ABSTRACT
BACKGROUND: The VALidation of IGA (VALIGA) study investigated the utility of the Oxford Classification of immunoglobulin A nephropathy (IgAN) in 1147 patients from 13 European countries. Methods. Biopsies were scored by local pathologists followed by central review in Oxford. We had two distinct objectives: to assess how closely pathology findings were associated with the decision to give corticosteroid/immunosuppressive (CS/IS) treatments, and to determine the impact of differences in MEST-C scoring between central and local pathologists on the clinical value of the Oxford Classification. We tested for each lesion the associations between the type of agreement (local and central pathologists scoring absent, local present and central absent, local absent and central present, both scoring present) with the initial clinical assessment, as well as long-term outcomes in those patients who did not receive CS/IS. RESULTS: All glomerular lesions (M, E, C and S) assessed by local pathologists were independently associated with the decision to administer CS/IS therapy, while the severity of tubulointerstitial lesions was not. Reproducibility between local and central pathologists was moderate for S (segmental sclerosis) and T (tubular atrophy/interstitial fibrosis), and poor for M (mesangial hypercellularity), E (endocapillary hypercellularity) and C (crescents). Local pathologists found statistically more of each lesion, except for the S lesion, which was more frequent with central review. Disagreements were more likely to occur when the proportion of glomeruli affected was low. The M lesion, assessed by central pathologists, correlated better with the severity of the disease at presentation and discriminated better with outcomes. In contrast, the E lesion, evaluated by local pathologists, correlated better with the clinical presentation and outcomes when compared with central review. Both C and S lesions, when discordant between local and central pathologists, had a clinical phenotype intermediate to double absent lesions (milder disease) and double present (more severe). CONCLUSION: We conclude that differences in the scoring of MEST-C criteria between local pathologists and a central reviewer have a significant impact on the prognostic value of the Oxford Classification. Since the decision to offer immunosuppressive therapy in this cohort was intimately associated with the MEST-C score, this study indicates a need for a more detailed guidance for pathologists in the scoring of IgAN biopsies.
Subject(s)
Glomerulonephritis, IGA/classification , Glomerulonephritis, IGA/pathology , Models, Statistical , Observer Variation , Patient Selection , Biopsy , Glomerular Filtration Rate , Glomerulonephritis, IGA/drug therapy , Humans , Immunosuppressive Agents/therapeutic use , Prognosis , Reproducibility of Results , Retrospective StudiesABSTRACT
BACKGROUND: There is a need for early identification of children with immunoglobulin A nephropathy (IgAN) at risk of progression of kidney disease. METHODS: Data on 261 young patients [age <23 years; mean follow-up of 4.9 (range 2.5-8.1) years] enrolled in VALIGA, a study designed to validate the Oxford Classification of IgAN, were assessed. Renal biopsies were scored for the presence of mesangial hypercellularity (M1), endocapillary hypercellularity (E1), segmental glomerulosclerosis (S1), tubular atrophy/interstitial fibrosis (T1-2) (MEST score) and crescents (C1). Progression was assessed as end stage renal disease and/or a 50 % loss of estimated glomerular filtration rate (eGFR) (combined endpoint) as well as the rate of renal function decline (slope of eGFR). Cox regression and tree classification binary models were used and compared. RESULTS: In this cohort of 261 subjects aged <23 years, Cox analysis validated the MEST M, S and T scores for predicting survival to the combined endpoint but failed to prove that these scores had predictive value in the sub-group of 174 children aged <18 years. The regression tree classification indicated that patients with M1 were at risk of developing higher time-averaged proteinuria (p < 0.0001) and the combined endpoint (p < 0.001). An initial proteinuria of ≥0.4 g/day/1.73 m2 and an eGFR of <90 ml/min/1.73 m2 were determined to be risk factors in subjects with M0. Children aged <16 years with M0 and well-preserved eGFR (>90 ml/min/1.73 m2) at presentation had a significantly high probability of proteinuria remission during follow-up and a higher remission rate following treatment with corticosteroid and/or immunosuppressive therapy. CONCLUSION: This new statistical approach has identified clinical and histological risk factors associated with outcome in children and young adults with IgAN.
