Adenopathy and Extensive Skin Patch Overlying a Plasmacytoma (AESOP) Syndrome

Adenopathy and extensive skin patch overlying a plasmacytoma is a very rare syndrome featuring a red-to-brown, violaceous skin patch along with a plasmacytoma. Only 11 case reports exist in the literature. Skin biopsies from the cutaneous patch overlying the plasmacytoma exhibit a dermal vascular hyperplasia with increased surrounding dermal mucin. Radiation therapy is used to treat and cure the plasmacytoma.Adenopathy and extensive skin patch overlying a plasmacytoma (AESOP) syndrome is a very rare constellation of findings seen in patients with a yet-to-be diagnosed solitary plasmacytoma.1,2 There are only 11 cases reported in the literature; the first report dates back to Sheinker in 1938 (3

TABLE 1

Summary of patients with AESOP syndrome ranked by ascending age

Adolescent Scalp Psoriasis: Update on Topical Combination Therapy

Plaque psoriasis can begin early in life and negatively affect quality of life. Topical agents are generally recommended as first-line therapy for plaque psoriasis. The synergy of a vitamin D analog and a steroid in a topical fixed-combination formulation provides more favorable effectiveness and tolerability as compared with either agent alone. The safety and effectiveness of a once-daily calcipotriene/betamethasone dipropionate topical suspension have been established in children 12 to 17 years of age with scalp plaque psoriasis. Combination topical formulations and once-daily dosing decrease regimen complexity and may increase adherence. Accommodation of vehicle preference may also improve adherence and real-life effectiveness.Psoriasis, a common dermatologic disorder affecting individuals of all ages, can begin early in life. Up to 35 percent of cases begin before 18 years of age, affecting 0.7 percent of children.1-3 This incidence doubled between 1970 and 1999 and is currently 40.8 cases per 100,000.4 The median age at diagnosis (10.6 years) has remained stable in the United States.4It is important for clinicians to appreciate the impact of psoriasis on children and teenagers. Even mild forms of psoriasis can affect childhood psychosocial functioning and quality of life (QoL).2,5-7 The scalp plaques and possible associated alopecia can be particularly troublesome during adolescence and detrimental to the individual’s sense of self during the transition to adulthood.8,9Topical therapy can be safe and effective in juvenile psoriasis. Topical treatments are a first-line option in adults, and some have been approved for use in adolescents (10-19 This article reviews the distinguishing features of psoriasis in younger patients and the considerations that enter into the choice of treatment.

TABLE 1

Approved topical corticosteroid formulations for adolescents10-14, 16-19

Primary Cutaneous Blastomycosis as a Cause of Acute Respiratory Distress Syndrom: Case Report and Literature Review

Blastomycosis is a fungal infection caused by Blastomyces dermatitidis. Exposure in endemic regions frequently occurs when spores in soil are disturbed and subsequently inhaled. Less commonly, primary cutaneous blastomycosis may follow after traumatic inoculation of the fungus into the skin. Most patients infected with blastomycosis are asymptomatic, but an unfortunate small number present with fulminant disease. Rarely, the infection can affect organs, such as the skin, bone, or genitourinary system. In a small percentage of cases, blastomycosis may cause acute respiratory distress syndrome, which is associated with a very high mortality rate. Increased survival rates have been shown when the clinician has a high index of suspicion and facilitates rapid evaluation and initiation of the appropriate therapy. We present a rare case of a patient presenting with primary cutaneous blastomycosis that progressed to disseminated disease causing acute respiratory distress syndrome. High clinical suspicion, prompt diagnostic testing, and therapy with amphotericin B, confirmed the diagnosis and resulted in a swift recovery.Blastomycosis is an infection caused by the fungus Blastomyces dermatitidis, which is endemic to areas of the United States and Canada including the Great Lakes Region and the Mississippi and Ohio River Valleys.^1,2 Exposure occurs in moist wooded areas during outdoor activities when fungal microhabitats existing in soil are disturbed. Inhaled conidia can result in a primary lung infection, which may then become disseminated.^3,4 Pulmonary disease is the most common manifestation of blastomycosis with isolated lung disease occurring in 60 to 75 percent of infected people.⁵ In the remaining group, dissemination to skin, bone, genitourinary, and other organ systems can be seen.⁴ In fewer than 10 percent of cases, blastomycosis can progress to acute respiratory distress syndrome (ARDS) with dyspnea, tachypnea, and hypoxemia as systemic manifestations.^6–12Palmer and McFadden reported the first case of disseminated blastomycosis causing ARDS in 1968.¹³ Since then, few studies have identified disseminated blastomycosis as a cause of ARDS (14 Thus, early suspicion of disseminated disease is especially helpful in endemic areas since rapid institution of therapy can improve morbidity and mortality.

Table 1

Case reports of blastomycosis causing acute respiratory distress syndrome in the literature

A Practical Approach to Monitoring Patients on Biological Agents for the Treatment of Psoriasis

