[Cardiac amyloidosis: a case series of 14 patients, description and prognosis]. / Amylose cardiaque : à propos d'une série de 14 patients, description et facteurs pronostiques.

PURPOSE: Cardiac amyloidosis is rare. The objective of this study was to report on a case series of 14 patients with cardiac amyloidosis and to study the prognostic factors. METHODS: Monocentric retrospective study of all adult patients who presented with cardiac amyloidosis, diagnosed at the Georges-Pompidou European hospital in Paris between 2003 and 2011. RESULTS: Fourteen patients were identified (10 men and four women). Median age at diagnosis was 66.5 years. Twelve patients were diagnosed with AL amyloidosis, one with AA amyloidosis, and one with transthyretin amyloidosis. All patients presented cardiac manifestations: heart failure (n=9), rhythm disorders (n=6). Eight patients presented extra-cardiac manifestations of amyloidosis: renal (n=8), gastrointestinal (n=5). Troponin serum level was increased in eight patients and BNP level was superior to 400 pg/L in 12 patients. When performed, the cardiac magnetic resonance imaging (MRI) showed, in six patients out of seven, chamber dilatation, concentric hypertrophy or late enhancement. Among patients with cardiac failure at diagnosis (n=9), seven died with a median survival of 1 month duration. Factors of poor prognosis were, in our study, heart failure, elevated levels of troponin and BNP, and the AL amyloidosis subtype. CONCLUSION: Cardiac amyloidosis, especially the AL type, has a very poor prognosis, essentially because of an underlying multiple myeloma and heart failure.

Collapsing glomerulopathy associated lupus in a black female with homozygous APOL1 mutation.

Collapsing glomerulopathy (CG), characterized by collapse of the glomerular capillary loops onto the mesangial stalks is rarely associated to systemic lupus erythematosus (SLE). Recently a genetic predisposition to HIV associated nephropathy (HIVAN) has been shown in Afro-Americans: MYH9 polymorhism in 2008 and then APOL1 variants (G1 and G2 alleles) in 2010 were shown to be strongly associated with HIVAN. We describe here for the first time the association of CG in a young Afro-American female with SLE having a homozygous mutation of APOL1. The clinical history, laboratory findings and immunofluorescence all confirmed a diagnosis of SLE. However, studies for factors associated with collapsing glomerulopathy in other situations were consistently negative. As this Afro-American patient developed a CG, we performed genotyping of APOL1. It was found that she is homozygotic for the G2 allele of APOL1. Despite.

Very late heart transplant rejection is associated with microvascular injury, complement deposition and progression to cardiac allograft vasculopathy.

In heart transplants, the significance of very late rejection (after 7 years post-transplant, VLR) detected by routine endomyocardial biopsies (EMB) remains uncertain. Here, we assessed the prevalence, histopathological and immunological phenotype, and outcome of VLR in clinically stable patients. Between 1985 and 2009, 10 662 protocol EMB were performed at our institution in 398 consecutive heart transplants recipients. Among the 196 patients with >7-year follow-up, 20 (10.2%) presented subclinical ≥3A/2R-ISHLT rejection. The VLR group was compared to a matched control group of patients without rejection. All biopsies were stained for C4d/C3d/CD68 with sera screened for the presence of donor-specific antibodies (DSAs). In addition to cellular infiltrates with myocyte damage, 60% of VLR patients had evidence of intravascular macrophages. C4d and/or C3d-capillary deposition was found in 55% VLR EMB. All cases of VLR associated with microcirculation injury had DSAs (mean DSA(max) -MFI = 1751 ± 583). This entity was absent from the control group (p < 0.0001). Finally, after a similar follow-up postreference EMB of 6.4 ± 1 years, the mean of CAV grade was 0.76 ± 0.18 in the control group compared to 2.06 ± 0.26 in the VLR group respectively, p = 0.001). There was no difference in patient survival between study and control groups. In conclusion, VLR is frequently associated with complement-cascade activation, microvascular injury and DSA, suggesting an antibody-mediated process. VLR is associated with a dramatic progression to severe CAV in long-term follow-up.