Subject(s)
Glomerulonephritis, IGA/epidemiology , Adrenal Cortex Hormones/therapeutic use , Age Factors , Biopsy , Child , Child, Preschool , Cohort Studies , Disease Progression , Endpoint Determination , Europe/epidemiology , Female , Glomerular Filtration Rate , Glomerulonephritis, IGA/drug therapy , Glomerulonephritis, IGA/pathology , Humans , Immunosuppressive Agents , Infant , Kidney/pathology , Kidney Failure, Chronic/epidemiology , Kidney Failure, Chronic/pathology , Male , Proteinuria/epidemiology , Proteinuria/pathology , Retrospective Studies , Risk Factors , Sex Factors , Survival AnalysisABSTRACT
BACKGROUND: Chronic T cell-mediated rejection (TCMR) in kidney graft is characterized by reduction of the vessel lumen with marked intimal thickening, fibrous hyperplasia of the small renal arteries and leukocyte infiltrates. The aim of this study was to find specific gene expression profiles in chronic TCMR kidney biopsies. METHODS: RNA extracted from archival formalin-fixed, paraffin-embedded renal biopsies was used for gene expression profiling. Our study included 14 patients with chronic TCMR and 10 with acute TCMR. Fifty-two cadaveric donors were used as controls. The results were validated in an independent set of kidney biopsies. RESULTS: We identified 616 and 243 differentially expressed genes with a fold change ≥1.5 and a false discovery rate <0.05 in chronic and acute TCMR, respectively. Pathway analysis revealed upregulation of OX40 signalling. This pathway is involved in the generation of CD8+ effector memory T cells and the upregulation of killer cell lectin-like receptor G1 (KLRG-1), B lymphocyte-induced maturation protein 1 (BLIMP-1) and CD25, which characterize CD8+ effector memory T cells. However, the enhanced OX40 signalling pathway was specific to chronic TCMR; a significant increase of KLRG-1+/CD8+ and BLIMP-1+/CD8+ was only detected in these specimens. CONCLUSIONS: These results suggest the involvement of memory-committed CD8+ effector T cells in chronic TCMR. The generation of effector memory T cells is mediated by the OX40 gene pathway, and could be considered a future target for the specific treatment of chronic TCMR.
Subject(s)
Graft Rejection/immunology , T-Lymphocytes/immunology , Adolescent , Adult , Aged , Female , Graft Rejection/metabolism , Graft Rejection/pathology , Humans , Kidney/immunology , Kidney/metabolism , Kidney/pathology , Kidney Transplantation , Male , Middle Aged , Receptors, OX40/genetics , Receptors, OX40/metabolism , Signal Transduction , T-Lymphocytes/metabolism , Transcriptome/immunology , Young AdultABSTRACT
BACKGROUND: The aim of this study was to evaluate whether asymptomatic recurrent (≥2) antibody-mediated rejection (pAMR 1+), defined as diffuse capillary C4d immunostaining (rAMR) on endomyocardial biopsies (EMBs), during the first year after heart transplantation impairs left ventricular (LV) function. METHODS: Fifty-four consecutive heart transplant patients who survived well (New York Heart Association ≤2 and EF≥55%) the first month after transplantation were enrolled and prospectively underwent 490 echocardiographies and EMB. Asymptomatic rAMR without histopathologic findings was evaluated as a risk factor for deterioration of graft function. Primary endpoint, assessed 1 year after transplantation, was development of LV dysfunction and/or adverse remodeling according to pre-specified echo parameters. RESULTS: During the first year from transplantation, rAMR occurred in five patients. Recurrent AMR was associated with a significant higher risk to develop LV concentric hypertrophy (OR 3.6, 95% CI: 1.8-7.0, P=.02) or reduced lateral S' peak velocity (OR 2.3, 95% CI: 1.5-3.6, P=.03). Patients with rAMR showed significative adverse graft remodeling (ΔLV end-diastolic volume: +16±12.3 vs -0.2±14.4 mL; P=.02) and deterioration of graft function (Δlateral S' peak velocity: -3.3±3 vs -0.4±2.9 cm/s; P=.03). CONCLUSIONS: Recurrent asymptomatic diffuse capillary C4d immunostaining may play a role in the early development of cardiac allograft adverse remodeling and dysfunction.