Psoriasis is a chronic, systemic, inflammatory skin condition that manifests predominantly as well-demarcated, erythematous, scaly plaques on the elbows, knees, and scalp. While mild cases (minimal body surface) often respond to various topical treatments and light therapy, patients with extensive disease (larger body surface and possibly joint involvement) may require systemic medications for remission. The development of biological agents provides dermatologists valuable ways to help treat psoriatic disease quite efficiently, but literature regarding the monitoring of patients on biological treatments is sparse. Clinical practice varies widely since there is modest strong evidence to recommend or refute most tests currently recommended by the United States Food and Drug Administration. The purpose of this article is to present a practical approach to monitoring patients on biological therapy based on the most up-to-date literature.The use of biological treatments has grown significantly since their introduction and now account for a significant proportion of the systemic therapies used for the treatment of psoriasis. Biological therapies target precise segments of the immune system, offering the advantage of being less immunosuppressive compared to the traditional systemic therapies that broadly cause immunosuppression. Currently, five biological agents (e.g., alefacept, etanercept, infliximab, adalimumab, and ustekinumab) are approved by the United States Food and Drug Administration (FDA) for the treatment of psoriasis, and other newer agents (e.g., ABT-874) are in various stages of development and clinical trials (1–6 The biologicals at present are divided into either tumor necrosis factor alpha (TNF-α) or T-cell lymphocyte inhibitors. Recently, CD4+ T helper (Th) 17 cells and interleukins (IL)-12 and IL-23 have been important in the pathogenesis of T-cell mediated disorders, such as psoriasis, and have influenced the development of medications that specifically target these key immunological players. Both IL-12 and IL-23 stimulate differentiation of naive T-cells into Th1 and Th17 cells, key cells that regulate the production of other pro-inflammatory cytokines significant in the pathogenesis of psoriasis.^7,8 Understanding of these immune cascade complexities has divulged this new class of biological agents that target cytokines (e.g., ustekinumab) important in the pathogenesis of inflammatory skin disease. Each drug class that is used in the treatment of psoriasis works by blocking different steps along the same immune-dysregulation pathway leading to psoriatic disease.

Table 1

Currently approved biological medications for the treatment of psoriasis^1–4,6

Considerations for use of Fluorouracil cream 0.5% for the treatment of actinic keratosis in elderly patients

Actinic keratosis (AK), the initial lesion in a disease continuum that may progress to squamous cell carcinoma, often begins with ultraviolet B light-induced photo damage and increases in prevalence with age. Topical 5-fluorouracil (5-FU) for the treatment of widespread multiple AK lesions has cure rates of more than 90 percent. The associated skin irritation, however, may lead patients to prematurely discontinue treatment. To improve treatment efficacy and tolerability, 5-FU cream 0.5%, a novel Microsponge^®-based formulation, was developed. In the elderly population, 5-FU cream 0.5% may be preferable because of its convenient (once daily) administration and its lower potential for irritation and systemic absorption, which may impact adherence to therapy and, thus, possibly increase cure rates.Actinic keratoses (AKs), also called solar keratoses, occur more commonly in individuals with fair skin who have had extensive exposure to the sun.^1,2 The prevalence of AK lesions in adults increases with age: less than 10 percent for 20- to 29-year-olds, approximately 80 percent for 60- to 69-year-olds, and greater than 80 percent for 70-year-olds and older.^3,4 In the first five decades of life, the prevalence of AK lesions in men is almost twice that in women; however, after age 50, prevalence rates are similar between men and women.^3,4 A study using data from the National Ambulatory Medical Care Survey from 1990 to 1999 found that 47 million visits to physicians involved an AK diagnosis, and more than 80 percent of patients with AK diagnoses were at least 50 years old.⁵ AK was the second most frequent diagnosis made by dermatologists.⁵ Because surveys and studies typically include only patients seen in clinics or by physicians, the actual number of patients with AK is probably higher.⁶ The incidence of AK is higher in individuals living close to the equator, but is increasing in men and women in general.⁷ 8

Table 1

Risk factors for actinic keratoses⁸

Central Forehead Reconstruction with a Simple Primary Vertical Linear Closure

Objective: Following Mohs surgery, medium-to-large defects on the central forehead can often be complicated to surgically reconstruct. In this paper, the authors discuss possible central forehead reconstructions and report their successful experience employing a simple primary vertical linear closure with a special technique to demarcate forehead rhytides rather than performing an overly complicated flap or graft. Case report: The patient was a 57-year-old man who presented with a broad superficial basal cell carcinoma that required treatment with Mohs surgery. For the resulting defect, the authors elected to perform a complex linear repair taking advantage of substantial side-to-side laxity in the supraperiosteal plane and carefully labeling and matching each forehead rhytide across the defect as the wound was sutured. Conclusion: The findings of this case demonstrate that medium-to-large wounds of the central forehead can be aesthetically repaired with a simple primary vertical linear closure. Carefully mapping and labeling horizontal forehead rhytides with a sterile surgical marking pen prior to anesthesia ensures accurate approximation during wound closure.Due to the prominence and broad surface of the central forehead, aesthetic reconstruction of medium to large forehead defects is imperative. Commonly utilized flaps include the island pedicle flap, rotation flaps, A-to-T flap, and O-to-T flaps (1-3

TABLE 1

Commonly utilized flaps

A Method for Working with Displeased Patients—Blast

Clinicians inevitably encounter patients with complaints and concerns about the quality of their care. This causes some to experience anxiety, fear, anger, resentment, guilt, and depression, especially when they believe they may have erred or caused harm. Lack of customer-service training and experience may contribute to these emotions. The “BLAST” technique is a complaint-resolution method that is useful in patient care and as a clinical teaching tool. The mnemonic stands for: Believe (what the patient is saying), Listen (actively, to assess and restate the patient’s unmet expectations), Apologize (for the patient’s unmet expectations), Satisfy (the patient), and Thank (the patient for expressing his/her concerns and providing a second chance to satisfy the patient). The technique appears to help clinicians become more at ease and confident when handling patient complaints. This may be especially helpful for clinicians who must routinely interact with post-treatment and post-procedure patients who commonly express surprise, concern, or complaints about their results and healing. BLAST may be an effective teaching tool enabling students, residents, and clinicians to become more comfortable and adept at working with displeased and concerned patients.Clinicians inevitably encounter patients with complaints and concerns about the quality of their care. Some experience anxiety, fear, anger, resentment, guilt, and depression when their care is criticized,1,2 especially when they believe they may have erred3 or caused harm.4 These reactions may, in part, be due to a lack of customer-service training5 and interfere with clinician effectiveness.1The BLAST technique is a complaint-resolution method developed by Albert Barneto. The mnemonic stands for Believe, Listen, Apologize, Satisfy, and Thank (6 This article describes its usefulness in patient care and as a clinical teaching tool. Anecdotal experience suggests its use helps clinicians remain more calm and effective when working with displeased patients.

