An Exploratory Study in Three Parts to Determine Sex-Specific Differences in Chronic Kidney Disease Recognition, Progression and Treatment
Conditions: Chronic Kidney Diseases
Sponsor: Assoc. Prof. Dr. Manfred Hecking, MD PhD

 
 
1 
 
 
 
 
An Exploratory Study in Three Parts to Determine Sex-
Specific Differences in Chronic Kidney Disease 
Recognition, Progression and Treatment  
(Explorative Studie in Drei Teilen zur Erhebung Geschlechtsspezifischer 
Unterschiede in der Identifizierung von Patienten mit präterminaler 
Niereninsuffizienz sowie bei Progression der Erkrankung und Beginn mit 
der Nierenersatztherapie) 
 
 
 
Antragsteller/In: 
 
Dr. Carolin Berner1 
 
Priv.-Doz. Dr. Manfred Hecking1, 2 
1Sozialmedizinisches Zentrum Süd 
(Kaiser-Franz-Josef-Spital 
mit Gottfried von Preyer‘schem Kinderspital) 
1. Medizinische Abteilung 
Kundratstrasse 3, 1010 Wien 
(für MH: Arbeitsverhältnis von 1.10.2015-30.9.2016) 
 
2Medizinische Universität Wien 
Klinik für Innere Medizin III 
Klin. Abt. für Nephrologie & Dialyse 
Währinger Gürtel 18-20 
1090 Wien 
(für MH: Arbeitsverhältnis von 1.10.2008-30.9.2015 und wiederum ab 1.10.2016) 

 
 
2 
 
Protocol authors 
Doz. Dr. Manfred Hecking, Dr. Carolin Berner 
Academic investigators 
Manfred Hecking1, Marcus Säemann1, Gere Sunder-Plassmann1, 
Rainer Oberbauer1, Eva Schernhammer2, Carolin Berner3, Isabella 
Exner3, Sabine Schmaldienst3, Manuela Födinger4, Emanuel Zitt5, 
Karl Lhotta5 
1 Department of Internal Medicine III, Clinical Division of Dialysis 
and Transplantation, Medical University of Vienna, Austria 
2Department of Epidemiology, Medical University of Vienna, 
Austria 
3First Medical Department, Kaiser-Franz-Josef-Spital, Vienna, 
Austria 
4Department for Laboratory Medicine, Kaiser-Franz-Josef-Spital, 
Vienna, Austria 
5Department of Nephrology and Dialysis, Academic Teaching 
Hospital Feldkirch, Austria 
Document type 
Clinical study protocol 
Document status 
Final version (Version 4.0.) 
Date 
28 July 2016 
Number of pages 
20 
 
 
 

 
 
3 
ZUSAMMENFASSUNG DES PROJEKTES 
Frauen stellen trotz größerem Anteil an der Gesamtpopulation den geringeren 
Patientenanteil an der Dialyse. Signifikante regionale und altersgruppenbezogene 
Unterschiede an der Ratio zwischen Frauen und Männern an der Dialyse und die 
Tatsache, dass die Prävalenz der chronischen Niereninsuffizienz zB. bei weiblichen 
US-Amerikanern höher ist als bei männlichen, lässt vermuten, dass eher 
psychosoziale bzw. sozioökonomische Ursachen als biologische Unterschiede dieser 
ungleichen Geschlechterverteilung zu Grunde liegen. Präliminäre internationale 
Daten der Chronic Kidney Disease Outcomes and Pratice Patterns Study 
(CKDOPPS) zeigen, dass in verschiedenen Ländern weibliche Patienten in den 
nephrologischen Ambulanzen (Chronische Niereninsuffizienz /CNI - Ambulanzen), 
relativ zum Frauenanteil in der Gesamtpopulation und angesichts der höheren 
Prävalenz der CNI, unterrepräsentiert sind. KDIGO empfiehlt offiziell die MDRD oder 
Cockroft-Gault Gleichung zur Bestimmung der Nierenfunktion. Zwar inkludieren diese 
Formeln das Geschlecht als Korrekturvariable jedoch wird vermutet, dass die 
Korrekturvariablen vor allem für Frauen <65 Jahren inkorrekt sein könnten. Es wäre 
anzunehmen, dass für Frauen mit ihrem niedrigeren Muskelanteil im Vergleich zu 
Männern die GFR (basierend auf dem Goldstandard der Kreatininclearence) 
niedriger geschätzt und somit eine Indikation zur Dialyse rascher gestellt würde. Im 
Vergleich zu Männer hatten Frauen in den USA jedoch ein 1,7-fach höheres Risiko 
eins späten (etwa bei GFR< 5 ml/min) Dialysebeginns. Eine geringere Awareness 
gegenüber ihrer Nierenerkrankung bei Frauen, wie in einer NHANES Studie gezeigt 
werden konnte, könnte zu diesen Phänomenen beitragen. Doch auch die 
Entscheidung des behandelnden Arztes und die Meinung der Familienangehörigen 
könnte einen größeren Einfluss zur Entscheidung für oder gegen eine 
Dialysetherapie darstellen als die persönliche Meinung der Patienten. Aus der 
kontrovers geführten Diskussion ob Männer eine schnellere CNI Progression zeigen 
als Frauen und aufgrund vorliegender Studien zur Mortalität bei CNI ergibt sich die 
Frage ob weibliche CNI Patienten möglicherweise ein höheres prä-dialyse 
Mortalitätsrisiko aufweisen als männliche. 
Basierend auf den Daten der Dialysis Outcomes and Practice Patterns Studie 
(DOPPS, o.a. Referenz) erscheint die Hypothese der CNI Missklassifikation und 
verzögerten CNI Progression bei Frauen unwahrscheinlich. So vermuten wir eher 
psychosoziale 
bzw. 
sozioökonomische 
Hintergründe 
als 
Ursache 
für 
die 
Unterrepräsentanz 
der 
Frauen 
an 
nephrologischen 
Ambulanzen 
und 
bei 
Nierenersatztherapien. 
Die Ziele der vorliegenden Studie sind die Darstellung geschlechtsspezifischer 
Unterschiede in der Population mit Nierenersatztherapie in Österreich, die Analyse 
geschlechtsspezifischer 
Unterschiede 
bei 
Therapie 
und 
Outcomes 
von 
hospitalisierten Patienten mit CNI und die Darstellung der Entscheidungsfindung 
betreffend der Einleitung eines Nierenersatzverfahrens.   