Subject(s)
Capillaries/immunology , Complement C4b/metabolism , Graft Rejection/complications , Graft Rejection/diagnosis , Heart Transplantation , Peptide Fragments/metabolism , Postoperative Complications/etiology , Ventricular Dysfunction, Left/etiology , Adult , Aged , Asymptomatic Diseases , Biomarkers/metabolism , Biopsy , Capillaries/pathology , Echocardiography, Doppler , Female , Follow-Up Studies , Graft Rejection/immunology , Graft Rejection/pathology , Humans , Male , Middle Aged , Myocardium/immunology , Myocardium/pathology , Outcome Assessment, Health Care , Postoperative Complications/diagnostic imaging , Prospective Studies , Recurrence , Transplantation, Homologous , Ventricular Dysfunction, Left/diagnostic imagingABSTRACT
The Oxford Classification of IgA Nephropathy (IgAN) identified mesangial hypercellularity (M), endocapillary proliferation (E), segmental glomerulosclerosis (S), and tubular atrophy/interstitial fibrosis (T) as independent predictors of outcome. Whether it applies to individuals excluded from the original study and how therapy influences the predictive value of pathology remain uncertain. The VALIGA study examined 1147 patients from 13 European countries that encompassed the whole spectrum of IgAN. Over a median follow-up of 4.7 years, 86% received renin-angiotensin system blockade and 42% glucocorticoid/immunosuppressive drugs. M, S, and T lesions independently predicted the loss of estimated glomerular filtration rate (eGFR) and a lower renal survival. Their value was also assessed in patients not represented in the Oxford cohort. In individuals with eGFR less than 30 ml/min per 1.73 m(2), the M and T lesions independently predicted a poor survival. In those with proteinuria under 0.5 g/day, both M and E lesions were associated with a rise in proteinuria to 1 or 2 g/day or more. The addition of M, S, and T lesions to clinical variables significantly enhanced the ability to predict progression only in those who did not receive immunosuppression (net reclassification index 11.5%). The VALIGA study provides a validation of the Oxford classification in a large European cohort of IgAN patients across the whole spectrum of the disease. The independent predictive value of pathology MEST score is reduced by glucocorticoid/immunosuppressive therapy.
Subject(s)
Glomerulonephritis, IGA/classification , Glomerulonephritis, IGA/pathology , Kidney Failure, Chronic/pathology , Kidney/pathology , Adolescent , Adult , Atrophy , Child , Disease Progression , Europe , Female , Fibrosis , Follow-Up Studies , Glomerular Filtration Rate , Glomerular Mesangium/pathology , Glomerulonephritis, IGA/drug therapy , Glomerulosclerosis, Focal Segmental/pathology , Humans , Immunosuppressive Agents/therapeutic use , Kidney/blood supply , Kidney Failure, Chronic/physiopathology , Kidney Tubules/pathology , Male , Middle Aged , Neovascularization, Pathologic/pathology , Predictive Value of Tests , Proteinuria/pathology , Renin-Angiotensin System/drug effects , Retrospective Studies , Young AdultABSTRACT
Two samples of highly pure multiwalled carbon nanotubes (MWCNTs) similar in hydrophobicity and surface reactivity were prepared with similar length, <5 µm, but markedly different diameter (9.4 vs 70 nm). The samples were compared for their cytotoxic activity, uptake, and ability to induce oxidative stress (ROS production and intracellular GSH depletion) in vitro in murine alveolar macrophages (MH-S). The in vivo toxicity was evaluated by measuring biochemical (LDH activity and total proteins) and cellular responses in bronchoalveolar lavage (BAL) after intratracheal instillation in rats. Both samples were internalized in MH-S cells. However, thin MWCNTs appeared significantly more toxic than the thicker ones, both in vitro and in vivo, when compared on a mass-dose basis. The data reported herein suggest that the nanotube diameter is an important parameter to be considered in the toxicological assessment of CNTs.
