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a Writing Group: Jürg Schmidli∗ (Bern, Switzerland), Matthias K. Widmer (Bern, Switzerland), Carlo Basile (Bari, Italy), Gianmarco de Donato (Siena, Italy), Maurizio Gallieni (Milan, Italy), Christopher P. Gibbons (Banbury, UK), Patrick Haage (Witten, Germany), George Hamilton (London, UK), Ulf Hedin (Stockholm, Sweden), Lars Kamper (Witten, Germany), Miltos K. Lazarides (Alexandroupoli, Greece), Ben Lindsey (London, UK), Gaspar Mestres (Barcelona, Spain), Marisa Pegoraro (Milan, Italy), Joy Roy (Stockholm, Sweden), Carlo Setacci (Siena, Italy), David Shemesh (Jerusalem, Israel), Jan H.M. Tordoir (Maastricht, The Netherlands), Magda van Loon (Maastricht, The Netherlands).
Jürg Schmidli
Correspondence
Corresponding author. Bern University Hospital, University of Bern, Freiburgstrasse, 3010 Bern, Switzerland. Tel: +41 31 632 2602; Fax: +41 31 632 2919.
a Writing Group: Jürg Schmidli∗ (Bern, Switzerland), Matthias K. Widmer (Bern, Switzerland), Carlo Basile (Bari, Italy), Gianmarco de Donato (Siena, Italy), Maurizio Gallieni (Milan, Italy), Christopher P. Gibbons (Banbury, UK), Patrick Haage (Witten, Germany), George Hamilton (London, UK), Ulf Hedin (Stockholm, Sweden), Lars Kamper (Witten, Germany), Miltos K. Lazarides (Alexandroupoli, Greece), Ben Lindsey (London, UK), Gaspar Mestres (Barcelona, Spain), Marisa Pegoraro (Milan, Italy), Joy Roy (Stockholm, Sweden), Carlo Setacci (Siena, Italy), David Shemesh (Jerusalem, Israel), Jan H.M. Tordoir (Maastricht, The Netherlands), Magda van Loon (Maastricht, The Netherlands).
a Writing Group: Jürg Schmidli∗ (Bern, Switzerland), Matthias K. Widmer (Bern, Switzerland), Carlo Basile (Bari, Italy), Gianmarco de Donato (Siena, Italy), Maurizio Gallieni (Milan, Italy), Christopher P. Gibbons (Banbury, UK), Patrick Haage (Witten, Germany), George Hamilton (London, UK), Ulf Hedin (Stockholm, Sweden), Lars Kamper (Witten, Germany), Miltos K. Lazarides (Alexandroupoli, Greece), Ben Lindsey (London, UK), Gaspar Mestres (Barcelona, Spain), Marisa Pegoraro (Milan, Italy), Joy Roy (Stockholm, Sweden), Carlo Setacci (Siena, Italy), David Shemesh (Jerusalem, Israel), Jan H.M. Tordoir (Maastricht, The Netherlands), Magda van Loon (Maastricht, The Netherlands).
Matthias K. Widmer
Footnotes
a Writing Group: Jürg Schmidli∗ (Bern, Switzerland), Matthias K. Widmer (Bern, Switzerland), Carlo Basile (Bari, Italy), Gianmarco de Donato (Siena, Italy), Maurizio Gallieni (Milan, Italy), Christopher P. Gibbons (Banbury, UK), Patrick Haage (Witten, Germany), George Hamilton (London, UK), Ulf Hedin (Stockholm, Sweden), Lars Kamper (Witten, Germany), Miltos K. Lazarides (Alexandroupoli, Greece), Ben Lindsey (London, UK), Gaspar Mestres (Barcelona, Spain), Marisa Pegoraro (Milan, Italy), Joy Roy (Stockholm, Sweden), Carlo Setacci (Siena, Italy), David Shemesh (Jerusalem, Israel), Jan H.M. Tordoir (Maastricht, The Netherlands), Magda van Loon (Maastricht, The Netherlands).
a Writing Group: Jürg Schmidli∗ (Bern, Switzerland), Matthias K. Widmer (Bern, Switzerland), Carlo Basile (Bari, Italy), Gianmarco de Donato (Siena, Italy), Maurizio Gallieni (Milan, Italy), Christopher P. Gibbons (Banbury, UK), Patrick Haage (Witten, Germany), George Hamilton (London, UK), Ulf Hedin (Stockholm, Sweden), Lars Kamper (Witten, Germany), Miltos K. Lazarides (Alexandroupoli, Greece), Ben Lindsey (London, UK), Gaspar Mestres (Barcelona, Spain), Marisa Pegoraro (Milan, Italy), Joy Roy (Stockholm, Sweden), Carlo Setacci (Siena, Italy), David Shemesh (Jerusalem, Israel), Jan H.M. Tordoir (Maastricht, The Netherlands), Magda van Loon (Maastricht, The Netherlands).
Carlo Basile
Footnotes
a Writing Group: Jürg Schmidli∗ (Bern, Switzerland), Matthias K. Widmer (Bern, Switzerland), Carlo Basile (Bari, Italy), Gianmarco de Donato (Siena, Italy), Maurizio Gallieni (Milan, Italy), Christopher P. Gibbons (Banbury, UK), Patrick Haage (Witten, Germany), George Hamilton (London, UK), Ulf Hedin (Stockholm, Sweden), Lars Kamper (Witten, Germany), Miltos K. Lazarides (Alexandroupoli, Greece), Ben Lindsey (London, UK), Gaspar Mestres (Barcelona, Spain), Marisa Pegoraro (Milan, Italy), Joy Roy (Stockholm, Sweden), Carlo Setacci (Siena, Italy), David Shemesh (Jerusalem, Israel), Jan H.M. Tordoir (Maastricht, The Netherlands), Magda van Loon (Maastricht, The Netherlands).
a Writing Group: Jürg Schmidli∗ (Bern, Switzerland), Matthias K. Widmer (Bern, Switzerland), Carlo Basile (Bari, Italy), Gianmarco de Donato (Siena, Italy), Maurizio Gallieni (Milan, Italy), Christopher P. Gibbons (Banbury, UK), Patrick Haage (Witten, Germany), George Hamilton (London, UK), Ulf Hedin (Stockholm, Sweden), Lars Kamper (Witten, Germany), Miltos K. Lazarides (Alexandroupoli, Greece), Ben Lindsey (London, UK), Gaspar Mestres (Barcelona, Spain), Marisa Pegoraro (Milan, Italy), Joy Roy (Stockholm, Sweden), Carlo Setacci (Siena, Italy), David Shemesh (Jerusalem, Israel), Jan H.M. Tordoir (Maastricht, The Netherlands), Magda van Loon (Maastricht, The Netherlands).
Gianmarco de Donato
Footnotes
a Writing Group: Jürg Schmidli∗ (Bern, Switzerland), Matthias K. Widmer (Bern, Switzerland), Carlo Basile (Bari, Italy), Gianmarco de Donato (Siena, Italy), Maurizio Gallieni (Milan, Italy), Christopher P. Gibbons (Banbury, UK), Patrick Haage (Witten, Germany), George Hamilton (London, UK), Ulf Hedin (Stockholm, Sweden), Lars Kamper (Witten, Germany), Miltos K. Lazarides (Alexandroupoli, Greece), Ben Lindsey (London, UK), Gaspar Mestres (Barcelona, Spain), Marisa Pegoraro (Milan, Italy), Joy Roy (Stockholm, Sweden), Carlo Setacci (Siena, Italy), David Shemesh (Jerusalem, Israel), Jan H.M. Tordoir (Maastricht, The Netherlands), Magda van Loon (Maastricht, The Netherlands).
a Writing Group: Jürg Schmidli∗ (Bern, Switzerland), Matthias K. Widmer (Bern, Switzerland), Carlo Basile (Bari, Italy), Gianmarco de Donato (Siena, Italy), Maurizio Gallieni (Milan, Italy), Christopher P. Gibbons (Banbury, UK), Patrick Haage (Witten, Germany), George Hamilton (London, UK), Ulf Hedin (Stockholm, Sweden), Lars Kamper (Witten, Germany), Miltos K. Lazarides (Alexandroupoli, Greece), Ben Lindsey (London, UK), Gaspar Mestres (Barcelona, Spain), Marisa Pegoraro (Milan, Italy), Joy Roy (Stockholm, Sweden), Carlo Setacci (Siena, Italy), David Shemesh (Jerusalem, Israel), Jan H.M. Tordoir (Maastricht, The Netherlands), Magda van Loon (Maastricht, The Netherlands).