Significance of C4d Banff scores in early protocol biopsies of kidney transplant recipients with preformed donor-specific antibodies (DSA).

The significance of C4d-Banff scores in protocol biopsies of kidney transplant recipients with preformed donor-specific antibodies (DSA) has not been determined. We reviewed 157 protocol biopsies from 80 DSA+ patients obtained at 3 months and 1 year post-transplant. The C4d Banff scores (1,2,3) were associated with significant increments of microcirculation inflammation (MI) at both 3 months and 1 year post-transplant, worse transplant glomerulopathy and higher class II DSA-MFI (p < 0.01). Minimal-C4d had injury intermediate between negative and focal, while focal and diffuse-C4d had the same degree of microvascular injury. A total of 54% of patients had variation of C4d score between 3 months and 1 year post-transplant. Cumulative (3 month + 1 year) C4d scores correlated with long-term renal function worsening (p = 0.006). However, C4d staining was not a sensitive indicator of parenchymal disease, 55% of C4d-negative biopsies having evidence of concomitant MI. Multivariate analysis demonstrated that the presence of MI and class II DSA at 3 months were associated with a fourfold increased risk of progression to chronic antibody-mediated rejection independently of C4d (p < 0.05). In conclusion, the substantial fluctuation of C4d status in the first year post-transplant reflects a dynamic humoral process. However, C4d may not be a sufficiently sensitive indicator of activity, MI and DSA being more robust predictors of bad outcome.

Bortezomib as the sole post-renal transplantation desensitization agent does not decrease donor-specific anti-HLA antibodies.

Persistence of donor-specific anti-HLA antibodies (DSA) associated with antibody-mediated graft injuries following kidney transplantation predicts evolution toward chronic humoral rejection and reduced graft survival. Targeting plasma cells, the main antibody-producing cells, with the proteasome inhibitor bortezomib may be a promising desensitization strategy. We evaluated the in vivo efficacy of one cycle of bortezomib (1.3 mg/m(2)x 4 doses), used as the sole desensitization therapy, in four renal transplant recipients experiencing subacute antibody-mediated rejection with persisting DSA (>2000 [Mean Fluorescence Intensity] MFI). Bortezomib treatment did not significantly decrease DSA MFI within the 150-day posttreatment period in any patient. In addition, antivirus (HBV, VZV and HSV) antibody levels remained stable following treatment suggesting a lack of efficacy on long-lived plasma cells. In conclusion, one cycle of bortezomib alone does not decrease DSA levels in sensitized kidney transplant recipients in the time period studied. These results underscore the need to evaluate this new desensitization agent properly in prospective, randomized and well-controlled studies.

Outcome of subclinical antibody-mediated rejection in kidney transplant recipients with preformed donor-specific antibodies.

This study describes clinical relevance of subclinical antibody-mediated rejection (SAMR) in a cohort of 54 DSA-positive kidney transplant recipients receiving a deceased donor. In 3 months screening biopsies, 31.1% of patients met the criteria of SAMR. A total of 48.9% had an incomplete form of SAMR (g+/ptc+/C4d-negative) whereas 20% had no humoral lesions. Patients with SAMR at 3 months had at 1 year: a higher C4d score, ptc score, and arteriosclerosis score, higher rate of IFTA (100% vs. 33.3%, p < 0.01) and a higher rate of transplant glomerulopathy (43% vs. 0%, p = 0.02) compared to patients without 3-month SAMR. Patients with SAMR at 3 months exhibited at 1 year a higher class II MFImax-DSA and a lower mGFR compared to patients without SAMR (39.2 +/- 13.9 vs. 61.9 +/- 19.2 mL/min/1.73 m(2) respectively, p < 0.01). The group of patients with C4d-negative SAMR at 3 months developed more ptc and IFTA lesions, and lower GFR at 1 year in comparison to biopsies without humoral lesions. SAMR is a frequent entity in KTR with preexisting DSAs and promotes subsequent GFR impairment and development of chronic AMR. C4d-negative SAMR patients displayed an intermediate course between the no-SAMR group and the C4d+ SAMR group. Screening biopsies may be useful to recognize patients more likely to develop SAMR.