Subject(s)
Lung/drug effects , Macrophages, Alveolar/drug effects , Nanotubes, Carbon/chemistry , Nanotubes, Carbon/toxicity , Animals , Biological Transport , Bronchoalveolar Lavage Fluid/chemistry , Bronchoalveolar Lavage Fluid/cytology , Cell Count , Female , Glutathione/metabolism , L-Lactate Dehydrogenase/metabolism , Lung/metabolism , Macrophages, Alveolar/metabolism , Mice , Microscopy, Electron, Transmission , Nanotubes, Carbon/ultrastructure , Particle Size , Rats , Rats, Wistar , Reactive Oxygen Species/metabolism , Spectrum Analysis, Raman , Surface PropertiesABSTRACT
This article describes the birth and development of the Renal Immunopathology Group of the Italian Society of Nephrology. It collects the stories of nephrologists and pathologists who, since the early Seventies up to the first decade of this century, devoted their professional lives to the study of renal pathology with a strong personal involvement, characterized by enthusiasm, commitment, ability, strong spirit of cooperation, and friendship. All this enabled the Group to: propose the criteria for a standardized histological and immuno-histological examination of renal biopsies and reporting; produce several multicenter studies, whose results were also published in important international journals; to set up a national registry of renal biopsies; to organize a number of courses, some of which were associated with the publication of monographs, on various renal diseases. This article also traces the history of renal pathology in Italy from the second half of the Sixties - when young Italian nephrologists and pathologists from different institutions moved to French laboratories to learn new techniques to apply to renal biopsies - up to the present days. It also shows us how Italian renal pathology has been an essential tool for the development of the nephrological clinical practice and the advancement of scientific research.
Subject(s)
Kidney Diseases , Nephrology , Humans , Italy , Kidney , Nephrologists , Nephrology/historyABSTRACT
We report a 42-year-old woman who presents a few days after a spontaneous incomplete abortion at the ninth week of pregnancy with hypertension and nephrotic syndrome. Curettage findings and increased values for the ß subunit of human chorionic gonadotrophin were suspicious for a trophoblastic disease. A uterine placental site trophoblastic tumor was diagnosed 2 months later after hysterectomy and treated successfully using chemotherapy. Kidney biopsy showed features consistent with an unusual form of thrombotic microangiopathy characterized by the presence of large thrombus-like structures occluding the capillary lumina and smaller aggregates in the mesangium and along glomerular basement membranes. These deposits were positive for immunoglobulin M, C4, C1q, κ and λ light chains, and fibrinogen. Electron microscopy showed fibrin deposits located primarily in the subendothelial space. The differential diagnosis of this presentation included pre-eclamptic nephropathy, Waldenström disease, lupus anticoagulant glomerulonephritis, systemic lupus erythematosus, and cryoglobulinemic glomerulonephritis. We review the pathogenic mechanisms involved in this case.
Subject(s)
Glomerulonephritis/etiology , Kidney Glomerulus/ultrastructure , Thrombotic Microangiopathies/complications , Trophoblastic Tumor, Placental Site/complications , Uterine Neoplasms/complications , Abortion, Spontaneous , Adult , Biopsy , Diagnosis, Differential , Female , Follow-Up Studies , Glomerulonephritis/diagnosis , Humans , Hysterectomy , Microscopy, Electron , Pregnancy , Thrombotic Microangiopathies/diagnosis , Trophoblastic Tumor, Placental Site/diagnosis , Trophoblastic Tumor, Placental Site/surgery , Uterine Neoplasms/diagnosis , Uterine Neoplasms/surgeryABSTRACT
BACKGROUND: Pre-transplant donor biopsy (PTDB) is a common practice in marginal donors, taking for granted that it represents the whole kidney state, but its reliability has not yet been thoroughly investigated. This prompted us to carry out a comparative study on a needle biopsy group (NBG) and a wedge biopsy group (WBG) and their corresponding untransplanted kidneys. METHODS: One hundred and fifty-four biopsies and matched kidneys were scored for four morphologic indexes, i.e. tubular atrophy, interstitial fibrosis, vascular damage and global glomerulosclerosis. Categorical indexes were statistically evaluated for concordance with the k index, and the percentage of sclerotic glomeruli with correlation and linear regression analysis. RESULTS: Agreement between biopsies and kidneys was similar in both NBG and WBG with high scores for vascular damage (k 0.74 and 0.75) and intermediate ones for tubular atrophy (k 0.54 and 0.50). Agreement as to fibrosis and glomerular sclerosis was intermediate in the WBG (k 0.56 and 0.55) and poor in the NBG (k 0. 34 and 0.18). Vascular damage was underscored and glomerulosclerosis overscored in both groups, whereas interstitial fibrosis was underscored in the NBG and overscored in WBG. The agreement for the total score, i.e. the sum of the single indexes, was high in the NBG (k 0.73) and intermediate in WBG (k 0.57). Agreement for glomerulosclerosis and total score rose consistently in both groups along with the increasing number of biopsy glomeruli. There was an agreement as to biopsy and kidney evaluation for fitness for transplantation in 85% of NBG and 81% of WBG. CONCLUSIONS: PTDB supplies reliable data on the actual kidney state, with better results for needle biopsy. Although the biopsy size plays a role, samples with over 10 glomeruli suffice for clinical purposes. Vascular damage is the most faithful single parameter, whereas global glomerulosclerosis estimation requires some caution.
