Angiotensin II receptor agonist antibodies are associated with microvascular damage in lupus nephritis.

Angiotensin II type 1 receptor agonist antibodies (AT1R-AAs) have been associated with hypertension, atherosclerosis and vascular inflammation in human diseases. The aim of the study was to evaluate the prevalence of AT1R-AAs in active lupus nephritis (LN) patients and their association with vascular damage. One hundred and seven active LN patients underwent a complete clinical examination, measurement of AT1R-AAs, ambulatory blood pressure monitoring, carotid intima-media thickness measurement and morphometric analysis of subintimal fibrosis and medial hyperplasia of the vessels in the kidney tissue. Plasma AT1R-AAs were positive in 58 (54.2%) patients. The Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K) score, complement C3 and C4 levels and titers of anti-dsDNA antibodies were higher in the group with positive AT1R-AAs compared with those with negative AT1R-AAs. The AT1R-AA titers correlated with anti-dsDNA antibody titers and with complement C3 and C4 serum levels. In the kidney biopsy, the percentage of subintimal fibrosis and the area of medial hyperplasia were greater in the AT1R-AA-positive patients. No differences in arterial pressure, carotid intima-media thickness and response to therapy were detected. In conclusion, AT1R-AAs are prevalent in active LN patients and are associated with histologic features of microvascular damage.

Tissue talks: immunophenotype of cells infiltrating the graft explains histological findings and the benefits of belatacept at 10 years.

Previously, we found a substantial number of regulatory T cells (Tregs ) and fewer senescent and T helper type 17 (Th17) and a decrease in interstitial fibrosis (IF) in 12-month graft biopsies in belatacept versus cyclosporin (CNI)-treated patients [Belatacept Evaluation of Nephroprotection and Efficacy as First-line Immunosuppression Trial (BENEFIT) study]. Seven years after kidney transplantation (KT), mean estimated glomerular filtration rate (eGFR), patient and graft survival were significantly higher with belatacept versus CNI treatment. The aim of this study was to determine whether the immunophenotypes of inflammatory and regulatory cell subsets infiltrating the grafts contribute to the BENEFIT's clinical findings a decade after KT. Twenty-three adult patients with functionally stable KT treated with belatacept and 10 treated with CNI were enrolled. Biopsies were analyzed by histomorphometry and immunohistochemistry for proliferation, senescence, apoptosis, inflammatory and regulatory cell markers in a blinded manner. Significantly lower percentages of inflammatory/fibrogenic cells [interleukin (IL)-22+ /Th17/Th2/M1 macrophages] were observed in patients treated with belatacept than in patients treated with CNI. By contrast, remarkably higher percentages of regulatory cells [Tregs /Bregs / plasmacytoid dendritic regulatory cells (pDCregs )/M2] were found in belatacept-treated patients than in CNI-treated patients. Conspicuously lower percentages of apoptosis and senescence and higher proliferation markers were found in belatacept-treated patients than in CNI-treated patients. Consequently, there was significantly more inflammation in the microvascular compartments as well as increased tubular atrophy and IF in CNI-treated patients. These findings strongly suggest that regulatory mechanisms, along with the absence of deleterious effects of CNI, contribute to the long-term graft histology and function stability in patients treated with belatacept.

Prognostic significance of renal vascular pathology in lupus nephritis.