Comparison of combination Plasmapheresis/IVIg/anti-CD20 versus high-dose IVIg in the treatment of antibody-mediated rejection.

Different strategies appear to improve the success in treatment of antibody-mediated rejection (AMR), although no one best method has yet emerged. The objective of this study was to compare the efficacy of the combination of Plasmapheresis/intravenous immunoglobulin (IVIg)/anti-CD20-based regimes versus high-dose IVIg alone in the treatment of AMR. Group A (12 patients) was treated with high-dose IVIg between January 2000 and December 2003; group B (12 patients) was treated by Plasmapheresis/IVIg/anti-CD20 between January 2004 and December 2005. Graft survival at 36 months was 91.7% in group B versus 50% in group A (p = 0.02). Donor-specific human leukocyte antigens (DSA) levels detected by Luminex single antigen (Luminex SA) and ELISA, 3 months postrejection are significantly lower in group B than in group A: DSA ELISA class 2 score 6-8 (p = 0.02), DSA mean intensity of fluorescence (MFI) max (p = 0.009) and DSA mean MFI (p = 0.0004). The persistence of elevated DSA levels posttreatment is more frequent in patients with graft loss as compared to those with preserved renal function: score 6-8 on ELISA (p = 0.04); mean MFI (p = 0.00009) and MFImax (p = 0.018). We conclude that: (1) high dose IVIg alone is inferior to Plasmapheresis/IVIg/anti-CD20 as therapy for AMR and (2)DSA postrejection can be quantified using solid phase assays, showing that 3 months after AMR, DSA levels are higher in patients with graft loss.

Clinical relevance of preformed HLA donor-specific antibodies in kidney transplantation.

Since the pioneering work of Patel and Terazaki, the presence of an anti-donor anti-body of the IgG isotype, as demonstrated by a lymphocytotoxic assay on T cells, has been a contraindication to transplantation, due to the very high rate of graft loss reported (>80% in the first few weeks posttransplant). The advent of more sensible and specific techniques of detection of anti-HLA antibodies (such as ELISA or Luminex techniques) has questioned this dogma, with a number of reports showing that transplantation, despite the presence of an donor-specific antibody (DSA), could be done without excessive graft losses, despite higher rates of rejection. We thus decided to retrospectively screen a cohort of 237 patients consecutively transplanted in our unit. This study analyzes the influence of preformed DSA, identified by HLA-specific ELISA assays, on graft survival and evaluates the incidence of antibody-mediated rejection (AMR). Kidney graft survival at 8 years was significantly worse in patients with DSA. The incidence of AMR in patients with DSA was 9-fold higher than in patients without DSA and led to a significantly worse graft survival. The prevalence for AMR in patients with DSA detected on historic serum was 32.3% and was significantly more elevated in patients with strongly positive DSA (score 6-8) and in patients with his-toric positive crossmatches. Interestingly, those patients with DSA that did not experience AMR had the same graft survival as patients without DSA. Thus, the presence of preformed DSA is strongly associated with increased graft loss in kidney transplants, related to an increased risk of AMR. Our findings demonstrate the importance of detection and charac-terization of DSA before transplantation. Stratification of this immunological risk should be used both to determine kidney allocation and to devise specific strategies for these patients.

[Antibody-mediated acute rejection]. / Rejet aigu médié par anticorps.