Subject(s)
Biopsy , Kidney Transplantation , Kidney/pathology , Tissue Donors , Adolescent , Adult , Aged , Aged, 80 and over , Female , Humans , Kidney Glomerulus/pathology , Male , Middle Aged , Reproducibility of Results , SclerosisABSTRACT
BACKGROUND: Polyomavirus-associated nephropathy (PVAN) is one of the most common viral disease affecting renal allograft, with BK being the most frequent causal agent and JCV being considered responsible in <3% of the cases. OBJECTIVES: To quantify polyomaviruses BK and JC load by real-time TaqMan PCR in tissue specimens (renal and ureteral) from kidney transplant recipients. STUDY DESIGN AND METHODS: One-hundred-thirty-eight specimens (125 kidneys, 13 ureters) obtained from 109 patients were evaluated by quantitative real-time PCR for the detection of BKV- and JCV-DNA. Demographic, virological, and histopathological data were collected. RESULTS: BKV-DNA was positive in 32 of 109 patients (29.6%) and JCV-DNA in 20 of 109 patients (18.3%). The highest BK viral loads (>10(4) genome equivalents/cell) were found in two renal samples with histopathologically confirmed PVAN; while JC viral load was >10(4) genome equivalents/cell in one ureteral sample. CONCLUSIONS: Although quantitation of viral DNA on renal allograft biopsies could be complementary to histopathological evaluation and the highest viral load are detectable in renal specimens with PVAN, the identification of a diagnostic cut-off should require further studies.
Subject(s)
BK Virus/isolation & purification , DNA, Viral/isolation & purification , JC Virus/isolation & purification , Kidney Transplantation/adverse effects , Kidney/virology , Polyomavirus Infections/diagnosis , Adult , Aged , BK Virus/genetics , Biopsy , DNA, Viral/genetics , Female , Humans , JC Virus/genetics , Male , Middle Aged , Polymerase Chain Reaction/methods , Transplantation, Homologous , Young AdultABSTRACT
BACKGROUND: No specific treatment for IgA nephropathy (IgAN) after kidney transplantation is currently available. METHODS: We conducted a retrospective single-center study on 29 patients with biopsy-proven de novo and recurrent IgAN after kidney transplantation, divided into two groups. Group 1 (n = 16) received intravenous methylprednisolone 500 mg per day for three consecutive days at the beginning of months 1, 3 and 5, plus oral prednisone 0.5 mg/kg every other day for 6 months. The control group (n = 13, Group 2) received supportive therapies. RESULTS: The two groups were comparable for serum creatinine (sCr) and proteinuria at the time of renal biopsy, but differed significantly at the end of follow-up. sCr was 1.8 ± 0.4 mg/dl in Group 1 vs. 2.7 ± 0.9 in Group 2 (p = 0.002), and proteinuria was 0.9 g/day in Group 1 vs. 1.9 in Group 2 (p = 0.04). The composite outcome of death-censored graft loss or doubling of sCr displayed 2 events in Group 1 (12.5 % of the entire group) and 5 events in Group 2 (38.5 % of the entire group), p = 0.19, odds ratio (OR) 4.4 [95 % confidence interval (CI) 0.7-27.8]. CONCLUSIONS: In the absence of therapeutic guidelines for de novo or recurrent IgAN after kidney transplantation, our study reports that therapy with pulse and oral steroids for 6 months is associated with an improved renal function. Nevertheless, further randomized controlled studies in larger patient cohorts are necessary to establish the gold standard treatment.