TABLE 1

The BLAST technique is a complaint-resolution method

Endothelin-A Receptor Antagonism Modifies Cardiovascular Risk Factors in CKD

Arterial stiffness and impaired nitric oxide (NO) bioavailability contribute to the high risk for cardiovascular disease in CKD. Both asymmetric dimethylarginine (ADMA), an endogenous inhibitor of NO production, and endothelin-1 (ET-1) oppose the actions of NO, suggesting that ET-1 receptor antagonists may have a role in cardiovascular protection in CKD. We conducted a randomized, double-blind, three-way crossover study in 27 patients with proteinuric CKD to compare the effects of the ET_A receptor antagonist sitaxentan, nifedipine, and placebo on proteinuria, BP, arterial stiffness, and various cardiovascular biomarkers. After 6 weeks of treatment, placebo and nifedipine did not affect plasma urate, ADMA, or urine ET-1/creatinine, which reflects renal ET-1 production; in contrast, sitaxentan led to statistically significant reductions in all three of these biomarkers. No treatment affected plasma ET-1. Reductions in proteinuria and BP after sitaxentan treatment was associated with increases in urine ET-1/creatinine, whereas reduction in pulse-wave velocity, a measure of arterial stiffness, was associated with a decrease in ADMA. Taken together, these data suggest that ET_A receptor antagonism may modify risk factors for cardiovascular disease in CKD.CKD is common, affecting 6%–11% of the population globally.¹ It is strongly associated with incident cardiovascular disease (CVD).² This increased cardiovascular risk is not adequately explained by conventional (Framingham) risk factors, such as hypertension, hypercholesterolemia, diabetes mellitus, and smoking, all of which are common in patients with CKD. Thus, emerging cardiovascular risk factors have been an area of intense investigation.³ Arterial stiffness⁴ makes an important independent contribution to CVD risk in CKD, and this is promoted by both conventional and emerging cardiovascular risk factors.Hyperuricemia and a shift in the balance of the vasodilator nitric oxide (NO) and vasoconstrictor endothelin (ET) systems have been identified as potential contributors to increased cardiovascular risk in patients with CKD.⁵ These are all common in a typical CKD population.^3,6 Epidemiologic studies report a relationship between serum uric acid and a wide variety of cardiovascular conditions, including hypertension, diabetes mellitus, coronary artery disease, cerebrovascular disease, and CKD.⁷ Indeed, serum uric acid is considered by some to be an independent risk factor for both CVD^8,9 and CKD.¹⁰ Others have noted that an elevated serum uric acid level predicts the development of hypertension and CKD.⁷ Of note, emerging clinical data show that decreasing serum uric acid levels has both cardiovascular and renal benefits.^11–13Asymmetric dimethylarginine (ADMA) is an endogenous inhibitor of NO synthases. By inhibiting NO formation, ADMA causes endothelial dysfunction, vasoconstriction, elevation of BP, and progression of experimental atherosclerosis.¹⁴ ADMA concentrations are increased in patients with CKD,¹⁴ and clinical data support ADMA as an independent marker of CKD progression, cardiovascular morbidity, and overall mortality.^15–17 Studies have shown a reduction in ADMA after therapy in patients with hypertension and hypercholesterolemia,^18,19 but not in patients with CKD.ET-1 is a potent endogenous vasoconstrictor produced within the vasculature. It is implicated in both the development and progression of CKD.²⁰ Its effects are mediated via two receptors, the ET_A and ET_B receptors; the major pathologic effects are ET_A receptor mediated.²⁰ We have recently shown that long-term selective ET_A receptor antagonist therapy using the orally active drug sitaxentan reduces proteinuria, BP, and arterial stiffness in patients with proteinuric CKD,²¹ effects that are potentially renoprotective. We hypothesized that in this same cohort of patients with CKD, sitaxentan would also reduce levels of serum uric acid, ADMA, and urine ET-1 (as a measure of renal ET-1 production) and so provide broader cardiovascular and renal protection. The current data show the effects of sitaxentan, as well as placebo and an active control agent, nifedipine, on these novel cardiovascular risk factors.As described elsewhere,²¹ after 6 weeks of dosing no significant differences were seen between sitaxentan and nifedipine in the reductions from baseline in BP measures. Despite this, sitaxentan reduced proteinuria to a significantly greater extent than did nifedipine. Pulse-wave velocity (PWV)—a measure of arterial stiffness—decreased to a similar degree with nifedipine as with sitaxentan. Placebo did not affect proteinuria, BP, or PWV (see

Functional Effector Memory T Cells Enrich the Peritoneal Cavity of Patients Treated with Peritoneal Dialysis

