Impact of hyperparathyroidism on allograft histology and function after kidney transplantation: Rethinking its causal role in graft dysfunction.

INTRODUCTION: The causal relationship between hyperparathyroidism and kidney graft dysfunction remains inconclusive. Applying Bradford-Hill's temporality and consistency causation principles, we assessed the effect of parathyroid hormone (iPTH) on graft histology and eGFR trajectory on kidney transplant recipients (KTRs) with normal time-zero graft biopsies. METHODS: Retrospective cohort study evaluating the effect of hyperparathyroidism on interstitial fibrosis and tubular atrophy (IF/TA) development in 1232 graft biopsies. Pre-transplant hyperparathyroidism was categorized by KDIGO or KDOQI criteria, and post-transplant hyperparathyroidism by iPTH >1× and >2× the URL 1 year after transplantation. RESULTS: We included 325 KTRs (56% female, age 38 ± 13 years, follow-up 4.2 years [IQR: 2.7-5.8]). Based on pre-transplant iPTH levels, 26% and 66% exceeded the KDIGO and KDOQI targets, respectively. There were no significant differences in the development of >25% IF/TA between KTRs with pre-transplant iPTH levels above and within target range according to KDIGO (53% vs. 62%, P = .16, HR.94 [95% CI:.67-1.32]) and KDOQI (60% vs. 60%, P = 1.0, HR 1.19 [95% CI:.88-1.60]) criteria. Similarly, there were no differences when using 1 year post-transplant iPTH cut-offs > 88 pg/mL (58% vs. 64%, P = .33) and > 176 pg/mL (55% vs. 62%, P = .19). After adjusting for confounders, no significant differences were observed in eGFR trajectories among the iPTH strata. CONCLUSION: In young KTRs who received a healthy graft, no association was found between increased pre- and post-transplant iPTH levels and graft dysfunction, as assessed histologically and through eGFR trajectory. The concept of hyperparathyroidism as a risk factor for graft dysfunction in recipients at low risk requires reevaluation.

Leukocyte Chemotactic Factor 2 Amyloidosis (ALECT2) Distribution in a Mexican Population.

OBJECTIVES: To assess the prevalence of leukocyte cell-derived chemotactic 2 (LECT2), its organ involvement, and its clinical association in autopsies from an ethnically biased population. METHODS: The tissues from all autopsies of individuals diagnosed with amyloidosis were reassessed and typed for amyloid light chain (AL) amyloidosis, amyloid A (AA) amyloidosis, transthyretin amyloidosis (ATTR), and leukocyte chemotactic factor 2 amyloidosis (ALECT2) by immunohistochemistry. Organ involvement was described and correlated with its clinical associations. RESULTS: Of 782 autopsies, 27 (3.5%) had a confirmed diagnosis of amyloidosis. Of these, 14 (52%) corresponded to ALECT2, 5 (19%) to AL amyloidosis, 2 (7%) to ATTR amyloidosis, 1 (4%) to AA amyloidosis, and 5 (21%) as undetermined-type amyloidosis. The LECT2 amyloid deposits were found in the kidneys, liver, spleen, and adrenal glands in most individuals. Except for the kidneys, there were no clinical signs suggestive of amyloid deposition in most of the affected organs. LECT2 amyloidosis was not associated with the cause of death in any case. No cases had heart or brain involvement. Potential subclinical effects of amyloid deposition in organs such as adrenal glands and spleen require further study. CONCLUSIONS: This autopsy study confirms the high prevalence of LECT2 amyloidosis in the Mexican population, with frequent amyloid deposition in the kidneys, liver, spleen, and adrenal glands.

Down-Regulation-Resistant STAT4 Risk Haplotype Contributes to Lupus Nephritis Through CD4+ T Cell Interferon-γ Production.

