Stefan Schaub

Universitätsspital Basel, Bâle, Basel-City, Switzerland

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Publications (62)260.23 Total impact

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    ABSTRACT: A modified single antigen bead (SAB) assay measuring C1q binding to human leukocyte antigen antibodies has recently been introduced. The aim of this study was to investigate the determinants of C1q binding on SAB.
    Transplantation 06/2014; · 3.78 Impact Factor
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    ABSTRACT: Non-HLA antibodies against the angiotensin II type 1 receptor (AT1 R) and the C-terminal fragment of perlecan (i.e., LG3) are associated with the development of renal allograft rejection. It is currently unknown how humans develop anti-AT1 R or anti-LG3 antibodies. The aim of this study was to investigate whether pregnancy-as a model of sensitization to polymorphic proteins-induces anti-AT1 R and/or anti-LG3 antibodies. We included 104 samples from women obtained after physiologic full-term pregnancy and 80 samples from healthy nonsensitized controls (40 women and 40 men). Both anti-AT1 R and anti-LG3 antibody levels were lower in pregnancy samples than in controls (both P < 0.05). By multivariate analysis, male gender was an independent predictor for high anti-AT1 R antibody levels (OR 3.66, P = 0.04) and pregnancy was predictive for low anti-LG3 antibody levels (OR 6.53, P = 0.0001). There was no correlation of anti-AT1 R with anti-LG3 antibody levels, either in the pregnancy or in the control samples (r(2) ≤ 0.03, P ≥ 0.26). In conclusion, physiologic full-term pregnancy does not induce anti-AT1 R or anti-LG3 antibodies and may even lower their levels. Therefore, anti-AT1 R and anti-LG3 antibodies are likely not caused by allosensitization. The lack of correlation of anti-AT1 R with anti-LG3 antibodies suggests different mechanisms of generation, which remain to be elucidated.
    Transplant International 02/2014; · 3.16 Impact Factor
  • Stefan Schaub, Patricia Hirt-Minkowski
    New England Journal of Medicine 11/2013; 369(19):1858. · 51.66 Impact Factor
  • Stefan Schaub, Gideon Hönger, Patrizia Amico
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    ABSTRACT: In the past years, our ability to detect HLA-antibodies has significantly improved allowing for a better assessment of the humoral immune response. The presence of donor-specific HLA-antibodies [DSA] both pre-transplant and de novo post-transplant is associated with the occurrence of antibody-mediated rejection [AMR] and inferior allograft survival (1,2). However, patients with DSA demonstrate variable clinical courses. Therefore, it is of major interest to better define the „pathogenicity” of individual DSA, which could help to guide diagnostic and therapeutic interventions. One possible approach is to explore the humoral immune response in more detail by measuring the IgG sublcasses and the IgA/IgM-factions of HLA-antibodies. This article is protected by copyright. All rights reserved.
    Transplant International 11/2013; · 3.16 Impact Factor
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    ABSTRACT: Control of polyomavirus BK (BKV) is achieved by reducing immunosuppression allowing an effective BKV-specific T-cell response. The morphology of resolving BKV-associated nephropathy (PyVAN) has not been systematically investigated. Ninety-nine surveillance biopsies of 35 patients with BKV viremia treated exclusively by immunosuppression reduction were scored according to Banff criteria and grouped relative to BKV viremia as pre-, increasing, decreasing and post-BKV viremia. Thirty-four of 35 patients (97%) cleared BKV viremia after a median of 9 months posttransplantation. The tubulitis score, extent of tubules with intraepithelial lymphocytes, and interstitial inflammation significantly increased from the time of increasing to decreasing viremia. Tubulointerstitial inflammation, to a lower extent, persisted after clearance. The number of SV40+ tubules correlated with the BKV load in plasma, but SV40 immunohistochemistry was frequently negative (60%). During decreasing viremia, 31% of PyVAN cases were plasma cell-rich and 40% showed tubular HLA-DR expression. Compared to baseline 1 month posttransplantation, allograft function remained stable or improved in 29/35 patients (83%) after a median follow-up of 48 months. Within 1 year after clearance of BKV viremia, clinical rejection occurred in 2/35 patients (6%). Our data suggest that resolving PyVAN is typically characterized by a self-limiting acute interstitial nephritis, morphologically indistinguishable from interstitial rejection.
