Niko Braun

Characterization and outcome following Puumala virus infection: a retrospective analysis of 75 cases

BACKGROUND Infection with the Puumala virus (PUUV), which belongs to the Hantavirus family, is a common but often neglected cause of acute kidney injury (AKI) in endemic areas of Europe. The objective of the present study was to systematically analyse clinical presentation and renal outcomes following PUUV infection. METHODS In a retrospective study, we analysed data from 75 patients who were admitted to two large hospitals in Germany over an 8-year period and who tested positive for PUUV infection. Clinical and laboratory data were collected from patient files; creatinine levels before admission and during follow-up were obtained from phone calls. RESULTS Patients were between 16 and 82 years old (average +/- SD, 40.4 +/- 13.4) with a male to female ratio of 2.5:1. They showed a wide variety of clinical presentations with renal failure being the cause of admission in only 50%. AKI developed in 95% of patients who showed maximum creatinine levels of 4.3 +/- 0.3 mg/dl. Four patients required temporary dialysis, and one patient died from pulmonary complications. Thrombocytopaenia (137 +/- 11 x 10(3)/microl) was present in almost all cases, and elevated levels of lactate dehydrogenase (LDH) and C-reactive protein (CRP) were observed in 57 and 100% of patients, respectively. Urinalysis revealed mild to nephrotic proteinuria in 85%, which was often associated with haemoglobinuria. All patients showed full recovery of renal function and return to pre-existing normal serum creatinine levels. CONCLUSION In a majority of cases, PUUV infection results in thrombocytopenic AKI. Fever is a requirement for diagnosis, while elevated LDH and CRP values are also frequently observed. Overall, early renal outcomes were excellent.

Podoplanin-positive cells are a hallmark of encapsulating peritoneal sclerosis

BACKGROUND Encapsulating peritoneal sclerosis (EPS) and simple peritoneal sclerosis are important complications of long-term peritoneal dialysis (PD). Podoplanin is expressed by mesothelial cells and lymphatic vessels, which are involved in inflammatory reactions in the peritoneal cavity. METHODS We studied 69 peritoneal biopsies from patients on PD (n = 16), patients with EPS (n = 18) and control biopsies taken at the time of hernia repair (n = 15) or appendectomy (n = 20). Immunohistochemistry was performed to localize podoplanin. Additionally, markers of endothelial cells, mesothelial cells, myofibroblasts (smooth muscle actin), proliferating cells, and double labelling for smooth muscle actin/podoplanin were used on selected biopsies. RESULTS Podoplanin was present on the endothelium of lymphatic vessels in the submesothelial fibrous tissue and on mesothelial cells. In patients on PD and in biopsies with appendicitis, the mesothelial cells demonstrated a cuboidal appearance and circumferential podoplanin staining, with gaps between the cells. The number of lymphatic vessels was variable, but prominent at sites of fibrosis. In patients with EPS, a diffuse infiltration of podoplanin-positive cells with a fibroblastic appearance was present in 15 out of 18 biopsies. This pattern was focally present in 3 out of 16 on PD and none in the 35 controls. The podoplanin-positive cells did not express the endothelial marker or the mesothelial marker (calretinin). CONCLUSIONS EPS is characterized by a population of podoplanin and smooth muscle actin double-positive cells. Podoplanin might be a suitable morphological marker supporting the diagnosis and might be involved in the pathogenesis of EPS.

Influence of Thyroid Function on Different Kidney Function Tests

Background/Aims: The commonly used kidney function tests have limitations, especially in thyroid dysfunction. Therefore, we studied the most commonly used kidney function tests in patients with hypo- and hyperthyroidism and after reaching euthyroidism. Methods: Prospective case series in 16 patients with thyroid dysfunction. Serum creatinine, 24-hour creatinine clearance, calculated glomerular filtration rate (GFR) by Cockroft-Gault, estimated GFR (eGFR) by the Chronic Kidney Disease Epidemiology Collaboration equation, serum cystatin C, eGFR based on cystatin C, eGFR based on a combined (cystatin C and creatinine) formula and plasma neutrophil gelatinase-associated lipocalin (NGAL) were measured in hypo- and hyperthyroidism and after gaining euthyroidism. Results: When free thyroxine (fT4) normalized in hypothyroid patients, creatinine decreased and creatinine-based eGFR increased significantly. In contrast, cystatin C increased and eGFR based on cystatin C decreased significantly. There was no significant change in NGAL levels. When fT4 normalized in patients with hyperthyroidism, creatinine increased and creatinine-based eGFR decreased significantly. In contrast, cystatin C decreased and cystatin-C-based GFR increased significantly. There was no significant change in NGAL levels. Conclusions: Thyroid function has a major influence on the vast majority of kidney function tests. Cystatin C is strongly influenced by the thyroid function and should be avoided in thyroid disorders. There was no effect on the plasma NGAL levels. The recommended kidney function test is a measurement of creatinine-based eGFR.

