Andreas L Serra

University of Zurich, Zürich, Zurich, Switzerland

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Publications (65)350.53 Total impact

  • Laura Rotar, Andreas L. Serra, Katja Petzold
    Schweiz Med Forum. 04/2014; 2014(14 (16-17)):350-351.
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    ABSTRACT: Diabetic nephropathy (DN) is one of the major late complications of diabetes. Treatment aimed at slowing down the progression of DN is available but methods for early and definitive detection of DN progression are currently lacking. The 'Proteomic prediction and Renin angiotensin aldosterone system Inhibition prevention Of early diabetic nephRopathy In TYpe 2 diabetic patients with normoalbuminuria trial' (PRIORITY) aims to evaluate the early detection of DN in patients with type 2 diabetes (T2D) using a urinary proteome-based classifier (CKD273). In this ancillary study of the recently initiated PRIORITY trial we aimed to validate for the first time the CKD273 classifier in a multicentre (9 different institutions providing samples from 165 T2D patients) prospective setting. In addition we also investigated the influence of sample containers, age and gender on the CKD273 classifier. We observed a high consistency of the CKD273 classification scores across the different centres with areas under the curves ranging from 0.95 to 1.00. The classifier was independent of age (range tested 16-89 years) and gender. Furthermore, the use of different urine storage containers did not affect the classification scores. Analysis of the distribution of the individual peptides of the classifier over the nine different centres showed that fragments of blood-derived and extracellular matrix proteins were the most consistently found. We provide for the first time validation of this urinary proteome-based classifier in a multicentre prospective setting and show the suitability of the CKD273 classifier to be used in the PRIORITY trial.
    Nephrology Dialysis Transplantation 03/2014; · 3.37 Impact Factor
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    ABSTRACT: Organ transplant recipients (OTR) are at high risk for cutaneous squamous cell carcinomas (SCC). We aimed to define clinically meaningful patient-reported warning signals predicting the presence of invasive SCC.Patient-reported signs and symptoms of 812 consecutively biopsied skin lesions from 410 OTR were determined by questionnaire and physical examination and related to the subsequent biopsy-proven diagnoses. Receiver-operating characteristic (ROC) curve analyses were used as a measure of distinction between the predictive values of patient-reported warning signals and the occurrence of SCC. Pain was an independent predictive patient-reported warning signal for a biopsy-proven invasive SCC. The odds ratio from the fully adjusted model predicting SCC was 4.4(95% confidence interval: 2.4–8.2). Higher scores on the visual analog scale (VAS) for pain were associated witha greater likelihood for the presence of SCC compared to none or mild pain. The for scores on the VAS from 1to 3, 4 to 6 and 7 to 10 were 4.9 (2.2–10.5), 2.3 (0.96–5.5)and 16.5 (3.6–75.8), respectively. Pain is the most powerful patient-reported warning signal for invasive cutaneous SCC in OTR. Empowerment of patients by education could accelerate diagnosis and treatment of cutaneous SCC.
    American Journal of Transplantation 03/2014; 14(3):668-76. · 6.19 Impact Factor
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    ABSTRACT: The complement system is involved in many immune complex-mediated kidney diseases, yet its role in the pathogenesis of autosomal dominant polycystic kidney disease (ADPKD) has not been examined in detail. Screening of the glycoproteome of urine samples from ADPKD patients revealed that levels of complement factor B (CFB), serpin peptidase inhibitor, complement component 1 inhibitor (SERPING1) and complement component 9 (C9) increased whereas complement component 1, r subcomponent-like (C1RL), CD55 and CD59 levels decreased with disease progression. Immunostaining and western blot analysis confirmed the enhanced expression of CFB and C9 in cystic kidneys from ADPKD patients. Immunostaining also showed that the expressions of CFB and C9 in renal biopsy tissues from patients with other types of chronic kidney disease were lower than in tissues from ADPKD patients. The effect of the complement inhibitor rosmarinic acid (RMA) was evaluated in Pkd1(-/-) mice and Han:SPRD Cy/+ rats. Compared with vehicle-treated Pkd1(-/-) animals, RMA-treated mice had significantly lower serum creatinine (-50%) and blood urea nitrogen (-78%) levels, two kidneys/body weight ratio (-60%) and renal cystic index (-60%). Similar results were found in Cy/+ rats. Lower numbers of Ki67-positive nuclei and inflammatory cells and reduced fibrosis were observed in both animal models upon treatment with RMA. These results suggest that excessive activation of the alternative complement pathway is associated with ADPKD progression, probably mediated by cyst-lining epithelial cell proliferation, tubulointerstitial inflammatory cell infiltration and fibrosis. Targeting the complement system might represent a new therapeutic strategy for ADPKD. This article is protected by copyright. All rights reserved.