 
 
4 
Die Studie wurde in 3 Substudien unterteilt, bestehend aus einer nationalen und 
einer lokalen retrospektiven Datenanalyse sowie einer Fragenbogenstudie: 
1) 
Darstellung 
und 
Analyse 
geschlechtsspezifischer 
Unterschiede 
von 
Hämodialysepatienten und Hämodialyse assoziierter Mortalität in Österreich 
Methode: Abfrage epidemiologischer, klinischer und Hämodialyse-spezifischer Daten 
aller Patienten aus dem österreichischen Dialyseregister (1965-2015). 
2) Erfassung geschlechtsspezifischer Unterschiede in Behandlung und Outcome von 
hospitalisierten 
Patienten 
im 
Krankenanstaltsverbund 
mit 
eingeschränkter 
Nierenfunktion. 
Methode: Geschlechtsspezifische Erfassung aller Patienten, welche mit einer GFR < 
60 mL/min/1.73m2 im Jahr 2015 auf einer internistischen Abteilung des 
Krankenanstaltsverbundes 
hospitalisiert 
wurden 
und 
deren 
Outcomes 
(Hospitalisierungsdauer, Mortalität während der Hospitalisierung, Dialyseinitiierung). 
3) Darstellung geschlechterspezifischer Unterschiede in der Entscheidungsfindung 
der Patienten mit terminaler Niereninsuffizienz und der betreuenden Ärzte bezüglich 
der Einleitung einer Nierenersatztherapie. 
Methode: Anonymisierter Patientenfragenbogen für Patienten und Ärzteteam an 
nephrologischen Ambulanzen. Adressiert werden alle nephrologischen Ambulanzen 
Österreichs. 

 
 
5 
 
TABLE OF CONTENTS 
1. INTRODUCTION ................................................................................................................................ 6 
1.1 Women are under-represented in the dialysis population .................................................. 6 
1.2 The under-representation of women in the dialysis population runs counter to their 
possibly higher prevalence of chronic kidney disease prevalence ........................................... 7 
1.3 Women could be under-represented in chronic kidney disease clinics .............................. 8 
1.4 A potential sex-bias in estimated glomerular filtration does not explain the under-
representation of women in the dialysis population ................................................................. 9 
1.5 Late dialysis initiation and poor kidney disease awareness among women ...................... 9 
1.6 The decision to initiate dialysis is doctor-driven ............................................................. 10 
1.7 Sex-specific differences in chronic kidney disease progression and death risk before the 
start of dialysis ....................................................................................................................... 10 
2. STUDY OBJECTIVES AND INVESTIGATIONAL PLAN /METHODOLOGY ........................... 13 
2.1 Description and analysis of sex-specific differences in hemodialysis patients and the 
associated male-to-female mortality in Austria ..................................................................... 13 
2.2 Description and analysis of sex-specific differences in treatment and outcomes in 
patients with chronic kidney disease. ..................................................................................... 14 
2.3 Descriptive analysis of decision-making by doctors and patients with regards to renal 
replacement therapy initiation ................................................................................................ 14 
3. TIME TABLE .................................................................................................................................... 17 
4. REFERENCES ................................................................................................................................... 18 
 

 
 
6 
1. INTRODUCTION 
1.1 Women are under-represented in the dialysis population 
 
A recent report from the international Dialysis Outcomes and Practice Patterns Study 
(DOPPS) followed the call of Nature1, 2 and Lancet3 to “put gender on the agenda“ 
and analyzed sex-specific differences in hemodialysis patients.4 As an addition to 
previous studies,5, 6 the principal goal was to identify aspects of dialysis care that 
could be improved for females and males on hemodialysis, by studying the 
interaction between sex and modifiable treatment practices on mortality. The most 
important result of this analysis was the suggestion that a large number of females 
are currently not being dialyzed at all. Specifically, among 206,374 patients from 12 
countries who participated in the DOPPS from 1996 through 2011, 59% were male 
and 41% female. The regional differences by age group and country were so large 
(Table 1) that they seemed unlikely explainable by biology.4  
 
