Immediate allograft dysfunction due to atheroembolic disease.

Atheroembolic disease is a known cause of renal failure following invasive vascular procedures in patients with atherosclerosis. It is, however, not generally associated with renal transplant dysfunction. We report on a case of donor-transmitted atheroembolic renal disease, which led to an immediate loss of the transplant kidney in the operating room. Risk factors associated with this condition and methods to prevent this complication are discussed.

A blinded retrospective analysis of renal allograft pathology using the Banff schema: implications for clinical management.

BACKGROUND: We sought to determine whether diagnoses established through the Banff schema for evaluation of renal allograft pathology have implications for clinical management, compared with diagnoses established using descriptive terminology. METHODS: All patients included in this study had mild to severe allograft rejection diagnosed, and, as part of a therapeutic protocol, they received OKT3 as primary anti-rejection therapy. We conducted a retrospective review of their renal allograft biopsy specimens and reclassified them, using the Banff schema, without knowledge of clinical information, laboratory data, or previous biopsy interpretation. Although there is no strict correspondence between descriptive diagnostic terminology and the criteria used in the Banff schema, for the purpose of comparisons, the following approximation was used: mild and mild to moderate rejection=Banff borderline and Banff grade 1, moderate and moderate to severe rejection=Banff grades 2A and 2B, and severe rejection=Banff grade 3. The diagnosis was considered concordant when the diagnosis by descriptive terminology and Banff grading were within the adopted approximation. RESULTS: Of 96 biopsies specimens with mild to severe allograft rejection, 10 were insufficient for diagnosis, and three had changes of chronic allograft rejection. Of the remaining 83 biopsy specimens, 34 (41%) were concordant in interpretation of rejection grades, whereas 49 (59%) were discrepant. The greatest degree of concordance was in grades 2A (66.7%, 18 of 27) and 2B (64.7% 11 of 17), and the lowest was in the borderline category (11.8%, 2 of 17). The greatest degree of discrepancy was in normal and grade 3 (100%, 3 of 3 and 2 of 2, respectively), and the lowest was in grade 2A (33.3%, 9 of 27). Although primary anti-rejection therapy with OKT3 resulted in a high reversal rate of rejection (98%), there were 5 deaths, 12 graft loses, six episodes of serious infections, and three malignancies in this group of patients during a mean follow-up period of approximately 38 months. CONCLUSIONS: Because patients with borderline changes and grades 1 and 2A rejection may be treated differently from patients with higher grades (2B and 3), the use of the Banff schema may allow for better adjustment of immunosuppressive therapy in response to specific grades of acute allograft rejection and may result in decreased complications of immunosuppressive therapy.

Cardiac magnetic resonance imaging: technique and anatomy.

Recent advances achieved in Magnetic Resonance Imaging equipment and procedures allow a thorough study of the heart, yielding anatomic, functional and angiographic information. Spin-echo sequences are specific for heart morphology while gradient-echo sequences are fundamental to the functional study. Fast sequences reduce the examination times with the possibility of single breath-hold images. Coronary arteries can be directly visualized and cardiac perfusion can be assessed. Velocity encoded images allow flow quantification and with myocardial tagging, cardiac mechanics is accurately defined.

The Banff 97 working classification of renal allograft pathology.

BACKGROUND: Standardization of renal allograft biopsy interpretation is necessary to guide therapy and to establish an objective end point for clinical trials. This manuscript describes a classification, Banff 97, developed by investigators using the Banff Schema and the Collaborative Clinical Trials in Transplantation (CCTT) modification for diagnosis of renal allograft pathology. METHODS: Banff 97 grew from an international consensus discussion begun at Banff and continued via the Internet. This schema developed from (a) analysis of data using the Banff classification, (b) publication of and experience with the CCTT modification, (c) international conferences, and (d) data from recent studies on impact of vasculitis on transplant outcome. RESULTS: Semiquantitative lesion scoring continues to focus on tubulitis and arteritis but includes a minimum threshold for interstitial inflammation. Banff 97 defines "types" of acute/active rejection. Type I is tubulointerstitial rejection without arteritis. Type II is vascular rejection with intimal arteritis, and type III is severe rejection with transmural arterial changes. Biopsies with only mild inflammation are graded as "borderline/suspicious for rejection." Chronic/sclerosing allograft changes are graded based on severity of tubular atrophy and interstitial fibrosis. Antibody-mediated rejection, hyperacute or accelerated acute in presentation, is also categorized, as are other significant allograft findings. CONCLUSIONS: The Banff 97 working classification refines earlier schemas and represents input from two classifications most widely used in clinical rejection trials and in clinical practice worldwide. Major changes include the following: rejection with vasculitis is separated from tubulointerstitial rejection; severe rejection requires transmural changes in arteries; "borderline" rejection can only be interpreted in a clinical context; antibody-mediated rejection is further defined, and lesion scoring focuses on most severely involved structures. Criteria for specimen adequacy have also been modified. Banff 97 represents a significant refinement of allograft assessment, developed via international consensus discussions.