    Journal of Internal Medicine 02/2014; · 6.46 Impact Factor
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    ABSTRACT: Fibroblast growth factor 23 (FGF23) regulates phosphate homeostasis and is linked to cardiovascular disease and all-cause mortality in chronic kidney disease. FGF23 rises in patients with CKD stages 2-3, but in patients with autosomal dominant polycystic kidney disease, the increase of FGF23 precedes the first measurable decline in renal function. The mechanisms governing FGF23 production and effects in kidney disease are largely unknown. Here we studied the relation between FGF23 and mineral homeostasis in two animal models of PKD. Plasma FGF23 levels were increased 10-fold in 4-week-old cy/+ Han:SPRD rats, whereas plasma urea and creatinine concentrations were similar to controls. Plasma calcium and phosphate levels as well as TmP/GFR were similar in PKD and control rats at all time points examined. Expression and activity of renal phosphate transporters, the vitamin D3-metabolizing enzymes, and the FGF23 co-ligand Klotho in the kidney were similar in PKD and control rats through 8 weeks of age, indicating resistance to FGF23, although phosphorylation of the FGF receptor substrate 2α protein was enhanced. In the kidneys of rats with PKD, FGF23 mRNA was highly expressed and FGF23 protein was detected in cells lining renal cysts. FGF23 expression in bone and spleen was similar in control rats and rats with PKD. Similarly, in an inducible Pkd1 knockout mouse model, plasma FGF23 levels were elevated, FGF23 was expressed in kidneys, but renal phosphate excretion was normal. Thus, the polycystic kidney produces FGF23 but is resistant to its action.Kidney International advance online publication, 8 January 2014; doi:10.1038/ki.2013.526.
    Kidney International 01/2014; · 7.92 Impact Factor
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    ABSTRACT: Autosomal dominant polycystic kidney disease (ADPKD) is a relentlessly progressing form of chronic kidney disease for which there is no cure. The aim of this study was to characterize Chinese patients with ADPKD and to identify the factors which predict cyst growth and renal functional deterioration. To analyze disease predicting factors we performed a prospective longitudinal observational study in a cohort of 541 Chinese patients with ADPKD and an eGFR ≥30 ml/min/1.73 m2. Patients were followed clinically and radiologically with sequential abdominal magnetic resonance imaging (MRI). Clinical characteristics and laboratory data were related to changes in estimated glomerular filtration rate (eGFR) and total kidney volume (TKV). A linear regression model was developed to analyze the factors which determine eGFR and TKV changes. The age range of this unselected cohort ranged from 4 to 77 years. Median follow-up time was 14.3±10.6 months. Although inter-individual differences in eGFR and TKV were large, there was a consistent link between these two parameters. Baseline log10-transformed TKV and urinary protein/creatinine ratio were identified as the major predictors for a faster eGFR decline and were associated with a higher TKV growth rate. Interestingly, a lower thrombocyte count correlated significantly with lower eGFR (r = 0.222) and higher TKV (r = 0.134). This large cohort of Chinese patients with ADPKD provides unique epidemiological data for comparison with other cohorts of different ethnicity. In Chinese patients we identified a lower thrombocyte count as a significant predictor of disease progression. These results are important for the design of future clinical trials to retard polycystic kidney disease progression.