    American Journal of Transplantation 06/2013; 13(6):1474-83. · 6.19 Impact Factor
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    ABSTRACT: One of the major tasks of human leukocyte antigen (HLA) laboratories is the pretransplant determination of unacceptable HLA antigen mismatches (UAM) in organ transplant recipients. HLA antigen specificities are determined against which the patient has circulating alloantibodies that are expected to harm the transplanted organ. Using the information on UAM, negative crossmatch (XM) prediction or 'virtual XM' is possible when a potential donor's complete HLA typing is available. Before the introduction of solid-phase antibody detection assays, UAM were determined using the complement-dependent cytotoxicity methodology. After the introduction of the single antigen bead technique, however, various UAM determination algorithms have emerged. In this report, six different laboratories worldwide present how they determine UAM in their collective of kidney transplant recipients in the pretransplant phase and proceed thereafter to transplantation.
    Tissue Antigens 05/2013; · 2.93 Impact Factor
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    ABSTRACT: BACKGROUND: Kidneys from pediatric donors weighing <10 kg are preferably transplanted en bloc, while kidneys from donors weighing >15 kg can be safely transplanted as single kidneys. However, single kidney transplantation from donors weighing 10-14 kg is controversial and has not been well investigated. METHODS: We analyzed the outcome of 15 recipients of single kidneys from donors weighing 10-14 kg (study group) with 40 recipients receiving an allograft from ideal deceased donors (control group). RESULTS: After a follow-up of three yr, death-censored graft survival was 100% in both groups. The calculated creatinine clearance was lower in the study group at six months (53 vs. 71 mL/min; p = 0.01) and similar at 12 months (68 vs. 68 mL/min; p = 0.48), 24 months (81 vs. 70 mL/min; p = 0.58), and 36 months (74 vs. 69 mL/min; p = 0.59). Urinary albumin/creatinine ratios were comparable between the two groups up to two yr. At three yr, urinary albumin/creatinine ratios were higher in the study group than the control group (10.5 vs. 0.9 mg/mmol; p = 0.007). Surveillance biopsies at three and six months post-transplant revealed no evidence for focal segmental glomerulosclerosis in the study group. CONCLUSIONS: Transplantation of single pediatric kidneys from donors weighing 10-14 kg into adult recipients provides excellent intermediate-term outcomes. Low-grade albuminuria, three yr post-transplant, might indicate late-onset hyperfiltration injury.
    Clinical Transplantation 03/2013; · 1.63 Impact Factor
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    ABSTRACT: The aim of this study was to define the frequency and determinants of pregnancy-induced child-specific sensitization shortly after full-term delivery using sensitive single HLA-antigen beads (SAB) and high resolution HLA-typing of the mothers and their children (n = 301). A positive SAB result was defined by a background normalized ratio >1 or a mean fluorescence intensity (MFI) >300, >500 and >1000, respectively. The overall frequency of pregnancy-induced sensitization determined by SAB shortly after full-term delivery was between 45% (MFI > 1000 cut-off) and 76% (ratio cut-off). The rate of child-specific sensitization at the HLA-A/B/C/DRB1 loci was between 28% (MFI > 1000 cut-off) and 38% (ratio cut-off). The number of live birth was associated with a higher frequency of sensitization, which was driven by child-specific, but not third party HLA-antibodies. There was a clear hierarchy of sensitization among the investigated loci (B-locus: 31%; A-locus: 26%; DRB1-locus: 20%; C-locus: 15%; p < 0.0001). Some mismatched paternal HLA-antigens led to a significantly higher rate of sensitization than the average (e.g. HLA-A2, HLA-B49, HLA-B51, HLA-C*15). Furthermore, the mother's own HLA-phenotype-especially HLA-A/B homozygosity-was associated with a higher rate and broadness of sensitization. The number of mismatched HLA-A/B/C eplets strongly correlated with the rate of child-specific class I sensitization.
    American Journal of Transplantation 01/2013; · 6.19 Impact Factor
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    ABSTRACT: The aim of this study was to evaluate risk factors and outcome of expanded-criteria donor (ECD) kidney transplants in patients with low immunological risk. We evaluated graft survival and graft function in 265 recipients with low immunological risk defined as the absence of pretransplant donor-specific HLA antibodies. A total of 112 (42%) kidneys derived from ECD and 153 (58%) from standard-criteria donors (SCDs). Overall, in a multivariate Cox regression, ECD status was the only significant risk factor for graft failure (hazard ratio [HR] 2.31, 95% confidence interval [CI] 1.22-4.37; p = 0.01). In the SCD group there was an increased risk for graft failure with increasing recipient age (HR 1.06 per year, CI 1.01-1.10; p = 0.02) and in the ECD group a trend for risk reduction for recipients treated with tacrolimus (Tac) (HR 0.46, CI 0.20‒1.06; p = 0.07). One, three and five-year graft survival of ECD kidneys was significantly better when recipients were treated with Tac (95%, 88% and 72%, respectively) than when they were treated without Tac (73%, 65% and 50%, respectively) (p = 0.008). At three years, ECD kidneys had a lower median estimated creatinine clearance (eCrCl) than SCD kidneys (37 vs 58 ml/min, p <0.001). Within the ECD group, recipients treated with Tac had a higher median eCrCl than those treated without Tac (41 ml/min vs 33 ml/min, p = 0.004). Graft function from one to three years was preserved in ECD recipients treated with Tac (median change 0.0 ml/min, p = 0.4) compared with those treated without Tac (median change -3.2 ml/min, p = 0.005). Tac-based immunosuppression seems to improve graft survival and to preserve graft function in ECD kidneys with low immunological risk.