We performed a retrospective cohort analysis to define the prognostic significance of vascular lesions documented in renal biopsies of lupus nephritis patients. A total of 429 patients were segregated into five groups: (1) no vascular lesions (NVL), (2) arterial sclerosis (AS), (3) non-inflammatory necrotizing vasculitis (NNV), (4) thrombotic microangiopathy (TMA), and (5) true renal vasculitis (TRV). Renal outcomes were analyzed by Cox regression models, and correlations between vascular lesions and activity/chronicity scores were determined by Spearman's coefficients. A total of 200 (46.6%) had NVL, 189 (44.0%) AS, six NNV (1.4%), 23 (5.4%) TMA, and 11 (2.6%) TRV. Patients with NVL were younger, with higher renal function; patients with TMA and TRV had lower renal function and higher arterial pressure at baseline. Antiphospholipid syndrome and positive lupus anticoagulant were more frequently observed in the TMA group. Five-year renal survival was 83% for NVL, 63% for AS, 67% for NNV, 31% for TMA, and 33% for TRV. NNV and TRV were significantly correlated with activity scores, while AS and chronic TMA were correlated with chronicity scores. Renal vascular lesions are associated with renal outcomes but do not behave as independent factors. The addition of vascular lesions to currently used scores should be further explored.

Renal flare prediction and prognosis in lupus nephritis Hispanic patients.

We performed a retrospective cohort analysis focusing on lupus nephritis renal flare incidence and outcome predictors. One hundred and eighteen patients with biopsy-proven lupus nephritis were segregated by induction/maintenance regimes. The primary outcome was the proportion of patients experiencing renal flare. Secondary assessment included doubling of serum creatinine and development of end-stage renal disease. After a median follow-up of 31 months (interquartile range 21-46) from the date of response to induction therapy, 47 patients (39.8%) developed a renal flare. Azathioprine-maintained patients had a higher risk of renal flare compared with mycophenolate mofetil-maintained patients (hazard ratio 2.53, 95% confidence interval 1.39-4.59, p < 0.01). Age (hazard ratio 0.96, 0.92-0.99, p = 0.03), serum creatinine at presentation (hazard ratio 1.76, 1.13-2.76, p = 0.01), complete remission after induction therapy (hazard ratio 0.28, 0.14-0.56, p < 0.001) and azathioprine maintenance therapy (hazard ratio 4.78, 2.16-10.6, p < 0.001) were associated with renal flare on multivariate analysis. Ten patients progressed to end-stage renal disease (8.5%) by a median 32.5 months. Age (hazard ratio 0.88, 0.77-0.99, p = 0.05), complete remission after induction therapy (hazard ratio 0.08, 0.01-0.94, p = 0.04) and severe nephritic flare (hazard ratio 13.6, 1.72-107.7, p = 0.01) were associated with end-stage renal disease development. Azathioprine maintenance therapy is associated with a higher incidence of relapse in the Mexican-mestizo population. Younger age and nephritic flares predict development of end-stage renal disease.

Fever, haematuria, and acute graft dysfunction in renal transplant recipients secondary to adenovirus infection: two case reports.

We report two cases of adenoviral infection in kidney transplant recipients that presented with different clinical characteristics under similar demographic and posttransplant conditions. The first case presented with fever, gross haematuria, and acute graft dysfunction 15 days following renal transplantation. A graft biopsy, analyzed with immunohistochemistry, yielded negative results. However, the diagnosis was confirmed with blood and urine real-time PCR for adenovirus 3 days after the initial clinical manifestations. The immunosuppression dose was reduced, and ribavirin treatment was started, for which the patient quickly developed toxicity. Antiviral treatment allowed for transient response; however, a relapse occurred. The viral real-time PCR became negative upon immunosuppression reduction and administration of IVIG; graft function normalized. In the second case, the patient presented with fever and dysuria 1 month after transplantation. The initial imaging studies revealed graft enlargement and areas of hypoperfusion. In this case, the diagnosis was also confirmed with blood and urine real-time PCR for adenovirus 3 days after the initial clinical manifestations. Adenoviral nephritis was confirmed through a graft biopsy analyzed with light microscopy, immunohistochemistry, and PCR in frozen tissue. The immunosuppression dose was reduced, and IVIG was administered obtaining excellent clinical results along with a negative real-time PCR.

High levels of IDO-expressing CD16+ peripheral cells, and Tregs in graft biopsies from kidney transplant recipients under belatacept treatment.

