John T. Crosson

Protective effect of T cell depletion in murine renal ischemia-reperfusion injury

Background. Ischemia-reperfusion injury (IRI) is the main cause of acute renal failure in both allograft and native kidney. Studies using T cell knockout mice have established an important role for T cells in renal IRI. T cell depletion strategies are effective in human allograft rejection. However, it is not known whether those are effective in renal IRI. Therefore, the effect of T cell depletion in a murine model of renal IRI using well-characterized antibodies (Abs) that have been effective in preventing experimental allograft rejection was studied. Methods. T cell depleting Abs to CD4 (GK1.5), CD8 (2.43) or pan-T cells (30.H12) were purified from hybridoma culture supernatant. Thymectomized C57BL/6 mice, treated with different combinations of T cell depleting Abs, underwent 30 min of bilateral renal IRI, followed by assessment of renal function, structure, and degree of T cell depletion in spleen, lymph nodes, and peripheral blood by flow cytometry. Results. Mice given both GK1.5 and 2.43 had considerable CD4 and CD8 cell depletion but no protection of renal function after ischemia-reperfusion (I/R) as measured by the rise in serum creatinine. However, when GK1.5 and 2.43 was administered combined with 30.H12, which more effectively depleted CD4 T cell numbers, a significant protection of renal function and structure was observed after I/R. Antibody combinations did not significantly alter other leukocyte populations. Conclusions. These data demonstrate that T cell depletion can improve the course of experimental renal IRI. However, more aggressive T cell depletion strategies were required compared with that needed to prevent experimental allograft rejection.

A Controlled Trial of Intravenous Immunoglobulin G in Chronic Fatigue Syndrome

PURPOSE Currently, there is no established therapy for chronic fatigue syndrome (CFS), a recently defined illness that has been associated with a variety of immunologic abnormalities. Based on the hypothesis that a chronic viral infection or an immunoregulatory defect is involved in the pathogenesis of CFS, the therapeutic benefit of intravenous immunoglobulin G (IV IgG) was evaluated in a group of patients with CFS. Additionally, serum immunoglobulin concentrations and peripheral blood lymphocyte subset numbers were measured at the outset of the study, and the effect of IV IgG therapy on IgG subclass levels was determined. PATIENTS AND METHODS Thirty patients with CFS were enrolled in a double-blind, placebo-controlled trial of IV IgG. The treatment regimen consisted of IV IgG (1 g/kg) or intravenous placebo (1% albumin solution) administered every 30 days for 6 months. Participants completed a self-assessment form prior to each of the six treatments, which was used to measure severity of symptoms, functional status, and health perceptions. Patients were also asked to report adverse experiences defined as worsening of symptoms occurring within 48 hours of each treatment. RESULTS Twenty-eight patients completed the trial. At baseline, all 28 patients complained of moderate to severe fatigue, and measures of social functioning and health perceptions showed marked impairment. Low levels of IgG1 were found in 12 (42.9%), and 18 (64.3%) had low levels of IgG3. At the end of the study, no significant therapeutic benefit could be detected in terms of symptom amelioration or improvement in functional status, despite restoration of IgG1 levels to a normal range. Major adverse experiences were observed in 20% of both the IV IgG and placebo groups. CONCLUSION The results of this study indicate that IV IgG is unlikely to be of clinical benefit in CFS. In addition to the ongoing need for placebo-controlled trials of candidate therapies for CFS, an expanded research effort is needed to define the etiology and pathogenesis of this disorder.

Mouse Model of X-Linked Alport Syndrome

X-linked Alport syndrome (XLAS) is a progressive disorder of basement membranes caused by mutations in the COL4A5 gene, encoding the alpha5 chain of type IV collagen. A mouse model of this disorder was generated by targeting a human nonsense mutation, G5X, to the mouse Col4a5 gene. As predicted for a nonsense mutation, hemizygous mutant male mice are null and heterozygous carrier female mice are mosaic for alpha5(IV) chain expression. Mutant male mice and carrier female mice are viable through reproductive age and fertile. Mutant male mice died spontaneously at 6 to 34 wk of age, and carrier female mice died at 8 to 45 wk of age, manifesting proteinuria, azotemia, and progressive and manifold histologic abnormalities of the kidney glomerulus and tubulointerstitium. Ultrastructural abnormalities of the glomerular basement membrane, including lamellation and splitting, were characteristic of human XLAS. The mouse model described here recapitulates essential clinical and pathologic findings of human XLAS. With alpha5(IV) expression reflecting X-inactivation patterns, it will be especially useful in studying determinants of disease variability in the carrier state.

Atubular Glomeruli and Glomerulotubular Junction Abnormalities in Diabetic Nephropathy