OBJECTIVE: Variants in STAT4 are associated with systemic lupus erythematosus (SLE) and other autoimmune diseases. We undertook this study to investigate how disease-associated variants affect STAT4 expression, in particular in CD4+ T cells where STAT4 plays an essential role. METHODS: We compared Th1 differentiation between naive CD4+ T cells from healthy donors homozygous for the risk (R/R) or nonrisk (NR/NR) alleles. We analyzed epigenetic marks in STAT4 and evaluated the relevance of its third intron, assessed the consequences of Stat4 overexpression in vivo in mice, and analyzed the effects of the STAT4 genotype in patients with lupus nephritis. RESULTS: Naive CD4+ T cells from NR/NR healthy donors down-regulated STAT4 in response to interleukin-12 (IL-12). In contrast, cells from R/R healthy donors maintained high levels. R/R cells exhibited a higher abundance of transcriptionally active STAT4 and increased interferon-γ production. Accordingly, R/R healthy donors exhibited a stronger induction of local active enhancer marks. Genetic editing confirmed the presence of a negative regulatory region in the STAT4 third intron, where most of the SLE-associated STAT4 single-nucleotide polymorphisms (SNPs) are located. In vivo forced expression demonstrated that increases in Stat4 levels in T cells enhanced glomerulonephritis in mice. Accordingly, the R/R genotype was associated with suboptimal response to treatment and with worse clinical outcomes in patients with proliferative lupus nephritis. CONCLUSION: The SLE-associated STAT4 haplotype correlates with an abnormal IL-12-mediated STAT4 transcriptional regulation. Carriers of the risk variant exhibit exaggerated CD4+ proinflammatory capacities that, in the context of SLE, contribute to more severe disease. R/R patients may benefit from blockade of the IL-12/STAT4 pathway.

ANCA-associated vasculitis and IgG4-related disease overlap syndrome: a case report and literature review.

Anti-neutrophil cytoplasmic antibodies (ANCA)-associated vasculitides are infrequent autoimmune diseases characterized by inflammation of the walls of small vessels leading to tissue and endothelial damage. On the other hand, IgG4-related disease is a fibroinflammatory disease characterized histologically by lymphoplasmacytic infiltrates with IgG4+ plasma cells, storiform fibrosis, and obliterative phlebitis that may affect nearly every organ of the body. There are similarities in clinical, serological, radiological, and histopathological features between both diseases, and hence, they usually mimic each other complicating the differential diagnosis. Furthermore, reports of patients with the coexistence of both conditions (overlap syndrome) have been reported. We herein report a patient with an unequivocal diagnosis of ANCA-associated vasculitis, specifically granulomatosis with polyangiitis (posterior uveitis, polyneuropathy, pauci-immune glomerulonephritis with crescent formation and granulomas, and MPO-ANCA positivity) and IgG4-related disease (thoracic aortitis, tubulointerstitial nephritis with prominent IgG4+ plasma cell infiltration, fibrosis, and obliterative arteritis, high levels of serum IgG4, and eosinophilia) overlap syndrome.

Sub-classification of borderline changes into diffuse or focal and its impact on long-term renal transplant outcomes.

BACKGROUND: Borderline changes (BL) with stable renal function is a controversial category in renal transplantation, given its contradictory outcomes. The aim of this study was to compare the clinical outcomes of BL in patients with stable renal function classified as focal and diffuse according to the extent of tubulitis. METHODS: Patients with no history of rejection with a surveillance graft biopsy at 3 or 12 months showing BL (n = 40), acute cellular rejection (n = 20) or normal biopsies (n = 20), were included in this study. Biopsies with BL were divided into diffuse BL (BLD) and focal BL (BLF) according to the extent of tubulitis. Because of the low frequency of subclinical ACR (ACRND) (n = 12), biopsies with ACR and graft dysfunction (ACRD) (n = 8) were also included. A composite outcome that included the presence of rejection in subsequent biopsies, graft loss, patient death, decrease in GFR ≥30% or presence of de novo DSA (dnDSA) during the first year of follow-up was evaluated. RESULTS: The primary composite outcome occurred in five patients of each of the Normal, BLF and ACRND, eight patients with BLD and six patients with ACRD (p = 0.105). A trend towards more rejection episodes was observed in the ACRND and ACRD. Also, a shorter time to rejection in the BLD, ACRND and ACRD groups compared to BLF and Normal groups (p = 0.039) was observed. During the first year of follow-up, no patient in the ACRND group developed dnDSA, compared to 15-25% in the other groups. The median time of dnDSA development in the BLF group was 45 months, and in the BLD group was 10 months (p = 0.020). CONCLUSION: Classifying BL biopsies with stable renal function into focal and diffuse categories, is a simple and feasible strategy that helps to differentiate between BLD with a phenotype that shows a trend towards worse outcomes, and BLF that behaves more similar to normal biopsies.