Maurizio Gallieni
Footnotes
a Writing Group: Jürg Schmidli∗ (Bern, Switzerland), Matthias K. Widmer (Bern, Switzerland), Carlo Basile (Bari, Italy), Gianmarco de Donato (Siena, Italy), Maurizio Gallieni (Milan, Italy), Christopher P. Gibbons (Banbury, UK), Patrick Haage (Witten, Germany), George Hamilton (London, UK), Ulf Hedin (Stockholm, Sweden), Lars Kamper (Witten, Germany), Miltos K. Lazarides (Alexandroupoli, Greece), Ben Lindsey (London, UK), Gaspar Mestres (Barcelona, Spain), Marisa Pegoraro (Milan, Italy), Joy Roy (Stockholm, Sweden), Carlo Setacci (Siena, Italy), David Shemesh (Jerusalem, Israel), Jan H.M. Tordoir (Maastricht, The Netherlands), Magda van Loon (Maastricht, The Netherlands).
a Writing Group: Jürg Schmidli∗ (Bern, Switzerland), Matthias K. Widmer (Bern, Switzerland), Carlo Basile (Bari, Italy), Gianmarco de Donato (Siena, Italy), Maurizio Gallieni (Milan, Italy), Christopher P. Gibbons (Banbury, UK), Patrick Haage (Witten, Germany), George Hamilton (London, UK), Ulf Hedin (Stockholm, Sweden), Lars Kamper (Witten, Germany), Miltos K. Lazarides (Alexandroupoli, Greece), Ben Lindsey (London, UK), Gaspar Mestres (Barcelona, Spain), Marisa Pegoraro (Milan, Italy), Joy Roy (Stockholm, Sweden), Carlo Setacci (Siena, Italy), David Shemesh (Jerusalem, Israel), Jan H.M. Tordoir (Maastricht, The Netherlands), Magda van Loon (Maastricht, The Netherlands).
Christopher P. Gibbons
Footnotes
a Writing Group: Jürg Schmidli∗ (Bern, Switzerland), Matthias K. Widmer (Bern, Switzerland), Carlo Basile (Bari, Italy), Gianmarco de Donato (Siena, Italy), Maurizio Gallieni (Milan, Italy), Christopher P. Gibbons (Banbury, UK), Patrick Haage (Witten, Germany), George Hamilton (London, UK), Ulf Hedin (Stockholm, Sweden), Lars Kamper (Witten, Germany), Miltos K. Lazarides (Alexandroupoli, Greece), Ben Lindsey (London, UK), Gaspar Mestres (Barcelona, Spain), Marisa Pegoraro (Milan, Italy), Joy Roy (Stockholm, Sweden), Carlo Setacci (Siena, Italy), David Shemesh (Jerusalem, Israel), Jan H.M. Tordoir (Maastricht, The Netherlands), Magda van Loon (Maastricht, The Netherlands).
a Writing Group: Jürg Schmidli∗ (Bern, Switzerland), Matthias K. Widmer (Bern, Switzerland), Carlo Basile (Bari, Italy), Gianmarco de Donato (Siena, Italy), Maurizio Gallieni (Milan, Italy), Christopher P. Gibbons (Banbury, UK), Patrick Haage (Witten, Germany), George Hamilton (London, UK), Ulf Hedin (Stockholm, Sweden), Lars Kamper (Witten, Germany), Miltos K. Lazarides (Alexandroupoli, Greece), Ben Lindsey (London, UK), Gaspar Mestres (Barcelona, Spain), Marisa Pegoraro (Milan, Italy), Joy Roy (Stockholm, Sweden), Carlo Setacci (Siena, Italy), David Shemesh (Jerusalem, Israel), Jan H.M. Tordoir (Maastricht, The Netherlands), Magda van Loon (Maastricht, The Netherlands).
Patrick Haage
Footnotes
a Writing Group: Jürg Schmidli∗ (Bern, Switzerland), Matthias K. Widmer (Bern, Switzerland), Carlo Basile (Bari, Italy), Gianmarco de Donato (Siena, Italy), Maurizio Gallieni (Milan, Italy), Christopher P. Gibbons (Banbury, UK), Patrick Haage (Witten, Germany), George Hamilton (London, UK), Ulf Hedin (Stockholm, Sweden), Lars Kamper (Witten, Germany), Miltos K. Lazarides (Alexandroupoli, Greece), Ben Lindsey (London, UK), Gaspar Mestres (Barcelona, Spain), Marisa Pegoraro (Milan, Italy), Joy Roy (Stockholm, Sweden), Carlo Setacci (Siena, Italy), David Shemesh (Jerusalem, Israel), Jan H.M. Tordoir (Maastricht, The Netherlands), Magda van Loon (Maastricht, The Netherlands).
a Writing Group: Jürg Schmidli∗ (Bern, Switzerland), Matthias K. Widmer (Bern, Switzerland), Carlo Basile (Bari, Italy), Gianmarco de Donato (Siena, Italy), Maurizio Gallieni (Milan, Italy), Christopher P. Gibbons (Banbury, UK), Patrick Haage (Witten, Germany), George Hamilton (London, UK), Ulf Hedin (Stockholm, Sweden), Lars Kamper (Witten, Germany), Miltos K. Lazarides (Alexandroupoli, Greece), Ben Lindsey (London, UK), Gaspar Mestres (Barcelona, Spain), Marisa Pegoraro (Milan, Italy), Joy Roy (Stockholm, Sweden), Carlo Setacci (Siena, Italy), David Shemesh (Jerusalem, Israel), Jan H.M. Tordoir (Maastricht, The Netherlands), Magda van Loon (Maastricht, The Netherlands).
George Hamilton
Footnotes
a Writing Group: Jürg Schmidli∗ (Bern, Switzerland), Matthias K. Widmer (Bern, Switzerland), Carlo Basile (Bari, Italy), Gianmarco de Donato (Siena, Italy), Maurizio Gallieni (Milan, Italy), Christopher P. Gibbons (Banbury, UK), Patrick Haage (Witten, Germany), George Hamilton (London, UK), Ulf Hedin (Stockholm, Sweden), Lars Kamper (Witten, Germany), Miltos K. Lazarides (Alexandroupoli, Greece), Ben Lindsey (London, UK), Gaspar Mestres (Barcelona, Spain), Marisa Pegoraro (Milan, Italy), Joy Roy (Stockholm, Sweden), Carlo Setacci (Siena, Italy), David Shemesh (Jerusalem, Israel), Jan H.M. Tordoir (Maastricht, The Netherlands), Magda van Loon (Maastricht, The Netherlands).
a Writing Group: Jürg Schmidli∗ (Bern, Switzerland), Matthias K. Widmer (Bern, Switzerland), Carlo Basile (Bari, Italy), Gianmarco de Donato (Siena, Italy), Maurizio Gallieni (Milan, Italy), Christopher P. Gibbons (Banbury, UK), Patrick Haage (Witten, Germany), George Hamilton (London, UK), Ulf Hedin (Stockholm, Sweden), Lars Kamper (Witten, Germany), Miltos K. Lazarides (Alexandroupoli, Greece), Ben Lindsey (London, UK), Gaspar Mestres (Barcelona, Spain), Marisa Pegoraro (Milan, Italy), Joy Roy (Stockholm, Sweden), Carlo Setacci (Siena, Italy), David Shemesh (Jerusalem, Israel), Jan H.M. Tordoir (Maastricht, The Netherlands), Magda van Loon (Maastricht, The Netherlands).
Ulf Hedin
Footnotes
a Writing Group: Jürg Schmidli∗ (Bern, Switzerland), Matthias K. Widmer (Bern, Switzerland), Carlo Basile (Bari, Italy), Gianmarco de Donato (Siena, Italy), Maurizio Gallieni (Milan, Italy), Christopher P. Gibbons (Banbury, UK), Patrick Haage (Witten, Germany), George Hamilton (London, UK), Ulf Hedin (Stockholm, Sweden), Lars Kamper (Witten, Germany), Miltos K. Lazarides (Alexandroupoli, Greece), Ben Lindsey (London, UK), Gaspar Mestres (Barcelona, Spain), Marisa Pegoraro (Milan, Italy), Joy Roy (Stockholm, Sweden), Carlo Setacci (Siena, Italy), David Shemesh (Jerusalem, Israel), Jan H.M. Tordoir (Maastricht, The Netherlands), Magda van Loon (Maastricht, The Netherlands).
a Writing Group: Jürg Schmidli∗ (Bern, Switzerland), Matthias K. Widmer (Bern, Switzerland), Carlo Basile (Bari, Italy), Gianmarco de Donato (Siena, Italy), Maurizio Gallieni (Milan, Italy), Christopher P. Gibbons (Banbury, UK), Patrick Haage (Witten, Germany), George Hamilton (London, UK), Ulf Hedin (Stockholm, Sweden), Lars Kamper (Witten, Germany), Miltos K. Lazarides (Alexandroupoli, Greece), Ben Lindsey (London, UK), Gaspar Mestres (Barcelona, Spain), Marisa Pegoraro (Milan, Italy), Joy Roy (Stockholm, Sweden), Carlo Setacci (Siena, Italy), David Shemesh (Jerusalem, Israel), Jan H.M. Tordoir (Maastricht, The Netherlands), Magda van Loon (Maastricht, The Netherlands).