 
18-44 
 
45-54 
 
55-64 
 
65-74 
 
75+ 
Country 
GP 
HDp 
HDi 
 
GP 
HDp 
HDi 
 
GP 
HDp 
HDi 
 
GP 
HDp 
HDi 
 
GP 
HDp 
HDi 
Aus-NZ 
49.8 
49.1 
25.3 
 
50.6 
42.3 
27.7 
 
50.3 
43.8 
41.6 
 
51.2 
42.4 
30.6 
 
58.4 
31.9 
24.6 
Belgium 
49.6 
42.5 
41.0 
 
49.7 
34.0 
39.8 
 
50.4 
42.1 
37.6 
 
53.4 
43.8 
38.1 
 
62.6 
42.1 
39.7 
Canada 
49.4 
43.9 
38.0 
 
50.0 
40.8 
33.5 
 
50.8 
42.9 
38.9 
 
52.2 
39.3 
38.4 
 
60.0 
48.9 
40.1 
France 
50.2 
35.6 
33.7 
 
51.1 
40.1 
37.2 
 
51.3 
36.2 
38.4 
 
53.9 
39.3 
33.1 
 
63.3 
45.9 
37.5 
Germany 
49.1 
39.4 
32.4 
 
49.4 
34.9 
47.1 
 
50.6 
39.8 
32.7 
 
52.9 
35.0 
31.3 
 
64.4 
45.9 
41.5 
Italy 
49.5 
35.6 
37.3 
 
50.6 
36.3 
37.1 
 
51.4 
38.5 
36.3 
 
53.7 
38.8 
32.9 
 
62.6 
45.5 
37.4 
Japan 
49.1 
29.4 
32.4 
 
49.9 
32.1 
27.5 
 
50.8 
35.8 
28.6 
 
52.9 
37.7 
30.0 
 
62.3 
43.6 
38.8 
Spain 
48.6 
34.4 
37.2 
 
50.2 
37.4 
32.8 
 
51.5 
36.3 
31.0 
 
53.8 
40.0 
27.4 
 
61.2 
42.9 
37.8 
Sweden 
48.9 
44.4 
27.0 
 
49.3 
42.6 
35.6 
 
49.9 
34.9 
26.0 
 
51.4 
32.9 
32.5 
 
60.4 
40.0 
35.1 
UK 
50.1 
40.9 
41.7 
 
50.5 
40.1 
26.9 
 
50.8 
39.2 
42.2 
 
52.3 
45.0 
37.7 
 
60.7 
40.2 
36.1 
US 
49.7 
41.5 
41.6 
  
50.8 
39.1 
42.5 
  
51.8 
44.9 
43.3 
  
53.6 
49.2 
39.3 
  
61.1 
46.3 
40.8 
 
Table 1: Percentage of women in the general population (GP) versus in the hemodialysis 
population (DOPPS) in the year 2009, by country and age group. 
Categories 18-44, 45-54, 55-64, 65-74, 75+ are age categories [in years]. General population (GP) data 
are from the Human Mortality Database, 2009. Hemodialysis prevalent population (HDp) data are 
from the initial census of patients in facilities at the start of DOPPS Phase 4 (2009), cross-sectional, 
regardless of duration of end-stage renal disease. Hemodialysis incident population (HDi) restricted to 
patients on dialysis <90 days, when added to the facility census of patients in the DOPPS (includes 
patients in DOPPS facilities at the start of DOPPS Phase 4 data collection as well as patients who 
started dialyzing at DOPPS facilities during 2009–2012). Abbreviations: GP, general population; 
HDp, hemodialysis prevalent population; HDi, hemodialysis incident population; Aus-NZ=Australia 
and New Zealand; UK=United Kingdom; US=United States. 
 
The percentage of women in the general population, derived from the „Human 
Mortality Database“, was 50% and above and increased throughout older age-
groups. By contrast, in the dialysis population, the percentage of women was 
consistently below 50% for both prevalent and incident patients, indicating that 
gender-specific differences in early dialysis mortality -if any such differences might 
exist- had not influenced the results. 
 

 
 
7 
Regional differences between men and women on dialysis were perhaps the most 
interesting finding: For example, only 31.9% of >75 year-old dialysis patients in 
Australia and New Zealand were females, while 48.9% in the same age group in 
Canada. These regional differences suggest that psycho-socio-economic factors, 
rather than biological ones are responsible for the under-representation of women on 
dialysis. 
 
 
1.2 The under-representation of women in the dialysis population runs counter 
to their possibly higher prevalence of chronic kidney disease prevalence 
Women could be under-represented in the hemodialysis population, because chronic 
kidney disease might affect more males than females. However, in the National 
Health and Nutrition Examination Survey (NHANES), chronic kidney disease among 
US individuals without end-stage renal disease has been found to be more frequent 
among women (Table 2). 
 
All CKD 
eGFR <60 ml/min/1.73m2 
ACR ≥30 mg/g 
1988-1994 
2005-2010 
1988-1994 
2005-2010 
1988-1994 
2005-2010 
Male 
10.2 
12.1 
4.1 
5.6 
7.4 
8.6 
Female 
14.2 
15.8 
5.6 
7.7 
10.2 
10.2 
 
Table 2: Prevalence [%] of chronic kidney disease in the NHANES population within gender 
category. 
Data published in the USRDS Annual Data Report 2013, page 44.7 
Abbreviations: CKD=chronic kidney disease, eGFR=estimated glomerular filtration 
rate, 
ACR=albumin creatinine ratio. 
 
Specifically, NHANES data showed for 2005-2010 that the percentage of individuals 
those with an albumin creatinine ratio ≥30 mg/g was substantially higher among all 
women analyzed (10.2%) than among all men analyzed (8.6%), and that the 
percentage of those with an eGFR <60 mL/min/1.73m2 was substantially higher 
among all women analyzed (7.7%) than among all men analyzed (5.6%, Table 2). 
 
Consistent with NHANES and still in the United States, data from a large, integrated 
system of health care delivery (Kaiser Permanente of Northern California) indicated 
that chronic kidney disease is more frequent among women.8 As compared to the 
general population in the United States where the percentage of women among all 
those who were aged 65-74 years in 2009 was 53.6% (Table 1), the percentage of 
women among all those who held their insurance with Kaiser Permanente and had 
an eGFR <60 mL/min/1.73m2 and ≥15 mL/min/1.73m2 was between 57.7% and 
60.7% (Table 3). 
 
eGFR [mL/min/1.73m2] ≥60 
45-59 
30-44 
15-29 
<15 
without dialysis 
Age [years] 
49.1 ±1 5.1 
65.4 ± 13.5 
71.2 ± 12.9 
70.1 ± 14.5 
63.0 ± 16.1 
Female Sex [%] 
53.4% 
60.7% 
61.6%  
57.7% 
50.6%  
 
Table 3: Percentage of women among individuals with chronic kidney disease. 
Data are derived from the analysis of a large, integrated system of health care delivery (Kaiser 
Permanente of Northern California).8 

 
 
8 
Abbreviation: eGFR=estimated glomerular filtration rate. 
 
Importantly, while the Kaiser Permanente data showed that the majority (57.7%) of all 
those with eGFR 15-29 mL/min/1.73m2 were women, the majority (50.6%) of those 
who had a dialysis indication (eGFR <15 mL/min/1.73m2) but still were without 
dialysis also were women. 
 
Data from NHANES and Kaiser Permanente are consistent with the majority of 
population-based studies.9 Specifically, most of the included studies presented a 
gender-specific prevalence of chronic kidney disease. In general, the prevalence of 
chronic kidney disease was greater in women than in men, regardless of age.10-12 
Also consistent with NHANES, proteinuria, as defined by dipstick result of trace or 
greater was more prevalent in women in a study of 107,192 Japanese volunteers, 
although fewer women than men ended up receiving renal replacement therapy 
during 10 years of follow-up.13 Finally, a most recent systematic analysis of 
worldwide population-based data showed consistently that the prevalence of chronic 
kidney disease stages 3-5 in 2010 was higher for women than for men in all 
countries, except for the age group of 20-29.14 
 
 
1.3 Women could be under-represented in chronic kidney disease clinics 
The Chronic Kidney Disease Outcomes and Practice Patterns Study (CKDOPPS) 
collects data on advanced chronic kidney disease and the transition of patients to 
end-stage renal disease, aiming to identify practices associated with the best 
outcomes.15 Data on chronic kidney disease patients are currently starting to become 
available from Germany16, France17, Brazil18 and the United States. Preliminary 
results from CKDOPPS indicate that 40%-52% of patients in chronic kidney disease 
clinics of France, Brazil, the United States and Germany are women (Figure 1). 
 