Subject(s)
Glomerulonephritis, IGA/drug therapy , Glucocorticoids/administration & dosage , Kidney Transplantation/adverse effects , Methylprednisolone/administration & dosage , Prednisone/administration & dosage , Administration, Intravenous , Administration, Oral , Adult , Clinical Protocols , Creatinine/blood , Female , Follow-Up Studies , Glomerulonephritis, IGA/etiology , Humans , Immunosuppression Therapy/methods , Male , Middle Aged , Proteinuria/drug therapy , Retrospective Studies , Treatment OutcomeABSTRACT
BACKGROUND: There is an increasing tendency to allocate kidneys from marginal donors in older recipients. This combination optimizes the uses of an expanded donor pool but demands attention for the higher nephrotoxic sensitivity of the kidney and the increased immunosuppression vulnerability of the elderly recipients. We aimed to reduce these hazards by means of a calcineurin-free induction therapy followed by a maintenance regimen targeted to minimize/withdraw steroid. METHODS: Eighty-eight single (43%) or double (57%) transplant recipients (58.4+/-5.7 years) from 88 marginal donors (67+/-8.3 years) received monoclonal anti-IL-2 receptor antibodies, mycophenolate mofetil (MMF), and steroid. When serum creatinine was less than 2.6 mg/dL, tacrolimus was started and MMF was withdrawn when the tacrolimus trough level was above 15 ng/ml. Steroid was tapered to 5 mg at day 45 and then progressively reduced. RESULTS: Overall patient and graft survival at the first and fourth year were respectively 100 and 96%, and 98 and 79%. Acute rejection rate was 13.6% (12/88), creatinine clearance remained stable (48.2 ml/min at the sixth month, 50.9 ml/min at 48th month). At the first, second, third, and fourth years, 23, 69, 80, and 100% of recipients were off steroids. For those on steroids, mean dose was respectively 2.6 mg/day from month 12. No recipient re-assumed steroids CONCLUSIONS: In the "old-for-old" allocation, the calcineurin-inhibitor avoidance at induction and the steroid withdrawal/minimization during the tacrolimus-based maintenance regimen allow a low acute rejection rate, a stable renal function, and favorable recipient and graft outcomes.
Subject(s)
Graft Rejection/prevention & control , Graft Survival , Immunosuppression Therapy/methods , Kidney Transplantation , Tissue Donors , Aged , Cadaver , Humans , Kidney/physiology , Kidney Transplantation/mortality , Tissue Donors/supply & distribution , Transplantation, HomologousABSTRACT
BACKGROUND: Although several studies have dealt with clinicopathological correlations in diabetic glomerulosclerosis (DGS), few have investigated the prognostic value of the renal biopsy. METHODS: One hundred and thirty-five type2 diabetes mellitus (DM) patients with bioptically proven DGS and a mean follow-up of 56.1 months were subdivided in 5 groups according to the outcome: 1) living with preserved renal function; 2) living with renal failure, not requiring dialysis; 3) living in dialysis; 4) dead in dialysis; 5) dead with preserved renal function. Duration of DM, creatininemia and proteinuria values at the time of biopsy and a histologic scoring (from 0 to 3) of 10 morphologic features were considered for statistical analysis. RESULTS: Statistically significant differences were observed in the distribution of the above mentioned parameters in the 5 groups with the exception of the duration of DM. The prognosis of DGS is poor: 79 patients needed dialysis and 60 died. Univariate analysis demonstrated the prognostic value of creatininemia (>or= 1.5 mg/dL), proteinuria (>or= 3 g/d) and histologic score (>or= 10) in assessing the relative risk of progression to dialysis (OR= 9.75, 4.12 and 11 respectively). The prognostic value of the histologic score (
Subject(s)
Diabetes Mellitus, Type 2/pathology , Diabetic Nephropathies/pathology , Kidney Glomerulus/ultrastructure , Adult , Aged , Aged, 80 and over , Biopsy, Needle , Diabetes Mellitus, Type 2/complications , Diabetic Nephropathies/complications , Disease Progression , Female , Follow-Up Studies , Humans , Male , Microscopy, Electron , Middle Aged , Prognosis , Retrospective StudiesABSTRACT
BACKGROUND: The C1q-binding properties of donor specific antibodies (DSA) may be related to antibody-mediated rejection and poor outcome. METHODS: We retrospectively studied 35 kidney transplant recipients with transplant glomerulopathy (TG) and de novo DSA (dnDSA). C1q dnDSA were measured in the serum stored at renal biopsy and the association among C1q-fixing dnDSA, C4d deposition and graft loss was examined. RESULTS: Of the 35 patients with dnDSA and TG, 15 (42.9%) had C1q-positive dnDSA and 20 (57.1%) had C1q-negative dnDSA. Ten out of 15 patients with C1q-positive dnDSA (66.6%) and 5 with C1q-negative dnDSA (25%) had C4d positive staining renal biopsies (P=0.02), being the C1q-negative dnDSA/C4d-negative TG 42.9% of the total. The C1q-positive dnDSA group has significantly higher IgG DSA Class II MFI than the C1q-negative dnDSA group (P=0.004). Patients with C4d deposits have significantly higher IgG DSA MFI for both Class I and Class II than those without C4d deposits (P=0.02). We found a trend toward higher graft loss in the C1q-positive dnDSA group (60%) versus the C1q-negative dnDSA group (40%) without a statistical significance (P=0.31). CONCLUSION: Our study provides further characterization of TG associated with dnDSA. The major part of dnDSA-associated TG was C1q-negative and the presence of C1q-fixing dnDSA did not significantly correlate with graft outcome.