Lars Kamper
Footnotes
a Writing Group: Jürg Schmidli∗ (Bern, Switzerland), Matthias K. Widmer (Bern, Switzerland), Carlo Basile (Bari, Italy), Gianmarco de Donato (Siena, Italy), Maurizio Gallieni (Milan, Italy), Christopher P. Gibbons (Banbury, UK), Patrick Haage (Witten, Germany), George Hamilton (London, UK), Ulf Hedin (Stockholm, Sweden), Lars Kamper (Witten, Germany), Miltos K. Lazarides (Alexandroupoli, Greece), Ben Lindsey (London, UK), Gaspar Mestres (Barcelona, Spain), Marisa Pegoraro (Milan, Italy), Joy Roy (Stockholm, Sweden), Carlo Setacci (Siena, Italy), David Shemesh (Jerusalem, Israel), Jan H.M. Tordoir (Maastricht, The Netherlands), Magda van Loon (Maastricht, The Netherlands).
a Writing Group: Jürg Schmidli∗ (Bern, Switzerland), Matthias K. Widmer (Bern, Switzerland), Carlo Basile (Bari, Italy), Gianmarco de Donato (Siena, Italy), Maurizio Gallieni (Milan, Italy), Christopher P. Gibbons (Banbury, UK), Patrick Haage (Witten, Germany), George Hamilton (London, UK), Ulf Hedin (Stockholm, Sweden), Lars Kamper (Witten, Germany), Miltos K. Lazarides (Alexandroupoli, Greece), Ben Lindsey (London, UK), Gaspar Mestres (Barcelona, Spain), Marisa Pegoraro (Milan, Italy), Joy Roy (Stockholm, Sweden), Carlo Setacci (Siena, Italy), David Shemesh (Jerusalem, Israel), Jan H.M. Tordoir (Maastricht, The Netherlands), Magda van Loon (Maastricht, The Netherlands).
Miltos K. Lazarides
Footnotes
a Writing Group: Jürg Schmidli∗ (Bern, Switzerland), Matthias K. Widmer (Bern, Switzerland), Carlo Basile (Bari, Italy), Gianmarco de Donato (Siena, Italy), Maurizio Gallieni (Milan, Italy), Christopher P. Gibbons (Banbury, UK), Patrick Haage (Witten, Germany), George Hamilton (London, UK), Ulf Hedin (Stockholm, Sweden), Lars Kamper (Witten, Germany), Miltos K. Lazarides (Alexandroupoli, Greece), Ben Lindsey (London, UK), Gaspar Mestres (Barcelona, Spain), Marisa Pegoraro (Milan, Italy), Joy Roy (Stockholm, Sweden), Carlo Setacci (Siena, Italy), David Shemesh (Jerusalem, Israel), Jan H.M. Tordoir (Maastricht, The Netherlands), Magda van Loon (Maastricht, The Netherlands).
a Writing Group: Jürg Schmidli∗ (Bern, Switzerland), Matthias K. Widmer (Bern, Switzerland), Carlo Basile (Bari, Italy), Gianmarco de Donato (Siena, Italy), Maurizio Gallieni (Milan, Italy), Christopher P. Gibbons (Banbury, UK), Patrick Haage (Witten, Germany), George Hamilton (London, UK), Ulf Hedin (Stockholm, Sweden), Lars Kamper (Witten, Germany), Miltos K. Lazarides (Alexandroupoli, Greece), Ben Lindsey (London, UK), Gaspar Mestres (Barcelona, Spain), Marisa Pegoraro (Milan, Italy), Joy Roy (Stockholm, Sweden), Carlo Setacci (Siena, Italy), David Shemesh (Jerusalem, Israel), Jan H.M. Tordoir (Maastricht, The Netherlands), Magda van Loon (Maastricht, The Netherlands).
Ben Lindsey
Footnotes
a Writing Group: Jürg Schmidli∗ (Bern, Switzerland), Matthias K. Widmer (Bern, Switzerland), Carlo Basile (Bari, Italy), Gianmarco de Donato (Siena, Italy), Maurizio Gallieni (Milan, Italy), Christopher P. Gibbons (Banbury, UK), Patrick Haage (Witten, Germany), George Hamilton (London, UK), Ulf Hedin (Stockholm, Sweden), Lars Kamper (Witten, Germany), Miltos K. Lazarides (Alexandroupoli, Greece), Ben Lindsey (London, UK), Gaspar Mestres (Barcelona, Spain), Marisa Pegoraro (Milan, Italy), Joy Roy (Stockholm, Sweden), Carlo Setacci (Siena, Italy), David Shemesh (Jerusalem, Israel), Jan H.M. Tordoir (Maastricht, The Netherlands), Magda van Loon (Maastricht, The Netherlands).
a Writing Group: Jürg Schmidli∗ (Bern, Switzerland), Matthias K. Widmer (Bern, Switzerland), Carlo Basile (Bari, Italy), Gianmarco de Donato (Siena, Italy), Maurizio Gallieni (Milan, Italy), Christopher P. Gibbons (Banbury, UK), Patrick Haage (Witten, Germany), George Hamilton (London, UK), Ulf Hedin (Stockholm, Sweden), Lars Kamper (Witten, Germany), Miltos K. Lazarides (Alexandroupoli, Greece), Ben Lindsey (London, UK), Gaspar Mestres (Barcelona, Spain), Marisa Pegoraro (Milan, Italy), Joy Roy (Stockholm, Sweden), Carlo Setacci (Siena, Italy), David Shemesh (Jerusalem, Israel), Jan H.M. Tordoir (Maastricht, The Netherlands), Magda van Loon (Maastricht, The Netherlands).
Gaspar Mestres
Footnotes
a Writing Group: Jürg Schmidli∗ (Bern, Switzerland), Matthias K. Widmer (Bern, Switzerland), Carlo Basile (Bari, Italy), Gianmarco de Donato (Siena, Italy), Maurizio Gallieni (Milan, Italy), Christopher P. Gibbons (Banbury, UK), Patrick Haage (Witten, Germany), George Hamilton (London, UK), Ulf Hedin (Stockholm, Sweden), Lars Kamper (Witten, Germany), Miltos K. Lazarides (Alexandroupoli, Greece), Ben Lindsey (London, UK), Gaspar Mestres (Barcelona, Spain), Marisa Pegoraro (Milan, Italy), Joy Roy (Stockholm, Sweden), Carlo Setacci (Siena, Italy), David Shemesh (Jerusalem, Israel), Jan H.M. Tordoir (Maastricht, The Netherlands), Magda van Loon (Maastricht, The Netherlands).
a Writing Group: Jürg Schmidli∗ (Bern, Switzerland), Matthias K. Widmer (Bern, Switzerland), Carlo Basile (Bari, Italy), Gianmarco de Donato (Siena, Italy), Maurizio Gallieni (Milan, Italy), Christopher P. Gibbons (Banbury, UK), Patrick Haage (Witten, Germany), George Hamilton (London, UK), Ulf Hedin (Stockholm, Sweden), Lars Kamper (Witten, Germany), Miltos K. Lazarides (Alexandroupoli, Greece), Ben Lindsey (London, UK), Gaspar Mestres (Barcelona, Spain), Marisa Pegoraro (Milan, Italy), Joy Roy (Stockholm, Sweden), Carlo Setacci (Siena, Italy), David Shemesh (Jerusalem, Israel), Jan H.M. Tordoir (Maastricht, The Netherlands), Magda van Loon (Maastricht, The Netherlands).
Marisa Pegoraro
Footnotes
a Writing Group: Jürg Schmidli∗ (Bern, Switzerland), Matthias K. Widmer (Bern, Switzerland), Carlo Basile (Bari, Italy), Gianmarco de Donato (Siena, Italy), Maurizio Gallieni (Milan, Italy), Christopher P. Gibbons (Banbury, UK), Patrick Haage (Witten, Germany), George Hamilton (London, UK), Ulf Hedin (Stockholm, Sweden), Lars Kamper (Witten, Germany), Miltos K. Lazarides (Alexandroupoli, Greece), Ben Lindsey (London, UK), Gaspar Mestres (Barcelona, Spain), Marisa Pegoraro (Milan, Italy), Joy Roy (Stockholm, Sweden), Carlo Setacci (Siena, Italy), David Shemesh (Jerusalem, Israel), Jan H.M. Tordoir (Maastricht, The Netherlands), Magda van Loon (Maastricht, The Netherlands).
a Writing Group: Jürg Schmidli∗ (Bern, Switzerland), Matthias K. Widmer (Bern, Switzerland), Carlo Basile (Bari, Italy), Gianmarco de Donato (Siena, Italy), Maurizio Gallieni (Milan, Italy), Christopher P. Gibbons (Banbury, UK), Patrick Haage (Witten, Germany), George Hamilton (London, UK), Ulf Hedin (Stockholm, Sweden), Lars Kamper (Witten, Germany), Miltos K. Lazarides (Alexandroupoli, Greece), Ben Lindsey (London, UK), Gaspar Mestres (Barcelona, Spain), Marisa Pegoraro (Milan, Italy), Joy Roy (Stockholm, Sweden), Carlo Setacci (Siena, Italy), David Shemesh (Jerusalem, Israel), Jan H.M. Tordoir (Maastricht, The Netherlands), Magda van Loon (Maastricht, The Netherlands).