Alternative complement pathway activation in thrombotic microangiopathy associated with lupus nephritis.

INTRODUCTION/OBJECTIVE: Thrombotic microangiopathy (TMA) in systemic lupus erythematosus is a rare manifestation associated with activation of the complement system. This study aimed to compare plasma and urine complement activation products between patients with active lupus nephritis (aLN) and those with acute TMA plus concomitant active LN (aTMA+aLN). METHODS: Plasma and urine samples were obtained from 20 patients with aTMA+aLN, 20 patients with aLN matched by the histological activity index, 5 patients with chronic TMA, 20 patients with inactive LN, and 10 kidney donors. Complement fragments C3a, C4a, C4d, Ba, C5a, C5bC9, and factor H were determined by ELISA; and kidney C4d deposition was detected by immunohistochemistry. Patients were followed for > 12 months and complement activation products re-measured after treatment in 10 aTMA+aLN patients. RESULTS: Both aTMA+aLN and aLN groups had increased circulating C3a, Ba, and C5bC9; and decreased circulating C3, C4, C4a, C4d, and factor H. Urinary C3a, C5a, Ba, and C5bC9 were higher in patients with aTMA+aLN than in aLN. After treatment, levels of circulating C3, C4, and factor H increased; while levels of urinary C3a, C5a, Ba, and C5bC9 decreased in patients with aTMA+aLN. These changes were observed at each aTMA episode in two patients studied during repeated TMA episodes. There was no difference in C4d deposition in glomerular capillaries, tubular basement membrane, peritubular capillaries, and arterioles between patients with aLN and those aTMA+aLN. CONCLUSIONS: Circulating and urine complement activation products suggest that thrombotic microangiopathy associated with LN is mediated through activation of the alternative complement pathway. Key Points • Immune-complex kidney disease in systemic lupus erythematosus (SLE) is associated with activation of the classical, lectin, and alternative complement pathways • Indirect evidence from measurement of circulating and urinary complement pathway activation products suggests that renal acute thrombotic microangiopathy in SLE is mediated by activation of the alternative complement pathway • C4d kidney immunohistochemistry may be positive in both immune complex nephritis and thrombotic microangiopathy. Therefore, it is not a specific marker of renal thrombotic microangiopathy in SLE.

Nephrotic syndrome in the setting of LECT2 amyloidosis: Take a look at the podocyte.

Amyloid light-chain (AL) amyloidosis represents the most common type of amyloid affecting the kidneys. As AL amyloidosis is frequently clinically manifested as nephrotic syndrome, this glomerular syndrome has been improperly linked to all other types of kidney amyloidosis. In this report, we highlight the importance of amyloid typing, as the deposition of several amyloidotic proteins in the kidneys is not associated with heavy proteinuria. We present two cases of patients who presented with sudden-onset nephrotic syndrome and kidney biopsies showing interstitial, vascular, and/or mesangial LECT2 amyloidosis. Further examination by electron microscopy demonstrated diffuse foot process effacement consistent with minimal change disease and no amyloid deposition in the glomerular basement membrane. Both patients had complete remission after glucocorticoid treatment. We conclude that the presence of nephrotic syndrome in a patient with LECT2 amyloidosis must alert for a potential concurrent podocytopathy.

A potential role of neutrophil extracellular traps (NETs) in kidney acute antibody mediated rejection.