 
Figure 1: Sex distribution of patients in chronic kidney disease clinics. 

 
 
9 
Preliminary data from the Chronic Kidney Disease Outcomes and Practice Patterns Study 
(CKDOPPS). 
 
Respective to the percentage of women in the general population (Table 1) and 
respective to the percentage of women among patients with chronic kidney disease 
(Table 3), the finding that only 40%-52% of patients in chronic kidney disease clinics 
are women might suggest their under-representation. 
 
 
1.4 A potential sex-bias in estimated glomerular filtration does not explain the 
under-representation of women in the dialysis population 
Most of the formulae used to assess renal function are based on serum creatinine.19 
Serum creatinine values are influenced among other things by protein intake and 
muscle mass. It is obvious that for the standard general population muscle mass is 
higher in men than in women, and therefore, creatinine-based formulas to estimate 
kidney function rightly include sex as a variable (MDRD equation without ethnicity 
factor: 175 x Serum Creatinine-1.154 x age-0.203 x 0.742 [if female]20). The correction 
factors for female sex in both MDRD and Cockroft-Gault formulae might be 
incorrect,10 although European validation studies support only some, but not large 
errors in correction factors between men and women.21 Specifically, for women aged 
<65 years, the bias of the MDRD formula (compared to Cr-EDTA clearance) was -
3.1±17.2 mL/min/1.73m2.21 These findings, however, did not discourage KDIGO from 
advising measurement of the kidney function by MDRD or Cockroft-Gould equation 
as a level A recommendation in both men and women, while measurement of 
creatinine clearance is advised in extraordinary health conditions (vegetarian diet, 
malnutrition or obesity). Importantly, misclassification of women with a presumably 
lower GFR than might be expected from performing the gold standard renal 
clearance would result in more women dialyzing, if GFR was used as the primary 
trigger for dialysis initiation. The opposite is the case, as shown by the 
aforementioned DOPPS study.4 US data analyzed at Arbor Research Collaborative 
for Health showed in accordance with the DOPPS,4 that the adjusted estimated 
glomerular filtration rate was 1.07 ml/min/1.73m2 lower in women than in men at 
dialysis initiation (95% CI 1.03–1.10 ml/min/1.73m2).22 
 
 
1.5 Late dialysis initiation and poor kidney disease awareness among women 
Kausz et al. have shown as early as 2000 that among those 23% of patients who 
began dialysis late in the United States between 1995 and 1997 (i.e. glomerular 
flitration rate <5 ml/min/1.73m2), women had an odds ratio of 1.70 compared with 
men, surpassing that of Hispanics and Asians (compared with Caucasians), 
uninsured patients (compared with private insurance), and employed patients 
(compared with unemployed).23 These data are consistent with more recent results.24, 
25 
 
Coresh et al. analyzed chronic kidney disease awareness among US adults using 
NHANES surveys conducted in 1999 to 2000 and found that less than one fifth 
(18.6±6.3%) of adults with chronic kidney disease stage 3 and albuminuria (>30 mg/g 
creatinine) reported previous knowledge/diagnosis of weak or failing kidneys. Among 

 
 
10
those in chronic kidney disease stage 3 but without proteinuria, less than one tenth 
(8.2±2.3%) of adults were aware of their chronic kidney disease. In the latter group, 
awareness levels were significantly lower among women (2.9±1.6% awareness in 
women versus 17.9±5.9% awareness in men).26 This observation might explain the 
potential under-representation of women in chronic kidney disease clinics (Figure 1). 
 
 
 
1.6 The decision to initiate dialysis is doctor-driven 
Davison et al. conducted a survey, asking the following question (Table 4) among 
584 patients with chronic kidney disease stages 4 and 5 as they presented to 
dialysis, transplantation or predialysis clinics in a Canadian, university-based renal 
program:27 
 
“If you are currently receiving dialysis, why did you choose dialysis over conservative 
care (no dialysis)?” 
Your doctor’s wish: 
 
51.9% 
Your own personal wish:  
34.2% 
Your family’s wish:  
 
13.9% 
 
Table 4: Excerpt from a survey on and-of-life care preferences and needs in patients with 
chronic kidney disease.27 
 
The response to the question asked by Davison et al. suggests that the decision to 
be treated with dialysis reflects physicians’ and family members’ preferences rather 
than personal choice.27 This opens room for the possibility that women are under-
represented in the dialysis population, because doctors might be more reluctant to 
initiate renal replacement therapy in women than in men. 
 
 
1.7 Sex-specific differences in chronic kidney disease progression and death 
risk before the start of dialysis 
The effect of sex on the progression of renal disease has been a matter of debate, 
until Neugarten et al., in a meta-analysis of 68 published studies, were able to show 
that men have a more rapid decline of renal function than women.28 However, of the 
eight studies that were selected for meta-analysis29-36, the association between sex 
and the rate of fall in glomerular filtration rate was attenuated in one study and 
became non-significant after adjusting for differences in blood pressure, proteinuria 
and high density lipoprotein cholesterol.29 Moreover, two studies33, 34 not only used 
decline in glomerular filtration rate, but also end stage renal failure as an outcome in 
order to define “progression to end stage renal disease”. This analytical strategy has 
been shared by a recent study conducted on 185,431 individuals in Austria, which 
found an increased risk of end stage renal disease, as defined by initiation of renal 
replacement therapy, for men.37 Clearly, if women were to initiate dialysis later, or not 
at all, in comparison to men, the bias that might be introduced by a sex-dependent 
decision to initiate renal replacement therapy would be carried over into the 
aforementioned analyses. Thus the progression in women might be underestimated 
due to the inclusion of dialysis initiation in the calculations. 
 