Joy Roy
Footnotes
a Writing Group: Jürg Schmidli∗ (Bern, Switzerland), Matthias K. Widmer (Bern, Switzerland), Carlo Basile (Bari, Italy), Gianmarco de Donato (Siena, Italy), Maurizio Gallieni (Milan, Italy), Christopher P. Gibbons (Banbury, UK), Patrick Haage (Witten, Germany), George Hamilton (London, UK), Ulf Hedin (Stockholm, Sweden), Lars Kamper (Witten, Germany), Miltos K. Lazarides (Alexandroupoli, Greece), Ben Lindsey (London, UK), Gaspar Mestres (Barcelona, Spain), Marisa Pegoraro (Milan, Italy), Joy Roy (Stockholm, Sweden), Carlo Setacci (Siena, Italy), David Shemesh (Jerusalem, Israel), Jan H.M. Tordoir (Maastricht, The Netherlands), Magda van Loon (Maastricht, The Netherlands).
a Writing Group: Jürg Schmidli∗ (Bern, Switzerland), Matthias K. Widmer (Bern, Switzerland), Carlo Basile (Bari, Italy), Gianmarco de Donato (Siena, Italy), Maurizio Gallieni (Milan, Italy), Christopher P. Gibbons (Banbury, UK), Patrick Haage (Witten, Germany), George Hamilton (London, UK), Ulf Hedin (Stockholm, Sweden), Lars Kamper (Witten, Germany), Miltos K. Lazarides (Alexandroupoli, Greece), Ben Lindsey (London, UK), Gaspar Mestres (Barcelona, Spain), Marisa Pegoraro (Milan, Italy), Joy Roy (Stockholm, Sweden), Carlo Setacci (Siena, Italy), David Shemesh (Jerusalem, Israel), Jan H.M. Tordoir (Maastricht, The Netherlands), Magda van Loon (Maastricht, The Netherlands).
Carlo Setacci
Footnotes
a Writing Group: Jürg Schmidli∗ (Bern, Switzerland), Matthias K. Widmer (Bern, Switzerland), Carlo Basile (Bari, Italy), Gianmarco de Donato (Siena, Italy), Maurizio Gallieni (Milan, Italy), Christopher P. Gibbons (Banbury, UK), Patrick Haage (Witten, Germany), George Hamilton (London, UK), Ulf Hedin (Stockholm, Sweden), Lars Kamper (Witten, Germany), Miltos K. Lazarides (Alexandroupoli, Greece), Ben Lindsey (London, UK), Gaspar Mestres (Barcelona, Spain), Marisa Pegoraro (Milan, Italy), Joy Roy (Stockholm, Sweden), Carlo Setacci (Siena, Italy), David Shemesh (Jerusalem, Israel), Jan H.M. Tordoir (Maastricht, The Netherlands), Magda van Loon (Maastricht, The Netherlands).
a Writing Group: Jürg Schmidli∗ (Bern, Switzerland), Matthias K. Widmer (Bern, Switzerland), Carlo Basile (Bari, Italy), Gianmarco de Donato (Siena, Italy), Maurizio Gallieni (Milan, Italy), Christopher P. Gibbons (Banbury, UK), Patrick Haage (Witten, Germany), George Hamilton (London, UK), Ulf Hedin (Stockholm, Sweden), Lars Kamper (Witten, Germany), Miltos K. Lazarides (Alexandroupoli, Greece), Ben Lindsey (London, UK), Gaspar Mestres (Barcelona, Spain), Marisa Pegoraro (Milan, Italy), Joy Roy (Stockholm, Sweden), Carlo Setacci (Siena, Italy), David Shemesh (Jerusalem, Israel), Jan H.M. Tordoir (Maastricht, The Netherlands), Magda van Loon (Maastricht, The Netherlands).
David Shemesh
Footnotes
a Writing Group: Jürg Schmidli∗ (Bern, Switzerland), Matthias K. Widmer (Bern, Switzerland), Carlo Basile (Bari, Italy), Gianmarco de Donato (Siena, Italy), Maurizio Gallieni (Milan, Italy), Christopher P. Gibbons (Banbury, UK), Patrick Haage (Witten, Germany), George Hamilton (London, UK), Ulf Hedin (Stockholm, Sweden), Lars Kamper (Witten, Germany), Miltos K. Lazarides (Alexandroupoli, Greece), Ben Lindsey (London, UK), Gaspar Mestres (Barcelona, Spain), Marisa Pegoraro (Milan, Italy), Joy Roy (Stockholm, Sweden), Carlo Setacci (Siena, Italy), David Shemesh (Jerusalem, Israel), Jan H.M. Tordoir (Maastricht, The Netherlands), Magda van Loon (Maastricht, The Netherlands).
a Writing Group: Jürg Schmidli∗ (Bern, Switzerland), Matthias K. Widmer (Bern, Switzerland), Carlo Basile (Bari, Italy), Gianmarco de Donato (Siena, Italy), Maurizio Gallieni (Milan, Italy), Christopher P. Gibbons (Banbury, UK), Patrick Haage (Witten, Germany), George Hamilton (London, UK), Ulf Hedin (Stockholm, Sweden), Lars Kamper (Witten, Germany), Miltos K. Lazarides (Alexandroupoli, Greece), Ben Lindsey (London, UK), Gaspar Mestres (Barcelona, Spain), Marisa Pegoraro (Milan, Italy), Joy Roy (Stockholm, Sweden), Carlo Setacci (Siena, Italy), David Shemesh (Jerusalem, Israel), Jan H.M. Tordoir (Maastricht, The Netherlands), Magda van Loon (Maastricht, The Netherlands).
Jan H.M. Tordoir
Footnotes
a Writing Group: Jürg Schmidli∗ (Bern, Switzerland), Matthias K. Widmer (Bern, Switzerland), Carlo Basile (Bari, Italy), Gianmarco de Donato (Siena, Italy), Maurizio Gallieni (Milan, Italy), Christopher P. Gibbons (Banbury, UK), Patrick Haage (Witten, Germany), George Hamilton (London, UK), Ulf Hedin (Stockholm, Sweden), Lars Kamper (Witten, Germany), Miltos K. Lazarides (Alexandroupoli, Greece), Ben Lindsey (London, UK), Gaspar Mestres (Barcelona, Spain), Marisa Pegoraro (Milan, Italy), Joy Roy (Stockholm, Sweden), Carlo Setacci (Siena, Italy), David Shemesh (Jerusalem, Israel), Jan H.M. Tordoir (Maastricht, The Netherlands), Magda van Loon (Maastricht, The Netherlands).
a Writing Group: Jürg Schmidli∗ (Bern, Switzerland), Matthias K. Widmer (Bern, Switzerland), Carlo Basile (Bari, Italy), Gianmarco de Donato (Siena, Italy), Maurizio Gallieni (Milan, Italy), Christopher P. Gibbons (Banbury, UK), Patrick Haage (Witten, Germany), George Hamilton (London, UK), Ulf Hedin (Stockholm, Sweden), Lars Kamper (Witten, Germany), Miltos K. Lazarides (Alexandroupoli, Greece), Ben Lindsey (London, UK), Gaspar Mestres (Barcelona, Spain), Marisa Pegoraro (Milan, Italy), Joy Roy (Stockholm, Sweden), Carlo Setacci (Siena, Italy), David Shemesh (Jerusalem, Israel), Jan H.M. Tordoir (Maastricht, The Netherlands), Magda van Loon (Maastricht, The Netherlands).
Magda van Loon
Footnotes
a Writing Group: Jürg Schmidli∗ (Bern, Switzerland), Matthias K. Widmer (Bern, Switzerland), Carlo Basile (Bari, Italy), Gianmarco de Donato (Siena, Italy), Maurizio Gallieni (Milan, Italy), Christopher P. Gibbons (Banbury, UK), Patrick Haage (Witten, Germany), George Hamilton (London, UK), Ulf Hedin (Stockholm, Sweden), Lars Kamper (Witten, Germany), Miltos K. Lazarides (Alexandroupoli, Greece), Ben Lindsey (London, UK), Gaspar Mestres (Barcelona, Spain), Marisa Pegoraro (Milan, Italy), Joy Roy (Stockholm, Sweden), Carlo Setacci (Siena, Italy), David Shemesh (Jerusalem, Israel), Jan H.M. Tordoir (Maastricht, The Netherlands), Magda van Loon (Maastricht, The Netherlands).
a Writing Group: Jürg Schmidli∗ (Bern, Switzerland), Matthias K. Widmer (Bern, Switzerland), Carlo Basile (Bari, Italy), Gianmarco de Donato (Siena, Italy), Maurizio Gallieni (Milan, Italy), Christopher P. Gibbons (Banbury, UK), Patrick Haage (Witten, Germany), George Hamilton (London, UK), Ulf Hedin (Stockholm, Sweden), Lars Kamper (Witten, Germany), Miltos K. Lazarides (Alexandroupoli, Greece), Ben Lindsey (London, UK), Gaspar Mestres (Barcelona, Spain), Marisa Pegoraro (Milan, Italy), Joy Roy (Stockholm, Sweden), Carlo Setacci (Siena, Italy), David Shemesh (Jerusalem, Israel), Jan H.M. Tordoir (Maastricht, The Netherlands), Magda van Loon (Maastricht, The Netherlands). b ESVS Guidelines Committee: Philippe Kolh (Liege, Belgium), chair), Gert J. de Borst (Utrecht, Netherlands, co-chair and guideline coordinator), Nabil Chakfe (Strasbourg, France), Sebastian Debus (Hamburg, Germany), Rob Hinchliffe (Bristol, UK), Stavros Kakkos (Patras, Greece), Igor Koncar (Belgrade, Serbia), Jes Lindholt (Odense, Denmark), Ross Naylor (Leicester, UK), Melina Vega de Ceniga (Galdakao, Spain), Frank Vermassen (Ghent, Belgium), Fabio Verzini (Perugia, Italy). c ESVS Guidelines Reviewers: Markus Mohaupt (Bern, Switzerland), Jean-Baptiste Ricco (Strasbourg, France), Ramon Roca-Tey (Barcelona, Spain).