    PLoS ONE 01/2014; 9(3):e92232. · 3.73 Impact Factor
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    ABSTRACT: Solid organ transplant recipients are highly susceptible to skin cancer. The major driving factors are immunosuppressive medication and ultraviolet light. Appropriate sun protection markedly reduces the development of skin cancer. Skin cancer recognized at an early stage can reliably be cured, and fatal outcomes can be prevented. The aim of this work is to educate organ transplant recipients and health care professionals involved in their care, to increase awareness of skin cancer in this high-risk population and thus to optimize the long-term outcome of patients with skin cancer. Our newly developed website provides free access to various educational materials, including leaflets, presentations and interactive elements using edutainment.
    Praxis 11/2013; 102(23):1415-20.
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    ABSTRACT: Tuberous Sclerosis Complex, Review, mTOR pathway
    swiss medical weekly. 09/2013; 13(36):696-702.
  • Katja Petzold, Andreas L Serra
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    ABSTRACT: Inherited cystic kidney diseases are a heterogeneous group of rare diseases. Based on molecular biological findings approved drugs have already been recently tested for the new indications for autosomal dominant polycystic kidney disease (ADPKD) and tuberous sclerosis complex. For ADPKD it is important to note that renal function remains stable for decades so the effectiveness of treatment is determined by renal size as a surrogate marker of disease burden. In a 3-year study of 1,445 ADPKD patients tolvaptan, an aquaretic agent, decreased the growth of kidneys, renal function loss and kidney pain. The long-acting somatostatins octreotide and lanreotide moderately decreased liver and kidney size in patients with ADPKD and polycystic liver disease. The mTOR inhibitors sirolimus and everolimus were ineffective for the indications of ADPKD while these drugs shrunk the renal angiomyolipomas associated with tuberous sclerosis. Health authorities will decide this year on the approval of tolvaptan for ADPKD and of everolimus for the indications for tuberous sclerosis complex.
    Der Nephrologe 09/2013; 2013(8):396-405.
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    ABSTRACT: Renal tubular epithelial cell proliferation and transepithelial cyst fluid secretion are key features in the progression of polycystic kidney disease (PKD). As the role of the apical renal sodium-glucose cotransporters in these processes is not known, we tested whether phlorizin inhibits cyst growth and delays renal disease progression in a rat model of PKD. Glycosuria was induced by subcutaneous injection of phlorizin in male heterozygous (Cy/+) and wild-type Han:SPRD rats. Phlorizin induced immediate and sustained glycosuria and osmotic diuresis in these rats. Cy/+ rats treated with phlorizin for 5 weeks showed a significant increase in creatinine clearance, a lower 2-kidneys/body weight ratio, a lower renal cyst index, and reduced urinary albumin excretion as compared with vehicle-treated Cy/+ rats. Measurement of Ki67 staining found significantly lower cell proliferation in dilated tubules and cysts of Cy/+ rats treated with phlorizin, as well as a marked inhibition of the activated MAP kinase pathway. In contrast, the mTOR pathway remained unaltered. Phlorizin dose dependently inhibited MAP kinase in cultured tubular epithelial cells from Cy/+ rats. Thus, long-term treatment with phlorizin significantly inhibits cystic disease progression in a rat model of PKD. Hence, induction of glycosuria and osmotic diuresis (glycuresis) by renal sodium-glucose cotransporters inhibition could have a therapeutic effect in polycystic kidney disease.Kidney International advance online publication, 29 May 2013; doi:10.1038/ki.2013.199.
    Kidney International 05/2013; · 7.92 Impact Factor
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    ABSTRACT: The mammalian target of rapamycin (mTOR) signaling pathway is aberrantly activated in polycystic kidney disease (PKD). Emerging evidence suggests that phospholipase D (PLD) and its product phosphatidic acid (PA) regulate mTOR activity. In this study, we assessed in vitro the regulatory function of PLD and PA on the mTOR signaling pathway in PKD. We found that the basal level of PLD activity was elevated in PKD cells. Targeting PLD by small molecule inhibitors reduced cell proliferation and blocked mTOR signaling, whereas exogenous PA stimulated mTOR signaling and abolished the inhibitory effect of PLD on PKD cell proliferation. We also show that blocking PLD activity enhanced the sensitivity of PKD cells to rapamycin and that combining PLD inhibitors and rapamycin synergistically inhibited PKD cell proliferation. Furthermore, we demonstrate that targeting mTOR did not induce autophagy, whereas targeting PLD induced autophagosome formation. Taken together, our findings suggest that deregulated mTOR pathway activation is mediated partly by increased PLD signaling in PKD cells. Targeting PLD isoforms with pharmacological inhibitors may represent a new therapeutic strategy in PKD.