[Ectopic thyroid and late-onset functional deficit of the thyroid gland]. / Ectopia tiroidea e deficit funzionale tiroideo ad esordio tardivo.

PURPOSE: To evaluate retrospectively the incidence of ectopic thyroid gland causing hypothyroidism in patients referred to "Di Venere" Hospital, Bari. PATIENTS AND METHODS: Over a period of 14 years, ectopic thyroid gland has been detected by thyroid scan in 56 out of 122 patients with hypothyroidism due to congenital thyroid abnormalities. Of these 56 patients, 48 were < 1 year old, 2 were < 2 years old, while 8 with late onset of the disease were 7 to 35 years old. RESULTS: Among the eight patients with late onset hypothyroidism, 3 had normal serum levels of thyroid hormones at birth. Overall, an ectopic thyroid gland was observed in 6 out of 32 (18.7%) patients with hypothyroidism beginning between 2.5 and 14 years of age. CONCLUSIONS: Thyroid scan is a safe and effective procedure in the diagnosis of ectopic thyroid gland in neonatal patients. It should be recommended as neonatal screening in order to prevent irreversible damage to central nervous system.

Efficacy of OKT3 as primary therapy for histologically confirmed acute renal allograft rejection.

BACKGROUND: OKT3 is often used as primary treatment for acute renal allograft rejection. In a retrospective study, we sought to determine the efficacy of OKT3 as a first-line agent in reversing histologically confirmed acute renal allograft rejection. METHODS: Patients with mild to moderate, moderate, or severe acute cellular and acute vascular rejection who had not received any other anti-rejection treatment were included in this analysis. A total of 88 patients, who received OKT3 between 1987 and 1995, fulfilled these criteria. RESULT: Seventy of these patients were renal transplant recipients, and 18 were combined kidney and pancreas transplant recipients. The median time to the diagnosis of rejection from transplantation was 32 days (range, 6 days to 13 years). On histology, 6 were graded as mild to moderate, 36 as moderate, 29 as moderate to severe, and 17 as severe rejection. The mean baseline serum creatinine was 1.62 mg/dl (range, 0.7-10.1 mg/dl), and the mean serum creatinine at the time of diagnosis of rejection was 2.60 mg/dl (range, 1.4-12.7 mg/dl) (P=<0.0001). The mean duration of OKT3 treatment was 11.2 days (range, 8-18 days). The mean serum creatinine at the end of OKT3 treatment was 1.73 mg/dl (range, 0.6-5.0 mg/dl; P=0.24 compared with baseline serum creatinine). Rejection was reversed in 86 (98%) patients. Graft survival at 1 year after OKT3 therapy was 87.5% (77 of 88). At a mean follow-up of 38 months, 8 patients had died and 26 grafts were lost. The mean serum creatinine level in the 64 patients with a functioning graft was 1.76 mg/dl (range, 0.8-4.0 mg/dl) at the last follow-up. CONCLUSION: OKT3 when utilized as first-line therapy reversed 98% of the acute rejection episodes, with a 1-year post-OKT3 graft survival of 87.5%.

Evaluation of pathologic criteria for acute renal allograft rejection: reproducibility, sensitivity, and clinical correlation.