Tunnelled cuffed central venous catheter (Synonym: indwelling catheter with cuff)
UDT
Ultrasound dilution technique
URR
Urea reduction ratio
VA
Vascular access
VAILI
Vascular access induced limb ischaemia
VAS
Vascular Access Society
VP
Venous pressure
VP/MAP
Venous pressure adjusted for the mean arterial pressure
WC
Writing Committee
1. Methodology and grading of recommendations
1.1 Purpose
The European Society for Vascular Surgery (ESVS), in line with its mission, appointed the Vascular Access (VA) Writing Committee (WC) to write the current clinical practice guidelines document for surgeons and physicians who are involved in the care of patients with haemodialysis (HD) and VA. The goal of these Guidelines is to summarise and evaluate all the currently available evidence to assist physicians in selecting the best management strategies for all patients needing VA or for pathologies derived from a VA. However, each physician must make the ultimate decision regarding the particular care of an individual patient.
Patients with VA for HD are complex and also subject to significant clinical practice variability, although a valid evidence base is available to guide recommendations. The significant technical and medical advances in VA have enabled guidelines to be proposed with greater supporting evidence than before. Potential increases in healthcare costs and risks due to industry and public driven use of novel treatment options make the current guidelines increasingly important.
Many clinical situations involving patients with HD and VA have not been studied by randomised clinical trials. Nevertheless, patient care must be delivered and clinical decisions made in these situations. Therefore, this document should also provide guidance when extensive level A evidence is unavailable and in these situations recommendations are determined on the basis of the best currently available evidence.
By providing information on the relevance and validity of the quality of evidence, the reader will be able to gather the most important and evidence based information relevant to the individual patient.
This document is intended to be a guide, rather than a set of rules, allowing flexibility for specific patients' circumstances. The current clinical practice guidelines document provides recommendations for the clinical care of patients with HD and VA including pre-operative, peri-operative and post-operative care and long-term maintenance.
1.2 Methodology
The VA WC was formed by members of the ESVS and Vascular Access Society (VAS) from different European countries, various academic and private hospitals, and includes vascular surgeons, nephrologists, radiologists and clinical nurses in order to maximise the applicability of the final guideline document. The WC met in September 2012 for the first time to discuss the purpose, contents, methodology and timeline of the following recommendations.
The VA WC has performed a systematic literature search in the MEDLINE, EMBASE and COCHRANE Library databases for each of the different topics that are discussed and reviewed in this guidelines document. The latest literature search was performed by August 31st 2017. With regard to the evidence gathered, the following eligibility criteria have been applied:
•
Only peer reviewed published literature has been considered
•
Published abstracts or congress proceedings have been excluded
•
Randomised clinical trials (RCT) as well as meta-analyses and systematic reviews were searched with priority
•
Non-RCTs, non-controlled trials and well conducted observational studies (cohort and case control studies) were also included
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Previous guidelines, position papers and published consensus documents have also been included as part of the review process when new evidence was absent
•
Minimising the use of reports of a single medical device or from pharmaceutical companies reduced the risk of bias across studies. A grading system based on the European Society of Cardiology (ESC) guidelines methodology was adopted.
The level of evidence classification provides information about the study characteristics supporting the recommendation and expert consensus, according to the categories shown in Table 1.
For each recommendation, two members of the WC assessed the strength of a recommendation and the quality of supporting evidence independently. A full master copy of the manuscript with all recommendations was electronically circulated and approved by all WC members. Recommendations that required consensus were discussed and voted upon at meetings and by email among all members of the WC. This system permitted strong recommendations supported by low or very low quality evidence from downgraded RCTs or observational studies only when a general consensus among the WC members and reviewers was achieved. Meta-analyses are quoted in the recommendations according to the following rule: if the recommendation was either of high or low quality the meta-analysis was quoted and the individual studies were not explored. If it was a “grey area” and mixed opinions on the included meta-analysis studies were present, the original data were examined to clearly present the “mixed” findings within several studies. Two members of the WC have prepared each part of the guidelines document. An internal review process was performed before the manuscript was sent to the ESVS Guidelines Committee and selected invited independent external reviewers. External reviewers made critical suggestions, comments and corrections on all preliminary versions of these guidelines. In addition, each member participated in the consensus process concerning conflicting recommendations. The final document has been approved by the ESVS Guidelines Committee and submitted to the European Journal of Vascular and Endovascular Surgery (EJVES). Further updated guidelines documents on VA will be provided periodically by the ESVS when new evidence and/or new clinical practice arise in this field, which could occur every three years.
To optimise the implementation of the current document, the length of the guidelines has been kept as short as possible to facilitate access to guideline information. Conflicts of interest from each WC member were collected prior to the writing process. These conflicts were assessed and accepted by each member of the WC and are reported in this document. In addition, the WC agreed that all intellectual work should be expressed without any interference beyond the honesty and professionalism of all its members during the writing process.
1.3 Definitions
1.3.1 Definition of vascular access
Patients with acute renal failure or end stage renal disease require renal replacement therapy, which includes peritoneal dialysis (PD), haemodialysis (HD) or kidney transplantation (Fig. 1). A VA is essential for patients on HD and can be accomplished with central venous catheters (CVC), but also with arterialisation of a vein or by interposition of a graft between an artery and a vein for the insertion of HD needles. The blood flow available for HD should reach at least 300 ml/min and preferably 500 ml/min depending on the VA modality to allow a sufficient HD.
Figure 1Flowchart of renal replacement treatment options.
Arteriovenous fistulas (AVFs) and arteriovenous grafts (AVGs) are established terms to characterise a special kind of VA in patients on HD. An AVF is defined as an autogenous anastomosis between an artery and a vein and an AVG is defined as a VA using a prosthetic graft.
At the beginning of this millennium interventional radiologists and vascular surgeons attempted to clarify the terminology dealing with HD access.
further refinements made; there is still ongoing discussion amongst VA specialists. Nevertheless outlined below are the definitions that are believed to be currently accepted by the majority of clinicians in the field.
Incidence is the proportion of a given population developing a new condition or experiencing an event within a specified period of time. This could be for example, the number of patients experiencing an event (e.g. patients undergoing VA creation) divided by the number of a given population (e.g. the number of patients undergoing HD). For a disease, incidence can be expressed as the number of patients per million population per year.
Prevalence is the total number of cases of a disease within a given population; it includes both new and continuing patients with a certain disease and is expressed as number of patients per million population. Prevalence is a function of incidence (new cases) and outcomes (death or cure).
Point prevalence in %: Number of patients using a specific type of VA at a given point of time multiplied by 100 and divided by the number of patients with a VA at this time.
Period prevalence in %: The mean number of patients using a specific VA over a given time (one year) multiplied by 100 and divided by all the patients using a VA during the same time period.
Hospitalisation days/1000 access days: The numerator is the total number of days of hospitalisation for the study population. The denominator is calculated as the number of days from VA creation or the start date of a study period to permanent (unsalvageable) VA failure, the end of study period, death of the patient, transfer from the dialysis unit or a change in renal replacement modality (PD or transplantation). The calculated rate is the total number of hospitalisation days ⁄ total number of VA days multiplied by 1000 to express the number of hospitalisation days per 1000 VA days.
Access abandonment: The day on which a VA is deemed to be permanently unusable or not suitable for cannulation.
Primary VA: Creation of a functioning VA for the first time.
Secondary VA: Ordinary VA creation with AVF or AVG at any location after a failed primary VA (tertiary VA excluded).
Tertiary VA: VA using great saphenous vein (GSV) or femoral vein (FV) translocated to the arm or leg. Unusual VA procedures such as upper or lower limb arterio-arterial loops are included in this category.
Transposition: Relocation of an autogenous vein to a new (more superficial) position in the soft tissues of the same anatomical area (e.g. an upper arm AVF with transposition of the basilic vein).