Antibody-mediated acute rejection is a frequent and severe complication of kidney transplantation. It has a poor prognosis and is often resistant to conventional treatment, which warrants treatment before transplantation to reduce the risk and after to improve the diagnosis, treatment, and follow-up. Before transplantation, the search for donor-specific anti-HLA antibodies using sensitive techniques (single antigen, ELISA) is essential to quantify the risk of acute rejection by antibodies, allowing grafts to be allocated in a fully informed manner. Monitoring and strict posttransplantation follow-up of at-risk patients also needs to be set up so that immunosuppression strategies can be modified if need be. After transplantation, treatment strategies consisting of (a) removing or blocking preexisting or de novo antibodies using high-dose IVIg or plasmapheresis or (b) inhibiting or depleting the cells producing antibodies by injecting anti-CD20 monoclonal antibodies or thymoglobulins have demonstrated their efficacy in treating antibody-mediated acute rejection. Since the persistence of donor-specific anti-HLA antibodies after an episode of antibody-mediated acute rejection is a factor of poor progression, suppression using these treatments and their posttransplantation follow-up are indispensable.

Renal histopathological lesions after lung transplantation in patients with cystic fibrosis.

We have analyzed the evolution of renal status beyond the perioperative period in patients with cystic fibrosis (CF) undergoing lung transplantation and presented histological analysis of 15 patients biopsied for an episode of accelerated renal function loss (RFL). Episodes of accelerated RFL after the perioperative period occurred in 32.5% of patients and significantly raised the risk of end-stage renal disease (ESRD) (p < 0.001). The histologic lesions associated with these episodes differed according to the time of onset. Early onset (10 cases) was associated with tubulointerstitial lesions in the form of oxalate nephropathy (50%) and/or a pigmented tubulopathy (80%). This latter was correlated with treatment with antiviral agents (p = 0.002) and aminoside and glycopeptide antibiotics (p = 0.03) administered in the month preceding biopsy. Lesions in late episodes of accelerated RFL (5 cases) were principally vascular: arteriosclerosis and arteriolosclerosis (p = 0.007, p = 0.00002), correlated with diabetic glomerulosclerosis or focal segmental glomerulosclerosis in the absence of prominent diabetic changes. Specific calcineurin-inhibitor nephrotoxicity was present in 93.3% of biopsies associated with thrombotic microangiopathy in 46.7% of cases. The identification of specific etiologies of progressive kidney disease in patients with CF after lung transplantation should permit more effective post-transplant care of these patients.

Clinical relevance of preformed HLA donor-specific antibodies in kidney transplantation.

This study analyzes the influence of preformed DSA, identified by HLA-specific ELISA assays, on graft survival and evaluates the incidence of antibody-mediated rejection (AMR) in patients with and without pregraft desensitization. Kidney graft survival at 8 years was significantly worse in patients with DSA (n = 43) than in those without DSA (n = 194)(p = 0.03). The incidence of AMR in patients with DSA is 9-fold higher than in patients without DSA (p < 0.001) and their graft survival is significantly worse than in DSA patients without AMR and in non-DSA patients (p = 0.005). The prevalence for AMR in patients with DSA detected on historic serum is 32.3% in nondesensitized patients and 41.7% in desensitized patients. The risk for AMR is significantly more elevated in patients with strongly positive DSA (score 6-8) compared to those with DSA score 4 (p < 0.001), and in patients with historic DSA+/CXM+ compared to those with DSA+/CXM- (p = 0.01). The presence of preformed DSA is strongly associated with graft loss in kidney transplants, related to an increased risk of AMR. Our findings demonstrate the importance of detection and characterization of DSA before transplantation. Stratification of this risk could be used to determine kidney allocation and to devise specific strategies for these patients.

Determinants of poor graft outcome in patients with antibody-mediated acute rejection.