This study was designed to evaluate the pathologic criteria used for acute renal allograft rejection that were developed by a panel of renal pathologists participating in the Cooperative Clinical Trials in Transplantation, a National Institutes of Health-supported, multicenter research group. The panel defined three categories of acute rejection. (1) Type I: mononuclear infiltrate in > or =5% of cortex, a total of at least three tubules with tubulitis in 10 consecutive high-power fields from the most severely affected areas, and at least two of the three following features: edema, activated lymphocytes, or tubular injury. (2) Type II: arterial, or arteriolar, endothelialitis with or without the preceding features. (3) Type III: arterial fibrinoid necrosis or transmural inflammation with or without thrombosis, parenchymal necrosis, or hemorrhage. Using these criteria, and without any knowledge of the clinical course or original diagnosis, a rotating panel of three pathologists agreed with the original study pathologist's diagnosis of the presence or absence of rejection in 259 of the 286 biopsies (91%) used for this analysis (kappa = 0.80). The sensitivity to establish the diagnosis of rejection was 91% for a single core and 99% for two cores. To validate the diagnostic criteria, the thresholds for number of tubules with tubulitis and the percent infiltrate were varied, and the pathologic diagnosis was compared with the clinical course. The greatest agreement occurred with a threshold of > or =1 tubule with tubulitis and > or =5% cortex with interstitial infiltrate (91%). Clinically severe rejection episodes were correlated with the type of rejection (type I, odds ratio [OR] 6.2; type II, OR 37.9). Type II rejection was more likely to be clinically severe than type I (OR 6.1). Analysis of other individual pathologic features revealed a correlation with clinical severity for endothelialitis (OR 13.2), interstitial hemorrhage (OR 13.2), and the presence of glomerulitis (OR 3.7) (all P < 0.05). The extent of tubulitis or of the interstitial infiltrate did not correlate with severity (P > 0.05). It is concluded that these criteria are simple, reproducible, and clinically relevant. These data should lead to further refinement of the diagnostic systems for renal allograft rejection.

Rescue therapy with tacrolimus after combined kidney/pancreas and isolated pancreas transplantation in patients with severe cyclosporine nephrotoxicity.

This study details 11 pancreas transplant recipients (10 combined kidney and pancreas and 1 pancreas after kidney) who were converted to tacrolimus (FK506) due to acute severe cyclosporine nephrotoxicity in 8 cases and persistent rejection with cyclosporine toxicity in three cases. Arteriolopathy was documented by renal histology in all cases. Cyclosporine was discontinued for 24 hr immediately prior to initiation of tacrolimus. Tacrolimus was started orally at 0.1 mg/kg twice daily with dose adjustments to maintain whole blood trough levels of 8-15 ng/mL by IMx. Tacrolimus was initiated a mean of 14.5 months (range 1-81) after pancreas transplantation. The mean serum creatinine level had increased to 2.9 mg/dl from 1.0 mg/dl at the diagnosis of cyclosporine arteriolopathy (P=0.003). The mean serum creatinine and blood glucose levels at the time of initiation of tacrolimus were 2.1 mg/dl and 104 mg/dl, respectively. Serum creatinine was 1.7 mg/dl, 1.9 mg/dl, 1.8 mg/dl, and 1.7 mg/dl after 1, 2, 3, and 6 months of tacrolimus therapy, respectively; ANOVA (P = 0.02). The corresponding blood glucose levels were 117 mg/dl, 112 mg/dl, 109 mg/dl, and 116 mg/dl, respectively (P=NS). Normal C-peptide levels were present before (5.9 ng/ml) and after (6.2 ng/ml), the initiation of tacrolimus therapy (P=NS), and mean HbA1C was 6.1% before and 6.3% after tacrolimus therapy, (P=NS). There were 4 episodes of acute rejection, 3 responded to intravenous methylprednisolone, and 1 required OKT3 during tacrolimus therapy. Reversible tacrolimus nephrotoxicity was noted in three patients without any evidence of progressive vasculopathy. All 11 patients are alive, and 10/11 kidney and pancreas grafts are functioning with a mean follow-up of 7.7 months (range 5-10). In this study, conversion from cyclosporine to tacrolimus in kidney and pancreas recipients resulted in improvement and stabilization of renal function while maintaining stable blood glucose, C peptide, and HbA1C levels.

Granulomatous interstitial nephritis.

Granulomatous interstitial nephritis is a rare condition whose pathogenesis is poorly understood. Of 203 renal biopsies performed between 1974 to 1994 in which interstitial nephritis was the predominant change, granulomata occurred in 12. The authors reviewed the records of these patients and performed immunopathologic and immunohistochemical studies in their biopsies to characterize the phenotype of infiltrating cells. The authors used markers for T cells, B cells, and macrophages, and determined whether they were activated through assessment of upregulation of HLA-DR molecules. Additionally, the authors attempted to delineate whether or not tubules contributed to giant cell formation through assessment of intermediate filament for keratins and macrophage markers in epithelioid cells. Drug (aspirin, gentamycin, or combination of drugs), infection (Echerichia coli or various organisms), and sarcoidosis accounted for granulomatous inflammation in three patients each, Wegener's granulomatosis and oxalosis resulting from intestinal bypass in one patient each, and in one patient the possible cause could not be determined. Except for biopsies of granulomatous inflammation resulting from infection, in which neutrophils predominated, in all other biopsies, T cells and macrophages made up most of the inflammatory cell infiltrate. HLA-DR was upregulated in mononuclear cells infiltrating the interstitium and was expressed in proximal tubular cells and endothelial cells in all but biopsies of patients with sarcoidosis. In no instance was there evidence that tubules contributed epithelial cells to giant cell formation. These findings are consistent with the notion that granulomatous interstitial nephritis is a cell-mediated form of tissue injury in which T cell-macrophage seem to play a major role.

