Jean L. Olson

Outcomes of Kidney Transplantation in HIV-Infected Recipients

BACKGROUND The outcomes of kidney transplantation and immunosuppression in people infected with human immunodeficiency virus (HIV) are incompletely understood. METHODS We undertook a prospective, nonrandomized trial of kidney transplantation in HIV-infected candidates who had CD4+ T-cell counts of at least 200 per cubic millimeter and undetectable plasma HIV type 1 (HIV-1) RNA levels while being treated with a stable antiretroviral regimen. Post-transplantation management was provided in accordance with study protocols that defined prophylaxis against opportunistic infection, indications for biopsy, and acceptable approaches to immunosuppression, management of rejection, and antiretroviral therapy. RESULTS Between November 2003 and June 2009, a total of 150 patients underwent kidney transplantation; survivors were followed for a median period of 1.7 years. Patient survival rates (±SD) at 1 year and 3 years were 94.6±2.0% and 88.2±3.8%, respectively, and the corresponding mean graft-survival rates were 90.4% and 73.7%. In general, these rates fall somewhere between those reported in the national database for older kidney-transplant recipients (≥65 years) and those reported for all kidney-transplant recipients. A multivariate proportional-hazards analysis showed that the risk of graft loss was increased among patients treated for rejection (hazard ratio, 2.8; 95% confidence interval [CI], 1.2 to 6.6; P=0.02) and those receiving antithymocyte globulin induction therapy (hazard ratio, 2.5; 95% CI, 1.1 to 5.6; P=0.03); living-donor transplants were protective (hazard ratio, 0.2; 95% CI, 0.04 to 0.8; P=0.02). A higher-than-expected rejection rate was observed, with 1-year and 3-year estimates of 31% (95% CI, 24 to 40) and 41% (95% CI, 32 to 52), respectively. HIV infection remained well controlled, with stable CD4+ T-cell counts and few HIV-associated complications. CONCLUSIONS In this cohort of carefully selected HIV-infected patients, both patient- and graft-survival rates were high at 1 and 3 years, with no increases in complications associated with HIV infection. The unexpectedly high rejection rates are of serious concern and indicate the need for better immunotherapy. (Funded by the National Institute of Allergy and Infectious Diseases; ClinicalTrials.gov number, NCT00074386.).

An Inactivating Point Mutation in the Inhibitory Wedge of CD45 Causes Lymphoproliferation and Autoimmunity

A model has been proposed for the regulation of CD45, and by homology other RPTPs, in which dimerization inhibits phosphatase activity through symmetrical interactions between an inhibitory structural wedge and the catalytic site. Here, we report the phenotype of mice with a single point mutation, glutamate 613 to arginine, that inactivates the inhibitory wedge of CD45. The CD45 E613R mutation causes polyclonal lymphocyte activation leading to lymphoproliferation and severe autoimmune nephritis with autoantibody production, resulting in death. Both homozygotes and heterozygotes develop pathology, indicating genetic dominance of CD45 E613R. The dramatic phenotype of CD45 E613R mice demonstrates the in vivo importance of negative regulation of CD45 by dimerization, supporting the model for regulation of CD45, and RPTPs in general.

Matrix metalloproteinase 2 and basement membrane integrity: a unifying mechanism for progressive renal injury

Chronic kidney disease (CKD) and failure are problems of increasing importance. Regardless of the primary etiology, CKD is characterized by tubular atrophy, interstitial fibrosis, and glomerulosclerosis. It has been assumed that diminished matrix metalloproteinase (MMP) activity is responsible for the accumulation of the extracellular matrix (ECM) proteins and collagens that typify the fibrotic kidney. Here we demonstrate that transgenic renal proximal tubular epithelial expression of a specific enzyme, MMP‐2, is sufficient to generate the entire spectrum of pathological and functional changes characteristic of human CKD. At the earliest point, MMP‐2 leads to structural alterations in the tubular basement membrane, a process that triggers tubular epithelial‐mesenchymal transition, with resultant tubular atrophy, fibrosis and renal failure. Inhibition of MMP‐2, specifically in the early, prefibrotic stages of disease may offer an additional approach for treatment of these disabling disorders.—Cheng, S., Pollock, A. S., Mahimkar, R., Olson, J. L., Lovett, D. H. Matrix metalloproteinase 2 and basement membrane integrity: a unifying mechanism for progressive renal injury. FASEB J. 20, E1248–E1256 (2006)

Arterial delivery of genetically labelled skeletal myoblasts to the murine heart: Long-term survival and phenotypic modification of implanted myoblasts☆