    PLoS ONE 01/2013; 8(8):e73173. · 3.73 Impact Factor
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    ABSTRACT: Treatment options for autosomal dominant polycystic kidney disease (ADPKD) will likely become available in the near future, hence reliable diagnostic and prognostic biomarkers for the disease are strongly needed. Here, we aimed to define urinary proteomic patterns in ADPKD patients, which aid diagnosis and risk stratification. By capillary electrophoresis online coupled to mass spectrometry (CE-MS), we compared the urinary peptidome of 41 ADPKD patients to 189 healthy controls and identified 657 peptides with significantly altered excretion, of which 209 could be sequenced using tandem mass spectrometry. A support-vector-machine based diagnostic biomarker model based on the 142 most consistent peptide markers achieved a diagnostic sensitivity of 84.5% and specificity of 94.2% in an independent validation cohort, consisting of 251 ADPKD patients from five different centers and 86 healthy controls. The proteomic alterations in ADPKD included, but were not limited to markers previously associated with acute kidney injury (AKI). The diagnostic biomarker model was highly specific for ADPKD when tested in a cohort consisting of 481 patients with a variety of renal and extrarenal diseases, including AKI. Similar to ultrasound, sensitivity and specificity of the diagnostic score depended on patient age and genotype. We were furthermore able to identify biomarkers for disease severity and progression. A proteomic severity score was developed to predict height adjusted total kidney volume (htTKV) based on proteomic analysis of 134 ADPKD patients and showed a correlation of r = 0.415 (p<0.0001) with htTKV in an independent validation cohort consisting of 158 ADPKD patients. In conclusion, the performance of peptidomic biomarker scores is superior to any other biochemical markers of ADPKD and the proteomic biomarker patterns are a promising tool for prognostic evaluation of ADPKD.
    PLoS ONE 01/2013; 8(1):e53016. · 3.73 Impact Factor
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    ABSTRACT: Fabry disease (FD) is an X-linked disorder of glycosphingolipid catabolism resulting in the accumulation of glycolipids including globotriaosylceramide in cells of various tissues resulting in end-organ manifestations. Initially, FD is typically characterized by angiokeratoma and recurrent episodes of neuropathic pain in the extremities occurring during childhood or adolescence. Most affected patients also exhibit a decreased ability to sweat. Later in life, FD results in left ventricular hypertrophy, proteinuria, renal failure and stroke. These later disease manifestations are non-specific and also common in diabetes, hypertension and atheromatosis and thus for most practitioners do not point into the direction of FD. As a consequence, FD is under-diagnosed and screening of high-risk groups is important for case finding, as is a thorough pedigree analysis of affected patients. In the nephrology clinic, we suggest to screen patients for FD when there is unexplained chronic kidney disease in males younger than 50 years and females of any age. In men, this can be performed by measuring α-galactosidase A activity in plasma, white blood cells or dried blood spots. In women, mutation analysis is necessary, as enzyme measurement alone could miss over one-third of female Fabry patients. A multidisciplinary team should closely monitor all known Fabry patients, with the nephrologist screening kidney impairment (glomerular filtration rate and proteinuria) on a regular basis. Transplanted Fabry patients have a higher mortality than the regular transplant population, but have acceptable outcomes, compared with Fabry patients remaining on dialysis. It is unclear whether enzyme replacement therapy (ERT) prevents deterioration of kidney function. In view of the lack of compelling evidence for ERT, and the low likelihood that a sufficiently powered randomized controlled trial on this topic will be performed, data of all patients with FD should be collected in a central registry.