Evolution of renal injury in a chronic model of IgA immune-complex-associated nephropathy.

BACKGROUND: IgA nephropathy (IgAN) is characterized by intense and diffuse IgA mesangial deposits, a variety of histopathological changes and unpredictable clinical course. To elucidate the cause of the discrepancy between the unvariable IgA deposition and the histological picture, we examined the short- and long-term influence of glomerular IgA immune complexes (IgA-IC) on the progression of renal lesions in experimental IgAN. METHODS: IgA-IC renal deposits were induced by sequential administration of IgA antiphosphorylcholine and pneumococcal C polysaccharide. Mice treated every other day by three injections (groups A) or nine injections (groups B) were sacrificed 24 h and 1, 4, or 8 weeks (groups 1-4) after cessation of treatment. RESULTS: Group A1 showed segmental glomerular necrosis and thrombosis. Lesions then converted to segmental mesangial proliferation (A2), more pronounced in A3 and minimal in A4. Group B1 showed severe proliferative glomerulonephritis and segmental necrosis. The pattern altered to mesangial expansion with glomerular/interstitial infiltration in B2, milder features in B3 and residual mesangial proliferation in B4. Proteinuria increased progressively during treatment reaching its maximum in group B1, but it returned to near normal levels in group B4. The development of proteinuria paralleled glomerular/interstitial T cell infiltration. CONCLUSIONS: These findings demonstrate that renal histopathological alterations observed in experimental IgA nephropathy are sustainable only by continuous deposition of nephritogenic IgA-IC.

Enhancement of renal disease in BXSB lupus prone mice after prior exposure to bacterial lipopolysaccharide.

The mechanism, or mechanisms, responsible for enhancement of renal disease after episodes of infection are poorly understood. We used the BXSB mouse as a lupus model of autoimmune disease and we used bacterial lipopolysaccharide (LPS) as a surrogate infectious agent to gain some insight into the mechanism by which infections promote enhancement of autoimmune disease to chronicity. BXSB mice were exposed to LPS for 5 weeks, LPS was withdrawn and various tests and measurements were performed 6 weeks thereafter. Matched BXSB mice exposed to vehicle injections for 5 weeks served as controls. We verified that previous exposure to LPS enhances polyclonal B cell activation, impairs carrier function of blood cells for immune complexes, increases deposition of immune complexes in the microcirculation and promotes glomerular inflammation and sclerosis. These changes occurred at 6 weeks after withdrawal of LPS in the presence of unimpaired function of mononuclear phagocytes. Some of the effects of LPS are reversible, others are partially so and others are irreversible. Altered immune functions elicited by prior exposure to LPS can result in enhanced involvement of various renal compartments and can result in renal insufficiency.

Long-lasting effects of bacterial lipopolysaccharide promote progression of lupus nephritis in NZB/W mice.

Lupus prone NZB/W mice repeatedly exposed to bacterial lipopolysaccharide (LPS) develop enhanced polyclonal B cell activation and exacerbated nephritis by a mechanism that results in increased deposits of immunoreactants in kidneys without measurable impairment of mononuclear phagocyte function. In this paper, we investigate whether the referenced effects of LPS are reversible after withdrawal of LPS, or whether their persistence could contribute to progression of nephritis to chronicity. In NZB/W mice previously exposed to LPS, features of enhanced polyclonal B cell activation, more severe glomerulonephritis with tubulointerstitial involvement, increased deposits of immunoreactants in glomeruli, and altered protein excretion persisted 6 weeks after LPS was discontinued. Additionally, mononuclear phagocyte function, assessed through liver uptake of radiolabeled immune complexes, was found to be impaired. The results indicate that some of the effects of prior exposure to LPS may be partially reversible; however, they last long after LPS has been discontinued, and additional impairment of immune function develops together with permanent glomerular dysfunction, thereby contributing to progression of nephritis to chronicity.