BACKGROUND: The aim of this study was to evaluate neutrophil extracellular traps (NETs) in kidney transplant recipients (KTR) and their potential involvement in acute antibody-mediated rejection (AAMR). METHODS: We studied 3 groups: KTR with AAMR (KTR-Cases, n = 14); KTR without any immunologic event (KTR-Controls, n = 14) and donors (n = 12). Spontaneous and lipopolysaccharide-induced NETosis were evaluated by immunofluorescence indirect (IFI) (NET/cells ratio). Plasmatic cH3-DNA complexes were evaluated by ELISA, (Optic Density Index - ODI). The expression of MPO and citrullinated histone 4 (cH4) was evaluated in renal biopsies. RESULTS: We found an enhanced spontaneous NETosis in KTR regardless of whether they had rejection. The Nets/cells ratio in spontaneous NETosis was 0.203 (IQR 0.12-0.34) in Total-KTR and 0.094 (IQR 0.01-0.17) in donors, p = .011. Likewise, the ODI of cH3-DNA was 1.41 (IQR 0.94-1.72) in Total-KTR, and 0.95 (IQR 0.83-1.27) in donors, p = .019. KTR-Cases had the higher amount of NETs 1.70 (IQR 1.19-1.91). In two KTR-Cases, expression of MPO and cH4 was found in biopsies. CONCLUSIONS: KTR show enhanced NETosis. This may indicate a permanent activation of neutrophils. Although more studies are needed, the higher amount of NETs and netting neutrophils in biopsies of KTR-Cases suggest a role of NETosis in AAMR.

Systemic BK Virus Infection in a Pediatric Patient With Severe Combined Immunodeficiency.

Human BK virus (BKV) infection is known to occur mostly during childhood with the establishment of latent infection with no tissue damage or clinical manifestations. However, conditions causing immunosuppression can lead to increased virus replication and tissue damage. Although the tissues most commonly involved are the kidneys, bladder, ureters and, to some extent, brain tissue, there are some reports that suggest that BKV may cause multisystemic infections. In this case, a 12-month-old child was seen to suffer from multiple gastrointestinal infections. This prompted a search for immunodeficiencies, which revealed the presence of severe combined immunodeficiency. The child was eventually hospitalized and continued showing recurrent bouts of gastroenteritis as well as lower respiratory infection. After multiple antibiotic courses, he developed acute kidney injury, a hemophagocytic syndrome, and eventually respiratory failure, which led to his death a year later. Autopsy findings revealed the presence of a disseminated BKV infection involving the kidneys, ureters, leptomeninges, and pancreas. Analysis of the literature failed to show any previous case of BKV pancreatitis. The present case suggests that BKV can damage more tissues than previously reported and may be responsible for systemic infections in immunosuppressed patients.

LECT2 Amyloidosis in Kidney Transplantation: A Report of 5 Cases.

Leukocyte chemotactic factor 2 (LECT2) amyloidosis is a recently recognized entity that often affects the kidneys. Little information is available regarding kidney transplant outcomes in patients with LECT2 amyloidosis or who received kidney allografts containing LECT2 amyloid. We present clinical findings and allograft outcomes of 5 patients who received kidneys with donor-derived LECT2 amyloidosis. In all 5, LECT2 amyloidosis was discovered during protocol biopsies or in evaluation of suspected rejection. Less than 10% of kidney parenchyma was involved, with mostly interstitial and vascular deposits. Allograft function was not impaired and the amyloid deposits persisted for up to 8 years of follow-up. We conclude that kidneys with limited and localized LECT2 amyloid deposits that are otherwise suitable for transplantation need not be automatically discarded.

Pretransplant angiotensin II type 1-receptor antibodies point to an increase in renal graft sub-intimal fibrosis in living- donor kidney transplant recipients.

The association between anti-AT1Rabs and microvascular injury observed in antibody-mediated rejection has been described in kidney graft Biopsies (KGBx). METHODS: We herein describe the histopathologic findings of KGBx performed during the first year of transplantation (Tx) in 134 patients tested for pre-Tx anti-AT1Rabs in cryopreserved sera (04/2009 to 09/2013). Protocol KGBx before implantation (time-zero), 1 year after Tx and for cause KGBx were included. 21/134 Tx patients were anti-AT1Rab positive (≥17 U/mL); 7/21 experienced acute rejection. For comparison a control group with anti-AT1Rabs <17 U/mL, with (n = 16) and without (n = 31) acute rejection was included. RESULTS: Preimplantation KGBx showed no differences in inflammatory and chronic findings, nor in subintimal fibrosis (25 vs 12.8%, p = .42) between patients with anti-AT1Rabs ≥17 U/mL and those with <17 U/mL. Follow-up KGBx revealed a significantly greater proportion of arterial sub-intimal fibrosis (52.3 vs. 27.6%, p = .049) and extension (15.7 vs. 5.3, p = .015) in anti-AT1Rabs ≥17 U/mL compared to anti-AT1Rabs <17 U/mL KGBx. No differences were observed in microcirculation inflammation, nor in interstitial fibrosis or tubular atrophy between groups. Also, anti-AT1Rabs ≥17 U/mL (ß 10.1, 2.3 to 17.8, p = .012) and more importantly anti-AT1Rabs ≥ 30 U/mL (ß12.1, 3.1 to 20.9, p < .01), were independent risk factors associated with vascular occlusion resulting from sub-intimal fibrosis. CONCLUSION: Our study findings have shown that anti-AT1Rab values ≥17 U/mL are significantly associated to sub-intimal fibrosis and a greater percentage of vessel occlusion in kidney graft biopsies obtained during the first year posttransplant, particularly in coexistence with inflammation and de novo DSA.