    Schweizerische medizinische Wochenschrift 01/2013; 143:w13883. · 1.68 Impact Factor
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    ABSTRACT: Progressive interstitial fibrosis and tubular atrophy (IF/TA) is a leading cause of chronic allograft dysfunction. Increased extracellular matrix remodelling regulated by matrix metalloproteases (MMPs) and their inhibitors (TIMPs) has been implicated in the development of IF/TA. The aim of this study was to investigate whether urinary/serum MMPs/TIMPs correlate with subclinical IF/TA detected in surveillance biopsies within the first 6 months post-transplant. We measured eight different MMPs/TIMPs simultaneously in urine and serum samples from patients classified as normal histology (n = 15), IF/TA 1 (n = 15) and IF/TA 2-3 (n = 10). There was no difference in urinary MMPs/TIMPs among the three groups, and only 1/8 serum MMPs/TIMPs (i.e. MMP-1) was significantly elevated in biopsies with IF/TA 2-3 (p = 0.01). In addition, urinary/serum MMPs/TIMPs were not different between surveillance biopsies demonstrating an early development of IF/TA (i.e. delta IF/TA ≥ 1 compared to a previous biopsy obtained three months before; n = 11) and stable grade of IF/TA (i.e. delta IF/TA = 0; n = 20). Next, we investigated whether urinary/serum MMPs/TIMPs levels are elevated during acute subclinical tubulitis in surveillance biopsies obtained within the first 6 months post-transplant (n = 25). Compared to biopsies with normal histology, serum MMPs/TIMPs were not different; however, all urinary MMPs/TIMPs levels were numerically higher during subclinical tubulitis (MMP-1, MMP-7, TIMP-1 with p ≤ 0.04). We conclude that urinary/serum MMPs/TIMPs do hardly correlate with existing or early developing IF/TA in surveillance biopsies obtained within the first 6 months post-transplant. This could be explained by the dynamic process of extracellular matrix remodelling, which seems to be active during acute tubulo-interstitial injury/inflammation, but not in quiescent IF/TA.
    Transplant Immunology 01/2013; · 1.52 Impact Factor
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    ABSTRACT: In this multicentre study, sera from 803 retransplant candidates, including 775 kidney transplant recipients, were analysed with regard to the presence and specificity of anti-HLA alloantibodies of the IgA isotype using a modified microsphere-based platform. Of the kidney recipients, nearly one-third (n = 237, 31%) had IgA alloantibodies. Mostly, these antibodies were found in sera that also harboured IgG alloantibodies that could be found in a total of 572 (74%) of patients. Interestingly, IgA anti-HLA antibodies were preferentially targeting HLA class I antigens in contrast to those of the IgG isotype, which targeted mostly both HLA class I and II antigens. Donor specificity of the IgA alloantibodies could be established for over half of the 237 patients with IgA alloantibodies (n = 124, 52%). A further 58 patients had specificities against HLA-C or HLA-DP, for which no information regarding donor typing was available. In summary, these data showed in a large cohort of retransplant candidates that IgA alloantibodies occur in about one-third of patients, about half of these antibodies being donor specific.