Translocation: The prepared vein is completely disconnected and inserted in a new anatomical area to create an AVF.
Superficialisation: The index vein is transposed in the subcutaneous tissue and positioned closer to the skin.
Kaplan-Meier life table analysis: A statistical method for calculating time dependent clinical outcomes can be documented such as VA patencies, or infection free survival rates.
Primary patency: The interval between VA creation and the first re-intervention (intervention free VA survival) for VA dysfunction or thrombosis, the time of measurement of patency or the time of its abandonment.
Assisted primary patency: The interval between VA creation and the first occlusion (thrombosis free VA survival) or measurement of patency including operative/endovascular interventions to maintain the VA.
Primary functional patency: The interval between the first use (first cannulation) of a newly created VA and the first re-intervention to rescue the VA or to its abandonment.
Secondary patency: The interval between VA creation and the abandonment of this VA (i.e. thrombosis) after one or more interventions or the time of measurement of patency including achievement of a censored event (death, change of HD modality, loss of follow-up).
Maturation and functionality of VA: Changes that occur in the VA after its creation (increase in VA flow and AVF diameter, wall structure changes, AVG tissue to graft incorporation) making it suitable over time for cannulation.
Mature VA: A VA that is expected to be suitable for HD access and considered appropriate for cannulation with two needles and expected to deliver sufficient blood flow throughout the HD. Therefore it is a pre-cannulation definition.
Functional VA: A VA is functional when it has been cannulated successfully with two needles, over a period of at least 6 HD sessions during a 30 day period, and delivered the prescribed blood flow throughout the HD and achieved adequate HD (usually at least 300 ml/ min). Therefore, it is a post-cannulation definition.
Monitoring: Examination and evaluation of the VA by means of physical examination to detect physical signs that suggest the presence of VA dysfunction.
Surveillance: Periodic evaluation of a VA using haemodynamic tests. This may trigger further diagnostic evaluation.
VA induced (limb) ischaemia: Extremity malperfusion after VA creation. It can be classified in four stages:
stage 1: slight coldness, numbness, pale skin, no pain
stage 2: loss of sensation, pain during HD or exercise
stage 3: rest pain
stage 4: tissue loss affecting the distal parts of the limb, usually the digits
This definition is more appropriate than ‘steal’ which describes the physiological phenomenon of (even retrograde) blood flow recruitment towards the AVF/AVG.
Recirculation: The return of dialysed blood to the systemic circulation without full equilibration (NKF-DOQI definition).
Kt/V: A parameter to quantify the adequacy of the HD: K=Dialyser clearance of urea, t=effective time of HD V=volume of urea distribution, approximately equal to the patient's body water (60% of the body mass).
Early VA failure: A VA that has occluded within 24 hours of creation.
Early dialysis suitability failure: A VA that cannot be used by the third month following creation despite radiological or surgical intervention.
Late dialysis suitability failure: A VA that is not usable after more than 6 months despite radiological or surgical intervention.
Cannulation failure: Failure is defined as the inability to place and secure two dialysis needles.
Non-tunnelled CVC (ntCVC): An uncuffed catheter providing temporary VA for HD.
Tunnelled cuffed CVC (tcCVC): A subcutaneously tunnelled dual lumen catheter with a cuff that can be used for VA if HD is expected to last for more than two weeks.
Catheter related bacteraemia:
Proven: Bacteraemia with at least one positive percutaneous peripheral vein blood culture and where either the same pathogen was cultured from the catheter tip or a blood culture drawn from a catheter that has a >3 fold greater bacterial colony count than those drawn from a peripheral vein.
Probable: Bacteraemia with positive blood cultures obtained from a catheter and/or peripheral vein in a patient where there is no clinical evidence of an alternative source of an infection.
Catheter exit site infection:
Proven: The presence of a purulent discharge or erythema, induration/and or tenderness at the catheter exit site with a positive bacteriological culture of the serous discharge.
Probable: The clinical signs of infection with negative cultures from the discharge or blood without signs of irritation from gauze, stitches or the cleansing agent.
Catheter tunnel infection:
Proven: The presence of purulent discharge from the tunnel or erythema, induration and/or tenderness over the catheter tunnel with a positive culture.
Probable: Clinical signs of infection around the catheter site with negative cultures from the discharge or blood.
Primary catheter site patency: Interval between catheter insertion and the first intervention to restore the catheter's function.
Secondary catheter site patency: Interval between catheter insertion and exchange or removal of the catheter for any reason.
Continuous catheter site: The time period from initial catheter insertion to catheter site abandonment for any reason including the time period after continuous catheter exchanges in the same target vessel. The time period and number of exchanges are documented e.g. 12 months [3 catheters].
Catheter dysfunction: This is the first occurrence of either a peak flow of 200 ml/minute or less for 30 minutes during HD, a mean blood flow of 250 ml/minute or less during two consecutive dialyses or the inability to initiate HD resulting from an inadequate blood flow, despite attempts to restore patency.
2. Epidemiology of chronic kidney disease (CKD) stage 5
2.1 Epidemiology of chronic kidney disease
Chronic kidney disease (CKD) is a worldwide public health problem. CKD is classified into five stages (Table 3), but renal insufficiency is restricted to stages 3–5, with a glomerular filtration rate (GFR) below 60 ml/min per 1.73 m2 for 3 months or more irrespective of the cause.
The true incidence and prevalence of CKD within a community are difficult to ascertain as early to moderate CKD is usually asymptomatic. Most studies point to a prevalence of CKD of around 10%, albuminuria of around 7%, and GFR below 60 ml/min per 1.73 m2 of around 3%.
CKD stage 5 (ESRD) is characterised by GFR below 15 ml/min per 1.73 m2 and includes two phases: the first one is treated conservatively without dialysis; when the second phase follows, the initiation of renal replacement therapy (RRT) in the form of dialysis or transplantation is required to sustain life.
The incidence of CKD stage 5 refers to the number of patients with ESRD beginning RRT, thus failing to take into account patients not treated by RRT and underestimating the overall true incidence of ESRD. In the dialysis population, prevalence is a function of the incidence (new cases) and outcome (transplantation or death) rates of ESRD.
2.1.1 Epidemiology of end stage renal disease
2.1.1.1 Incidence
The number of patients per year starting RRT has shown an exponential rise.
Such a large number of CKD patients requiring dialysis may have three main causes: patient selection, competitive risks and a true increase in CKD incidence:
1. Selection of patients for RRT: the steep increase in the incidence of older patients suggests that those very old and/or those affected by particularly severe comorbidities were not given access to dialysis in the first decades of RRT, compared with the more recent years.
2. Competitive risks: a study suggested that the number of deaths where CKD is the underlying cause of death increased by 82% between 1990 (27th in the global death rank) and 2010 (18th in the global death rank).
Global and regional mortality from 235 causes of death for 20 age groups in 1990 and 2010: a systematic analysis for the Global Burden of Disease Study 2010.
Kidney disease as a risk factor for development of cardiovascular disease: a statement from the American Heart Association Councils on Kidney in Cardiovascular Disease, High Blood Pressure Research, Clinical Cardiology, and Epidemiology and Prevention.
Substantial improvements in the treatment of cardiac diseases and in survival have occurred in recent decades and this has allowed many patients to survive in the more advanced CKD stages and to require RRT.
3. The true increase in CKD incidence: it may also be possible that the increased incidence of ESRD reflects increases in the underlying prevalence of CKD. The Framingham Heart Study has shown that the incidence of type 2 diabetes has doubled from the 1970s to the 1990s.
Furthermore, potentially nephrotoxic drugs, such as non-steroidal anti-inflammatory drugs, antibiotics and chemotherapy agents are used more commonly. Finally, reduced mortality from cardiovascular diseases and cancer may be associated with an increase in the number of patients reaching ESRD.
2.1.1.2 Prevalence
Data related to the prevalence of CKD stage 5 are lacking, except for those of registries of ESRD patients treated by dialysis or transplantation. In the USA, of the 547,982 prevalent ESRD patients in 2008, 70 percent were being treated by dialysis while 30 percent had a functioning kidney transplant. In 2008 alone, 112,476 patients entered the US ESRD program. Adjusted rates for incident and prevalent ESRD are 351 and 1,699 cases per million population, respectively. Diabetes and hypertension account for 44% and 27.9% of all causes of incident ESRD, respectively.
The prevalence of a disease increases if the patient survival increases with a constant incidence rate or if the incidence rate increases with a constant survival rate. Thus the rising prevalence of treated ESRD can be attributed either to the increase in the number of patients who start RRT each year and/or to the increased survival of patients with ESRD. Since the incidence rates of treated ESRD have flattened in recent years, longer lifespans of prevalent ESRD patients may partially explain the steady growth of this population.
Continuing global efforts should be made in the prevention and treatment of acute and especially chronic conditions potentially leading to ESRD, in particular diabetes and hypertension.