 
 
11
 
If more women than men have chronic kidney disease don’t they progress? An 
alternative explanation is that they either die more often or die before they reach 
dialysis: A meta-analysis on two million participants (54% women) from general 
population and high-risk cohorts conducted by the Chronic Kidney Disease Prognosis 
Consortium analyzed the mortality risk for women and men, by eGFR.38 As shown in 
Figure 2, the slopes of the risk relationship for all-cause mortality and for 
cardiovascular mortality were steeper in women as compared to men. Specifically, 
compared with an estimated glomerular filtration rate of 95 ml/min/1.73m2, the 
adjusted hazard ratio for all-cause mortality at estimated glomerular filtration rate 45 
ml/min/1.73m2 was 1.32 (95% CI 1.08 to 1.61) in women and 1.22 (1.00 to 1.48) in 
men (Pinteraction <0.01). 
 
 
 
 
Figure 2: Hazard ratios of all-cause mortality according to estimated glomerular filtration rate 
in men (red) versus women (green). 
Data are derived from general population cohorts and high cardiovascular risk cohorts.38 Panel A 
shows sex-specific hazard ratios including a main effect for male sex at the reference point. Panel B 
shows hazard ratios within each sex, thus visually removing the baseline difference between men and 
women.38 
 
The slope being steeper for women led to the authors’ conclusion that “kidney 
disease is not less important in women than in men”.38 However, our interpretation is 
that women are likely to die before reaching delayed dialysis. The abridged life table 
method was applied in the Alberta Network Healhcare extraction (Canada) to 
calculate the life expectancies of men and women from age 30 to 85 years by levels 
of kidney function:39 In agreement with the notion that women live longer, women 
aged 30-60 years with chronic kidney disease stage 3 had a life expectancy of 3-5 
years more than men. However, women aged 30-60 years lived 1-2 more years than 
men if having chronic kidney disease stage 4 and actually lived 1-2 years less than 
men if having chronic kidney disease stage 5. 
 
No analysis has, to our knowledge tested the hypothesis that death 
competes with the possibility to reach dialysis and that this may 
explain the controversy among studies analyzing progression rates 
by sex.39 
 
 
 

 
 
12
The large regional differences in dialysis prevalence observed in the DOPPS-study 4 
(Table 2) render the previous hypotheses of chronic kidney disease misclassification 
among women and delayed chronic kidney disease progression unlikely. Psycho-
socio-economic factors, rather than biological ones could be responsible for the fact 
that fewer women than men are dialyzing, consistent with the findings that dialysis 
initiation is later among women than among men, and that women are more likely to 
die in the late, pre-dialysis chronic kidney disease stages (Figure 2).38 
 
 
The present study aims at further investigating sex-specific differences in recognition, 
progression and treatment of chronic kidney disease in Austria.  
 
 
 

 
 
13
2. STUDY OBJECTIVES AND INVESTIGATIONAL PLAN /METHODOLOGY 
 
Objectives 
This study aims to describe sex specific differences of the hemodialysis population in 
Austria, to quantify sex specific differences in treatment and outcomes in hospitalized 
patients with chronic kidney disease and to examine decision making by doctors and 
patients with regards to hemodialysis initiation.  
 
To adequately serve the needs of these research questions, the study is divided into 
3 parts (sub-studies).  
 
1. Description and analysis of sex-specific differences in hemodialysis patients 
and the associated male-to-female mortality in Austria. 
     
2. Description and analysis of sex-specific differences in treatment and outcomes 
in hospitalized patients with chronic kidney disease.  
 
3. Descriptive analysis of decision-making by doctors and patients with regard to 
hemodialysis initiation.  
 
 
2.1 Description and analysis of sex-specific differences in hemodialysis 
patients and the associated male-to-female mortality in Austria 
 
Hypothesis:  
 
There are sex-specific differences in hemodialysis incidence/prevalence and mortality 
among hemodialysis patients in Austria.  
There are differences in male-to-female mortality among hemodialysis patients as 
compared to the general population in Austria.  
 
Methodology:  
 
Data extraction will be performed from the Austrian Dialysis registry which holds 
complete longitudinal entries of all Austrian hemodialysis patients since 197040 and 
contains data of all patients undergoing hemodialysis in Austria since the year 1965.  
Demographic data, laboratory values, clinical characteristics and hemodialysis 
specific data will be collected for every patient registered in the Austrian Dialysis 
registry between 1865 and 2015.  
Male and female population structure and mortality data of the Austrian general 
population will be retrieved from the ´Statistik Austria´ registry 
 
Statistics: 
 
Standard descriptive statistics will be used for tabulations of patient characteristics by 
sex and decade, of the Austrian hemodialysis population versus general population 
by sex and age group over time. The unadjusted male-to-female mortality rate ratio in 

 
 
14
the hemodialysis population will be compared with that of the Austrian general 
population. Adjusted hazard ratios for the male-to-female mortality risk in 
hemodialysis patients, by region will be performed using Cox regression analysis. 
Statistical modeling will closely follow a previously published study of hemodialysis 
data, analyzed by sex and country/region.4 All obtained p-values will be considered 
exploratory in nature. 
 
2.2 Description and analysis of sex-specific differences in treatment and 
outcomes in patients with chronic kidney disease.  
 
Hypothesis: 
 
There are sex-specific differences in treatment, length of hospitalization, mortality 
and dialysis initiation in patients with chronic kidney disease admitted to internal 
medicine wards.   
 
Methodology:  
 
Patients hospitalized at internal medicine wards of the Krankenanstaltsverbund 
(KAV) between Jan 1st 2015 and Dec 31st 2015 with eGFR <60 mL/min/1.73m will 
be included.  
Primary study endpoints are length of hospital stay, death within hospitalization and 
dialysis initiation. Secondary endpoints are renal function parameters (eGFR, serum 
creatinine, blood urea nitrogen) and proteinuria during hospital stay. Laboratory data 
will be extracted from the KAV laboratory database and patient characteristics will be 
derived from the KAV patient management database. 
 