BACKGROUND: Indoleamine 2,3-dioxygenase (IDO) is a tryptophan-degrading enzyme that suppresses T-lymphocyte activity. Costimulation blockade through CTLA4lg increases IDO in antigen-presenting cells. The suppressive effect of IDO is thought to be mediated by Foxp3+CD4+CD25+ regulatory T-cells (Tregs). OBJECTIVE: In this descriptive study, we evaluated the percentage of IDO-expressing peripheral cell subpopulations as well as Tregs in 27 stable kidney transplant recipients receiving either belatacept (LEA29Y), a daughter compound of abatacept (CTLA4lg; n = 19) or cyclosporine (n = 8). METHODS: Blood samples were obtained at 24 ± 2 months (belatacept) and 23 ± 6 months (cyclosporine) of treatment. Intracellular IDO was analyzed by flow cytometry in CD14+, CD11c+, CD16+, CD56+, and CD8+ cell subpopulations. Tregs were assessed by intracellular Foxp3 detection in CD4+CD25+ cells. CD3+, CD4+, CD8+, CD20+, CD68+, IDO+, and Foxp3+ cells were evaluated by immunohistochemistry on graft biopsies obtained preimplantation, at 12 months posttransplant, and in subjects with dysfunction during the first 12 months. RESULTS: Only percentages of CD16+/IDO+-expressing peripheral monocytes were significantly increased among the group receiving belatacept. No differences were observed in peripheral Tregs between the groups. In contrast, higher percentages of Tregs, CD4+, CD8+, and CD68+ cells were noted in dysfunction and at 12 months vs baseline among graft biopsies in subjects receiving belatacept, and also among dysfunction cohorts of belatacept vs Cyclosporine treatment. CONCLUSION: Patients receiving belatacept showed greater amounts of peripheral blood CD16+/IDO+ cells and Tregs on graft biopsies than those under cyclosporine treatment.

Risk factors for Banff borderline acute rejection in protocol biopsies and effect on renal graft function.

INTRODUCTION: The interpretation and handling of Banff borderline acute rejection observed in protocol biopsies from patients with stable renal function continues to be controversial. Our objective was to identify the risk factors for borderline acute rejection on 1-year protocol biopsies and to evaluate their effect on renal graft function after 2 years' follow-up. METHODS: We included 82 kidney transplant recipients (KTR), who underwent 1-year protocol biopsies with normal or stable graft function. All KTR had follow-up of at least 2 years posttransplantation. We formed three groups: (1) KTR with a normal biopsy, (2) KTR with borderline changes, and (3) KTR with interstitial fibrosis/tubular atrophy (IF/TA). We searched for risk factors related to borderline injury. The main outcome to evaluate was renal function at 1 month, at protocol biopsy, and 2 years posttransplant. RESULTS: The 82 patients included in this study showed no differences in immunosuppression, gender, etiology of renal failure, or percentage of panel-reactive antibodies. The risk factors associated with borderline lesions were: at least one biopsy due to allograft dysfunction and acute rejection events during the first year posttransplant (P = .011 and P = .021, respectively). Increased serum creatinine and estimated glomerular filtration rate decline were greater among the borderline lesion than the normal group, but similar to patients with IF/TA. CONCLUSION: Renal function decline was greater among borderline and IF/TA groups. However, the sum of insults, and not only the borderline injury itself, produces greater declines in renal function with greater risk for graft loss.

Collecting duct renal cell carcinoma: two different clinical stages, two different clinical outcomes.

Collecting duct carcinoma (CDC) of Bellini is a rare variant of renal cell carcinoma. It tends to be more aggressive when locally advanced or when having distant spread on diagnosis. The only favorable prognosis factor is low-stage, low-grade, with disease-free survival reported up to 5 years. We reviewed our renal cell carcinoma database and found 2 cases of CDC, namely 1 young female with locally advanced disease with supraclavicular metastasis and a dismissal prognosis, and 1 male with localized disease with 10-year disease-free survival.