The frequency and severity of episodes of peritonitis adversely affect the structure and function of the peritoneal membrane in patients treated with peritoneal dialysis (PD), but the underlying mechanisms are not well understood. Alterations in the phenotype and function of resident peritoneal cells may contribute. Because effector memory T cells play a pivotal role in maintaining peripheral tissue immunity, we hypothesized that these cells may initiate or perpetuate the peritoneal inflammatory response. Here, we characterized the phenotype and effector function of peritoneal memory T cells. We found that functional effector memory T cells capable of mounting long-term recall responses enrich the peritoneal cavity of PD patients. Peritoneal T cells were able to mount a Th1-polarized response to recall antigens, and these responses were greater in peritoneal T cells compared with T cells in the peripheral blood. We also observed that the peritoneal T cells had altered telomeres; some cells had ultrashort telomeres, suggesting a highly differentiated local population. In summary, we describe a resident population of memory T cells in the peritoneum of PD patients and speculate that these cells form part of the first line of defense against invading pathogens.Despite advances in treatment, peritoneal infection remains one of the main causes of technique failure in peritoneal dialysis (PD) patients. There is a strong association between peritonitis (frequency and severity) and the loss of membrane function.^1–3 In view of this, there has been considerable interest in understanding the basic processes that regulate peritoneal early responses to infection. Most of these studies have focused on the contribution of peritoneal macrophages or mesothelial cells to these processes.^4–9 Despite representing up to 25% of the resident peritoneal leukocyte population and forming a significant proportion of the leukocyte population present in resolving peritonitis, the function and phenotype of human peritoneal T cells is poorly defined.^10–12 Consequently we understand very little about the adaptive arm of the peritoneal immune responseRecent developments in the field of immunology have greatly enhanced our understanding of T cell phenotype, activation status, differentiation, and tissue homing capacity. Many studies have highlighted the important role of T cells in providing long-term immunological memory.^13–19 According to current definitions, memory T cells are distinguished from naïve T cells (which are yet to encounter their cognate antigen) by the expression of CD45RO (rather than CD45RA).²⁰ Within the memory T cell population, distinct functional subsets have been characterized based on the expression the lymph node homing signal CCR7.^13–19 These subsets differ in both their tissue homing capability and in their response to antigenic stimulation.^15,17,18 Central memory (T_CM) cells (CD45RO/CCR7⁺) are thought to migrate through lymph tissue, whereas effector memory (T_EM) cells (CD45RO /CCR7⁻), which lack lymph node homing signals, are thought to reside primarily in peripheral tissue.^16,17 The T_EM subset rapidly produces effector cytokines such as IFN-γ and IL-4 and are thought to form a first line of defense in vulnerable peripheral tissues. In contrast, T_CM cells lack immediate effector function but retain proliferative capacity and are capable of generating a secondary wave of antigen-specific effector T cells.^17–19 The memory subsets also differ in their replicative history and degree of differentiation. Within the T cell population, telomere lengths decrease from naïve through T_CM through T_EM cells, suggesting that the latter have undergone more cell divisions and are a more highly differentiated population.^17,20Most of our current understanding of T cell memory is derived from murine data or from experiments performed on peripheral blood T cells. Because of the logistical difficulties involved in sample collection, there are very little data available regarding the phenotype and function of memory T cells in human peripheral tissue. The aim of our study was to characterize the phenotype, replicative history, and effector function of the peritoneal memory T cell population during steady-state (non-infected) PD.Our results demonstrate that as compared with peripheral blood, the peritoneal cavity is enriched in cells displaying a T_EM phenotype, with very few intraperitoneal naïve T cells (Figure 1, A and B) (we found no significant difference in the proportion of T_CM cells between blood and peritoneum). Subgroup analysis shows that neither time on PD nor recurrent peritonitis have a significant effect on the proportion of T_EM within the peritoneal cavity, suggesting that T_EM enrichment is a characteristic of the quiescent peritoneal cavity (Supplementary Figure 1). Further phenotypic analysis demonstrated increased expression of the proinflammatory chemokine receptor CCR5 on the T_EM subset, but only low-level expression of the lymph node homing signal CD62L (Figure 1C).Open in a separate windowFigure 1.Paired samples of peripheral blood mononuclear cells (PBMCs) and peritoneal leukocytes were collected from PD patients. Cells were labeled with fluorescently conjugated monoclonal antibody directed against CD4/CD8/CCR7 and CD45RO. A combined gate was set on peritoneal T cells on the basis of CD4 or CD8 expression and their FSC:SSC profiles. (A) Representative example of CD4 data. (B) Summary of data obtained from paired blood and peritoneal T cells obtained from 20 patients. Differences between groups were tested using the Wilcoxon signed ranks test (*P < 0.05). (C) Peritoneal leukocytes were collected from ten separate PD patients. Cells were labeled with fluorescently conjugated monoclonal antibody directed against CD4/CCR7/CD45RO and CD62L or CCR5. A combined gate was set on peritoneal T cells on the basis of CD4 expression and their FSC:SSC profiles. Further gate was plotted on the T_EM subset and percentage CD62L⁺/CCR5⁺ within this calculated subset. See ​and22 for patient demographics.

Table 1.