Identification of the PTPN22 functional variant R620W as susceptibility genetic factor for giant cell arteritis

Objective To analyse the role of the PTPN22 and CSK genes, previously associated with autoimmunity, in the predisposition and clinical phenotypes of giant cell arteritis (GCA). Methods Our study population was composed of 911 patients diagnosed with biopsy-proven GCA and 8136 unaffected controls from a Spanish discovery cohort and three additional independent replication cohorts from Germany, Norway and the UK. Two functional PTPN22 polymorphisms (rs2476601/R620W and rs33996649/R263Q) and two variants of the CSK gene (rs1378942 and rs34933034) were genotyped using predesigned TaqMan assays. Results The analysis of the discovery cohort provided evidence of association of PTPN22 rs2476601/R620W with GCA (PFDR=1.06E-04, OR=1.62, CI 95% 1.29 to 2.04). The association did not appear to follow a specific GCA subphenotype. No statistically significant differences between allele frequencies for the other PTPN22 and CSK genetic variants were evident either in the case/control or in stratified case analysis. To confirm the detected PTPN22 association, three replication cohorts were genotyped, and a consistent association between the PTPN22 rs2476601/R620W variant and GCA was evident in the overall meta-analysis (PMH=2.00E-06, OR=1.51, CI 95% 1.28 to 1.79). Conclusions Our results suggest that the PTPN22 polymorphism rs2476601/R620W plays an important role in the genetic risk to GCA.

Encapsulating peritoneal sclerosis – an overview

Encapsulating peritoneal sclerosis (EPS) is a rare but life-threatening complication of peritoneal sclerosis (PD). In 2000, the International Society for Peritoneal Dialysis outlined diagnostic guidelines and a clinical definition of EPS. Over the intervening years, new evidence was published and several centers became more experienced managing patients with EPS. Although, further networking was initiated (European EPS Working Group), evidence regarding therapy and diagnosis of EPS is still lacking. Multicenter trials are needed to establish evidence regarding the management of EPS. Risk factors for EPS are identified and patients at risk should be monitored closely. In case of emerging signs of EPS, patients should be referred to an EPS-center before initiation of therapy. Morphology and immunohistochemistry will play a central role in the near future. Nowadays, most pathologists are not sophisticated in the pathology of peritoneal biopsies. Clear histological criteria are warranted. For the outcome of the patient, it is crucial that an EPS experienced surgeon conducts surgery.

Influence of the IL17A locus in giant cell arteritis susceptibility

Objective Different lines of evidence have highlighted the role of IL-17A in the inflammatory process occurring in giant cell arteritis (GCA). The aim of the present study was to assess whether the IL17A locus influences GCA susceptibility and its clinical subphenotypes. Methods We carried out a large meta-analysis including a total of 1266 biopsy-proven GCA patients and 3779 healthy controls from four European populations (Spain, Italy, Germany and Norway). Five IL17A polymorphisms (rs4711998, rs8193036, rs3819024, rs2275913 and rs7747909) were selected by tagging and genotyped using TaqMan assays. Allelic combination and dependency tests were also performed. Results In the pooled analysis, two of the five analysed polymorphisms showed evidence of association with GCA (rs2275913: PMH=1.85E−03, OR=1.17 (1.06–1.29); rs7747909: PMH=8.49E–03, OR=1.15 (1.04–1.27)). A clear trend of association was also found for the rs4711998 variant (PMH=0.059, OR=1.11 (1.00–1.23)). An independent effect of rs2275913 and rs4711998 was evident by conditional regression analysis. In addition, the haplotype harbouring the risk alleles better explained the observed association than the polymorphisms independently (likelihood p value <10−05). Conclusions Polymorphisms within the IL17A locus show a novel association with GCA. This finding supports the relevant role of the Th17 cells in this vasculitis pathophysiology.

Encapsulating peritoneal sclerosis: a rare, serious but potentially curable complication of peritoneal dialysis–experience of a referral centre in Germany

BACKGROUND Chronic peritoneal dialysis (PD) can be complicated by encapsulating peritoneal sclerosis (EPS), the most severe complication associated with long-term PD. METHODS In this study, we retrospectively analysed 49 EPS patients regarding clinical presentation, histopathological findings, treatment and long-term clinical outcome at our referral centre. Patients were divided into two clinical categories: severe and mild/moderate. RESULTS All patients in the severe group and most patients in the mild/moderate group had symptoms consistent with EPS. The most common computed tomographic findings were peritoneal thickening in both groups. Small bowel dilatation was frequently present in the severe group. The time of onset of symptoms consistent with EPS to the surgical procedure was median 5 months with an inter-quartile range of 2-12 months in the severe group. To date, 25 of 31 patients in the severe group (follow-up 45.6 ± 39.0 months after surgery) are alive. In the mild/moderate group, 8 of 11 patients are alive (follow-up 41.6 ± 21.6 months). The histological features were consistent with EPS in all biopsies. CONCLUSIONS The outcome of patients even with severe EPS is not worse. It is a precondition that these patients are treated in specialized referral centres. The time of first clinical symptoms consistent with EPS to requirement of surgery is very short. Earlier diagnosis of the disease is mandatory, even in asymptomatic patients.