Atubular glomeruli (AG) have been described in several renal disorders. However, little attention has been paid to AG in diabetic nephropathy (DN). Preliminary studies suggested that tip lesions were frequently present in type 1 diabetic (D) patients with proteinuria. The aim of this study was to determine the frequency of AG and their possible relationship with tip lesions in DN. Renal biopsies from eight proteinuric type 1 D patients with normal to moderately reduced GFR (76 +/- 26 ml/min per 1.73 m(2)) and eight normal subjects were studied by light (LM) and electron microscopy (EM). Glomerular volume, volume of the glomerular corpuscle, which is tuft, and the fractional volumes of proximal, distal, and atrophic tubules per cortex were estimated using appropriate stereologic methods. Glomerulotubular junctions were examined on serial sections and classified into glomeruli attached to: normal tubules (NT); short atrophic tubules (SAT); long atrophic tubules (LAT); atrophic tubules with no observable glomerular opening (ATNO); and atubular glomeruli (AG). EM studies showed typical diabetic changes in biopsies, including increased GBM width (P < 0.00001) and mesangial fractional volume (P < 0.0001) and decreased filtration surface density (P < 0.01) compared with normal subjects. Seventeen percent of glomeruli in the D patients were atubular, and 51% were attached to atrophic tubules. Tip lesions were present in all SAT, 64% of LAT, 82% of ATNO, and only 9% of NT and were never observed in normal subjects. The relative volume of AG was smaller than glomeruli in other categories (P < 0.05). Fractional volume of proximal (P < 0.01) and distal (P <0.01) tubules per cortex were decreased, while fractional volume of cortical interstitium (P <0.00001) and atrophic tubules (P <0.01) were increased in D patients. Fractional volume of atrophic tubules, %AG, and percent of glomeruli with tip lesion explained 94% of the GFR variability in diabetic patients (P <0.05). Thus, AG and glomerulotubular junction abnormalities may be important in the development and progression of DN.

Radiation-induced renal disease: A clinicopathologic study

Radiation injury to the renal parenchyma is an unusual cause of renal insufficiency. Light, immunofluorescence and electron microscopic studies were performed on the renal tissue from two patients in whom renal insufficiency developed within a year after they received abdominal irradiation. The glomerular lesion in both patients was similar. Mild endothelial cell swelling and basement membrane splitting were noted consistently on light microscopy. The electron microscopic examination revealed marked subendothelial expansion with electron-lucent material associated with deposition of basement membrane-like material adjacent to the endothelial cells. In some capillary loops, the endothelial cell lining appeared to be completely lost. The pathogenesis of radiation-induced renal injury is still uncertain. It is speculated that local activation of the coagulation system with consequent thrombosis of the renal microvasculature may be extremely important.

An automated system for bedside verification of the match between patient identification and blood unit identification.

Background: The administration of blood to the wrong patient remains the leading cause of acute hemolytic transfusion reactions and subsequent death. A process control system for blood administration was developed that verifies, at the bedside, the match between barcoded patient identification and blood unit identification.

Glomerulotubular junction abnormalities are associated with proteinuria in type 1 diabetes.

Glomerulotubular junction abnormalities, frequent in proteinuric patients with type 1 diabetes, may contribute to the progressive GFR loss in overt diabetic nephropathy. Glomerulotubular junction abnormalities were examined in patients who have type 1 diabetes with a wide range of albumin excretion rates (AER). Renal biopsies from five normoalbuminuric patients, five microalbuminuric patients, six proteinuric patients, and five control subjects were studied by light and electron microscopy. Light microscopy specimens were serially sectioned to find and classify glomerulotubular junctions. Glomerular structural parameters were estimated using stereologic methods. Glomerulotubular junction abnormalities were found in 2% of glomeruli from control and normoalbuminuric patients and in 4% of glomeruli from microalbuminuric patients. In contrast, 71% of glomeruli from proteinuric patients had glomerulotubular junction abnormalities, including five (8%) atubular glomeruli. Electron microscopy findings were typical of diabetic nephropathy. Piece-wise linear regression models with glomerular, glomerulotubular junction, and interstitial parameters as independent variables provided greater GFR (92%; P < 0.005) and AER (95%; P < 0.01) prediction than multiple regression models (81% for GFR and 72% for AER). Thus, glomerular adhesions and glomerulotubular junction abnormalities help to explain the progressive GFR loss that is associated with onset of proteinuria in type 1 diabetes. Moreover, nonlinear models provide better fit for structural-functional relationships in patients with type 1 diabetes.

Minocycline-related lupus erythematosus with associated liver disease

A young woman developed minocycline-related lupus erythematosus with associated autoimmune hepatitis. All clinical and laboratory abnormalities returned to normal when the drug was stopped. The symptoms worsened dramatically upon rechallenge, strongly suggesting the reaction was related to the minocycline.

Immune-Complex Nephritis in Mixed Connective Tissue Disease

Excerpt Mixed connective tissue disease has been recognized as a rheumatic syndrome with features similar to those of systemic lupus erythematosus, progressive systemic sclerosis, and polymyositis,...

De novo immunotactoid glomerulopathy of the renal allograft : possible association with cytomegalovirus infection

A 59-year-old man with end-stage renal failure from systemic vasculitis developed de novo immunotactoid glomerulopathy of the renal allograft, with clinical evidence of hematuria, proteinuria, and acute renal failure 6 weeks after cadaveric renal transplantation. The morphologic lesion of immunotactoid glomerulopathy and the clinical renal disease resolved during the following 2 weeks. The disease had not recurred in the subsequent 20 months of posttransplant follow-up. During the same period, the patient also developed systemic cytomegalovirus (CMV) infection with viremia, acute hepatitis, and bone marrow suppression. The clinical manifestations of CMV illness and the renal disease have subsided following the withdrawal of immunosuppressive agents and simultaneous treatment with ganciclovir. Although there is no direct proof that CMV infection was responsible for the development of immunotactoid glomerulopathy, the circumstantial evidence in this patient strongly suggests that these two disease were temporally linked. To our knowledge, the association between CMV infection and immunotactoid glomerulopathy has not been documented previously.