Patient demographics

High Prevalence of Sickle Cell Trait in African Americans with ESRD

Sickle cell trait (HbAS) associates with impaired urinary concentration, hematuria, and renal papillary necrosis, but its prevalence among African Americans with ESRD is unknown. We performed a cross-sectional study reviewing available hemoglobin phenotypes for 188 of 206 adult African-American patients receiving renal replacement therapy in four dialysis units. Results from the state newborn screening program in corresponding counties provided the local population prevalence of sickle trait among African Americans. Compared with the general African-American population, HbAS was twice as common among African Americans with ESRD (15% versus 7%, P < 0.001). Prevalence of hemoglobin C trait (HbAC) was similarly more common (5% versus 2%, P < 0.01). The higher prevalence of HbAS and HbAC in the ESRD population raises the possibility that these hemoglobinopathies contribute to a decline in kidney function, either alone or in conjunction with other known risk factors for renal disease. The potential effect of HbAS on the development and progression of CKD and its effect on the course and management of patients with ESRD deserve further study.Sickle cell trait (HbAS) is present in 7 to 9% of African Americans^1,2 and has typically been described as a benign carrier state with little effect on the health of affected individuals. Although uncommon, several adverse effects of HbAS have been reported in settings of low oxygen tension or high oxygen demand, including splenic infarction at high altitude, sudden death with extreme physical exertion, venous thromboembolism, and glaucoma from anterior chamber hemorrhage.^1,3–7 The low oxygen content of the renal medulla provides a propitious setting for intravascular sickling. HbAS has been associated with fewer and disrupted vessels of the vasa recta,^8,9 which likely translates clinically to the highly prevalent impaired urinary concentration.^3,6,7,10,11 Renal microvascular obstruction also occurs with HbAS, presenting most frequently as asymptomatic hematuria and most dramatically as renal papillary necrosis.^3,6,7,10,11The rare renal medullary carcinoma is seen almost exclusively among HbAS patients.^6,11,12In epidemiologic studies, the presence of HbAS has been associated with microalbuminuria and proteinuria, particularly among diabetic men,^13,14 and African Americans with autosomal dominant polycystic kidney disease (ADPKD) and HbAS have been shown to progress to ESRD more rapidly than those without the trait.¹⁵ With its associated structural and physiologic changes, HbAS could adversely affect renal function, especially in the setting of comorbid disease, and may represent a potential risk factor for kidney disease.^16,17 We postulated that HbAS may be more common among African Americans with ESRD and examined the prevalence of HbAS in a group of African Americans receiving renal replacement therapy.Hemoglobin phenotyping was performed on 188 of the 206 African-American patients receiving treatment through four of our affiliated dialysis centers, 172 of whom were receiving hemodialysis and 21 receiving peritoneal dialysis. We obtained newborn hemoglobinopathy screening results in the corresponding three North Carolina counties from the inception of the newborn screening program to the planned date of the study. This included 6729 African-American individuals born between January 1, 1994 and November 30, 2008 who were used to determine the local population prevalence.Among the tested African-American ESRD patients, 28 (14.9%) patients had HbAS, 9 (4.8%) were heterozygous for hemoglobin C [hemoglobin C trait (HbAC)], and 1 (0.5%) was heterozygous for β-thalassemia (β-thalassemia minor). In comparison, the local population prevalence among screened newborns was 7.1% (P < 0.001) for HbAS and 1.9% for HbAC (P < 0.01) (Figure 1).Open in a separate windowFigure 1.Prevalence of hemoglobin variants from North Carolina newborn screening data and among ESRD patients. North Carolina screening data from newborn screening of African-American live births (n = 6729) from January 1, 1994 to November 30, 2008 were obtained for the three counties in which African-American ESRD patients (n = 188) from four dialysis clinics were based. *Fisher''s exact test with Bonferroni correction for repeat testing. HbAS, sickle cell trait; HbAC, hemoglobin C trait.We also sought to determine if there were any major differences among the ESRD patients when separated by hemoglobin phenotype (CharacteristicHbAA^b (%) (n = 150)HbAS (%) (n = 28)HbAC (%) (n = 9)PAge, years (SD)58.4 (14.8)59.8 (12.5)59.7 (16.8)0.9Gender, n (SD)0.9    female71 (47.3)13 (46.4)5 (55.6)    male79 (52.7)15 (53.6)4 (44.4)Age of ESRD onset, years (SD)54.1 (15.5)54.0 (13.8)54.5 (18.6)1.0Dialysis vintage, median years (interquartile range)3.0 (1.2 to 5.8)5.5 (2.2 to 8.5)5.5 (1.8 to 6.5)0.05Modality0.8    in-center hemodialysis137 (91.3)25 (89.3)9 (100)    peritoneal dialysis13 (8.7)3 (10.7)0Cause of ESRD^c0.1    diabetes mellitus59 (39.3)10 (35.7)6 (66.7)    hypertension52 (34.7)15 (53.6)1 (11.1)    GN24 (16.0)1 (3.6)0    cystic disease3 (2.0)00    other12 (8.0)2 (7.1)2 (22.2)Open in a separate window^aOne patient heterozygous for β-thalassemia (β-thalassemia minor, β-thalassemia trait) is not included here. This patient was a 32 year-old female on hemodialysis with hypertension as cause of ESRD and onset of ESRD at age 22.^bHbAA, normal adult hemoglobin phenotype.^cAs reported in Medicare CMS-2728 form.Differences were noted in ascribed cause of ESRD, although these did not reach statistical significance (P = 0.1). Diabetes mellitus was the cause of ESRD in over one third of patients with normal adult hemoglobin phenotype and HbAS and two thirds of patients with HbAC. More patients with HbAS had hypertension as their cause of ESRD. Only one (4%) patient with HbAS had GN, compared with 24 (16%) from the portion of patients with normal adult hemoglobin phenotype. Only three patients in the entire cohort were identified as having cystic kidney disease, all of whom had normal hemoglobin phenotypes. The one 32 year-old female patient with β-thalassemia minor and hypertensive ESRD at age 22 was not included in the above analyses.In this study of 188 African-American patients receiving dialysis, we found that the prevalence of HbAS was more than twice that of the general population, present in one in seven ESRD patients. We also found that HbAC was more common in the dialysis patients.To our knowledge, this study is the first to evaluate the prevalence of these hemoglobinopathies among African-American ESRD patients relative to an appropriate reference population. Our analysis, which was based on an a priori hypothesis, is exploratory in nature. HbAS, as examined in a group of prevalent ESRD patients, could be a risk factor or risk indicator for ESRD or merely associated at a statistical level. Acknowledging that we cannot exclude residual confounding, we propose potential mechanisms for our observation.First, HbAS may directly lead to loss of renal function. Episodic sickling could lead to chronic parenchymal ischemia and eventually fibrotic changes as reported in autopsy and biopsy studies.