The ability to replace damaged myocardial tissue with new striated muscle would constitute a major advance in the treatment of diseases that irreversibly injure cardiac muscle cells. The creation of focal grafts of skeletal muscle has been reported following the intramural injection of skeletal myoblasts into both normal and injured myocardium. The goals of this study were to determine whether skeletal myoblast-derived cells can be engrafted into the murine heart following arterial delivery. The murine heart was seeded with genetically labeled C2C12 myoblasts introduced into the arterial circulation of the heart via a transventricular injection. A transventricular injection provided access to the coronary and systemic circulations. Implanted cells were characterized using histochemical staining for beta-galactosidase, immunofluorescent staining for muscle-specific antigens, and electron microscopy. Initially the injected cells were observed entrapped in myocardial capillaries. One week after injection myoblasts were present in the myocardial interstitium and were largely absent from the myocardial capillary bed. Implanted cells underwent myogenic development, characterized by the expression of a fast-twitch skeletal muscle sarcoendoplasmic reticulum calcium ATPase (SERCA1) and formation of myofilaments. Four months following injection myoblast-derived cells began to express a slow-twitch/cardiac protein, phospholamban, that is normally not expressed by C2C12 cells in vitro. Most surprisingly, regions of close apposition between LacZ labeled cells and native cardiomyocytes contained structures that resembled desmosomes, fascia adherens junctions, and gap junctions. The cardiac gap junction protein, connexin43, was localized to some of the interfaces between implanted cells and cardiomyocytes. Collectively, these findings suggest that arterially delivered myoblasts can be engrafted into the heart, and that prolonged residence in the myocardium may alter the phenotype of these skeletal muscle-derived cells. Further studies are necessary to determine whether arterial delivery of skeletal myoblasts can be developed as treatment for myocardial dysfunction.

Polyomavirus-induced interstitial nephritis in two renal transplant recipients: Case reports and review of the literature

We present two case reports of renal polyomavirus infection leading to renal allograft dysfunction, review the literature of this entity, and discuss the role of specific immunosupressives. Histologically, the virus caused an interstitial infiltrate composed of plasma cells and lymphocytes, interstitial fibrosis, and tubular atrophy. Viral inclusions were seen within tubular cells on light microscopy. Electron microscopy showed viral particles of 40 to 50 nm in a characteristic paracrystalline array. Both patients had been on FK-506-based immunosuppression. In both patients, the virus appeared to clear histologically and renal function stabilized when the patients were converted to cyclosporine-based immunosuppression. Contrary to prior reports, our patients have not lost their grafts and continue to have stable, albeit reduced, graft function at 2.5 years and 4.5 years following the initial diagnosis of renal polyomavirus infection.

Ehlers-Danlos syndrome with abnormal collagen fibrils, sinus of Valsalva aneurysms, myocardial infarction, panacinar emphysema and cerebral heterotopias

A 30 year old woman with marked joint hypermobility had severe, progressive lung disease, seizures, aneurysms of the sinuses of Valsalva and myocardial infarction documented during life. She died of intractable ventricular fibrillation, and postmortem examination showed myocardial injury in the distribution of the left coronary artery but no occlusive coronary artery disease. Severe panacinar emphysema was found in the lungs. Cerebral heterotopias with peculiar vascularization were present and were a likely cause of the seizure disorder. Electron microscopy showed dermal collagen fibrils to be heterogeneous in size, reduced in number, and irregular and frayed in appearance. This patient had a form of the Ehlers-Danlos syndrome, different from the 10 distinct variants described thus far, associated with lethal internal manifestations.

The Fcγ receptor IIIA-158F allele is a major risk factor for the development of lupus nephritis among Caucasians but not non-Caucasians

OBJECTIVE To determine whether inheritance of Fcgamma receptor (FcgammaR) alleles conferring lower affinity for IgG binding increases the risk of developing lupus nephritis. METHODS We compared the frequency of low-affinity alleles of two FcgammaR polymorphisms (FcgammaRIIA and FcgammaRIIIA) among 235 patients with systemic lupus erythematosus (SLE) and proven nephritis (nephritis patients) and among 352 SLE patients with no evidence of renal disease (non-nephritis control subjects). The ethnic distribution of patients in the study was 49% Caucasian, 20% Hispanic, 17% Asian/Pacific Islander, 12% African American, and 2% from other ethnic groups. All patients were genotyped for the FcgammaRIIA-131R/H and FcgammaRIIIA-158V/F polymorphisms. We used contingency table analysis to compare allele and genotype distributions for nephritis patients and nonnephritis control subjects, including ethnic-specific strata. Multivariate logistic regression analyses included sex and disease duration as covariates. RESULTS Univariate and multivariate analyses demonstrated a striking association between the low-affinity FcgammaRIIIA-158F allele and FF genotype and the risk of nephritis among Caucasians, but not among non-Caucasians (multivariate odds ratio [OR] 2.6 for Caucasians with FF genotype), (P = 0.0017). This association was even stronger among Caucasians with severe nephritis (OR 4.4, P < 0.0001). In contrast, inheritance of the low-affinity FcgammaRIIA-131R allele (and RR genotype) was not associated with an increased risk of lupus nephritis among any of the ethnic groups examined. CONCLUSION The FcgammaRIIIA-158F allele is a major risk factor for the development of lupus nephritis among Caucasians, but not among non-Caucasians. These results suggest that ethnic variation is critical in defining the specific genetic factors underlying the pathogenesis of SLE, and they have important prognostic and therapeutic implications as well.

