We compared protection of mycophenolate mofetil (MMF) and azathioprine (AZA) against acute cellular rejection (ACR) and chronic allograft nephropathy (CAN) in kidney transplant recipients on ...steroid-free, low-dose cyclosporine (CsA) microemulsion maintenance immunosuppression. ATHENA, a pragmatic, prospective, multicenter trial conducted by 6 Italian transplant centers, compared the outcomes of 233 consenting recipients of a first deceased donor kidney transplant induced with low-dose thymoglobulin and basiliximab and randomized to MMF (750 mg twice/day, n = 119) or AZA (75 to 125 mg/day, n = 114) added-on maintenance low-dose CsA microemulsion and 1-week steroid. In patients without acute clinical or subclinical rejections, CsA dose was progressively halved. Primary endpoint was biopsy-proven CAN. Analysis was by intention to treat. Chronicity scores other than CAN predict long-term graft outcome. Study limitations include small sample size and unblinded design. In this study, we found that in deceased donor kidney transplant recipients on low-dose CsA and no steroids, MMF had no significant benefits over AZA. This finding suggests that AZA, due to its lower costs, could safely replace MMF in combination with minimized immunosuppression.
Apolipoprotein A-I is the main protein of high-density lipoprotein particles, and is encoded by the APOA1 gene. Several APOA1 mutations have been found, either affecting the lecithin:cholesterol ...acyltransferase activity, determining familial HDL deficiency, or resulting in amyloid formation with prevalent deposits in the kidney and liver. Evaluation of familial tubulointerstitial nephritis in patients with the Leu75Pro APOA-I amyloidosis mutation resulted in the identification of 253 carriers belonging to 50 families from Brescia, Italy. A total of 219 mutation carriers underwent clinical, laboratory, and instrumental tests. Of these, 62% had renal, hepatic, and testicular disease; 38% were asymptomatic. The disease showed an age-dependent penetrance. Tubulointerstitial nephritis was diagnosed in 49% of the carriers, 13% of whom progressed to kidney failure requiring dialysis. Hepatic involvement with elevation of cholestasis indices was diagnosed in 30% of the carriers, 38% of whom developed portal hypertension. Impaired spermatogenesis and hypogonadism was found in 68% of male carriers. The cholesterol levels were lower than normal in 80% of the mutation carriers. Thus, tubulointerstitial nephritis was highly prevalent in this large series of patients with Leu75Pro apoA-I amyloidosis. Persistent elevation of alkaline phosphatase, reduced HDL cholesterol plasma levels, and hypogonadism in men are key diagnostic features of this form of amyloidosis.
We evaluated the usefulness of the tight-junction associated protein Claudin 4 (CL-4) in the diagnosis of mesothelioma and mimickers, analyzing biopsies from 454 tumors, including 82 mesotheliomas, ...336 carcinomas of different origin (278 primary, 58 metastatic to serosae), 36 nonepithelial spindle cell neoplasms, as well as 97 cytological samples from reactive effusions (12), mesothelioma (23) and metastatic carcinomas (62). CL-4 was consistently negative in normal and reactive mesothelium, as well as in all 82 mesotheliomas. In contrast, strong reactivity was found in 57/58 serosal metastasis, and in 245/278 primary carcinomas, with uppermost expression (150/153) in those most frequently involved in the differential with mesothelioma (lung, breast, gastrointestinal tract, pancreas, ovary, primary serous papillary carcinoma of peritoneum). On effusions, reactive and neoplastic mesothelial cells were regularly negative, while metastatic tumor cells stained positively in 60/62 (96.8%) cases. Among spindle cell neoplasms, only 2/9 biphasic synovial sarcomas and 4/4 follicular dendritic cell sarcomas stained positively. Results indicate that CL-4 reacts with the majority of epithelial neoplasms that often metastasize to serous membranes, representing a pancarcinoma marker with extremely high sensitivity and specificity. CL-4 may be considered a primary immunohistochemical reagent to rule out the diagnosis of mesothelioma.
