Renal AA-amyloidosis in intravenous drug users - a role for HIV-infection?

Background: Chronic renal disease is a serious complication of long-term intravenous drug use (IVDU). Recent reports have postulated a changing pattern of underlying nephropathy over the last decades. Methods: Retrospective investigation including all patients with prior or present IVDU that underwent renal biopsy because of chronic kidney disease between 01.04.2002 and 31.03.2012 in the city of Frankfurt/Main, Germany. Results: Twenty four patients with IVDU underwent renal biopsy because of progressive chronic kidney disease or proteinuria. Renal AA-amyloidosis was the predominant cause of renal failure in 50% of patients. Membranoproliferative glomerulonephritis (GN) was the second most common cause found in 21%. Patients with AA-amyloidosis were more likely to be HIV infected (67 vs.17%; p=0.036) and tended to have a higher rate of repeated systemic infections (92 vs. 50%; p=0.069). Patients with AA-amyloidosis presented with progressive renal disease and nephrotic-range proteinuria but most patients had no peripheral edema or systemic hypertension. Development of proteinuria preceded the decline of GFR for approximately 1--2 years. Conclusions: AA-amyloidosis was the predominant cause of progressive renal disease in the last 10 years in patients with IVDU. The highest rate of AA-amyloidosis observed was seen in HIV infected patients with IVDU. We speculate that chronic HIV-infection as well as the associated immunosuppression might promote development of AA-amyloidosis by increasing frequency and duration of infections acquired by IVDU

Grundlagen der Nierenpathologie für Pathologen – Teil 2 : Nichtentzündliche Veränderungen

Zusammenfassung: Die Nierenbiopsiediagnostik bei medizinisch indizierten Biopsien und Nierentransplantatbiopsien wird überwiegend in Zentren mit ausgebildeten Nephropathologen betrieben. Veränderungen im nichtneoplastischen Nierenparenchym bei tumorbedingten Nephrektomien, insbesondere nichtentzündliche, ischämisch und vaskulär bedingte Veränderungen oder diabetische Nephropathie, können bei Patienten mit lokalisiertem Nierenkarzinomen und gutem tumorassoziiertem Überleben prognostisch von größerer Bedeutung sein als das Tumorleiden an sich. In diesem Teil zu den Grundlagen der Nierenpathologie für Pathologen sollen die häufigsten nichtentzündlichen Nierenerkrankungen im vaskulären, glomerulären und tubulointerstitiellen Kompartiment beleuchtet werden. Abstract: The evaluation of kidney biopsies for specific renal diseases or kidney transplant biopsies is mainly restricted to specialized centers. Lesions in nonneoplastic renal tissue in partial nephrectomies or nephrectomies due to renal tumors, especially noninflammatory, ischemic, vascular changes or diabetic nephropathy can be of greater prognostic significance than the tumor itself in patients with a localized tumor and good tumor-associated survival. In this part of basic nephropathology for pathologists, the most common noninflammatory lesions of the vascular, glomerular and tubulo-interstitial compartment are discussed

Incidental Monotypic (Fat-Poor) Renal Angiomyolipoma Diagnosed by Core Needle Biopsy

We present the case of a 55-year-old patient with a history of chemotherapy and bone marrow transplantation because of acute myeloid leukaemia. An incidental 4 × 3 cm measuring renal mass was detected while performing a magnetic resonance imaging (MRI) for lumbago. The lesion was suspected to be either a renal cell carcinoma (RCC) or a leukemic infiltration. To decide about further treatment a percutaneous core needle biopsy was performed. Histology showed a monotypic angiomyolipoma, a relatively rare benign renal lesion. Interestingly, in cross-sectional imaging, angiomyolipoma was not taken into differential diagnostic account because of lack of a fatty component. Due to bleeding after biopsy the feeding artery of the tumor was occluded by microcoils. This case demonstrates the utility of biopsy of renal tumors, in particular when small tumor-like lesions are incidentally detected to decide about the right treatment and thereby avoiding nephrectomy

Complement activation via the lectin and alternative pathway in patients with severe COVID-19