    Nephrology Dialysis Transplantation 12/2012; · 3.37 Impact Factor
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    ABSTRACT: Background Klotho and fibroblast growth factor 23 (FGF23) are key regulators of mineral metabolism in renal insufficiency. FGF23 levels have been shown to increase early in chronic kidney disease (CKD); however, the corresponding soluble Klotho levels at the different CKD stages are not known.Methods Soluble Klotho, FGF23, parathyroid hormone (PTH), 1,25-dihydroxy vitamin D(3) (1,25D) and other parameters of mineral metabolism were measured in an observational cross-sectional study in 87 patients. Locally weighted scatter plot smoothing function of these parameters were plotted versus estimated glomerular filtration rate (eGFR) to illustrate the pattern of the relationship. Linear and non-linear regression analyses were performed to estimate changes in mineral metabolism parameters per 1mL/min/1.73 m(2) decline.ResultsIn CKD 1-5, Klotho and 1,25D linearly decreased, whereas both FGF23 and PTH showed a baseline at early CKD stages and then a curvilinear increase. Crude mean Klotho level declined by 4.8 pg/mL (95% CI 3.5-6.2 pg/mL, P < 0.0001) and 1,25D levels by 0.30 ng/L (95% CI 0.18-0.41 ng/L, P < 0.0001) as GFR declined by 1 mL/min/1.73 m(2). After adjustment for age, gender, serum 25-hydroxyvitamin D levels and concomitant medications (calcium, supplemental vitamin D and calcitriol), we estimated that the mean Klotho change was 3.2 pg/mL (95% CI 1.2-5.2 pg/mL, P = 0.0019) for each 1 mL/min/1.73 m(2) GFR change. FGF23 departed from the baseline at an eGFR of 47 mL/min/1.73 m(2) (95% CI 39-56 mL/min/1.73 m(2)), whereas PTH departed at an eGFR of 34 mL/min/1.73 m(2) (95% CI 19-50 mL/min/1.73 m(2)).Conclusions Soluble Klotho and 1,25D levels decrease and FGF23 levels increase at early CKD stages, whereas PTH levels increase at more advanced CKD stages.
    Nephrology Dialysis Transplantation 11/2012; · 3.37 Impact Factor
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    ABSTRACT: Transplant recipients in whom cutaneous squamous-cell carcinomas develop are at high risk for multiple subsequent skin cancers. Whether sirolimus is useful in the prevention of secondary skin cancer has not been assessed. In this multicenter trial, we randomly assigned transplant recipients who were taking calcineurin inhibitors and had at least one cutaneous squamous-cell carcinoma either to receive sirolimus as a substitute for calcineurin inhibitors (in 64 patients) or to maintain their initial treatment (in 56). The primary end point was survival free of squamous-cell carcinoma at 2 years. Secondary end points included the time until the onset of new squamous-cell carcinomas, occurrence of other skin tumors, graft function, and problems with sirolimus. Survival free of cutaneous squamous-cell carcinoma was significantly longer in the sirolimus group than in the calcineurin-inhibitor group. Overall, new squamous-cell carcinomas developed in 14 patients (22%) in the sirolimus group (6 after withdrawal of sirolimus) and in 22 (39%) in the calcineurin-inhibitor group (median time until onset, 15 vs. 7 months; P=0.02), with a relative risk in the sirolimus group of 0.56 (95% confidence interval, 0.32 to 0.98). There were 60 serious adverse events in the sirolimus group, as compared with 14 such events in the calcineurin-inhibitor group (average, 0.938 vs. 0.250). There were twice as many serious adverse events in patients who had been converted to sirolimus with rapid protocols as in those with progressive protocols. In the sirolimus group, 23% of patients discontinued the drug because of adverse events. Graft function remained stable in the two study groups. Switching from calcineurin inhibitors to sirolimus had an antitumoral effect among kidney-transplant recipients with previous squamous-cell carcinoma. These observations may have implications concerning immunosuppressive treatment of patients with cutaneous squamous-cell carcinomas. (Funded by Hospices Civils de Lyon and others; TUMORAPA ClinicalTrials.gov number, NCT00133887.).
