded by an intra-arterial mass of smooth muscle. He underwent a unilateral nephrectomy of an …

Modified Ham test for atypical hemolytic uremic syndrome.

Atypical hemolytic uremic syndrome (aHUS) is a thrombotic microangiopathy (TMA) characterized by excessive activation of the alternative pathway of complement (APC). Atypical HUS is frequently a diagnosis of exclusion. Differentiating aHUS from other TMAs, especially thrombotic thrombocytopenic purpura (TTP), is difficult due to overlapping clinical manifestations. We sought to develop a novel assay to distinguish aHUS from other TMAs based on the hypothesis that paroxysmal nocturnal hemoglobinuria cells are more sensitive to APC-activated serum due to deficiency of glycosylphosphatidylinositol- anchored complement regulatory proteins (GPI-AP). Here, we demonstrate that phosphatidylinositol-specific phospholipase C-treated EA.hy926 cells and PIGA-mutant TF-1 cells are more susceptible to serum from aHUS patients than parental EA.hy926 and TF-1 cells. We next studied 31 samples from 25 patients with TMAs, including 9 with aHUS and 12 with TTP. Increased C5b-9 deposition was evident by confocal microscopy and flow cytometry on GPI-AP-deficient cells incubated with aHUS serum compared with heat-inactivated control, TTP, and normal serum. Differences in cell viability were observed in biochemically GPI-AP-deficient cells and were further increased in PIGA-deficient cells. Serum from patients with aHUS resulted in a significant increase of nonviable PIGA-deficient TF-1 cells compared with serum from healthy controls (P < .001) and other TMAs (P < .001). The cell viability assay showed high reproducibility, sensitivity, and specificity in detecting aHUS. In conclusion, we developed a simple, rapid, and serum-based assay that helps to differentiate aHUS from other TMAs.

Variable Clinical Presentation of an MUC1 Mutation Causing Medullary Cystic Kidney Disease Type 1

BACKGROUND AND OBJECTIVES The genetic cause of medullary cystic kidney disease type 1 was recently identified as a cytosine insertion in the variable number of tandem repeat region of MUC1 encoding mucoprotein-1 (MUC1), a protein that is present in skin, breast, and lung tissue, the gastrointestinal tract, and the distal tubules of the kidney. The purpose of this investigation was to analyze the clinical characteristics of families and individuals with this mutation. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS Families with autosomal dominant interstitial kidney disease were referred for genetic analysis over a 14-year period. Families without UMOD or REN mutations prospectively underwent genotyping for the presence of the MUC1 mutation. Clinical characteristics were retrospectively evaluated in individuals with the MUC1 mutation and historically affected individuals (persons who were both related to genetically affected individuals in such a way that ensured that they could be genetically affected and had a history of CKD stage IV or kidney failure resulting in death, dialysis, or transplantation). RESULTS Twenty-four families were identified with the MUC1 mutation. Of 186 family members undergoing MUC1 mutational analysis, the mutation was identified in 95 individuals, 91 individuals did not have the mutation, and111 individuals were identified as historically affected. Individuals with the MUC1 mutation suffered from chronic kidney failure with a widely variable age of onset of end stage kidney disease ranging from 16 to >80 years. Urinalyses revealed minimal protein and no blood. Ultrasounds of 35 individuals showed no medullary cysts. There were no clinical manifestations of the MUC1 mutation detected in the breasts, skin, respiratory system, or gastrointestinal tract. CONCLUSION MUC1 mutation results in progressive chronic kidney failure with a bland urinary sediment. The age of onset of end stage kidney disease is highly variable, suggesting that gene-gene or gene-environment interactions contribute to phenotypic variability.

Predictors of Complication after Percutaneous Ultrasound-Guided Kidney Biopsy in HIV-Infected Individuals: Possible Role of Hepatitis C and HIV Co-infection

BACKGROUND AND OBJECTIVES HIV-infected patients often undergo kidney biopsy. The risks of percutaneous ultrasound-guided kidney biopsy in this population are not well established. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS This was a case-control, single-center study of 1116 (243 with HIV infection and 873 without) consecutive ultrasound-guided biopsies from 1024 patients. The primary outcome was any major or minor complication. Major complications included biopsy-associated bleeding that required transfusion, angiography, or surgery; hypotension that required intervention; and death. Minor complications included development of a hematoma or gross hematuria. The odds of complication was assessed with logistic regression. RESULTS Overall complication rates (8.6 versus 7.2%) did not significantly differ between HIV-infected and noninfected individuals. HIV-positive status did not predict complication. In the entire cohort, hepatitis C infection was associated with a 2.08 (95% confidence interval [CI] 1.47 to 2.93) increased odds of complication, and each 10,000-cells/mm(3) decrease in prebiopsy platelet count a 1.05 (95% CI 1.02 to 1.08) increased odds of complication. In addition, prebiopsy hematocrit <30% and estimated GFR <30 ml/min per 1.73 m(2) were associated with major complication. Whereas the association of prebiopsy platelet count was not modified by HIV infection, hepatitis C/HIV co-infection was associated with a 5.71 (95% CI 1.89 to 17.2) increased odds of complication as compared with 1.27 (95% CI 0.73 to 2.19) in hepatitis C-positive/HIV-negative individuals. CONCLUSIONS Ultrasound-guided percutaneous kidney biopsy is a relatively safe, well-tolerated procedure in the HIV-infected population. HIV-infected individuals who are co-infected with hepatitis C seem to be at greatest risk.