¹⁸ Although not proven to be causative, the presence of HbAS has even been reported in the setting of GN.^19,20 Second, HbAS could accelerate the effects of another process. Medullary structural and physiologic abnormalities provide a background pathology in which a primary disease would have an accelerated effect. Although HbAS may not be sufficient to cause ESRD by itself, it could contribute to progression of renal insufficiency to ESRD in the presence of additional factors, such as diabetes or hypertension. As noted previously, microalbuminuria and proteinuria have been reported in higher frequency among diabetic men with HbAS,¹⁴ further suggesting this possibility.If HbAS is a cofactor for renal disease, identifying HbAS in patients otherwise at risk for chronic kidney disease could be important for preventive measures. Overt sickle cell disease (HbSS) is associated with lesions of glomerular hypertension, and angiotensin converting enzyme inhibitors improve proteinuria in these patients.²¹ Similar pathology may occur in the HbAS state and identifying these patients would allow aggressive monitoring for albuminuria and early intervention with antiproteinuric agents.The presence of abnormal hemoglobin, particularly HbAS, may also affect the course and care of ESRD patients. HbAS may be an independent risk factor among African Americans for venous thromboembolism^1,5 and could add to the already high risk for pulmonary embolism among ESRD patients.²² Additionally, this predisposition for thrombosis could affect arteriovenous fistula failure and access loss, already known to occur at higher rates among African Americans.²³ African Americans with ESRD also appear to require larger doses of erythropoiesis stimulating agents (ESAs) to achieve their hemoglobin targets.²⁴ Results of the Correction of Hemoglobin and Outcomes in Renal Insufficiency study suggested higher target hemoglobin may be associated with more cardiovascular outcomes,²⁵ and adverse outcomes were seen primarily in those who failed to reach their target hemoglobin.²⁶ The presence of HbAS and other hemoglobinopathies may play a role in this relative resistance, placing these patients at higher risk with increasing ESA exposure.Heterozygosity for HbAC was also twice as common in this cohort compared with the geographically matched African-American population and to the reported national prevalence.² Hemoglobin C is more likely to precipitate, and when present with hemoglobin S it leads to a syndrome similar to but less severe than HbSS disease. Heterozygosity is thought to be clinically silent.²⁷ The elevated prevalence of HbAC in our cohort is of unclear significance but may have similar consequences as those of HbAS.Of note, mean age of onset of ESRD in our study population was similar among all groups, whereas dialysis vintage was higher in the groups with either hemoglobinopathy by a median of 2.5 years. The small sample size and borderline statistical significance limit our ability to conjecture a potential explanation or draw meaningful conclusions from this difference. However, the greater length of vintage, in part, could influence our assessment of prevalence. The extended presence of those with hemoglobinopathies in this ESRD population could increase the prevalence of HbAS when surveyed in a cross-sectional manner.The findings of this study must be interpreted in the context of several limitations. Primarily, the assessment of population prevalence of hemoglobinopathies via newborn screening results may not be accurately reflective of the population from which our ESRD cohort is derived. North Carolina newborn screening results include births occurring after 1994, and our cohort is of a different era. Any large migration into or out of these regions would lead to prevalence discrepancies between the time of our cohort and the advent of newborn screening. However, because our measured prevalence is similar to that found in the general African-American population nationally,^1,2 we do feel confident in our assessment of the baseline population prevalence.Our findings may not translate to all African-American ESRD populations. The aforementioned study of African-American ADPKD patients¹⁵ did include an assessment of HbAS in ESRD patients without ADPKD, finding it in only 6 of their 80 patients (7.5%). Although the local prevalence of HbAS was not evaluated, this discrepancy from our study does implicate that our findings should be confirmed in another cohort, perhaps larger and more geographically diverse.Lastly, the cross-sectional design prevents the determination of the exact nature of the observed associations. Initial cross-sectional findings are primarily useful for informing subsequent prospective studies. The size of the cohort is also relatively small and geographically compact, such that any familial clustering might provide an exaggeration of the prevalence.The prevalence of abnormal hemoglobin, HbAS and HbAC in this African-American ESRD cohort, was found to be over twice that of the baseline African-American population in the same geographic region. The high prevalence of these hemoglobinopathies suggests that they may contribute to progression to ESRD by providing a background of renal injury. Our findings also raise questions as to how the presence of HbAS or HbAC may affect management of ESRD patients. Longevity of hemodialysis access and response to ESAs may be altered. Although these results require confirmation, knowledge of a patient''s hemoglobin status may be important to the management of ESRD patients and before ESRD may even identify individuals who would benefit from aggressive interventions to attenuate progression of renal disease.     

