Role of Glomerular Proteoglycans in IgA Nephropathy

Mesangial matrix expansion is a prominent feature of the most common form of glomerulonephritis, IgA nephropathy (IgAN). To find molecular markers and improve the understanding of the disease, the gene and protein expression of proteoglycans were investigated in biopsies from IgAN patients and correlated to clinical and morphological data. We collected and microdissected renal biopsies from IgAN patients (n = 19) and from healthy kidney donors (n = 14). Patients were followed for an average time of 4 years and blood pressure was according to target guidelines. Distinct patterns of gene expression were seen in glomerular and tubulo-interstitial cells. Three of the proteoglycans investigated were found to be of special interest and upregulated in glomeruli: perlecan, decorin and biglycan. Perlecan gene expression negatively correlated to albumin excretion and progress of the disease. Abundant decorin protein expression was found in sclerotic glomeruli, but not in unaffected glomeruli from IgAN patients or in controls. Transforming growth factor beta (TGF-β), known to interact with perlecan, decorin and biglycan, were upregulated both on gene and protein level in the glomeruli. This study provides further insight into the molecular mechanisms involved in mesangial matrix expansion in IgAN. We conclude that perlecan is a possible prognostic marker for patients with IgAN. In addition, the up-regulation of biglycan and decorin, as well as TGF-β itself, indicate that regulation of TGF-β, and other profibrotic markers plays a role in IgAN pathology

Successful Treatment of AA Amyloidosis in Ankylosing Spondylitis Using Tocilizumab : Report of Two Cases and Review of the Literature

Historically, secondary amyloidosis has been a feared complication of chronic inflammatory conditions. The fibril protein AA derives from the acute phase reactant serum amyloid A (SAA). Long-term elevation of SAA levels remains a major risk factor for the development of AA amyloidosis in rheumatic diseases, and the prognosis may be unpredictable. Nowadays, with increased availability of effective biological agents, the incidence of AA amyloidosis seems to be declining. Still, genetically predisposed subjects with slowly progressive disease and mild symptoms combined with ongoing systemic inflammation may be at risk. Interleukin-6 (IL-6) is one of the drivers of SAA release and effectiveness of the humanized anti-IL-6 receptor antibody tocilizumab (TCZ) for the treatment of AA amyloidosis has been observed in some rheumatic conditions. Herein, we report two male subjects with longstanding ankylosing spondylitis (AS) complicated by renal amyloidosis who received TCZ with rapid and beneficial effects regarding inflammation and proteinuria. To the best of our knowledge, the use of TCZ in AS patients with this extra-articular manifestation has not previously been described. The paper includes histopathology, clinical follow-up, and longitudinal data of the two cases along with a comprehensive review of relevant literature. Mechanisms behind amyloid-mediated tissue damage and organ dysfunction are discussed. Altogether, our data highlight that blocking IL-6 signaling may represent a promising therapeutic option in patients with renal AA amyloidosis.Funding Agencies|King Gustaf V and Queen Victorias Freemasons Foundation; Region Ostergotland (ALF grants); Swedish Rheumatism Association</p

Histological diagnosis from kidney transplant biopsy can contribute to prediction of graft survival

Aim: The primary aim of this study was to in depth examine if the histological findings in a transplanted kidney biopsy can predict the prognosis for the graft and the patient. The secondary aim was to extend knowledge of the impact of time elapsed on biopsy findings. Methods: Data from 1462 patients were merged from a kidney transplantation registry and a biopsy registry during 1 January 2007 and 30 September 2017. Kaplan–Meier analysis and multivariate Cox-regression analysis were performed and hazard ratios (HR) with 95% confidence intervals (CI) were presented. Results: Compared to normal biopsy findings, graft survival after biopsy (gsaBiopsy) was shorter for patients with glomerular diseases (HR 8.2, CI:3.2–21.1), rejections (HR 4.2, CI:1.7–10.3), chronic changes including IFTA (HR 3.2, CI:1.3–8.0), acute tubular injuries (HR 3.0, CI:1.2–7.8), and borderline changes (HR 2.9, CI:1.1–7.6). Sub-analysis of rejections showed shorter gsaBiopsy for chronic TCMR (HR 4.7, CI:1.9–11.3), active ABMR (HR 3.6, CI:1.7–7.7) and chronic ABMR (HR 3.5, CI:2.0–6.0). Patients with TCMR Banff grade II (HR 0.35, CI:0.20–0.63) and grade I (HR 0.52, CI:0.29–0.93) had a better gsaBiopsy compared to all other types of rejections. Conclusion: Shorter gsaBiopsy was noted in kidneys with glomerular diseases, rejections, acute tubular injuries and borderline changes. TCMR Banff rejections grade I and II were associated with a better prognosis

Low-level exposure to lead, cadmium and mercury, and histopathological findings in kidney biopsies