Afección renal confirmada mediante biopsia y pronóstico en 13 pacientes hispanos con síndrome de Sjögren primario / Biopsy-proven renal involvement and prognosis in 13 hispanic patients with primary Sjögren syndrome

Antecedentes: El objetivo de este estudio fue describir una serie de casos de 13 pacientes hispanos con síndrome de Sjögren primario (SSp) y compromiso renal confirmado mediante biopsia. Métodos: Describimos las características clínicas, séricas e histológicas, y el pronóstico de un grupo de pacientes con SSp y compromiso renal confirmado mediante biopsia, tratados en 2 unidades nefrológicas de referencia de la Ciudad de México. Resultados: Se practicó biopsia renal (BR) a 13 pacientes con SSp, durante un período de 27 años. La mediana de duración entre el diagnóstico de SSp y la BR fue de 13,9 meses. Siete pacientes (54%) tenían glomerulonefritis y 6 (46%), nefritis tubulointersticial. Todos los pacientes fueron tratados con corticosteroides y/o inmunosupresores. Ocho pacientes (62%) permanecieron estables o con mejoría de su función renal en una mediana de seguimiento de 12 meses. Conclusiones: Esta serie de casos refleja el amplio espectro del daño renal en el SSp. Observamos que en nuestra población hispana, el involucro glomerular fue la alteración más frecuente, y en particular la glomerulopatía membranosa, seguida de la enfermedad tubulointersticial. La atrofia tubular y la fibrosis intersticial fueron también hallazgos comunes en la biopsia. El tratamiento con corticosteroides u otros agentes inmunosupresores parece disminuir la progresión de la enfermedad renal (AU)

Background: The aim of this study was to describe a case series of 13 Hispanic patients with primary Sjögren syndrome (pSS) and biopsy-proven renal involvement. Methods: We describe the clinical, serological and histological characteristics as well as the prognosis in a group of patients with pSS and biopsy-proven renal involvement, treated in 2 referral nephrology units in Mexico City. Results: Thirteen patients with pSS underwent kidney biopsy (KB) over a period of 27 years. The median duration from pSS diagnosis to KB was 13.9 months. Seven patients (54%) had glomerulonephritis and 6 patients (46%) had tubulointerstitial nephritis. All patients were treated with corticosteroids and/or immunosuppressants. Eight patients (62%) remained stable or their renal function improved after a median follow-up of 12 months. Conclusions: This case series reflects the broad spectrum of renal involvement in pSS. We observed that in our Hispanic population, glomerular involvement was the most frequent abnormality, mainly membranous glomerulopathy, followed by tubulointerstitial disease. Tubular atrophy and interstitial fibrosis were also common biopsy findings. Treatment with corticosteroids or other immunosuppressive agents appear to slow renal disease progression (AU)

Biopsy-proven renal involvement and prognosis in 13 hispanic patients with primary Sjögren syndrome. / Afección renal confirmada mediante biopsia y pronóstico en 13 pacientes hispanos con síndrome de Sjögren primario.