Kidney Stones Associate with Increased Risk for Myocardial Infarction

Kidney stones are a risk factor for chronic kidney disease (CKD), which, in turn, is a risk factor for myocardial infarction (MI). The objective of this study was to determine whether kidney stones associate with an increased risk for MI. We matched 4564 stone formers (1984 through 2003) on age and gender with 10,860 control subjects among residents in Olmsted County, Minnesota. We identified incident MI by diagnostic codes and validated events by chart review through 2006. We used diagnostic codes to determine incidence of kidney stones and presence of comorbidities (CKD, hypertension, diabetes, obesity, dyslipidemia, gout, alcohol dependence, and tobacco use). During a mean of 9 years of follow-up, stone formers had a 38% (95% confidence interval 7 to 77%) increased risk for MI, which remained at 31% (95% confidence interval 2% to 69%) after adjustment for CKD and other comorbidities. In conclusion, kidney stone formers are at increased risk for MI, and this risk is independent of CKD and other risk factors.Kidney stones have been identified as a risk factor for chronic kidney disease (CKD).¹ Of great concern with the development of CKD is an increased risk for coronary heart disease. Reduction in both GFR and albuminuria is associated with coronary heart disease in the general population.^2,3 It was hypothesized that the increased risk for CKD in individuals with kidney stones would lead to an increased risk for coronary heart disease. Alternatively, biological pathways that cause calcium kidney stones may also contribute to coronary artery calcification, a risk factor for coronary heart disease events. Myocardial infarction (MI) surveillance in Olmsted County, Minnesota, has been in place since 1979.^4–7 We sought to determine whether kidney stone formers in Olmsted County were at an increased risk for MI and whether this risk is related to the development of CKD.A total of 5081 incident stone formers and 14,144 matched control subjects were identified from the Olmsted County general population between 1984 and 2003. The International Classification of Diseases, Ninth Revision (ICD-9) code used to identify stone formers was 592 (calculus of kidney and ureter) in 4467 (88%), 594 (calculus of lower urinary tract) in 613 (12%), and 274.11 (uric acid nephrolithiasis) in one (<1%). Prevalent MIs were similar between stone formers (n = 178 [3.5%]) and control subjects (n = 489 [3.5%]). After exclusion of individuals with prevalent MI and those who lacked clinic visits at least 90 days after the index date, 4564 stone formers and 10,860 control subjects were followed for incident MI. Only 2.1% of these individuals were nonwhite, consistent with the racial distribution of the community (96% white in 1990). As a consequence of the matching, stone formers and control subjects were similar with respect to age (mean 44.6 versus 44.4 year), gender (59 versus 58% male), length of medical record documentation before the index date (mean 18.4 versus 21.9 years), and length of follow-up to last clinic visit or death (mean 8.7 versus 9.0 years). As shown in ComorbidityStone Formers (n = 4564; n [%])Control Subjects (n = 10,860; n [%])PCKD116 (2.5)200 (1.8)0.0051Hypertension848 (18.6)1748 (16.1)0.0002Diabetes420 (9.2)771 (7.1)<0.0001Obesity1017 (22.3)2155 (19.9)0.0007Dyslipidemia860 (18.8)1802 (16.6)0.0007Gout135 (3.0)255 (2.4)0.028Alcohol dependence235 (5.2)777 (7.2)<0.0001Tobacco use619 (13.6)1598 (14.7)0.063Open in a separate windowThere were incident MIs in 96 stone formers and 166 control subjects. Stone formers were at increased risk for MI in analyses that were unadjusted (hazards ratio [HR] 1.43; 95% confidence interval [CI] 1.11 to 1.84; Figure 1), adjusted for age and gender (HR 1.38; 95% CI 1.07 to 1.77), further adjusted for CKD (HR 1.38; 95% CI 1.07 to 1.77), and fully adjusted for all comorbidities (HR 1.31; 95% CI 1.02 to 1.69). The risk for MI remained with adjustment for the number of comorbidities (excluding alcohol dependence), age, and gender (HR 1.35; 95% CI 1.05 to 1.73). By coding subgroup, the risk for MI adjusted for age and gender was statistically significant for ICD-9 code 592 (HR 1.40; 95% CI 1.07 to 1.84) but not for ICD-9 code 594 (HR 1.24; 95% CI 0.70 to 2.21).Open in a separate windowFigure 1.Increased risk for MI in stone formers than in controls among Olmsted County, Minnesota residents.After adjustment for age and gender, most comorbidities were associated with MI: CKD (HR 2.97; 95% CI 1.86 to 4.72), hypertension (HR 1.54; 95% CI 1.18 to 2.01), diabetes (HR 2.18; 95% CI 1.61 to 2.94), obesity (HR 1.77; 95% CI 1.38 to 2.27), dyslipidemia (HR 1.65; 95% CI 1.27 to 2.15), gout (HR 1.40; 95% CI 0.88 to 2.22), alcohol dependence (HR 1.22; 95% CI 0.76 to 1.95), and tobacco use (HR 2.23; 95% CI 1.67 to 2.96). After exclusion of individuals with these comorbidities at baseline, there remained 2366 stone formers with 25 incident MIs and 5818 control subjects with 42 incident MIs, and the risk for MI with kidney stones remained elevated but not statistically significant (HR 1.50; 95% CI 0.92 to 2.47). There was no detectable interaction between these comorbidities and the risk for MI with kidney stones (P ≥ 0.10 for each comorbidity × stone former interaction).We found stone formers to be at a 38% increased risk for MI. A consideration is that this association reflects shared risk factors for both MI and kidney stones, namely, hypertension, diabetes, obesity, and dyslipidemia⁸; however, the risk for MI in stone formers remained elevated with adjustment for these and other known risk factors for MI, including CKD. This finding adds to the literature that kidney stones should be viewed as a metabolic disorder with clinical relevance beyond symptomatic urinary tract obstruction.⁹A Medline (Ovid Technologies) search of English-language human studies on February 2010 with the terms “kidney/renal stone(s)/calculi or nephrolithiasis or urolithiasis” and “MI or coronary heart/artery disease” revealed 67 articles. Among these articles, there were six relevant studies, with most having small samples sizes.^8,10–14 Several studies showed increased risk for MI in stone formers,^8,10,12,14 and other studies showed no association.^11,13 Lack of effective calcification inhibitors may be a common mechanism linking coronary artery calcification to calcium kidney stones (80% of stone formers).¹⁵ High-dosage calcium supplements may overwhelm calcification inhibitors and have been associated with an increased risk for both MI¹⁶ and kidney stones.¹⁷The study strengths include general population cohorts with validated MI end points. Although there was likely some nondifferential misclassification of comorbidities by diagnostic codes, these comorbidities did have the expected associations with kidney stones and with MI. The risk for MI may vary by stone composition just as the risk for CKD may vary by stone composition.¹⁸ Limitations include lack of information on stone burden, stone composition, diet, medications, and laboratory test results. Furthermore, because study participants were mostly non-Hispanic white individuals, a population at increased risk for kidney stones,¹⁹ inferences to other ethnic groups are limited.In conclusion, the increased risk for MI with kidney stones suggests these two diseases share a common pathophysiologic pathway. This could be a target for future intervention strategies. A history of kidney stones may also be a useful addition in risk stratification algorithms for MI. Further studies are needed to assess the relevance of stone composition and stone burden to risk for MI.     