This study analyzes the incidence and course of antibody-mediated rejection (AMR) in a cohort of 237 renal transplant patients followed for 30 +/- 20 months. Among these, 32 patients were considered to be at risk for AMR and received intravenous immunoglobulin (IVIg), either as preconditioning (Group A, n = 18) or at the time of transplant (Group B, n = 14). The prevalence of AMR was 27.8% in Group A, 57.1% in Group B and 3.9% in the remainder of the population. Although graft loss remains greater among AMR than for acute cellular rejection (ACR) or the overall transplant population, we have identified a good outcome group (GFR > 15 mL/min/1.73 m(2)) (n = 13), whose renal function at the end of follow-up was comparable to that of the general transplant population. The factors associated with bad outcome are: (1) immunologic: presence and/or persistence of donor-specific anti-HLA antibodies post-transplantation and (2) histologic: neutrophilic glomerulitis, peritubular capillary dilatation with neutrophil infiltrates and interstitial edema at the time of first biopsy; and at the time of late biopsy (3-6 months): lesions of vascular rejection, and monocyte/macrophage infiltrates in glomeruli and dilated peritubular capillaries. Persistence of C4d does not predict outcome. This study outlines for the first time the immunologic and histologic profiles of AMR patients with poor prognosis.

Acute oxalate nephropathy: A new etiology for acute renal failure following nonrenal solid organ transplantation.

Acute renal insufficiency (ARI) is a frequent complication of nonrenal solid organ transplantation and may be responsible for an unfavorable outcome, particularly if dialysis is required. The etiology of post-transplantation ARI is poorly understood, with only isolated clinical cases being reported, most imputed to drug toxicity. We report here, the first three observations of irreversible ARI associated with acute oxalate nephropathy (AON) in the course of nonrenal organ transplants: a lung transplant and a lung-liver transplant in two patients with mucoviscidosis, and a cardiac transplant. The diagnosis of AON was made histologically. In all three cases, the ARI supervened after prolonged consumption of antibiotics capable of interfering with the colonic flora, and leading to enteric hyperoxaluria. The recognition of AON as a cause of post-transplantation, ARI underlines hyperoxaluria and digestive hyperabsorption of oxalate as specific risk factors for AON and should permit better posttransplant care of these patients.

Membranous nephropathy and cancer: Epidemiologic evidence and determinants of high-risk cancer association.

The association between membranous nephropathy (MN) and cancer is often mentioned in textbooks but poorly substantiated, and the characteristics of cancer-associated MN are unknown. To address these questions, we studied a cohort of 240 patients with MN, among them 24 had malignancy at the time of renal biopsy or within a year thereafter. The incidence of cancer was significantly higher in these patients than in the general population (standardized incidence ratio 9.8 [5.5-16.2] for men and 12.3 [4.5-26.9] for women). The frequency of malignancy increased with age. At the time of diagnosis, clinical presentation did not differ between the patients with cancer-associated MN and those with idiopathic MN, but smoking was more frequent among patients with cancer. Analysis of renal biopsies revealed that the number of inflammatory cells infiltrating the glomeruli was significantly higher in patients with cancer-associated MN (P = 0.001). The best cutoff value for distinguishing malignancy-related cases from controls was eight cells per glomerulus. Using this threshold led to a diagnosis of cancer-associated MN with a specificity of 75% and a sensitivity of 92%. In patients with cancer-associated MN, there was a strong relationship between reduction of proteinuria and clinical remission of cancer (P < 0.001). In conclusion, our study provides epidemiologic evidence of an excess of cancer risk in patients with MN. It also shows that age, smoking, and the presence of glomerular leukocytic infiltrates strongly increase the likelihood of malignancy in MN patients.

Minimal change nephrotic syndrome and classical Hodgkin's lymphoma: report of 21 cases and review of the literature.