Pathological disorders of the gastric mucosa surrounding carcinomas and primary lymphomas.

OBJECTIVE: Gastritis, intestinal metaplasia, atrophy, and dysplasia are disorders that frequently precede the full development of gastric adenocarcinoma. On the other hand, primary gastric lymphomas seem to arise from mucosa-associated lymphoid tissue. It is well accepted that these histological changes are caused by Helicobacter pylori infection. The objective of this study is to determine the frequency and characteristics of epithelial and lymphoid tissue disorders of the gastric mucosa surrounding primary carcinomas and lymphomas. METHODS: We studied 111 gastrectomies from patients harboring primary adenocarcinomas (30 intestinal and 30 diffuse type) and 51 gastric lymphomas. For comparative purposes, we analized 86 stomachs from patients who died of diseases other than gastric malignancies. Histopathological disorders of the gastric mucosa adjacent to primary neoplasms such as atrophy, intestinal metaplasia, and dysplasia were recorded. Lymphoid follicles were classified in two groups, with or without expansion. Expansion was characterized by increased size, irregular borders, enlarged marginal zone, and expanded germinal centers. Differences were statistically evaluated with chi2 and Fisher exact tests, odds ratio, and relative risk, with 95% CI. p values <0.05 were considered statistically significant. RESULTS: Most intestinal-type adenocarcinomas showed atrophy (76.6%) and intestinal metaplasia (86.6%) and less frequently, dysplasia (23.3%), in the surrounding gastric mucosa. Expansive lymphoid follicles were more frequent among lymphomas than in adenocarcinomas (56.8% vs 25%); however, a high percentage of lymphomas were also associated with atrophy (50.9%), intestinal metaplasia (62.7%), and rarely dysplasia (11.8%). On the contrary, diffuse-type adenocarcinoma displayed less frequently atrophy (33%), intestinal metaplasia (50%), and dysplasia (3%). Gastric mucosa from patients without any gastric neoplasia was almost normal (84%), whereas the remaining 16% showed, both or alone, atrophy and intestinal metaplasia. CONCLUSION: Histopathological disorders of the gastric mucosa are not specific for any neoplasm, but intestinal-type adenocarcinomas frequently showed atrophy, intestinal metaplasia, and not uncommonly, dysplasia of the surrounding non-neoplastic gastric mucosa. Diffuse-type adenocarcinomas did not frequently show such lesions. Primary lymphomas displayed expansive lymphoid follicles and also a high percentage of atrophy and intestinal metaplasia of the surrounding gastric mucosa. The presence of intestinal metaplasia, atrophy, and lymphoid follicles with expansion in endoscopic biopsies could suggest a higher suceptibility for the development of gastric intestinal-type adenocarcinoma or gastric lymphoma. Patients harboring such histopathological changes must receive eradication therapy against H. pylori and probably closer follow-up.

[Comparison of the usefulness of intraoperative examination and fine needle aspiration biopsy in thyroid lesions. Analysis of discordant cases in aspiration biopsy]. / Comparación de la utilidad del estudio transoperatorio y la biopsia por aspiración con aguja delgada en lesiones de tiroides. Análisis de casos discordantes en biopsias por aspiración.