Statistics: 
Descriptive statistics will be used for presentation of demographic and clinical patient 
characteristics and prevalence of chronic kidney disease in women as compared to 
men.  
Further statistical methods will be chosen according to data availability and quality:  
The present plans include logistic regression to calculate the male-to-female odds of 
reaching one of the endpoints, conditional logistic regression for pair-matched data or 
logistic regression with propensity scoring. 
 
 
2.3 Descriptive analysis of decision-making by doctors and patients with 
regards to renal replacement therapy initiation 
 
Hypothesis 
 
There are sex-specific differences in decision-making of doctors and patients with 
end-stage renal disease with regards to renal replacement therapy initiation. 
 
Methodology  
 

 
 
15
Questionnaires will be sent to every Austrian chronic kidney disease outpatient clinic 
willing to participate. Doctors and patients will complete the questionnaire 
anonymously and questionnaires will be sent back after a 3 months-time period of 
data collection /questionnaire completion.  
 
The following questions will be included in the questionnaire:  
 
Doctor level: 
In your chronic kidney disease clinic 
1. How many men (a) and how many women (b) were registered in the year 2016? 
2. According to the first lab result that was taken in 2016, how many men (a) and 
how many women (b) were in chronic kidney disease stage 4, 3a, 3b, and 2?  
3. How many times did the registered men (a) and the registered women (b) have 
their labs checked and saw the doctor during the year 2016? Please subdivide 
also by chronic kidney disease stage. 
4. How many men (a) and how many women (b) have you informed they will likely 
need renal replacement therapy (RRT) in the next 12 months? 
5. How many men (a) and how many women (b) already have a fistula, and how 
many have a graft for vascular access? 
6. How many men (a) and how many women (b) have you informed about pre-
emptive transplantation as an option for RRT? 
7. How many men (a) and how many women (b) have you informed about peritoneal 
dialysis as an option for RRT? 
8. How many men (a) and how many women (b) have you informed about 
hemodialysis as an option for RRT? 
9. How many men (a) and how many women (b) ended up on RRT (HD, PD or 
preemptive transplantation) during the year 2016? 
10. How many men (a) and how many women (b) did you consider end stage and 
thus in need of undergoing RRT in 2016? 
11. How many men (a) and how many women (b) refused RRT in 2016 despite your 
advice? 
12. Among those whom you considered end stage in the year 2016, in how many 
men (a) and how many women (b) was the decision to withhold or not do RRT 
mutual (taken by doctor and patient together)? 
13. How many men (a) and how many women (b) started RRT in 2016 against your 
advice? 
14. How would you judge your own decision making regarding RRT initiation 
a) Influenced by patient sex, with men more likely to start RRT 
b) Influenced by patient sex, with women more likely to start RRT 
c) Not influenced by patient sex 
 
 
To obtain adequate data, a reimbursement based on the number of patients seen by 
the center will be offered to the medical director of the outpatient clinic in December 
2016. A specific plan on how to arrive at answering the questions correctly must be 
submitted; in principle, this plan should encompass several meetings with the 
outpatient clinic doctors in early 2017, in order to obtain an answer from all of them 
together (only question 14 must be individually answered). 
 
 
Patient level: 

 
 
16
1. I am a man (a), a woman (b). 
2. My age is … years. 
3. My nationality is Austrian (a), Non-Austrian (b). 
4. My native language is German (a), not German (b). 
5. I am married (a), living with my partner (b), separated or divorced (c), 
single (d), widowed (e). 
6. My highest level of education is less than high school. 
7. I know the reason (a), don’t know the reason (b) why my kidneys are weak or 
failing. 
8. The most important reason why my kidneys are weak or failing, to the best of 
my knowledge is hypertension (a), diabetes (b), glomerulonephritis (c), 
polycystic kidney disease (d); another reason not mentioned here (e). 
9. I come to the clinic seldom [once a year at the most] (a), frequently [at least 3 
times a year] (b) in order to check my labs and/or discuss treatment and 
progression of my disease. 
10. A doctor at this clinic has told me (a) has not told me (b) that I will likely need 
renal replacement therapy (RRT) within the next 12 months. 
11. I already have (a) / don’t yet have (b) a fistula or graft for vascular 
hemodialysis access. 
12. A doctor at this clinic has informed me (a) has not informed me (b) about the 
possibility to undergo pre-emptive transplantation as an option for RRT. 
13. A doctor at this clinic has informed me (a) has not informed me (b) about 
peritoneal dialysis as an option for RRT. 
14. A doctor at this clinic has informed me (a) has not informed me (b) about the 
possibility to undergo hemodialysis as an option for RRT. 
1. I consider myself end stage and thus in need of 
undergoing RRT within the next 12 months. 
15. RRT is not an option for me. I would rather die than go on dialysis. 
16. I suffer from nausea/vomiting (a), fatigue/tiredness (b), edema (c), 
dyspnea (d). 
17. I can take care (a), cannot take care (b) of my household. 
 
 
 
Methodological Note: The questionnaire will be handed out to all patients coming to 
the outpatient clinic in the year 2017 by non-medical (administrative) personnel. The 
number of returned questionnaires will be counted and compared to the number of 
questionnaires that was handed out. Only the sex of the patient receiving the 
questionnaire will be recorded. The return of the questionnaire will be anonymous, by 
placing a box in the patient waiting area. 
 
 
 
Statistics:  
 
Data will be entered into an IBM SPSS statistics database. Descriptive analysis and 
graphical illustrations will be performed.  
 