Abstract Recent evidences suggest a significant role of Plasmacytoid dendritic cells (PDC) role in the pathogenesis of lupus erythematosus (LE) via production of type I IFN. Taking advantage on the ...availability of multiple reagents (CD123, BDCA2, and CD2ap) specifically recognizing PDC on fixed tissues, we investigated the occurrence of PDC in a cohort of 74 LE patients. The large majority of LE biopsies (67/74; 90.5%) showed cutaneous infiltration of PDC. PDC were more frequently observed (96.4 vs 72.2) and numerous in cutaneous LE compared to systemic LE (SLE) and correlated with the density of the inflammatory infiltrate ( r =0.40; p <0.001). PDC reduction in SLE might be related to a broader tissue distribution of this cellular population, as indicated by their occurrence in kidneys in 11 out of 24 (45.8%) cases studied. The distribution of cutaneous PDC showed two distinct patterns. More commonly, PDC were observed within perivascular inflammatory nodules in the dermis, associated with CD208+ mature DC and T-bet+ cells D-PDC. A second component was observed along the dermal-epithelial junction J-PDC, in association with cytotoxic T-cells in areas of severe epithelial damage. Notably, chemerin reactivity was observed in 64% of LE biopsies on endothelial cells and in the granular layer keratinocytes. Cutaneous PDC in LE strongly produced type I IFN, as indicated by the diffuse MxA expression, and the cytotoxic molecule granzyme B. This study confirms cutaneous PDC infiltration as hallmark of LE. The topographical segregation in D-PDC and J-PDC suggests a novel view of the role of these cells in skin autoimmunity.
Abstract Purpose The surface, intermediate, and basis (SIB) is a system based on surgeon׳s visual assessment of the thickness of healthy parenchyma remaining on the intrarenal portion of the tumor. ...This system has been proposed to standardize the nomenclature of the resection technique (RT) during partial nephrectomy (PN). Our study aims at evaluating whether the SIB score visually assigned is related to the thickness of parenchyma measured by microscopy. Materials and methods Data of 52 patients submitted to PN from April to October 2015 were perspectively collected. All the excisions were performed following a “nonanatomical” strategy according to our institutional intention to resect the tumor with a visible margin of parenchyma. After the removal of the specimen, 2 trained examiners applied the SIB system: the intrarenal portion of the nodule was ideally divided into 3 circumferential sectors (surface, intermediate, and basis); on each of these was identified the area covered by the lowest amount of parenchyma (score specific area SSA); and a score descriptive of the thickness of parenchyma was assigned to each area. The RT performed (enucleation, enucleoresection, or wedge resection) was defined by the sum of the scores. The same examiners inked every SSAs with a different color and then dedicated pathologists, blinded of the scores assigned, and microscopically measured the parenchyma covering each SSA. The relationship between these values and the SIB scores was assessed. Results According to the SIB nomenclature, the technique performed was enucleation for 31 patients (60%), enucleoresection for 16 (31%), and wedge resection for 5 (9%). For the surface SSA, the median/mean values of the thickness for S = 0 vs. S = 1 was 0.35/0.84 vs. 2.00/2.26 mm and for the intermediate or base SSA, the median/mean value of the thickness for S = 0 vs. 1 vs. 2 was 0.35/0.47 vs. 1.00/1.50 vs. 2.00.5/2.33 mm. All the comparison reached statistical significance. Conclusions The visual description of the surgical plane followed during PN according to the SIB system is related to the microscopic thickness of healthy parenchyma covering the tumor. The SIB system can correctly discriminate among different R techniques, and therefore could be a crucial tool to standardize the nomenclature of PN.
Objective
To evaluate the features and the predictors of “very late” recurrences after surgery for localized renal cell carcinoma.
Methods
Since 1983, an institutional database with data of more than ...2300 consecutive patients treated for renal cancer has been prospectively maintained. Patients N0/NxM0 followed for a minimum of 10 years without recurrences were retrieved. The site, time and treatment of recurrences observed afterwards were recorded, and the predictors were investigated by Cox regression analysis.