2.2 Demographics of end stage renal disease
The global epidemiology of ESRD is heterogeneous and influenced by several factors. Consequently, the incidence and prevalence of ESRD are markedly different from country to country (Table 4). Disparities in the incidence and prevalence of ESRD within and between developed countries reflect racial and ethnic diversities as well as their impact on the prevalence of diabetes and hypertension in respective countries and communities. The incidence is higher among African and Native Americans and aboriginal people of Australia and New Zealand.
in: Hoerl W.H. Koch K.M. Lindsay R.M. Ronco C. Winchester J. Replacement of renal function by dialysis. 5th ed. Kluwer Academic Publishers,
Dordrecht2004: 1411-1453
Diabetes as a cause of ESRD is particularly frequent in these populations. Disparities with developing countries are likely to reflect availability of and access to RRT in low and middle income economies rather than a lower incidence of CKD. Diabetes as the primary cause of CKD affects a particularly high percentage of incident patients in the USA.
Table 4Global incidence and prevalence of RRT (per million population) in different parts of the world in 2002 and 2006.
UK renal registry 13th annual report (December 2010): chapter 7: the relationship between the type of vascular access used and survival in UK RRT patients in 2006.
In the United States, the proportion of patients >65 years of age starting dialysis has increased by nearly 10% annually, representing an overall increase of 57% between 1996 and 2003.
Researchers have speculated that more liberal acceptance of the very elderly (≥80 years) into dialysis programs has contributed to the increase in patients with ESRD.
The contribution of increased diabetes prevalence and improved myocardial infarction and stroke survival to the increase in treated end-stage renal disease.
CKD is expected to be a major 21st century medical challenge. In developing nations, the growing prevalence of CKD has severe implications on health and economic output.
The rapid rise of common risk factors such as diabetes, hypertension and obesity, especially among the poor, will result in even greater and more profound burdens that developing nations are not equipped to handle.
VA care is characterised by similar issues, but with a different magnitude. Obesity, type 2 diabetes, and peripheral vascular disease, independent predictors of CVC use, are growing problems globally, which could lead to more difficulties in native AVF creation and survival.
Nevertheless, in the USA following the establishment of the Fistula First Initiative, AVF use among prevalent HD patients increased steadily from 34.1% in December 2003 to 60.6% in April 2012.
In incident patients, VA statistics at the start of chronic HD in 2009 were: AVF in use 14.3%; AVG in use 3.2%; CVC in use 81.8%; AVF maturing 15.8%; AVG maturing 1.9%. Figures were similar in 2014.
United States renal data system annual data report; end-stage renal disease in the United States; chapter 4: vascular access 2015 [20.09.2016]. Available from: http://www.usrds.org/2015/view.
Between 2005 and 2007, a native AVF was used by 67–91% of prevalent patients in Japan, Italy, Germany, France, Spain, the UK, Australia and New Zealand, and 50–59% in Belgium, Sweden and Canada. From 1996 to 2007, AVF use rose from 24% to 47% in the USA but declined in Italy, Germany and Spain. Across three phases of data collection, patients were consistently less likely to use an AVF versus other VA types if female, of greater age, having greater body mass index, diabetes, and peripheral vascular disease. In addition, countries with a greater prevalence of diabetes in HD patients had a significantly lower percentage of patients using an AVF. Despite poorer outcomes for CVCs, catheter use rose 1.5–3 fold among prevalent patients in many countries from 1996 to 2007, even among non-diabetic patients 18–70 years old. Furthermore, 58–73% of incident patients used a CVC for the initiation of dialysis in five countries despite 60–79% of patients having been seen by a nephrologist more than 4 months prior to ESRD. The median time from referral to VA creation varied from 5–6 days in Italy, Japan and Germany to 40–43 days in the UK and Canada. Surgery waiting time, along with time from VA creation to first cannulation, significantly affected the possibility of starting HD with a permanent VA.
Patient preference for a CVC varied across countries, ranging from 1% of HD patients in Japan and 18% in the United States, to 42%–44% in Belgium and Canada.
Preference for a CVC was positively associated with age, female sex, and former or current catheter use. The observed considerable variation in patient preference for VA suggests that patient preference may be influenced by socio-cultural factors and thus could be modifiable.
The use of CVCs carries a significant risk of serious complications. Lately, in non-renal patients the peripherally inserted central venous catheter (PICC) has gained in popularity due to presumed advantages over other CVCs. However, the use of PICC lines is not indicated in CKD patients because of subsequent adverse VA outcomes, i.e. a lower likelihood (15%–19%) of having a functioning fistula or graft.
Early referral of ESRD patients to the nephrologist is strongly recommended. This approach may minimise the use of catheters and reduce catheter related morbidity and the need for hospitalisation.
Early referral to the nephrologist is also required for interventions to delay progression of renal damage and to correct hypertension, anaemia and the metabolic effects of renal failure, discussion of renal replacement treatment options, including living related transplantation and peritoneal dialysis, and psychological preparation for dialysis.
Successful HD treatment is only possible with a well functioning VA. The ideal VA should allow cannulation using two needles, deliver a minimum blood flow of at least 300 ml/min through the artificial kidney, is resistant to infection and thrombosis and should have minimum adverse events. The first option for the construction of a VA is the creation of an autogenous AVF. Secondary and tertiary options are prosthetic AVG and CVCs. The reason for creating autogenous AVFs is that observational studies show a lower incidence of post-operative complications and fewer endovascular and surgical revisions for AVF failure in comparison to AVGs.
In addition, the use of CVCs results in a significantly higher morbidity and mortality rate. The risk of hospitalisation for VA related reasons and particularly for infection is highest for patients on HD with a catheter at initiation and throughout follow-up.
The strategy is to start HD in incident patients with a distal autogenous AVF preferably in the non-dominant upper extremity. In cases of a failed distal VA a more proximally located AVF can be performed.
3.2 Timing of referral for vascular access surgery
Timely patient referral for VA creation is of importance for the outcome of the VA. Early referral results in more well functioning autogenous AVFs,
Association between vascular access creation and deceleration of estimated glomerular filtration rate decline in late-stage chronic kidney disease patients transitioning to end-stage renal disease.
Also, HD initiation with a CVC and a long AVF maturation time, results in poorer long-term AVF patency rates. The same factors that predict worse primary AVF survival are also associated with greater risk of final failure. The presence of cardiovascular disease, use of catheters at HD initiation, and early cannulation are independent predictors of final failure. A short time to cannulation is associated with the greatest risk of final failure.
(Figure 2, Figure 3) Frequent (every 3 months) pre-nephrology visits (PNV) are related to improved patient survival during the first year after initiation of HD, indicating the possible survival benefit with increased attention to PNV, particularly for elderly and diabetic patients.
From the DOPPS data, significant differences between European countries in referral type and time of VA creation have been reported. Planning of VA surgery varies between <5 days (Italy) to >42 days (UK) after referral to the VA surgeon.
Figure 2Kaplan-Meier curves of time to AVF failure (primary patency from first cannulation) by use of catheters (CVC) at the initiation of HD (left) and by the time to maturation in days (right). Reproduced with permission from Ravani et al.
Figure 3Risk factors associated with primary and secondary access failure. Hazard ratios plotted using a logarithmic scale. Reproduced with permission from Ravani et al.
Enhanced training in vascular access creation predicts arteriovenous fistula placement and patency in hemodialysis patients: results from the Dialysis Outcomes and Practice Patterns Study.
However, there remain large regional differences between hospitals, concerning the number of autogenous AVFs created and the probability of successful maturation.
3.3.1 Primary option for vascular access – autogenous arteriovenous fistula
The radiocephalic AVF (RCAVF) at the level of the wrist is the first choice for VA creation. When successfully matured, the RCAVF can function for years with a minimum of complications, revisions and hospital admissions. The RCAVF is preferentially created in the non-dominant arm, but the dominant extremity may be chosen if the vessels in the non-dominant arm are unsuitable. The indication to perform a wrist RCAVF depends on the outcome of physical examination (inspection and palpation of distal veins and arteries) and additional ultrasound examination. A minimum internal vessel diameter for both radial artery and cephalic vein of 2.0 mm using a proximal tourniquet is considered to be adequate for successful fistula creation and maturation. For brachiocephalic (BCAVF) and brachiobasilic (BBAVF) AVFs a minimum arterial and venous diameter of 3 mm is sufficient.
Major disadvantages are the risk of early thrombosis and non-maturation and, ultimately, access failure. A meta-analysis showed a 17% mean early failure rate.
However, recent studies have shown higher failure rates of up to 46%, with one year patencies from 52% to 83% (Table 5). An elderly dialysis population with concurrent comorbidities and poor upper extremity vessels is the reason for these high early failure rates.
Vascular access survival and incidence of revisions: a comparison of prosthetic grafts, simple autogenous fistulas, and venous transposition fistulas from the United States Renal Data System Dialysis Morbidity and Mortality Study.
Autogenous radial-cephalic or prosthetic brachial-antecubital forearm loop AVF in patients with compromised vessels? A randomized, multicenter study of the patency of primary hemodialysis access.