BACKGROUND: The aim of this study was to describe a case series of 13 Hispanic patients with primary Sjögren syndrome (pSS) and biopsy-proven renal involvement. METHODS: We describe the clinical, serological and histological characteristics as well as the prognosis in a group of patients with pSS and biopsy-proven renal involvement, treated in 2 referral nephrology units in Mexico City. RESULTS: Thirteen patients with pSS underwent kidney biopsy (KB) over a period of 27 years. The median duration from pSS diagnosis to KB was 13.9 months. Seven patients (54%) had glomerulonephritis and 6 patients (46%) had tubulointerstitial nephritis. All patients were treated with corticosteroids and/or immunosuppressants. Eight patients (62%) remained stable or their renal function improved after a median follow-up of 12 months. CONCLUSIONS: This case series reflects the broad spectrum of renal involvement in pSS. We observed that in our Hispanic population, glomerular involvement was the most frequent abnormality, mainly membranous glomerulopathy, followed by tubulointerstitial disease. Tubular atrophy and interstitial fibrosis were also common biopsy findings. Treatment with corticosteroids or other immunosuppressive agents appear to slow renal disease progression.

Graft immunologic events in deceased donor kidney transplant recipients with preformed HLA-donor specific antibodies.

INTRODUCTION: Pretransplant donor-specific HLA alloantibodies detected with the Single Antigen Bead (SAB) assay reflect an increased risk for acute antibody-mediated rejection (AMR). We herein report the incidence of both acute AMR and acute cellular rejection (ACR) during the first year posttransplantation, in a cohort of kidney transplant recipients (KTR) of deceased donor (DD) grafts, according to their DSA status. Pretransplant DSA do not preclude DD-KT in negative CDC-XM recipients at our center. PATIENTS AND METHODS: 246 KT were performed at our center between 01/2012 and 12/2015 and 100 KTR obtained from a DD were analyzed; 24% harbored DSA by SAB assay, MFI values >500 were considered positive. All recipients received thymoglobulin induction and generic tacrolimus-based maintenance therapy. Graft biopsies were performed by protocol on months 3 and 12 as well as per indication. The incidence of AMR and ACR was correlated with the existence of pretransplant DSA. RESULTS: Overall, 34% of patients developed an acute rejection episode, 54.2% in the DSA group versus 27.6% in the non-DSA group (p=0.032), and most of these events were detected as subclinical conditions in protocol biopsies. AMR events developed in 33.3% and 19.7% (p=0.176) in the DSA and the non-DSA groups, respectively. ACR events were found in 16.6% and 6.6% (p=0.127) in the DSA and non-DSA groups, respectively. Graft function was similar between groups at the end of the 1st year posttransplant and no immunological graft loss occurred. CONCLUSION: Despite the use of depleting induction therapy and adequate tacrolimus trough levels along with MMF and steroids, a high rate of rejection events was observed during the first year post-transplantation.

Immunosuppressive treatment for pure membranous lupus nephropathy in a Hispanic population.

Optimal treatment for pure membranous lupus nephritis (MLN) remains unknown. The aim of this study was to evaluate the response to immunosuppressive treatment of Hispanics with pure MLN. This was a retrospective cohort analysis from a tertiary care center. Pure MLN patients were segregated into three groups according to the received induction treatment. All patients received adjunctive steroids. Outcomes included complete remission (CR), partial remission (PR), flare incidence, adverse events, and renal and patient survival. All outcomes were analyzed by Cox regression analysis. A total of 60 patients diagnosed with pure MLN between 2004 and 2014 were segregated into mycophenolate mofetil (MMF) (n = 18), intravenous cyclophosphamide (IVC) (n = 16), or azathioprine (AZA) (n = 26) groups. Complete remission rates at 6, 12, and 24 months were 33.3, 52.9, and 76.4 %, respectively, for MMF; 26.9, 42.3, and 54.6 %, respectively, for AZA; and 6.2, 14.8, and 26.9 %, respectively, for IVC. Based on Cox-adjusted analysis, treatment with MMF was associated with higher CR rates (hazard ratio (HR) 4.43, 1.19-16.4, p = 0.026) compared to IVC. There were no differences in CR rates between MMF and AZA groups. Patients treated with adjunctive antimalarial drugs were more likely to achieve CR (HR 2.46, 1.08-5.64, p = 0.032) and had a non-significant trend to lower incidence of thrombotic events (odds ratio (OR) 0.10, 0.010-1.14, p = 0.064). There were no differences in adverse events, renal flares, and renal or patient survival between groups. MMF might be superior to IVC as induction treatment for pure MLN in Hispanics, while AZA might remain as a valid alternative for treatment. Adjunctive treatment with an antimalarial drug may enhance renal response to therapy.