Reversible cell-cycle entry in adult kidney podocytes through regulated control of telomerase and Wnt signaling

Mechanisms of epithelial cell renewal remain poorly understood in the mammalian kidney, particularly in the glomerulus, a site of cellular damage in chronic kidney disease. Within the glomerulus, podocytes—differentiated epithelial cells crucial for filtration—are thought to lack substantial capacity for regeneration. Here we show that podocytes rapidly lose differentiation markers and enter the cell cycle in adult mice in which the telomerase protein component TERT is conditionally expressed. Transgenic TERT expression in mice induces marked upregulation of Wnt signaling and disrupts glomerular structure, resulting in a collapsing glomerulopathy resembling those in human disease, including HIV-associated nephropathy (HIVAN). Human and mouse HIVAN kidneys show increased expression of TERT and activation of Wnt signaling, indicating that these are general features of collapsing glomerulopathies. Silencing transgenic TERT expression or inhibiting Wnt signaling through systemic expression of the Wnt inhibitor Dkk1 in either TERT transgenic mice or in a mouse model of HIVAN results in marked normalization of podocytes, including rapid cell-cycle exit, re-expression of differentiation markers and improved filtration barrier function. These data reveal an unexpected capacity of podocytes to reversibly enter the cell cycle, suggest that podocyte renewal may contribute to glomerular homeostasis and implicate the telomerase and Wnt–β-catenin pathways in podocyte proliferation and disease.

Frequency of recurrent lupus nephritis among ninety-seven renal transplant patients during the cyclosporine era

OBJECTIVE To determine the frequency of recurrent lupus nephritis (LN) in patients with systemic lupus erythematosus (SLE) who underwent renal transplantation. METHODS We reviewed the posttransplant clinical course and renal biopsy results in 97 consecutive SLE patients who underwent a total of 106 renal transplantation procedures at our center from January 1984 to September 1996. RESULTS There were 81 female and 16 male patients, with a mean age of 35 years. Mean duration of dialysis prior to transplantation was 33.5 months; 9 patients were never dialyzed. In all patients, the disease was clinically and serologically quiescent at the time of transplantation. The mean posttransplantation followup period was 62.6 months. Patients underwent a total of 143 posttransplant biopsies. Nine patients had pathologic evidence of recurrent LN. Six of the patients with recurrence had cadaveric grafts, 2 had living-related grafts, and 1 had a living-unrelated graft. Recurrence occurred an average of 3.1 years after transplantation; the longest interval was 9.3 years and the shortest, 5 days. Histopathologic diagnoses on recurrence included diffuse proliferative glomerulonephritis, focal proliferative glomerulonephritis, membranous glomerulonephritis, and mesangial glomerulonephritis. In 4 patients, recurrent LN contributed to graft loss. Three of the patients with recurrence had serologic evidence of active lupus, but only 1 had symptoms of active lupus (arthritis). Three patients who lost their grafts secondary to recurrent LN underwent second renal transplantation procedures and had functioning grafts at 7, 30, and 35 months, respectively. CONCLUSION In the largest single medical center series of renal transplant patients with SLE, recurrent LN was more common than reported in the literature, but was not always associated with allograft loss. Recurrent LN was often present in the absence of clinical and serologic evidence of active SLE.

Mucoepidermoid carcinoma of the bronchus: An electron microscopic study of the low grade and the high grade variants

Two cases of mucoepidermoid carcinoma of the bronchus‐one a low grade tumor and the other a high grade tumor—are presented with findings by light and electron microscopy. This represents the first report of the ultrastructure of mucoepidermoid carcinoma of the bronchus and demonstrates the ultrastructural similarities between the low grade exophytic tumor confined to the bronchus and the high grade infiltrating tumor with lymph node and pulmonary metastases. The ultrastructural features are similar to those described for mucoepidermoid carcinoma of the salivary gland and are consistent with the proposed origin of the tumor from the submucosal bronchial gland duct. These two cases and a review of previously reported cases indicate that, analogous to mucoepidermoid carcinoma of the salivary glands, mucoepidermoid carcinoma of the bronchus may occur as either a low grade or high grade variant which can be identified on the basis of growth characteristics and histologic features.