    International Journal of Immunogenetics 12/2012; · 1.36 Impact Factor
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    ABSTRACT: Soluble CD30 (sCD30) has been proposed as a promising noninvasive biomarker for clinical renal allograft rejection, but its diagnostic characteristics regarding detection of subclinical rejection have not been assessed. We investigated sCD30 in 146 consecutive kidney allograft recipients under tacrolimus-mycophenolate-based immunosuppression having 250 surveillance biopsies at 3 and 6 months as well as 52 indication biopsies within the first year post-transplant. Allograft histology results were classified as (i) acute Banff score zero or interstitial infiltrates only, (ii) tubulitis t1, (iii) tubulitis t2-3 and (iv) isolated vascular compartment inflammation. sCD30 correlated well with the extent of clinical (P < 0.0001), but not subclinical tubulointerstitial rejection (P = 0.06). To determine diagnostic characteristics of sCD30, histological groups were assigned to two categories: no relevant inflammation (i.e. acute Banff score zero and interstitial infiltrates only) versus all other pathologies (tubulitis t1-3 and isolated vascular compartment inflammation). For clinical allograft inflammation, AUC was 0.87 (sensitivity 89%, specificity 79%; P = 0.0006); however, for subclinical inflammation, AUC was only 0.59 (sensitivity 50%, specificity 69%; P = 0.47). In conclusion, sCD30 correlated with clinical, but not subclinical renal allograft rejection limiting its clinical utility as a noninvasive rejection screening biomarker in patients with stable allograft function receiving tacrolimus-mycophenolate-based immunosuppression.
    Transplant International 11/2012; · 3.16 Impact Factor
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    ABSTRACT: Delayed graft function (DGF) is considered as a risk factor for renal allograft rejection, but this association might be confounded by diagnostic biases (e.g., higher biopsy frequency in patients with DGF, inclusion of clinically diagnosed rejection episodes, and limited details on the rejection phenotype). This retrospective study including 329 deceased donor transplantations aimed to clarify a causal relationship between DGF and rejection. DGF occurred in 93/329 recipients (28%), whereas immediate graft function (IGF) in 236/329 recipients (72%). The percentage of patients with ≥1 allograft biopsy within the first year post-transplant was similar between the DGF and IGF group (96% vs. 94%; p = 0.60). The cumulative one-yr incidence of biopsy-proven clinical (35% vs. 34%; p = 0.62) and combined (sub)clinical rejection (58% vs. 60%; p = 0.79) was not different between the two groups. Furthermore, there were no differences regarding rejection phenotypes/severities and time frame of occurrence. By multivariable Cox regression analysis, donor-specific HLA antibodies, younger recipient age, and immunosuppressive regimens were independent predictors for clinical rejection, while DGF was not. These results in an intermediate sized, but thoroughly investigated patient population challenge the concept that DGF is a risk factor for rejection and highlights the need for additional studies in this regard.
    Clinical Transplantation 10/2012; · 1.63 Impact Factor
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    ABSTRACT: Urinary CXCL10 is a promising noninvasive biomarker for tubulo-interstitial allograft inflammation, but its diagnostic characteristics have not been assessed in a real-life setting. We investigated urinary CXCL10 in 213 consecutive renal allograft recipients having 362 surveillance biopsies at 3/6 months and 80 indication biopsies within the first year posttransplant. Allograft histology results were classified as (i) acute Banff score zero, (ii) interstitial infiltrates only, (iii) tubulitis t1, (iv) tubulitis t2-3 and (v) isolated vascular compartment inflammation. For clinical and subclinical pathologies, urinary CXCL10 correlated well with the extent of tubulo-interstitial inflammation. To determine diagnostic characteristics of urinary CXCL10, histological groups were separated into two categories: no relevant inflammation (i.e. acute Banff score zero and interstitial infiltrates only) versus all other pathologies (i.e. tubulitis t1-3 and isolated vascular compartment inflammation). For subclinical pathologies, AUC was 0.69 (sensitivity 61%, specificity 72%); for clinical pathologies, AUC was 0.74 (sensitivity 63%, specificity 80%). A urinary CXCL10-guided biopsy strategy would have reduced performance of surveillance and indication biopsies by 61% and 64%, respectively. Missed (sub)clinical pathologies were mostly tubulitis t1 and isolated vascular compartment lesions. In real life, urinary CXCL10 had clinically useful diagnostic properties making it a candidate biomarker to guide allograft biopsies.
    American Journal of Transplantation 03/2012; 12(7):1811-23. · 6.19 Impact Factor
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    ABSTRACT: A high prevalence of vitamin D insufficiency has been found in the general population, in patients with chronic kidney disease and in kidney transplant patients. During winter there is a higher prevalence of vitamin D insufficiency due to the lack of solar ultraviolet B (UVB) exposure. Kidney transplant patients are advised to avoid sun exposure because of their high risk of skin cancer. This is considered to be one of the main reasons for the very high prevalence of vitamin D insufficiency in these patients. Whether circannual rhythm of vitamin D is totally reversed in kidney transplant patients is not known. In this single centre prospective observational study, 50 kidney transplant patients visiting our outpatient clinic in January and February 2011 were included. Serum concentration of 25-hydroxvitamin D (25[OH]D), 1-25-hydroxvitamin D (1-25[OH]D) and intact parathormone (iPTH) were measured at study entry and 6 months later in summer. A total of 90% (45/50) of the study population had vitamin D deficiency 25(OH)D (<50 nmol/l) during winter. There was a rise of 25(OH)D in 94% (47/50) of patients from winter to summer (p <0.0001) leading to a decline of 25(OH)D deficiency from 90 to 60%, to a rise of 25(OH)D insufficiency from 6 to 26% and normal 25(OH)D from 4 to 14%, respectively (p = 0.0024). Vitamin D insufficiency during winter is very common in kidney transplant patients at our centre. Despite avoidance of exposure to UVB there is a preserved circannual rhythm of vitamin D in kidney transplant patients.