The impact of hepatitis C coinfection on kidney disease related to human immunodeficiency virus (HIV): a biopsy study.

Approximately 1 in 4 individuals infected with the human immunodeficiency virus (HIV) in the United States is coinfected with the hepatitis C virus. Both conditions increase the risk for the development and progression of kidney disease. The effect, however, of coexisting HIV and hepatitis C infection on the spectrum and progression of kidney disease is not well known. To compare the clinical features, histopathologic kidney diagnoses, and proportion of individuals progressing to end-stage kidney disease (ESKD), we reviewed the clinical records of HIV-infected individuals with and without hepatitis C coinfection who underwent ultrasound-guided percutaneous kidney biopsies between February 7, 1995, and March 30, 2009.Of the 249 HIV-infected individuals included in this study, 58% were coinfected with hepatitis C. Coinfected individuals were older (mean age, 46 ± 7 vs. 44 ± 10 yr, respectively; p < 0.01) and more likely to have used illicit drugs (85% vs. 14%, respectively; p < 0.01) compared to HIV-infected individuals without hepatitis C. HIV-associated nephropathy was the most common histopathologic diagnosis in both groups. Immune-complex glomerulonephritides (ICGNs), including lupus-like nephritis, postinfectious glomerulonephritis, membranous glomerulopathy, membranoproliferative glomerulonephritis, IgA nephropathy, and nonspecific ICGNs, occurred more frequently in individuals coinfected with hepatitis C than in those not coinfected (22% vs. 11%, respectively; p = 0.02). Although the proportion of those who died was similar between the 2 groups, hepatitis C coinfection was independently associated with a greater risk of progression to ESKD (hazard ratio, 1.81; 95% confidence interval, 1.09-2.99; p = 0.02).The current study demonstrates that coinfection with hepatitis C in individuals infected with HIV predisposes these individuals to immune-complex glomerulonephritides and is associated with increased risk of ESKD in the biopsied population.Abbreviations: CI = confidence interval, eGFR = estimated glomerular filtration rate, ESKD = end-stage kidney disease, HAART = highly active antiretroviral therapy, HIV = human immunodeficiency virus, HIVAN = HIV-associated nephropathy, HR = hazard ratio, ICGN = immune complex glomerulonephritis, MPGN = membranoproliferative glomerulonephritis.

Association of Single-Nucleotide Polymorphisms in JAK3, STAT4, and STAT6 With New Cardiovascular Events in Incident Dialysis Patients

BACKGROUND Increasing evidence supports a role for cell-mediated immunity in the pathogenesis of cardiovascular disease. Single-nucleotide polymorphisms (SNPs) in JAK3, STAT4, and STAT6 of the Janus kinase-signal transducer and activator of transcription (Jak-Stat) signal transduction pathway were examined for association with time to new cardiovascular events in incident dialysis patients from the Choices for Healthy Outcomes in Caring for End-Stage Renal Disease Study. STUDY DESIGN Prospective cohort study. SETTING & PARTICIPANTS 764 white (n = 518) and black (n = 246) participants from 79 dialysis centers. PREDICTOR SNPs in JAK3, STAT4, and STAT6 selected using a pairwise approach to identify a maximally informative set of tag SNPs for populations of European and African descent. OUTCOMES & MEASUREMENTS Cox proportional hazards models were used to estimate unadjusted and multivariable-adjusted hazard ratios (HRs) for incident cardiovascular disease events after dialysis therapy initiation associated with each race-specific SNP. RESULTS 2 European tag SNPs (rs3212780 and rs3213409) in JAK3 were associated with new cardiovascular disease events in white patients with unadjusted HRs of 1.92 (P < 0.001) and 1.82 (P = 0.07), respectively. One dual-tag SNP (rs3212752) in JAK3 was associated with new cardiovascular events in white patients with an unadjusted HR of 2.09 (P < 0.001) and in black patients with an HR of 2.07 (P = 0.007). SNP rs3213409 codes for a valine to isoleucine change at amino acid 722, a potentially functional mutation. SNPs in STAT4 and STAT6 were not associated with cardiovascular events after the initiation of dialysis therapy. LIMITATIONS This study does not provide direct evidence for the mechanism of increased risk. Replication in independent cohorts is necessary. CONCLUSIONS Genetic polymorphisms in the Jak-Stat signaling pathway are associated with an increased risk of new cardiovascular events in incident dialysis patients.