Subject(s)
Complement C1q/immunology , Complement C4/immunology , Glomerulonephritis, Membranous/immunology , Isoantibodies/immunology , Kidney Transplantation , Kidney/immunology , Adult , Aged , Female , Glomerulonephritis, Membranous/pathology , Graft Rejection/immunology , Graft Rejection/pathology , Humans , Kidney/pathology , Male , Middle Aged , Retrospective StudiesABSTRACT
The benefits of tonsillectomy in IgA nephropathy (IgAN) are still debated. Tonsillectomy may remove pathogen sources and reduce the mucosal associated lymphoid tissue (MALT), limiting degalactosylated IgA1 (deGal-IgA1) production, which is considered to be the initiating pathogenetic event leading to IgA glomerular deposition. In the European network VALIGA, 62/1147 IgAN patients underwent tonsillectomy (TxIgAN). In a cross-sectional study 15 of these patients were tested and compared to 45 non-tonsillectomized IgAN (no-TxIgAN) and healthy controls (HC) regarding levels of deGal-IgA1, and markers of innate immunity and oxidative stress, including toll-like receptors (TLR)2, 3, 4 and 9 mRNAs, proteasome (PS) and immunoproteasome (iPS) mRNAs in peripheral blood mononuclear cells (PBMC), and advanced oxidation protein products (AOPP). Levels of deGal-IgA1 were lower in TxIgAN than in no-TxIgAN (p = 0.015), but higher than in HC (p = 0.003). TLR mRNAs were more expressed in TxIgAN than in HC (TLR4, p = 0.021; TLR9, p = 0.027), and higher in TxIgAN than in no-TxIgAN (p ≤ 0.001 for TLR2, 4, 9). A switch from PS to iPS was detected in PBMC of TxIgAN in comparison to HC and it was higher than in no-TxIgAN [large multifunctional peptidase (LMP)2/ß1, p = 0.039; LPM7/ß5, p < 0.0001]. The levels of AOPP were significantly higher in TxIgAN than HC (p < 0.001) and no-TxIgAN (p = 0.033). In conclusion, the activation of innate immunity via TLRs and ubiquitin-proteasome pathways and the pro-oxidative milieu were not affected by tonsillectomy, even though the levels of aberrantly galactosylated IgA1 were lower in patients with IgAN who had tonsillectomy. The residual hyperactivation of innate immunity in tonsillectomized patients may result from extra-tonsillar MALT.