Complement plays an important role in the direct defense to pathogens, but can also activate immune cells and the release of pro-inflammatory cytokines. However, in critically ill patients with COVID-19 the immune system is inadequately activated leading to severe acute respiratory syndrome (SARS) and acute kidney injury, which is associated with higher mortality. Therefore, we characterized local complement deposition as a sign of activation in both lungs and kidneys from patients with severe COVID-19. Using immunohistochemistry we investigated deposition of complement factors C1q, MASP-2, factor D (CFD), C3c, C3d and C5b-9 as well as myeloperoxidase (MPO) positive neutrophils and SARS-CoV-2 virus particles in lungs and kidneys from 38 patients who died from COVID-19. In addition, tissue damage was analyzed using semi-quantitative scores followed by correlation with complement deposition. Autopsy material from non-COVID patients who died from cardiovascular causes, cerebral hemorrhage and pulmonary embolism served as control (n=8). Lung injury in samples from COVID-19 patients was significantly more pronounced compared to controls with formation of hyaline membranes, thrombi and edema. In addition, in the kidney tubular injury was higher in these patients and correlated with lung injury (r=0.361*). In autopsy samples SARS-CoV-2 spike protein was detected in 22% of the lungs of COVID-19 patients but was lacking in kidneys. Complement activation was significantly stronger in lung samples from patients with COVID-19 via the lectin and alternative pathway as indicated by deposition of MASP-2, CFD, C3d and C5b9. Deposits in the lung were predominantly detected along the alveolar septa, the hyaline membranes and in the alveolar lumina. In the kidney, complement was significantly more deposited in patients with COVID-19 in peritubular capillaries and tubular basement membranes. Renal COVID-19-induced complement activation occurred via the lectin pathway, while activation of the alternative pathway was similar in both groups. Furthermore, MPO-positive neutrophils were found in significantly higher numbers in lungs and kidneys of COVID-19 patients and correlated with local MASP-2 deposition. In conclusion, in patients who died from SARS-CoV-2 infection complement was activated in both lungs and kidneys indicating that complement might be involved in systemic worsening of the inflammatory response. Complement inhibition might thus be a promising treatment option to prevent deregulated activation and subsequent collateral tissue injury in COVID-19

Periodontal structures in horses with pituitary pars intermedia dysfunction: A histological evaluation

IntroductionPituitary pars intermedia dysfunction (PPID) and dental disorders are of major concern in horses older than 15 years. Although PPID in geriatric horses and dental disorders in all age groups are well described, a connection between this endocrine disease and pathological changes in equine dental structures has not yet been investigated. In humans, periodontitis is considered to be a complication of systemic diseases like diabetes mellitus type 2, obesity and various conditions leading to an impaired immune response. In PPID, cross links to insulin and immune dysregulations are proven. The aim of this study was to compare histological findings of the gingiva and the sub gingival periodontal ligament of PPID affected horses with control horses.MethodsIn a case-control morphometric descriptive study, 145 dental locations of 10 PPID affected horses (27.3 ± 2.06 years) were compared with 147 dental locations of 10 controls (21.4 ± 4.12 years). Histological parameters were leukocyte infiltration, keratinization of gingival epithelium, blood vessel supply of the periodontium and structure of cementum.ResultsThe distribution and localization of gingival leukocyte infiltrations (LI) in PPID affected horses was more often multifocal to coalescing (p = 0.002) and reached into deeper parts of the periodontium, sometimes down to the sub gingival periodontal ligament (PDL). Aged animals of both groups showed higher prevalence (PPID: OR 1.66; controls: OR 1.15) for severe leukocyte infiltration in the PDL. PPID was not significantly associated with increased LI. The cementum bordering the soft tissue in interdental locations showed four times more irregularities in PPID affected horses than in controls which predisposes for interdental food impaction and periodontal diseases.DiscussionIn summary, multifocal to coalescing leukocytes and irregular cementum are seen more often in PPID than in controls - however our findings mainly reflect an association of older age with periodontal disease

Filariasis of the Axilla in a Patient Returning from Travel Abroad: A Case Report