Minimal change nephrotic syndrome (MCNS) is described as a paraneoplastic manifestation of classical Hodgkin's lymphoma (cHL). We reassessed the pathophysiological and clinical significance of this association. A retrospective study was performed to evaluate a cohort of adult patients who developed MCNS and cHL. Twenty-one patients recruited in 15 French centers were analyzed. cHL was associated with inflammatory and general symptoms in most cases. The morphological subtype was predominantly nodular sclerosis (71.4%). MCNS appeared before the diagnosis of lymphoma in eight patients (38.1%) and in this case, it was characterized by a nephrotic syndrome (NS) frequently resistant (50%) or dependent (12.5%) to steroid treatment. Interestingly, diagnosis (3-120 months after MCNS) and effective treatment of the hemopathy were associated with the disappearance of the MCNS. cHL was diagnosed before MCNS in nine patients (42.9%), and in this case, glomerulopathy was associated with cHL relapse in 55.5% of cases. In four patients (19%), the two diseases occurred simultaneously. Extensive immunohistochemical study of lymph nodes was performed in eight patients and did not reveal particular features. In conclusion, MCNS associated with cHL is frequently dependent or resistant to steroid regimen, but remission of NS is obtained with the cure of lymphoma.

Intra-vascular large B-cell lymphoma revealed by a nephrotic syndrome: a one year remission induced by a high frequency CHOP and rituximab.

Intra-vascular lymphoma is usually reported as a rare and fatal disorder. We describe here the first case of an intra-vascular lymphoma revealed by a nephrotic syndrome for which a durable remission has been obtained by 8 cycles of bi-mensual CHOP and Rituximab therapy. In this report, 18 fluorodesoxyglucose tomoscintigraphy is discussed as a tool for intra-vascular lymphoma extension and follow-up.

Proteinuria and tubulointerstitial lesions in lupus nephritis.

BACKGROUND: Response of the renal tubules to proteinuria is implicated in progression of renal disease. Experimentally, proteinuria causes increased tubular synthesis of macrophagic and other chemokines, with increased tubular cellular proliferation and apoptosis, leading to interstitial inflammation and fibrosis. Clinically, diminution of proteinuria leads to the slowing of progression, but whether this leads to reduction in tubular lesions has not been directly demonstrated in humans. METHODS: Initial (Bx1) and systematic six-month biopsies (Bx2) from 71 patients with lupus nephritis were studied, with a subset of 34 biopsies also stained for proliferating cell nuclear antigen (PCNA), the macrophage marker PGM1, and cytokeratins (AE1/AE3), and morphometric cell and tubular profile counts performed. RESULTS: Positive correlations were found between increasing levels of proteinuria and the following light microscopic parameters: tubular epithelial pyknosis, tubular epithelial nuclear "activation," tubular lumenal macrophages, interstitial inflammation and fibrosis, but not with tubulointerstitial immunofluorescence. Significant positive correlations also were found with the following immunohistochemical parameters: PCNA in epithelial cells (r = 0.74) and tubular luminal cells (r = 0.47); tubular lumenal macrophages (r = 0.63) and tubular epithelial cells with acquired PGM1 staining (r = 0.36); and pyknotic tubular epithelial cells (r = 0.47). All showed strong correlations with serum creatinine (S(Cr)) as well. All were reduced at Bx2, generally in parallel to the reduction in proteinuria. Tubulointerstitial immune deposits appear to play only a minor role in the development of tubular epithelial lesions and the progression of renal disease in lupus. They show only limited correlation with SCr and no correlation with proteinuria. By multiple regression, they are not associated with tubular epithelial lesions, interstitial inflammation or interstitial fibrosis at either biopsy, whereas tubular epithelial lesions are strongly associated with interstitial inflammation at Bx1 and with interstitial fibrosis at Bx2. Cytokeratin correlated strongly with S(Cr) (r = 0.53, P = 0.002) but not with proteinuria (r = 0.27, NS), and was the sole immunohistochemical parameter to increase at Bx2. It appears to be a sensitive marker for tubular atrophy. CONCLUSIONS: In this study both proteinuria and SCr showed a hierarchy of correlations with morphologic variables: Tubular epithelial cell changes> tubular macrophages> interstitial inflammation> interstitial fibrosis, corresponding to current experimental models, but not previously demonstrated in humans.