 
 

 
 
17
3. TIME TABLE 
 
 
Task 
Year 1 
Year 2 
Year 3 
 
 
Q1 Q2 
Q3 Q4 
Q1 Q2 
Q3 
Q4 
Q1 Q2 
Q3 Q4 
1 
Objective 1 (data 
collection, data analysis, 
manuscript [MS]) 
 
 
 
 
 
 
 
 
2 
Study objective 2 (data 
source identification & 
approval of data 
collection, analysis, MS) 
 
 
 
 
 
 
 
 
 
 
 
 
3 
Objective 5 
(questionnaire 
development & testing, 
distribution, retrieval, 
data analysis, MS) 
 
 
 
 
 
 
 
 

 
 
18
4. REFERENCES 
 
1. Putting gender on the agenda. Nature, 465: 665, 2010. 
2. Kim, AM, Tingen, CM, Woodruff, TK: Sex bias in trials and treatment must end. Nature, 465: 
688-689, 2010. 
3. Carrero, JJ, de Jager, DJ, Verduijn, M, Ravani, P, De Meester, J, Heaf, JG, Finne, P, Hoitsma, AJ, 
Pascual, J, Jarraya, F, Reisaeter, AV, Collart, F, Dekker, FW, Jager, KJ: Cardiovascular and 
noncardiovascular mortality among men and women starting dialysis. Clinical journal of the 
American Society of Nephrology : CJASN, 6: 1722-1730, 2011. 
4. Hecking, M, Bieber, BA, Ethier, J, Kautzky-Willer, A, Sunder-Plassmann, G, Saemann, MD, 
Ramirez, SP, Gillespie, BW, Pisoni, RL, Robinson, BM, Port, FK: Sex-Specific Differences in 
Hemodialysis Prevalence and Practices and the Male-to-Female Mortality Rate: The Dialysis 
Outcomes and Practice Patterns Study (DOPPS). PLoS medicine, 11: e1001750, 2014. 
5. Villar, E, Remontet, L, Labeeuw, M, Ecochard, R: Effect of age, gender, and diabetes on excess 
death in end-stage renal failure. Journal of the American Society of Nephrology : JASN, 18: 
2125-2134, 2007. 
6. Carrero, JJ, de Mutsert, R, Axelsson, J, Dekkers, OM, Jager, KJ, Boeschoten, EW, Krediet, RT, 
Dekker, FW: Sex differences in the impact of diabetes on mortality in chronic dialysis 
patients. Nephrology, dialysis, transplantation : official publication of the European Dialysis 
and Transplant Association - European Renal Association, 26: 270-276, 2011. 
7. U.S. Renal Data System, USRDS 2012 Annual Data Report: Atlas of Chronic Kidney Disease and 
End-Stage Renal Disease in the United States, National Institutes of Health, National 
Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD, 2012. 1.1.a.i. 
8. Go, AS, Chertow, GM, Fan, D, McCulloch, CE, Hsu, CY: Chronic kidney disease and the risks of 
death, cardiovascular events, and hospitalization. The New England journal of medicine, 
351: 1296-1305, 2004. 
9. Zhang, QL, Rothenbacher, D: Prevalence of chronic kidney disease in population-based studies: 
systematic review. BMC public health, 8: 117, 2008. 
10. Nitsch, D, Felber Dietrich, D, von Eckardstein, A, Gaspoz, JM, Downs, SH, Leuenberger, P, 
Tschopp, JM, Brandli, O, Keller, R, Gerbase, MW, Probst-Hensch, NM, Stutz, EZ, 
Ackermann-Liebrich, U: Prevalence of renal impairment and its association with 
cardiovascular risk factors in a general population: results of the Swiss SAPALDIA study. 
Nephrology, dialysis, transplantation : official publication of the European Dialysis and 
Transplant Association - European Renal Association, 21: 935-944, 2006. 
11. Brown, WW, Peters, RM, Ohmit, SE, Keane, WF, Collins, A, Chen, SC, King, K, Klag, MJ, 
Molony, DA, Flack, JM: Early detection of kidney disease in community settings: the Kidney 
Early Evaluation Program (KEEP). American journal of kidney diseases : the official journal 
of the National Kidney Foundation, 42: 22-35, 2003. 
12. Chadban, SJ, Briganti, EM, Kerr, PG, Dunstan, DW, Welborn, TA, Zimmet, PZ, Atkins, RC: 
Prevalence of kidney damage in Australian adults: The AusDiab kidney study. Journal of the 
American Society of Nephrology : JASN, 14: S131-138, 2003. 
13. Iseki, K, Iseki, C, Ikemiya, Y, Fukiyama, K: Risk of developing end-stage renal disease in a 
cohort of mass screening. Kidney Int, 49: 800-805, 1996. 
14. Mills, KT, Xu, Y, Zhang, W, Bundy, JD, Chen, CS, Kelly, TN, Chen, J, He, J: A systematic 
analysis of worldwide population-based data on the global burden of chronic kidney disease 
in 2010. Kidney Int, 88: 950-957, 2015. 
15. Arbor Research Website: The Chronic Kidney Disease Outcomes and Practice Patterns Study. 
http://wwwdoppsorg/CKDOPPS/AbouttheCKDoppsaspx. 
16. Kleophas, W, Bieber, B, Robinson, BM, Duttlinger, J, Fliser, D, Lonnemann, G, Rump, LC, 
Pisoni, RL, Port, FK, Reichel, H: Implementation and first results of a German chronic 
kidney disease registry. Clinical nephrology, 79: 184-191, 2013. 
17. Stengel, B, Combe, C, Jacquelinet, C, Briancon, S, Fouque, D, Laville, M, Frimat, L, Pascal, C, 
Herpe, YE, Deleuze, JF, Schanstra, J, Pisoni, RL, Robinson, BM, Massy, ZA: The French 
Chronic Kidney Disease-Renal Epidemiology and Information Network (CKD-REIN) cohort 
study. Nephrology, dialysis, transplantation : official publication of the European Dialysis 
and Transplant Association - European Renal Association, 29: 1500-1507, 2014. 
18. de Oliveira, RB, Lopes, AA, Sesso, R, de Campos, LG, Mariani, L, Lugon, JR, Robinson, BM, 
Pisoni, RL, Pecoits-Filho, RF: The chronic kidney disease outcomes and practice patterns 
study Brazil (CKDopps-Brazil): design, data and methodology. Jornal brasileiro de 
nefrologia : 'orgao oficial de Sociedades Brasileira e Latino-Americana de Nefrologia, 36: 
96-101, 2014. 