    Schweizerische medizinische Wochenschrift 01/2012; 142. · 1.68 Impact Factor
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    ABSTRACT: The subclass of IgG antibodies contributes to their capability to activate complement. It is currently unknown whether the pretransplant IgG subclass composition allows distinguishing harmful from presumably irrelevant donor-specific human leukocyte antigen (HLA) antibodies (HLA-DSA) detected by single-antigen flow beads (SAFB). Seventy-four patients transplanted in the presence of HLA-DSA were investigated. HLA-DSA characteristics were not different between patients experiencing antibody-mediated rejection (AMR) (n=40) and patients who did not (n=34) experience AMR. Sera were reanalyzed using SAFB with IgG subclass-specific reporter antibodies. The 74 patients had in total 141 HLA-DSA. IgG1 was the predominant subclass (78%), followed by IgG2 (49%), IgG3 (36%), and IgG4 (20%). When grouped according to the complement-activating capability, only 4 of 74 patients (5%) had exclusively weak/no complement-activating HLA-DSA (i.e., IgG2 and IgG4), 21 of 74 patients (28%) had isolated strong complement-activating HLA-DSA (i.e., IgG1 and IgG3), and 46 of 74 patients (62%) had a mixture of both. There was no difference between the strong complement-activating and the mixture group regarding incidence of AMR (57% vs. 54%; P=0.81), phenotypes of AMR (P=0.70), and death-censored allograft survival at 5 years (78% vs. 78%; P=0.74). Interestingly, patients with exclusively weak/no complement-activating HLA-DSA (n=4) had a numerically lower incidence of AMR (25%) and no allograft loss has occurred yet. In 90% of patients, pretransplant HLA-DSA are composed of isolated strong or a mixture of strong and weak/no complement-activating IgG subclasses. Because outcomes in these two groups were similar, pretransplant IgG subclass analysis is likely not providing substantial value beyond the standard IgG SAFB assay for pretransplant risk stratification.
    Transplantation 07/2011; 92(1):41-7. · 3.78 Impact Factor
  • R A Bray, C Murphey, S Schaub
    American Journal of Transplantation 03/2011; 11(4):650-1. · 6.19 Impact Factor
  • Scandinavian Journal of Immunology 02/2011; 73(2):156-8. · 2.20 Impact Factor
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    ABSTRACT: The virtual crossmatch (virtual-XM) has been proposed for accurate identification of donor-specific HLA-antibodies, but large prospective studies assessing its value for pretransplant risk stratification are lacking. A total of 233 consecutive renal allograft recipients were prospectively stratified according to the virtual-XM. In patients with a negative virtual-XM (n=190, 82%), prospective cytotoxicity crossmatches (CDC-XM) were omitted, and they received standard immunosuppression. Virtual-XM positive patients were only transplanted if CDC-XM were negative. They received additional induction with anti-T-lymphocyte-globulin and intravenous immunoglobulins (n=43, 18%). The cumulative incidence of clinical/subclinical antibody-mediated rejection (AMR) at 1 year was lower in the negative virtual-XM than in the positive virtual-XM group [15/190 (8%) vs. 18/43 (42%); P<0.0001]. After a median follow-up of 2.6 years, allograft loss because of AMR occurred less often in the negative virtual-XM group (1% vs. 7%; P=0.04) and death-censored allograft survival at 2 years was higher (98% vs. 91%; P=0.02). Serum creatinine was not different at the last follow-up (129 μm vs. 130 μm; P=0.58). We conclude that a negative virtual-XM defines patients at low risk for AMR and early allograft loss, while a positive virtual-XM represents a significant risk for AMR despite enhanced induction therapy. This supports the utility of the virtual-XM for risk stratification and treatment allocation.
    Transplant International 02/2011; 24(6):560-9. · 3.16 Impact Factor
  • Human Immunology - HUM IMMUNOL. 01/2011; 72.