INTRODUCTION: Fine-needle aspiration biopsy (FNAB) is currently considered the most reliable and cost effective examination for diagnosis of solitary thyroid nodules prior to surgery. Because of its great utility the indication of intraoperative examination (IOE) (macroscopic examination, cytology and frozen section), has recently been questioned. OBJECTIVE: To compare the accuracy of the FNAB and IOE, in those patients with nodular thyroid disease who undergo thyroidectomy. As well as to analyse the, discrepant cases by FNAB. MATERIAL AND METHODS: The results of IOE and FNAB were compared in a period of two years (1997-98) at the Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán (INCMNSZ). In all cases the diagnosis established from paraffin embedded tissue sections was considered to be the gold standard. The cytologyc smears and the histologic sections of the discrepant cases were reviewed. RESULTS: One thousand and fourteen IOE were done during two consecutive years; from these cases, 136 (13.4%) were thyroid lesions. Half of the thyroid lesions (69 cases) corresponded to carcinomas, the others were follicular adenomas (13 cases) and non-neoplasic lesions (54 cases). The analysis of the copacity to discriminate between malignant and benign diseases with IOE and FNAB demonstrated sensitivity of 89% (CI: 78.2-95.1) and 97.7% (CI: 86.8-99.9), specificity of 100% (CI: 93.1-100) and 90% (CI: 90.4-96.7). The positive predictive value of 100% and 91.6%, negative predictive value of 90.4% and 97.3%, and equal accuracy (94.6% and 94.1% respectively). When the analysis of capacity to stratify diseases was performed, IOE and FNAB showed similar percentages in all the cases, including the follicular adenomas and carcinomas. The causes of false positive and false negative cases by FNAB, reproduce what has been written in the literature. CONCLUSIONS: FNAB preoperative examination is adequate for the selection of patients that undergo thyroidectomy. Nevertheless, IOE should be done in most of the cases, and routinely in those cases with inconclusive FNAB results and in cases of follicular tumor.

[Hirschsprung disease in the adult. Report of a case]. / Enfermedad de Hirschsprung en el adulto. Informe de un caso.

OBJECTIVE: To describe a case of Hirschsprung's disease (HD) in an adult patient. BACKGROUND: HD is diagnosed in the newborn in 80 to 90% of cases. HD is rare in the adult, and usually affects an ultrashort segment of the bowel. CASE REPORT: A 49-year-old woman with a history of constipation since birth is involved. She was submitted to an abdominal laparotomy because of fecal impaction. A colostomy was performed. The diagnosis of HD affecting, the descending colon was established with manometry and histopathology. She underwent surgery, and a proctectomy and left hemicolectomy with colo-anal anastomosis was performed. CONCLUSION: Adult HD is an infrequently diagnosed entity that must be suspected in a patient with chronic, intractable constipation from infancy, evidence of megacolon, and typical manometric and histopathologic features. The short and ultrashort-segment disease are more often found in older children and adults. The differential diagnosis includes idiopathic megarectum, functional constipation, and colonic pseudo-obstruction.

[Leiomyosarcoma associated with Epstein-Barr virus in an adult with renal transplant]. / Leiomiosarcoma asociado con el virus de Epstein-Barr en un adulto con trasplante renal.

Recently the association between the Epstein-Barr virus (EBV) and smooth muscle lesions has been described in immunosuppressed children but it is infrequent in adults. The role of EBV in the pathogenesis of these lesions is obscure. We presents a 28 year old man with end stage renal disease transplanted in 1994. Two years later he developed several nodular lesions that affected both lungs, liver, spleen, retroperitoneal ganglia and the left thigh; one year later he died. The surgical specimen from the thigh and a liver biopsy were diagnosed as leiomyosarcoma. Immunohistochemical reactions against vimentin and smooth muscle actin were positive. In situ hybridization disclosed positivity against EBV nuclear antigens (EBNA-2) in neoplasic cells. This is the first case of sarcoma in transplanted patients of our institution and represents a rare case of leiomyosarcoma associated with EBV in adults.

Tall cell variant of papillary thyroid carcinoma. A cytohistologic correlation.