 
 
19
19. Stevens, LA, Coresh, J, Greene, T, Levey, AS: Assessing kidney function--measured and 
estimated glomerular filtration rate. N Engl J Med, 354: 2473-2483, 2006. 
20. Levey, AS, Coresh, J, Greene, T, Stevens, LA, Zhang, YL, Hendriksen, S, Kusek, JW, Van Lente, 
F: Using standardized serum creatinine values in the modification of diet in renal disease 
study equation for estimating glomerular filtration rate. Annals of internal medicine, 145: 
247-254, 2006. 
21. Froissart, M, Rossert, J, Jacquot, C, Paillard, M, Houillier, P: Predictive performance of the 
modification of diet in renal disease and Cockcroft-Gault equations for estimating renal 
function. Journal of the American Society of Nephrology : JASN, 16: 763-773, 2005. 
22. Li, Y, Kapke, A, Jin, Y, Pearson, J, Port, FK, Robinson, B: Estimated GFR at Dialysis Initiation: 
Associations with Clinical and Non-Clinical Factors. Journal of the American Society of 
Nephrology : JASN, 24: 745A. Abstract SA-PO516, 2013. 
23. Kausz, AT, Obrador, GT, Arora, P, Ruthazer, R, Levey, AS, Pereira, BJ: Late initiation of dialysis 
among women and ethnic minorities in the United States. Journal of the American Society 
of Nephrology : JASN, 11: 2351-2357, 2000. 
24. Crews, DC, Scialla, JJ, Liu, J, Guo, H, Bandeen-Roche, K, Ephraim, PL, Jaar, BG, Sozio, SM, 
Miskulin, DC, Tangri, N, Shafi, T, Meyer, KB, Wu, AW, Powe, NR, Boulware, LE: Predialysis 
health, dialysis timing, and outcomes among older United States adults. Journal of the 
American Society of Nephrology : JASN, 25: 370-379, 2014. 
25. Slinin, Y, Guo, H, Li, S, Liu, J, Morgan, B, Ensrud, K, Gilbertson, DT, Collins, AJ, Ishani, A: 
Provider and care characteristics associated with timing of dialysis initiation. Clinical journal 
of the American Society of Nephrology : CJASN, 9: 310-317, 2014. 
26. Coresh, J, Byrd-Holt, D, Astor, BC, Briggs, JP, Eggers, PW, Lacher, DA, Hostetter, TH: Chronic 
kidney disease awareness, prevalence, and trends among U.S. adults, 1999 to 2000. 
Journal of the American Society of Nephrology : JASN, 16: 180-188, 2005. 
27. Davison, SN: End-of-life care preferences and needs: perceptions of patients with chronic 
kidney disease. Clinical journal of the American Society of Nephrology : CJASN, 5: 195-
204, 2010. 
28. Neugarten, J, Acharya, A, Silbiger, SR: Effect of gender on the progression of nondiabetic renal 
disease: a meta-analysis. Journal of the American Society of Nephrology : JASN, 11: 319-
329, 2000. 
29. Coggins, CH, Breyer Lewis, J, Caggiula, AW, Castaldo, LS, Klahr, S, Wang, SR: Differences 
between women and men with chronic renal disease. Nephrology, dialysis, transplantation : 
official publication of the European Dialysis and Transplant Association - European Renal 
Association, 13: 1430-1437, 1998. 
30. Hannedouche, T, Chauveau, P, Kalou, F, Albouze, G, Lacour, B, Jungers, P: Factors affecting 
progression in advanced chronic renal failure. Clinical nephrology, 39: 312-320, 1993. 
31. Jungers, P, Hannedouche, T, Itakura, Y, Albouze, G, Descamps-Latscha, B, Man, NK: 
Progression rate to end-stage renal failure in non-diabetic kidney diseases: a multivariate 
analysis of determinant factors. Nephrology, dialysis, transplantation : official publication of 
the European Dialysis and Transplant Association - European Renal Association, 10: 1353-
1360, 1995. 
32. Hunt, LP, Short, CD, Mallick, NP: Prognostic indicators in patients presenting with the nephrotic 
syndrome. Kidney Int, 34: 382-388, 1988. 
33. Rosman, JB, Langer, K, Brandl, M, Piers-Becht, TP, van der Hem, GK, ter Wee, PM, Donker, AJ: 
Protein-restricted diets in chronic renal failure: a four year follow-up shows limited 
indications. Kidney international Supplement, 27: S96-102, 1989. 
34. Ruggenenti, P, Gaspari, F, Perna, A, Remuzzi, G: Cross sectional longitudinal study of spot 
morning urine protein:creatinine ratio, 24 hour urine protein excretion rate, glomerular 
filtration rate, and end stage renal failure in chronic renal disease in patients without 
diabetes. BMJ, 316: 504-509, 1998. 
35. Simon, P, Ramee, MP, Autuly, V, Laruelle, E, Charasse, C, Cam, G, Ang, KS: Epidemiology of 
primary glomerular diseases in a French region. Variations according to period and age. 
Kidney Int, 46: 1192-1198, 1994. 
36. Williams, PS, Fass, G, Bone, JM: Renal pathology and proteinuria determine progression in 
untreated mild/moderate chronic renal failure. The Quarterly journal of medicine, 67: 343-
354, 1988. 
37. Pscheidt, C, Nagel, G, Zitt, E, Kramar, R, Concin, H, Lhotta, K: Sex- and Time-Dependent 
Patterns in Risk Factors of End-Stage Renal Disease: A Large Austrian Cohort with up to 20 
Years of Follow-Up. PloS one, 10: e0135052, 2015. 
38. Nitsch, D, Grams, M, Sang, Y, Black, C, Cirillo, M, Djurdjev, O, Iseki, K, Jassal, SK, Kimm, H, 
Kronenberg, F, Oien, CM, Levey, AS, Levin, A, Woodward, M, Hemmelgarn, BR: 
Associations of estimated glomerular filtration rate and albuminuria with mortality and 
renal failure by sex: a meta-analysis. BMJ, 346: f324, 2013. 

 
 
20
39. Turin, TC, Tonelli, M, Manns, BJ, Ravani, P, Ahmed, SB, Hemmelgarn, BR: Chronic kidney 
disease and life expectancy. Nephrol Dial Transplant, 27: 3182-3186, 2012. 
40. Kainz, A, Mayer, B, Kramar, R, Oberbauer, R: Association of ESA hypo-responsiveness and 
haemoglobin variability with mortality in haemodialysis patients. Nephrology, dialysis, 
transplantation : official publication of the European Dialysis and Transplant Association - 
European Renal Association, 25: 3701-3706, 2010.