Subject(s)
Adaptive Immunity , Glomerulonephritis, IGA/immunology , Glomerulonephritis, IGA/surgery , Immunity, Innate , Tonsillectomy , Adolescent , Adult , Advanced Oxidation Protein Products/blood , Case-Control Studies , Cross-Sectional Studies , Cysteine Endopeptidases/genetics , Female , Galactose/metabolism , Gene Expression , Glomerulonephritis, IGA/pathology , Healthy Volunteers , Humans , Immunoglobulin A/blood , Male , Middle Aged , Proteasome Endopeptidase Complex/genetics , RNA, Messenger/blood , Toll-Like Receptor 2/genetics , Toll-Like Receptor 3/genetics , Toll-Like Receptor 4/genetics , Toll-Like Receptor 9/genetics , Toll-Like Receptors/genetics , Young AdultABSTRACT
The frequency of various types of renal changes in patients with type 2 diabetes is not clearly defined in the literature. Reported discrepancies likely are caused by ethnic and geographic factors. However, policies used in nephrological centers for the selection of patients to undergo renal biopsy also may have an influence. The present study reports 393 renal biopsies in patients with type 2 diabetes performed in a group of centers in northwestern Italy using different (restricted [CRPs] or unrestricted [CUP]) biopsy policies. On the basis of light microscopic, immunofluorescence, and ultrastructural findings, cases were subdivided into three classes characterized by the presence of diabetic glomerulosclerosis (class 1), prevailing vascular (arterioarteriolosclerotic) and ischemic glomerular changes (class 2), other glomerulonephritides superimposed on diabetic glomerulosclerosis (class 3a), or glomerulonephritides without the presence of diabetic glomerulosclerosis (class 3b). Although no significant differences were found for class 2 (detected in 15% and 16% of patients from CRPs and the CUP, respectively), the frequency of the other two classes was strongly biased by the biopsy policy. Class 1 was found in 29% and 51% of cases, and class 3 in 57% and 33% of cases from CRPs and the CUP, respectively. Moreover, class 3a was more common (67%) in the CUP, and class 3b (78%) in CRPs. Our findings may explain conflicting data from the literature and the influence that type of adopted biopsy policy may have on an epidemiological evaluation. This study helps clarify the frequency of renal changes in patients with type 2 diabetes and suggests more extensive use of renal biopsy to obtain reliable prognostic indications and plan a rational therapeutic approach.
Subject(s)
Diabetes Mellitus, Type 2/complications , Diabetic Nephropathies/etiology , Biopsy , Diabetes Mellitus, Type 2/pathology , Diabetic Nephropathies/pathology , Female , Humans , Male , Middle AgedABSTRACT
Despite many studies on the subject, the causal relationships between viruses and presentation/exacerbation of autoimmune diseases are still elusive. The possibility of false positive IgM antibody tests for human cytomegalovirus (CMV) in patients with systemic lupus erythematosus (SLE) has been pointed out. Here we report a case of a patient who developed lupus nephritis, with biochemical and clinical markers of CMV infection with intestinal involvement. At first, the antibodies to CMV were regarded as spurious aspecific signs of autoimmune disease. The patient had had serious flare-ups of the disease, hemolytic-uremic syndrome with thrombotic microangiopathy superimposed on SLE nephritis, and life-threatening infections for three years until CMV infection was confirmed by the persistence of anti-CMV IgM-antibodies coupled with positive results of tests for viral replication. After therapy with ganciclovir, his clinical and biochemical condition improved and remained stable for three years, with only very low maintenance steroid coupled with hydroxychloroquine. IgM anti-CMV were no longer detectable in spite of the persistence of other autoantibodies such as anti-DNA and ANA. Keeping in mind that CMV-IgM has been reported in only 5% of patients with SLE nephritis, the history of our patient indicates that CMV infection must be carefully excluded before IgM antibodies against CMV can be simply classified as an aspecific sign of cross-reacting autoantibodies formed in SLE patients.
Subject(s)
Antibodies, Viral/blood , Cytomegalovirus Infections/immunology , Cytomegalovirus/immunology , Lupus Nephritis/immunology , Adult , Autoantibodies/blood , Cytomegalovirus Infections/complications , Cytomegalovirus Infections/diagnosis , Diagnosis, Differential , Humans , Immunoglobulin M/blood , Lupus Nephritis/complications , Lupus Nephritis/diagnosis , MaleABSTRACT
Alport Syndrome is a heritable progressive renal disease that, despite the large number of published studies, because of its genetic, clinical, immunohistochemical, and ultrastructural heterogeneity, still remains a diagnostic challenge. The focus of the discussion is on electron microscopy and immunohistochemistry Col (IV) chains. The differential diagnosis from thin glomerular basement membrane disease is discussed in depth, because both are familial, and can have similar clinical presentation and even ultrastructural pathology, but with a different outcome. The diagnostic role of molecular genetics, which identified the presence of collagen IV gene mutations and its relationship to the phenotypic expression of the renal damage, is also discussed.