Results
A total of 554 patients (231 women, 323 men; age 59.3 ± 11.6 years) followed for a mean/median time of 15.1/13.6 years (range 10.0–34.1 years) were analyzed. A recurrence was observed in 26 patients (4.6%) after a mean/median interval of 13.3/12.3 years (range 10.5–30.2 years). The pathological stage 2/3 was the only independent predictor of recurrence (P = 0.003), and it was related also to the latency of recurrence (mean/median latency 15.4/14.0, 11.4/10.8 and 12.5/12.0 years, respectively, for stage 1, 2 and 3; P < 0.005 for stage 1 vs stage 2 or 3). The contralateral kidney was the most frequent site of relapse in patients with stage pT1, whereas multiple sites were more frequent for stage pT2 and pT3.
Conclusions
The risk of a “very late” recurrence of renal cancer is approximately 5%, and it depends on the pathological stage. For stage pT1, the kidney/s should be surveilled for indefinite time, preferably by ultrasound to reduce the X‐ray exposition; for stage pT2 and pT3, the abdomen and the lungs should be monitored, by computed tomography scan during the first years, and then by abdominal ultrasound and chest X‐ray.
The recent discovery of mutations in the uromodulin gene (
UMOD) in patients with medullary cystic kidney disease type 2 (MCKD2), familial juvenile hyperuricemic nephropathy (FJHN), and ...glomerulocystic kidney disease (GCKD) provides the opportunity for a revision of pathogenic aspects and puts forth the basis for a renewed classification. This review focuses on clinical, pathological, and cell biology advances in
UMOD-related pathological states, including a review of the associated clinical conditions described to date in the literature. Overall, 31
UMOD mutations associated with MCKD2 and FJHN (205 patients) and 1 mutation associated with GCKD (3 patients) have been described, with a cluster at exons 4 and 5. Most are missense mutations causing a cysteine change in uromodulin sequence. No differences in clinical symptoms between carriers of cysteine versus polar residue changes have been observed; clinical phenotypes invariably are linked to classic MCKD2/FJHN. A common motif among all reports is that many overlapping symptoms between MCKD2 and FJHN are present, and a separation between these 2 entities seems unwarranted or redundant. Cell experiments with mutant variants indicated a delay in intracellular maturation and export dynamics, with consequent uromodulin storage within the endoplasmic reticulum (ER). Patchy uromodulin deposits in tubule cells were found by means of immunohistochemistry, and electron microscopy showed dense fibrillar material in the ER. Mass spectrometry showed only unmodified uromodulin in urine of patients with
UMOD mutations. Lack of uromodulin function(s) is associated with impairments in tubular function, particularly the urine-concentrating process, determining water depletion and hyperuricemia. Intracellular uromodulin trapping within the ER probably has a major role in determining tubulointerstitial fibrosis and renal failure. We propose the definition of uromodulin storage diseases for conditions with proven
UMOD mutations.
Abstract Objectives To investigate features of ipsilateral relapse (IR) after partial nephrectomy (PN) with the intention to generate a classification descriptive of the pathogenesis of the relapse. ...Materials and Methods Retrospective consultation of an institutional database that stores data of 683 patients submitted to PN since 1993. The clinical, radiological and follow-up data of the cases submitted to salvage nephrectomy due to an IR were analyzed. The slides of the sections from the tumor-parenchyma interface of PN and the bed of resection from the specimen of nephrectomy were reviewed. Results 18 patients were submitted to salvage nephrectomy for an IR. In 12 cases the IR harbored into the site of PN and a mixture of cancer cells and granulomatous reaction was found at the resection bed (IR type A). In the remaining 6, microscopy of the resection bed found only fibrosis: 3 of these cases had a clear cell RCC with diffuse microvascular embolization and the relapse in the same portion of the kidney of the primary tumor (IR type B); the other 3 had a non-clear cell RCC and the primary and relapsing tumor were located into distinct portions of the kidney (IR type C). 6 patients (4 IR type A, 2 type B) had a further progression and 5 of them deceased due to RCC. Conclusions More frequently an IR is due to the incomplete resection of the primary tumor (IR type A), in a minority of the cases to the local spread of the tumor by microvascular embolization (IR type B) or true multifocality (IR type C). The prognosis of IR not due to multifocality (type A and B) is poor, despite salvage nephrectomy.
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