OBJECTIVE: To identify the cytologic characteristics of the tall cell variant of papillary thyroid carcinoma in fine needle aspiration biopsies and make a cytohistologic correlation. STUDY DESIGN: The study group consisted of six patients subjected to fine needle aspiration biopsy of the thyroid prior to surgical resection of the tumor. RESULTS: Nineteen cases of the tall cell variant were identified in 229 cases of papillary thyroid carcinoma (8.5%) from 1957 to 1993. Six cases had aspirates with tall cells. The patients were females with a median age of 43 years, and all had aggressive neoplastic diseases. The tumors had > 30% tall cells. The fine needle aspiration biopsy findings included nuclear grooves and abundant oxyphilic cytoplasm (100%), pseudonuclear inclusions (83.3%) and ground glass chromatin (67%). The majority of neoplastic cells had a nuclear/cytoplasmic ratio of 1:2. A tadpole shape was observed in noncohesive cells, and a respiratory epithelium-like arrangement was seen in cohesive cells. CONCLUSION: Fine needle aspiration biopsy is the best method of identifying tall cells preoperatively. Nuclear and cytoplasmic changes should be added to make a firm diagnosis of the tall cell variant and to rule out columnar cell carcinoma or squamous metaplasia in goiter or usual thyroid papillary carcinoma.

[Effects of polydioxanone and silk on normal cicatrisation of surgically injured myocardial tissue. An experimental model]. / Effecto de la polidioxanona y la seda en el proceso de cicatrización normal del tejido miocárdico lesionado quirúrgicamente. modelo experimental.

The wound healing is the principal process of tissue repair. In the heart this phenomenon is done under special circumstances, because of the constant movement of this organ. An experimental study was done in 15 dogs. By left anterolateral thoracotomy the free left ventricular wall was incised. This incision was done 1 cm long and 3 mm deep and afterwards it was repaired with silk (Group I) and with polydioxanone (Group II). The wound was allowed to heal during 5 weeks, then the scar area was analyzed by light microscope with Masson and HE technics. The results showed the presence of lymphocytes in the scar tissue of group II (p = 0.04).

[Clear-cell eccrine carcinoma of the plantar region. Follow-up of a case using histochemistry, immunohistochemistry, and flow cytometry]. / Carcinoma ecrino de células claras en región plantar. Seguimiento de un caso por histoquímica, immunohistoquímica y citometría de flujo.

Clear cell eccrine carcinomas of the skin are rare and have been reported with several names. Of the 47 cases found in the literature, only one had the lesion in the sole. The present case is a 38 year old woman with an 18 year history of a 3.2 cm lesion in the lateral portion of the sole in the right foot. The patient developed inguinal metastases four and five months after the plantar resection, and suffered a local recurrence on two occasions. The histopathologic analysis of the sole lesion showed a neoplasm with more than 80% of clear cells, and less clear cells in the metastatic and recurrent lesions. Clear cells showed diffuse positivity to PAS with diastase lability. PAS reactivity was related to the presence of clear cells. Focal reactivity of mucin and colloidal iron in sebaceous-like cells and tubular structures was seen. Also, we found diffuse cytoplasmic and membrane surface positivity of epithelial membrane antigen in the clear cells, and focal in poroid and sebaceous cells and in tubular structures. The carcinoembryonic antigen showed a focal positivity in poroid and sebaceous cells and in tubular structures. We also identified focal positivity of S-100 protein in the sebaceous-like cells. Cytophotometric measurement of the nuclear DNA showed euploid cells in the primary and metastatic lesions. We conclude that clear cell eccrine carcinomas comprise a heterogeneous group of lesions with variable biological behavior, but with morphological, histochemical and immunohistochemical markers useful in their diagnosis.

[A case of angiosarcoma of the pelvis associated with angiomatosis of the spine]. / Caso de angiosarcoma de pelvis asociado a angiomatosis de columna.

Primary angiosarcoma of the bone is an infrequent lesion and it is seldom associated with other bone lesions, i.e. only two cases have been informed related with skeletal angiomatosis. We present the case of a 62 year old woman who complained of a gluteal tumor and disability to walk 11 months before death. In the autopsy an angiosarcoma originated from the bones of the pelvis was found. It eroded and destroyed the iliac bone and acetabulum, and extended to the soft tissues of the gluteal region and the retroperitoneum, with renal capsule metastases. Angiomatosis of the vertebral bodies was identified.