Pretransplant angiotensin II type 1-receptor antibodies are a risk factor for earlier detection of de novo HLA donor-specific antibodies.

BACKGROUND: Angiotensin II type 1 receptor antibodies (AT1Rabs) have been associated with significantly reduced graft survival. Earlier graft loss has been observed in patients who had pretransplant AT1Rabs and posttransplant donor-specific antibodies (DSA). METHODS: The main goal of this retrospective cohort study was to examine the association between AT1Rabs and the time period to detection of de novo human leukocyte antigen (HLA-DSA) posttransplantation in living donor kidney transplant recipients (KTR). The analysis included 141 KTRs. Pretransplant frozen serum samples were tested for AT1Rabs by ELISA and HLA-DSA by SAB (Luminex) at both the pre- and post-KT time points. RESULTS: The median AT1Rab level was 9.13 U (interquartile range 5.22-14.33). After a mean follow-up period of 3.55 years, 48 patients were found to harbour de novo HLA-DSAs. The presence of AT1Rabs [hazard ratio (HR) 1.009, 95% confidence interval (CI) 1.002-1.01, P = 0.010], male-to-male transplantation (HR 2.57, 95% CI 1.42-4.67, P = 0.002) and antecedent borderline changes or acute cellular rejection (ACR) (HR 2.47, 95% CI 1.29-4.75, P = 0.006) were significantly associated with de novo DSA detection. A dose-dependent association between AT1Rab levels (<10 U, 10.1-16.9 U, 17-29.9 U and >30 U) and de novo DSA detection was observed (log-rank P = 0.0031). After multivariate analysis of AT1Rab levels (continuous variable), AT1Rabs >30 U, male-to-male transplantation, donor age, higher class I percentage of Panel Reactive Antibody and antecedent borderline changes or ACR remained as independent significant risk factors for the detection of de novo DSAs. CONCLUSIONS: The findings suggest that higher levels of pretransplant circulating antibodies against AT1R (>30 U) in kidney graft recipients constitute an independent risk factor for earlier de novo HLA-DSA detection during the posttransplant period.

Clinical presentation and outcome prediction of clinical, serological, and histopathological classification schemes in ANCA-associated vasculitis with renal involvement.

Several classification schemes have been developed for anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV), with actual debate focusing on their clinical and prognostic performance. Sixty-two patients with renal biopsy-proven AAV from a single center in Mexico City diagnosed between 2004 and 2013 were analyzed and classified under clinical (granulomatosis with polyangiitis [GPA], microscopic polyangiitis [MPA], renal limited vasculitis [RLV]), serological (proteinase 3 anti-neutrophil cytoplasmic antibodies [PR3-ANCA], myeloperoxidase anti-neutrophil cytoplasmic antibodies [MPO-ANCA], ANCA negative), and histopathological (focal, crescenteric, mixed-type, sclerosing) categories. Clinical presentation parameters were compared at baseline between classification groups, and the predictive value of different classification categories for disease and renal remission, relapse, renal, and patient survival was analyzed. Serological classification predicted relapse rate (PR3-ANCA hazard ratio for relapse 2.93, 1.20-7.17, p = 0.019). There were no differences in disease or renal remission, renal, or patient survival between clinical and serological categories. Histopathological classification predicted response to therapy, with a poorer renal remission rate for sclerosing group and those with less than 25 % normal glomeruli; in addition, it adequately delimited 24-month glomerular filtration rate (eGFR) evolution, but it did not predict renal nor patient survival. On multivariate models, renal replacement therapy (RRT) requirement (HR 8.07, CI 1.75-37.4, p = 0.008) and proteinuria (HR 1.49, CI 1.03-2.14, p = 0.034) at presentation predicted renal survival, while age (HR 1.10, CI 1.01-1.21, p = 0.041) and infective events during the induction phase (HR 4.72, 1.01-22.1, p = 0.049) negatively influenced patient survival. At present, ANCA-based serological classification may predict AAV relapses, but neither clinical nor serological categories predict renal or patient survival. Age, renal function and proteinuria at presentation, histopathology, and infectious complications constitute the main outcome predictors and should be considered for individualized management.