    New England Journal of Medicine 07/2012; 367(4):329-39. · 51.66 Impact Factor
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    ABSTRACT: Background. Autosomal dominant polycystic kidney disease (ADPKD) is an inherited disorder that results in the growth of cysts in the kidneys and other organs. Multisystemic involvement is common including affection of the central nervous system with cerebral aneurysms and ara-chnoid cysts. Methods. This is a prospective cohort study to investigate the prevalence and growth rate of ara-chnoid cysts in ADPKD patients. Participants enrolled in the SUISSE ADPKD cohort were offered cranial imaging for the detection of intracranial alterations. In the case of identified arachnoid cysts, patients were suggested to undergo follow-up imaging to assess the growth rate of the cysts. Volume of arachnoid cysts at the baseline and at follow-up visits was assessed by manual segmentation on a dedicated workstation. Results. A total of 109 ADPKD patients agreed to undergo cranial imaging. In 14 (12.8%) patients (9 males and 5 females), 18 singular arachnoid cysts were identified. The baseline volumes of individual cysts ranged from 1.8 to 337.6 cm 3 . During a mean follow-up period of 24 months, the volume changes of 12 individual arachnoid cysts of nine patients ranged from −3.1 to 3.7 cm 3 . Cystic lesions were mostly localized in the middle fossa. All affected patients were clinically asymptomatic. Conclusions. We found a higher prevalence of arachnoid cysts in ADPKD patients with more ad-vanced disease. There was a large variability in size and growth. These arachnoid cysts were clini-cally silent and their growth pattern was subtle and unpredictable, in contrast to the much more foreseeable growth of the renal cysts.
    Clin Kidney J. 07/2012; 5(5):405-411.
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    ABSTRACT: Autosomal dominant polycystic kidney disease (ADPKD) is associated with a urine-concentrating defect attributed to renal cystic changes. As PKD genes are expressed in the brain, altered central release of arginine vasopressin could also play a role. In order to help determine this we measured central and nephrogenic components of osmoregulation in 10 adults and 10 children with ADPKD, all with normal renal function, and compared them to 20 age- and gender-matched controls. Overnight water deprivation caused a lower rise in urine osmolality in the patients with ADPKD than controls, reflecting an impaired release of vasopressin and a peripheral defect in the patients. The reactivity of plasma vasopressin to water deprivation, as found in controls, was blunted in the patients with the latter showing lower urine osmolality for the same range of plasma vasopressin. The maximal urine osmolality correlated negatively with total kidney volume. Defective osmoregulation was confirmed in the children with ADPKD but was unrelated to number of renal cysts or kidney size. Thus, patients with ADPKD have an early defect in osmoregulation, with a blunted release of arginine vasopressin. This reflects expression of polycystins in hypothalamic nuclei that synthesize vasopressin, and this should be considered when evaluating treatments targeting the vasopressin pathway in ADPKD.Kidney International advance online publication, 20 June 2012; doi:10.1038/ki.2012.225.
    Kidney International 06/2012; · 7.92 Impact Factor
  • New England Journal of Medicine 03/2012; 366(11):1062-4. · 51.66 Impact Factor
  • Praxis 01/2012; 101(2):75-83.
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    ABSTRACT: Solid organ transplant recipients (SOTR) have an increased risk of skin cancer due to their long-term immunosuppressive state. As the number of these patients is increasing, as well as their life expectancy, it is important to discuss the screening and management of skin cancer in this group of patients. The role of the dermatologist, in collaboration with the transplant team, is important both before transplantation, where patients are screened for skin lesions and the individual risk for skin cancer development is assessed, and after transplantation. Posttransplant management consists of regular dermatological consultations (the frequency depends on different factors discussed below), where early skin cancer screening and management, as well as patient education on sun protective behavior is taught and enforced. Indeed, SOTR are very sensitive to sun damage due to their immunosuppressive state, leading to cumulative sun damage which results in field cancerization with numerous lesions such as in situ squamous cell carcinoma, actinic keratosis and Bowen's disease. These lesions should be recognized and treated as early as possible. Therapeutic options discussed will involve topical therapy, surgical management, adjustment of the patient's immunosuppressive therapy (i.e. reduction of immunosuppression and/or switch to mammalian target of rapamycin inhibitors) and chemoprevention with the retinoid acitretin, which reduces the recurrence rate of squamous cell carcinoma. The dermatological follow-up of SOTR should be integrated into the comprehensive posttransplant care.
    Current problems in dermatology 01/2012; 43:57-70.