HLA-A2-matched peripheral blood mononuclear cells from type 1 diabetic patients, but not nondiabetic donors, transfer insulitis to NOD-scid/γc(null)/HLA-A2 transgenic mice concurrent with the expansion of islet-specific CD8+ T cells

OBJECTIVE

Type 1 diabetes is an autoimmune disease characterized by the destruction of insulin-producing β-cells. NOD mice provide a useful tool for understanding disease pathogenesis and progression. Although much has been learned from studies with NOD mice, increased understanding of human type 1 diabetes can be gained by evaluating the pathogenic potential of human diabetogenic effector cells in vivo. Therefore, our objective in this study was to develop a small-animal model using human effector cells to study type 1 diabetes.

RESEARCH DESIGN AND METHODS

We adoptively transferred HLA-A2–matched peripheral blood mononuclear cells (PBMCs) from type 1 diabetic patients and nondiabetic control subjects into transgenic NOD-scid/γc^null/HLA-A*0201 (NOD-scid/γc^null/A2) mice. At various times after adoptive transfer, we determined the ability of these mice to support the survival and proliferation of the human lymphoid cells. Human lymphocytes were isolated and assessed from the blood, spleen, pancreatic lymph node and islets of NOD-scid/γc^null/A2 mice after transfer.

RESULTS

Human T and B cells proliferate and survive for at least 6 weeks and were recovered from the blood, spleen, draining pancreatic lymph node, and most importantly, islets of NOD-scid/γc^null/A2 mice. Lymphocytes from type 1 diabetic patients preferentially infiltrate the islets of NOD-scid/γc^null/A2 mice. In contrast, PBMCs from nondiabetic HLA-A2–matched donors showed significantly less islet infiltration. Moreover, in mice that received PBMCs from type 1 diabetic patients, we identified epitope-specific CD8⁺ T cells among the islet infiltrates.

CONCLUSIONS

We show that insulitis is transferred to NOD-scid/γc^null/A2 mice that received HLA-A2–matched PBMCs from type 1 diabetic patients. In addition, many of the infiltrating CD8⁺ T cells are epitope-specific and produce interferon-γ after in vitro peptide stimulation. This indicates that NOD-scid/γc^null/A2 mice transferred with HLA-A2–matched PBMCs from type 1 diabetic patients may serve as a useful tool for studying epitope-specific T-cell–mediated responses in patients with type 1 diabetes.NOD mice develop spontaneous diabetes due to autoimmune destruction of pancreatic β-cells. These mice have served as a useful tool for understanding many aspects of type 1 diabetes (1,2). For example, the identification of certain pathogenic epitopes were originally found in NOD mice and subsequently observed in the blood of type 1 diabetic patients (3). The major shortcoming of these studies is their inability to evaluate the human autoreactive effector cells directly. Researchers have identified a number of pathogenic autoreactive epitopes of CD4⁺ and CD8⁺ T cells that recognize and result in β-cell killing. Epitopes for islet-specific glucose-6-phosphatase catalytic subunit-related protein (IGRP), insulin, and preproinsulin have been identified in the islets of NOD mice (4). T cells specific for epitopes from these proteins and other islet proteins, including islet amyloid polypeptide (IAPP), have been found in the blood of type 1 diabetic patients (5). At the same time, however, many of the findings in NOD mice have not directly translated to human type 1 diabetes. Importantly, a large number of therapies appear to “cure” diabetes in NOD mice, but these therapies have not readily translated to humans. Anti-CD3 antibody therapy, which is extremely effective in NOD mice (6,7), is less effective in patients (8,9). These immunomodulatory therapies still leave concerns about their effects, as discussed by Santamaria (10). Other immune therapies aimed at targeting B cells, such as anti-CD20 monoclonal antibody treatment, also offer short-term CD19⁺ B-cell depletion and partially preserve β-cell function (11).Development of humanized mice in which HLA-matched peripheral blood mononuclear cells (PBMCs) from type 1 diabetic patients are adoptively transferred into immune-deficient mice would provide a means of studying human immune cells without the restrictions inherent to human studies (12). Specifically, it would be possible to identify human autoreactive epitope-specific T cells that infiltrate the islets directly ex vivo. A small-animal model that recapitulates the clinical manifestations of type 1 diabetes would also assist in identifying novel therapeutic targets and in developing and testing novel immunotherapeutic agents. Furthermore, we would be able to investigate the mechanisms involved in disease pathogenesis of many other autoimmune diseases, especially those with disease-associated epitopes, shared between humans and mice (13,14).During the past several years, many investigators have used human hematopoietic stem cells (HSCs) for engraftment into immunodeficient mice (15–17). These studies have attempted to develop a complete human immune system in a murine host. In many cases, successful engraftment and cell differentiation was observed. Most recently, investigators showed that functional human CD4⁺ and CD8⁺ T cells developed after being transferred into immune-deficient HLA transgenic mice and that these T cells demonstrated HLA-restricted responses (18). In contrast, our goal was not to recapitulate the entire autoimmune process; rather, we sought to develop a humanized mouse model that would be useful for identifying pre-existing autoreactive diabetogenic circulating T cells from type 1 diabetic patients that are important in the direct pathogenesis of type 1 diabetes.In NOD mice, β-cell–specific CD8⁺ T-cell clones are found in the peripheral blood and pancreatic islets (19). In patients with type 1 diabetes, epitope-specific T cells display T-lymphocyte cytotoxic activity toward human β-cells (20). Humans and mice also share many of the protein sequences of identified epitopes (21). Therefore, because it is likely that lymphocytes that have been exposed to islet antigens circulate within the blood of patients with type 1 diabetes, we adoptively transferred peripheral blood mononuclear cells (PBMCs) from HLA-A2–matched type 1 diabetic patients into transgenic NOD-scid/γc^null/HLA-A*0201 (NOD-scid/γc^null/A2) mice (22).

TABLE 1

Type 1 diabetic and nondiabetic haplotype-matched PBMC donors used in transfer experiments^*