Background: Lead (Pb), cadmium (Cd) and mercury (Hg) are all nephrotoxic metals, and a large part of the body burden of Cd and Hg is found in the kidneys. There are, however, few studies on associations between exposure to these toxic metals and renal biopsy findings, and none at low-level exposure. Aim: To examine the hypothesis that low-level concentration of Pb, Cd or Hg in the kidneys is associated with histopathological changes in the kidneys. Methods: We determined concentrations of Pb, Cd and Hg in kidney, blood and urine in 109 healthy kidney donors, aged 24–70 years. The renal biopsies were scored according to the Banff classification regarding tubular atrophy, interstitial fibrosis, glomerulosclerosis, arteriosclerosis, and arteriolohyalinosis. Kidney function was assessed based on glomerular filtration rate (GFR) as well as urinary excretion of albumin, low molecular weight proteins, kidney injury molecule 1 and N-acetylglucose aminidase. Associations between metal concentrations and histopathological changes, were assessed in models also including age, sex and smoking. Results: The median kidney concentrations of Pb, Cd and Hg were 0.08, 13 and 0.21 μg/g, respectively. There were signs of tubular atrophy in 63%, interstitial fibrosis in 21%, glomerulosclerosis in 71%, arteriosclerosis in 47%, and arteriolohyalinosis in 36% of the donors, but, as could be expected, the histopathological findings were limited, mostly Banff grade 1. In models adjusted for age, sex and smoking, kidney Cd was positively associated with tubular atrophy (p = 0.03) and possibly with arteriolohyalinosis (p = 0.06). Kidney Hg was associated with arteriosclerosis (p = 0.004). Discussion and conclusions: The results suggest that even low levels of Cd in the kidney can induce a mild degree of tubular atrophy. This is in line with previous findings at high-level Cd exposure. The association between kidney Hg and renal arteriosclerosis was unexpected, and may be a chance finding

Foreign body reactions, marginal bone loss and allergies in relation to titanium implants

Aim: To describe general observations of immunological reactions to foreign materials and to realize that CP titanium gives rise to a foreign body reaction with subsequent bone embedment when placed as oral implants. To analyse the possibility of titanium allergy. Materials and methods: The present paper is of a narrative review type. Hand and Medline searches were performed to evaluate marginal bone loss of oral implants and the potential of titanium allergy. Results: Immunological reactions to foreign substances include Type I hypersensitivity reactions such as allergy, Type II hypersensitivity reactions characterised by IgM or IgG antibodies that may react with blood group antigens at transfusion, and Type III hypersensitivity caused by antigen-antibody immune complexes exemplified by acute serum sickness. There is also Type IV hypersensitivity, or delayed hypersensitivity, which is typically found in drug and foreign body reactions. It proved very difficult to find a universally acceptable definition of reasons for marginal bone loss around oral implants, which lead to most varying figures of so-called peri-implantitis being 1% to 2% in some 10-year follow-up papers to between 28% and 56% of all placed implants in other papers. It was recognised that bone resorption to oral as well as orthopaedic implants may be due to immunological reactions. Today, osseointegration is seen as an immune-modulated inflammatory process where the immune system is locally either up- or downregulated. Titanium implant allergy is a rare condition, if it exists. The authors found only two papers presenting strong evidence of allergy to CP titanium, but with the lack of universally accepted and tested patch tests, the precise diagnosis is difficult. Conclusions: CP titanium acts as a foreign body when placed in live tissues. There may be immunological reasons behind marginal bone loss. Titanium allergy may exist in rare cases, but there is a lack of properly designed and analysed patch tests at present

Immunohistochemical Studies on Galectin Expression in Colectomised Patients with Ulcerative Colitis.

Introduction. The aetiology and pathogenesis of ulcerative colitis (UC) are essentially unknown. Galectins are carbohydrate-binding lectins involved in a large number of physiological and pathophysiological processes. Little is known about the role of galectins in human UC. In this immunohistochemical exploratory study, both epithelial and inflammatory cell galectin expression were studied in patients with a thoroughly documented clinical history and were correlated with inflammatory activity. Material and Methods. Surgical whole intestinal wall colon specimens from UC patients (n = 22) and controls (n = 10) were studied. Clinical history, pharmacological treatment, and modified Mayo-score were recorded. Tissue inflammation was graded, and sections were stained with antibodies recognizing galectin-1, galectin-2, galectin-3, and galectin-4. Results. Galectin-1 was undetectable in normal and UC colonic epithelium, while galectin-2, galectin-3, and galectin-4 were strongly expressed. A tendency towards diminished epithelial expression with increased inflammatory grade for galectin-2, galectin-3, and galectin-4 was also found. In the inflammatory cells, a strong expression of galectin-2 and a weak expression of galectin-3 were seen. No clear-cut correlation between epithelial galectin expression and severity of the disease was found. Conclusion. Galectin expression in patients with UC seems to be more dependent on disease focality and individual variation than on degree of tissue inflammation