When a wrist RCAVF is not possible or has failed, a more proximally located AVF in the forearm, antecubital region or upper arm may be performed. These accesses are called mid-forearm, brachial/radial-deep perforating vein,
brachial-median cubital vein, BCAVF and BBAVF. Brachial artery based AVFs deliver a high access flow which favours high HD flows, but may result in reduced distal arterial perfusion and cardiac overload.
These types of AVFs show good one year patencies (Table 6, Table 7) with a low incidence of thrombosis (0.2 events per patient/year) and infection (2%).
Table 6Early failure (within one month of access creation) and one year secondary patency rate of brachiocephalic AVF (including brachiocephalic/perforating vein AVF).
Evaluation of the efficacy of the transposed upper arm arteriovenous fistula: a single institutional review of 190 basilic and cephalic vein transposition procedures.
A randomized multicenter study of the outcome of brachial-basilic arteriovenous fistula and prosthetic brachial-antecubital forearm loop as vascular access for hemodialysis.
If direct arteriovenous anastomoses are impossible, vein transposition/translocation can be performed, with redirection of a suitable vein to an available artery (forearm radial/ulnar-basilic AVF) or GSV harvesting from the leg and subsequent implantation between an arm artery and vein (see Chapter 8).
A basilic vein transposition (BVT) in the upper arm is a good choice when RCAVFs or BCAVFs have failed or are not feasible. BBAVFs can be performed in either one or two stage operations.
3.3.1.1 Patient variables and outcome of vascular access
Various studies have shown the important influence of patient variables on choice and outcome of VA. Age and diabetes mellitus negatively influence fistula maturation and increase the risk of AVF failure.
A systematic review of the literature showed a tendency towards an increased risk of deep vein thrombosis and a decreased risk of catheter occlusion with a PICC.
Advantages and disadvantages of peripherally inserted central venous catheters (PICC) compared to other central venous lines: a systematic review of the literature.
An anatomical region at high risk of thrombosis is the antecubital fossa. Elbow veins represent a valuable source for the creation of a VA for HD, especially in obese patients, elderly patients, diabetics and patients affected by peripheral artery disease.
Women usually have smaller vessels than men, which may result in poorer maturation and lower long-term patency. Some studies show that females need more VA revisions and the creation of more AVGs,
Vascular access survival and incidence of revisions: a comparison of prosthetic grafts, simple autogenous fistulas, and venous transposition fistulas from the United States Renal Data System Dialysis Morbidity and Mortality Study.
while others, including a meta-analysis, could not demonstrate any significant differences in vessel diameters and the probability of maturation between men and women.
Diabetes mellitus and arteriosclerosis are the most important causes of renal failure and HD treatment and can have a negative influence on successful use of the VA.
When there are no options for creating an autogenous AVF, an AVG VA with the implantation of synthetic (expanded polytetrafluoroethylene [ePTFE]; polyurethane; nanograft=electrospun ePTFE graft) or biological material (ovine graft/Omniflow®) can be created. ePTFE is frequently used as an AVG with reasonable short-term patency but long-term patency is hampered by thrombotic occlusions, due to stenoses caused by progressive neointimal proliferation. One and two year primary patency varies between 40–50% and 20–30%, respectively. The secondary patency varies from 70 to 90% (at one year) and 50 to 70% at two years. Multiple interventions to prevent and treat thrombosis are required to achieve these outcomes.
An important consideration for AVG use (in particular “early stick grafts”) might be the avoidance of CVCs with their inherent high risk of infection, in particular when (sub)acute HD treatment is necessary and AVF creation/maturation is problematic.
3.3.3 Lower extremity vascular access
The indications for lower extremity VA are bilateral central venous occlusive disease (CVOD) or inability to create access in the upper extremity. Primary options are autogenous GSV
In a meta-analysis the results of femoral vein transpositions and AVGs are described. The one year primary and secondary patency was 83% and 48% and 93% and 69%, for FV transpositions and AVGs respectively. VA loss due to infection was primarily seen in AVGs (18% vs. 1.6%; p<.05). Ischaemia occurs more with lower extremity AVFs than AVGs (21% vs. 7.1%, p<.05).
In another study the outcome of 70 FV accesses was published with good results but with an 18% incidence of critical ischaemia, for which revision surgery was indicated.
3.3.4 Indications for a permanent catheter for vascular access
Temporary CVCs are frequently used for acute HD or as bridging VA during fistula maturation and complications. Permanent tcCVCs may be indicated in patients with severe VA induced ischaemia, cardiac failure or limited life expectancy. Patients with PD peritonitis or waiting for a planned living related renal transplant can also be dialysed through a CVC for a limited period.
The primary location for a CVC is the right internal jugular vein followed by the left jugular, femoral and subclavian veins as alternative insertion locations. Femoral and subclavian vein CVCs should only be used for short periods, because of the risk of infection and CVOD.
HD via a CVC has increased in the USA, Canada and Europe, with a significantly greater morbidity and mortality risk due to infectious complications in comparison with the use of AVFs and AVGs (Fig. 4).
Figure 4Survival (%) of patients with peritoneal dialysis (PD) versus central venous catheters (HD-CVC) and arteriovenous fistulas/grafts (HD-AVF/AVG), adjusted on the basis of a stratified Cox proportional Hazards model stratified by HD-CVC, PD, and HD-AVF/AVG and adjusted for age, race, gender, era of dialysis initiation, end stage renal disease comorbidity index, primary renal diagnosis, serum albumin, eGFR, province of treatment, and late referral. Reproduced with permission from Perl et al.
The reason for the increased CVC use is the inability to create functioning AVFs because of poor vessel quality in the elderly, comorbid population.
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Referral of chronic kidney disease patients to the nephrologist and/or surgeon for preparing vascular access is recommended when they reach stage 4 of chronic kidney disease (glomerular filtration rate<30 ml/min/1.73 m2), especially in cases of rapidly progressing nephropathy.
Tunnelled cuffed central venous catheters as a long standing haemodialysis modality should be considered when the creation of arteriovenous fistulas or grafts is impossible or in patients with limited life expectancy.
Besides a detailed pre-operative history and physical examination, non-invasive ultrasound imaging plays an important role in VA selection. Pre-operative duplex ultrasound (DUS) enhances the success of creation and the outcome of autogenous AVFs.
DUS assessment can measure arterial diameters and flow as well as reveal stenotic segments especially where physical tests (poor radial pulse, unsuitable forearm veins) suggest impaired arterial inflow.
In addition, DUS identifies patients with inadequate vessels in specific VA locations. In a study of 211 consecutive patients DUS found that 50% of them had inadequate arterial inflow for distal RCAVF creation.
Currently, a minimum pre-operative internal diameter of 2.0 mm for both arteries and veins is recommended before RCAVF creation and a minimum of 4.0 mm for the outflow vein in the elbow for AVG implantation.
Furthermore DUS provides important information for the planning of potential future AVF superficialisation.
Digital subtraction angiography (DSA) is helpful in only a small group of selected patients with significant peripheral vascular disease and suspected proximal arterial stenosis. The pre-operative endovascular approach allows identification and treatment in one procedure. However, the risk of potential contrast induced nephropathy must be carefully considered if iodinated contrast is used.
However, contrast enhanced magnetic resonance angiography (CE-MRA) is not recommended, since use of gadolinium is associated with the potential risk of a nephrogenic systemic fibrosis, especially in patients with severely impaired renal function.
Promising preliminary results for the pre-operative visualisation of arterial and venous vascular structures with non-contrast enhanced MRA (NCE-MRA) are available.
In patients with a history of previous CVCs additional pre-operative imaging of the central veins should be performed, e.g. venography or intravascular ultrasound.
Pre-operative ultrasonography of bilateral upper extremity arteries and veins is recommended in all patients when planning the creation of a vascular access.
Stenosis detection in failing hemodialysis access fistulas and grafts: comparison of color Doppler ultrasonography, contrast-enhanced magnetic resonance angiography, and digital subtraction angiography.
Duplex ultrasound scanning in the assessment of arteriovenous fistulas created for hemodialysis access: comparison with digital subtraction angiography.
If CVOD cannot be reliably excluded by DUS, additional imaging methods (e.g. DSA) will be necessary. Surveillance by DUS is reported to prolong AVG patency.
Only a few studies are available on DUS as a tool for ultrasound guided percutaneous transluminal angioplasty (PTA) of failing or non-maturing VA, which may be particularly indicated in patients with iodine contrast allergy or with residual kidney function.
Stenosis detection in failing hemodialysis access fistulas and grafts: comparison of color Doppler ultrasonography, contrast-enhanced magnetic resonance angiography, and digital subtraction angiography.
Multislice computed tomography requires the use of iodinated contrast and radiation and should therefore only be used if no equivalent technique is available. However, compared with DSA computed tomography angiography (CTA) is a less invasive technique that provides important information for further treatment (surgery or PTA) and is less expensive than purely diagnostic DSA.
For the detection of CVOD the sensitivity of CTA is dependent on the applied examination protocols. In suspected CVOD, CTA should be considered only when DUS or DSA are inconclusive, e.g. for the evaluation of the central veins and visualisation of the vascular tree.
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