Thrombotic Microangiopathy: Focus on Atypical Hemolytic Uremic Syndrome

Thrombotic microangiopathies (TMA) such as atypical hemolytic uremic syndrome (aHUS) have evolved from rare, fulminant childhood afflictions to uncommon diseases with acute and chronic phases involving both children and adults. Breakthroughs in complement and coagulation regulation have allowed redefinition of specific entities despite substantial phenotypic mimicry. Reconciliation of phenotypes and delivery of life saving therapies require a multidisciplinary team of experts. The purpose of this review is to describe advances in the molecular pathophysiology of aHUS and to share the 2014 experience of the multidisciplinary Johns Hopkins TMA Registry in applying diagnostic assays, reporting disease associations, and genetic testing.

Drug Interactions and Antiretroviral Drug Monitoring

Owing to the improved longevity afforded by combination antiretroviral therapy (cART), HIV-infected individuals are developing several non-AIDS-related comorbid conditions. Consequently, medical management of the HIV-infected population is increasingly complex, with a growing list of potential drug-drug interactions (DDIs). This article reviews some of the most relevant and emerging potential interactions between antiretroviral medications and other agents. The most common DDIs are those involving protease inhibitors or non-nucleoside reverse transcriptase inhibitors, which alter the cytochrome P450 enzyme system and/or drug transporters such as p-glycoprotein. Of note are the new agents for the treatment of chronic hepatitis C virus infection. These new classes of drugs and others drugs that are increasingly used in this patient population represent a significant challenge with regard to achieving the goals of effective HIV suppression and minimization of drug-related toxicities. Awareness of DDIs and a multidisciplinary approach are imperative in reaching these goals.

Acute renal failure in a patient with antiphospholipid syndrome and immune thrombocytopenic purpura treated with eltrombopag.

Antiphospholipid syndrome (APS) is an autoimmune disorder characterized by the presence of antibodies directed against phospholipid-binding proteins such as beta-2 glycoprotein I and prothrombin, venous and/or arterial thromboembolism, and recurrent fetal loss. To fulfill diagnostic criteria, patients must have thrombotic or obstetrical morbidity and consistently positive antiphospholipid testing on two occasions separated by at least 12 weeks [2]. Other clinical manifestations include thrombocytopenia, renal insufficiency, vasculitis, and cardiac valvular abnormalities. Thrombocytopenia occurs in 20-40% of patients with APS while renal dysfunction develops in ~25% of patients with primary APS [3,4]. Thrombocytopenia is thought to be primarily due to the presence of autoantibodies directed against platelet membrane glycoproteins, although platelet activation and aggregation by APS-associated antibodies have also been implicated. Thrombocytopenia in patients with APS is typically moderate in severity with platelet counts remaining greater than 50,000 cells/mm3 in most cases,so therapy is often unnecessary. When treatment is required, therapies used for immune thrombocytopenic purpura (ITP) are often effective. Corticosteroids, intravenous immunoglobulin, dapsone, and rituximab have all been shown to be effective in APS patients with thrombocytopenia[5-7]. Since November 2008, eltrombopag (Promacta; GlaxoSmithKline,Middlesex, United Kingdom), a nonpeptide thrombopoietin receptor agonist that stimulates the development of megakaryocytes, has been approved for use in the management of chronic ITP. To date, no reports of renal toxicity have emerged with its use. We report the case of a patient with APS and steroid-dependent thrombocytopenia who developed partially reversible acute renal failure after initiation of eltrombopag that recurred on rechallenge.

A novel bedside cardiopulmonary physical diagnosis curriculum for internal medicine postgraduate training

BackgroundPhysicians spend less time at the bedside in the modern hospital setting which has contributed to a decline in physical diagnosis, and in particular, cardiopulmonary examination skills. This trend may be a source of diagnostic error and threatens to erode the patient-physician relationship. We created a new bedside cardiopulmonary physical diagnosis curriculum and assessed its effects on post-graduate year-1 (PGY-1; interns) attitudes, confidence and skill.MethodsOne hundred five internal medicine interns in a large U.S. internal medicine residency program participated in the Advancing Bedside Cardiopulmonary Examination Skills (ACE) curriculum while rotating on a general medicine inpatient service between 2015 and 2017. Teaching sessions included exam demonstrations using healthy volunteers and real patients, imaging didactics, computer learning/high-fidelity simulation, and bedside teaching with experienced clinicians. Primary outcomes were attitudes, confidence and skill in the cardiopulmonary physical exam as determined by a self-assessment survey, and a validated online cardiovascular examination (CE).ResultsInterns who participated in ACE (ACE interns) by mid-year more strongly agreed they had received adequate training in the cardiopulmonary exam compared with non-ACE interns. ACE interns were more confident than non-ACE interns in performing a cardiac exam, assessing the jugular venous pressure, distinguishing ‘a’ from ‘v’ waves, and classifying systolic murmurs as crescendo-decrescendo or holosystolic. Only ACE interns had a significant improvement in score on the mid-year CE.ConclusionsA comprehensive bedside cardiopulmonary physical diagnosis curriculum improved trainee attitudes, confidence and skill in the cardiopulmonary examination. These results provide an opportunity to re-examine the way physical examination is taught and assessed in residency training programs.