Difference in the expression of hormone receptors and fibrotic markers in the human peritoneum--implications for therapeutic targets to prevent encapsulating peritoneal sclerosis.

♦ Objective: Encapsulating peritoneal sclerosis (EPS) is a rare but life-threatening complication of peritoneal dialysis (PD). The optimal management of patients with EPS is uncertain. In the present study, we investigated differences in the expression of nuclear receptors [progesterone (PR), androgen (AR), vitamin D (VDR), and glucocorticoid (GCR)] in the human peritoneum. We also investigated estrogen receptor (ER), matrix metalloproteinase 9 (MMP9), and transforming growth factor β1 (TGFβ1) in the context of their potential role in tamoxifen therapy. ♦ Methods: We analyzed clinical and histologic characteristics of 72 peritoneal biopsy specimens (22 from EPS patients, 11 from PD patients, 15 from uremic patients, and 24 from control subjects undergoing hernia repair). For immunophenotyping, we used antibodies against VDR, GCR, ER, PR, AR, MMP9, and TGFβ1. ♦ Results: In human peritoneum, VDR and GCR are highly expressed (98.6% and 87.3% respectively). Except in the case of VDR (p = 0.0012), we observed no significant difference in receptor expression between the groups. Expression of ER and PR was sparse (11.4% and 31% respectively), with higher expression in women, and AR was absent. Minimal MMP9 expression and moderate TGFβ1 expression were observed in all groups. The differences between the groups were nonsignificant. ♦ Conclusions: Nuclear receptors are present in human peritoneum. Except in the case of VDR, the pattern for any one group is nonspecific. Glucocorticoids, vitamin D, and angiotensin converting-enzyme inhibitors or angiotensin II receptor blockers (via the vitamin D/angiotensin II pathway) might be suitable interventions for preservation of the integrity of the peritoneal membrane. The mechanism of action of tamoxifen is still not elucidated, ER expression in the peritoneum is sparse, and data about the studied pathways (MMP9, TGFβ) are inconsistent.

A COLLABORATIVE APPROACH TO UNDERSTANDING EPS: THE EUROPEAN PERSPECTIVE

Manchester Royal Infirmary,1 Manchester, UK; University Medical Center Utrecht,2 Utrecht, Netherlands; Robert-Bosch-Hospital,3 Stuttgart, Germany; Erasmus Medical Center,4 Rotterdam, Netherlands; Hans Mak Institute,5 Naarden, Netherlands; University Hospital of North Staffordshire,6 Stoke-on-Trent, UK; Azienda Ospedaliera Universitaria Senese,7 Siena, Italy; Universite catholique de Louvain,8 Brussels, Belgium; Albert Schweitzer Hospital,9 Dordrecht, Netherlands; Karolinska Institutet,10 Stockholm, Sweden; Baxter Healthcare SA,11 Zurich, Switzerland; University of Amsterdam,12 Amsterdam, Netherlands; Leiden University Medical Center,13 Leiden, Netherlands; Rene Dubos Hospital,14 Pontoise, France; and University Medical Center Groningen,15 Groningen, Netherlands

Acute kidney injury and tools for risk-stratification in 456 patients with hantavirus-induced nephropathia epidemica

BACKGROUND Puumala virus (PUUV) is the most common species of hantavirus in Central Europe. Nephropathia epidemica (NE), caused by PUUV, is characterized by acute kidney injury (AKI) and thrombocytopenia. The major goals of this study were to provide a clear clinical phenotyping of AKI in patients with NE and to develop an easy prediction rule to identify patients, who are at lower risk to develop severe AKI. METHODS A cross-sectional prospective survey of 456 adult patients with serologically confirmed NE was performed. Data were collected from medical records and prospectively at follow-up visit. Severe AKI was defined by standard criteria according to the RIFLE (Risk, Injury, Failure, Loss, End-stage kidney disease) classification. Fuller statistical models were developed and validated to estimate the probability for severe AKI. RESULTS During acute NE, 88% of the patients had AKI according to the RILFE criteria during acute NE. A risk index score for severe AKI was derived by using three independent risk factors in patients with normal kidney function at time of diagnosis: thrombocytopenia [two points; odds ratios (OR): 3.77; 95% confidence intervals (CI): 1.82, 8.03], elevated C-reactive protein levels (one point; OR: 3.02; 95% CI: 1.42, 6.58) and proteinuria (one point; OR: 3.92; 95% CI: 1.33, 13.35). On the basis of a point score of one or two, the probability of severe AKI was 0.18 and 0.28 with an area under the curve of 0.71. CONCLUSION This clinical prediction rule provides a novel and diagnostically accurate strategy for the potential prevention and improved management of kidney complications in patients with NE and, ultimately, for a possible decrease in unnecessary hospitalization in a high number of patients.