Background: The term filariasis comprises a group of parasitic infections caused by helminths belonging to different genera in the superfamily Filaroidea. The human parasites occur mainly in tropical and subtropical regions, but filariae are also found in temperate climates, where they can infect wild and domestic animals. Humans are rarely infected by these zoonotic parasites. Patients and Methods: A 55-year-old patient presented with a new-onset, subcutaneous, non-tender palpable mass in the right axilla. Ultrasonography showed a 1.3-cm, solid, singular encapsulated node. Sonography of the breast on both sides, axilla and lymphatic drainage on the left side, lymphatic drainage on the right side, and mammography on both sides were without pathological findings. The node was excised under local anesthesia as the patient refused minimal invasive biopsy. Results: On histopathological examination, the tail of a parasite of the group of filariae was found. The patient revealed that she had stayed in Africa and Malaysia for professional reasons. 6 months before the time of diagnosis, she had also suffered from a fever and poor general condition after a trip abroad. The patient was referred for further treatment to the Institute for Tropical Medicine at the University of Dusseldorf, where a treatment with ivermectin was conducted on the basis of positive staining with antibodies against filariae. Conclusion: Our case demonstrates the importance of interdisciplinary collaboration between breast center, pathology, and other specialties such as microbiology and tropical medicine

Multiplex gene analysis reveals T-cell and antibody-mediated rejection-specific upregulation of complement in renal transplants

In renal transplantation, complement is involved in ischemia reperfusion injury, graft rejection and dysfunction. However, it is still unclear how induction of complement and its activation are initiated. Using allograft biopsies of a well-characterized cohort of 28 renal transplant patients with no rejection (Ctrl), delayed graft function (DGF), acute T-cell-mediated (TCMR) or antibody-mediated rejection (ABMR) we analyzed differences in complement reaction. For that mRNA was isolated from FFPE sections, quantified with a multiplex gene expression panel and correlated with transplant conditions and follow-up of patients. Additionally, inflammatory cells were quantified by multiplex immunohistochemistry. In allograft biopsies with TCMR and ABMR gene expression of C1QB was 2-4 fold elevated compared to Ctrl. In TCMR biopsies, mRNA counts of several complement-related genes including C1S, C3, CFB and complement regulators CFH, CR1 and SERPING1 were significantly increased compared to Ctrl. Interestingly, expression levels of about 75% of the analyzed complement related genes correlated with cold ischemia time (CIT) and markers of inflammation. In conclusion, this study suggest an important role of complement in transplant pathology which seems to be at least in part triggered by CIT. Multiplex mRNA analysis might be a useful method to refine diagnosis and explore new pathways involved in rejection

Is Early Complement Activation in Renal Transplantation Associated with Later Graft Outcome?

Background/Aims: Complement activation is important in post-transplantation renal injury, but data on its role as predictor of transplant outcome/complications when assessed in donor kidneys are lacking. Methods: In human renal transplant biopsies with delayed graft function (DGF, n=12), antibody mediated rejection (ABMR, n=8), T-cell mediated rejection (TCMR, n=11), 1 year protocol biopsies (control, n=10) and corresponding zero-biopsies we performed immunohistochemical analyses of 6 complement factors using FFPE sections and correlated the findings with kidney function, as assessed by serum creatinine, and morphological changes including interstitial fibrosis and tubular atrophy (IF/TA). Results: In DGF, TCMR and ABMR significant complement deposition was observed, which was less pronounced in corresponding zero-biopsies. Zero-biopsies with subsequent ABMR showed glomerular complement factor D and C3c expression. Moreover, glomerular C3c and C9 and tubular MASP-2 and Collectin-11 expression in zero-biopsies significantly correlated with serum creatinine at diagnosis of DGF, TCMR or ABMR. Glomerular C1q was significantly increased in ABMR, but not in DGF and TCMR. In contrast, peritubular C1q was significantly enhanced in DGF and TCMR compared to zero-biopsies. Using C3d as a surrogate marker for complement activity we could confirm that stained complement factors are frequently associated with complement activity. Conclusion: Complement deposition strongly correlated with histopathological changes observed in renal transplants. All 3 complement pathways were operational in biopsies with DGF, TCMR and ABMR albeit with differential abundance and localization. Since complement deposition in zero-biopsies correlated with graft function and morphological changes, early specific complement inhibition in renal transplantation may be a new therapeutic option to prevent graft loss