UvA-DARE (Digital Academic Repository) Late effects of renal … · Denguee...

UvA-DARE is a service provided by the library of the University of Amsterdam (http://dare.uva.nl)

UvA-DARE (Digital Academic Repository)

Late effects of renal insufficiency in children. A national long-term follow-up study

Groothoff, J.W.

Link to publication

Citation for published version (APA):Groothoff, J. W. (2002). Late effects of renal insufficiency in children. A national long-term follow-up study.

General rightsIt is not permitted to download or to forward/distribute the text or part of it without the consent of the author(s) and/or copyright holder(s),other than for strictly personal, individual use, unless the work is under an open content license (like Creative Commons).

Disclaimer/Complaints regulationsIf you believe that digital publication of certain material infringes any of your rights or (privacy) interests, please let the Library know, statingyour reasons. In case of a legitimate complaint, the Library will make the material inaccessible and/or remove it from the website. Please Askthe Library: https://uba.uva.nl/en/contact, or a letter to: Library of the University of Amsterdam, Secretariat, Singel 425, 1012 WP Amsterdam,The Netherlands. You will be contacted as soon as possible.

Download date: 15 Feb 2021

https://dare.uva.nl/personal/pure/en/publications/late-effects-of-renal-insufficiency-in-children-a-national-longterm-followup-study(293b0433-12a9-400e-be17-60d9ad804d1b).html

4.. Mortality and causes of death of end-stage renall disease in children: a Dutch cohort study

Jaapp W Groothoff

Marikenn P Gruppen

Martinn Offringa

Jeroenn Hutten

Marcc R Lilien

Nicolee CAJ van de Kar

Ericc D Wolff

Jeann Claude Davin

Hugoo SA Heymans

KidneyKidney International 61: 621-629, 2002

41 1

4.. Mortality and Causes of Death

Abstract. .

Background:Background: To establish mortality rates, causes of death, and determinants of mortalityy in children with end-stage renal disease (ESRD), we performed a nationall long-term follow up study.

Methods:Methods: Mortality rate was determined in all Dutch patients with onset of ESRDD at age 0-14 years in the period between 1972 and 1992. Causes of death andd mortality determinants were investigated in all patients of this cohort who weree born before 1979. Data were derived from the Dutch Registry for patients onn RRT, medical charts and National Health Database.

Results:Results: Of all 381 patients 85 had died. The overall Mortality Rate (MR) was 1.57/1000 patient years; the Standardized Mortality Rate (SMR) was 31.0. The MRR for patients 0-5 and 6-10 years old at onset of ESRD decreased from, respectively,, 7.0 (range 0-14.9) to 3.9 (1.2-6.7) and 4.3 (1.1-7.5) to 1.6 (0.3-2.8) betweenn the periods 1972-1981 and 1982-1992. The mortality hazard ratio of relativelyy long-standing dialysis and of long-standing hypertension were, respectively,, 7.2 (4.4-11.8) and 3.1 (2.1-4.6), of cyclosporine-introduction in transplantedd patients 0.3 (0.1-0.4). Overall cerebrovascular accidents (24%) and infectionss (21%) were the most common causes of death; after 10 years of RRT cardiacc death (7/21) was most prevalent. Cardiovascular death was most prominentt in dialysis as well as transplanted patients.

Conclusion:Conclusion: Survival in children with ESRD has increased over the last 20 years, butt the SMR remains high. Early transplantation and a more vigorous approach towardss hypertension and infection may be mandatory in order to further reducee mortality.

In t roduct ion. .

Sincee the early seventies of the last century renal replacement therapy (RRT) has becomee an established treatment for children with end-stage renal disease (ESRD).. Improvement in dialysis technique and supportive therapy over the lastt two decades has placed chronic RRT in most children beyond controversy. Notablyy the introduction of bicarbonate-buffer replacing acetate in hemodialysis,, of continuous cycling peritoneal dialysis, and the use of recombinantt human erythropoietin (EPO) and Growth Hormone (GH) therapy havee been associated with a decrease in acute morbidity and mortality. Althoughh treatment of infants is still under debate, recent studies advocate the initiationn of RRT even in this group [1].

Nevertheless,, detailed information of long-term outcomes of RRT in children is lacking.. Previous studies on morbidity and mortality in these children have

42 2

4.4. Mortality and Causes of Death

relativelyy short follow up times, show only crude and incomplete registry data, orr describe isolated groups of transplanted children or children on dialysis [2-9].. We therefore conducted a National retrospective and prospective cross-sectionall study in order to evaluate Late physical, social and psychological Effectss of Renal Insufficiency (LERIC) in all Dutch children, who started RRT betweenn 1972 and 1992. This paper reports the mortality and causes of death.

Methods. .

1.1. Participants: the total cohort and the LERIC cohort. LERIC was designed to study thee physical, social and psychological consequences of pediatric ESRD at adult age.. In 1972 the first Dutch center for pediatric dialysis was officially opened. Beforee this year only a few children had been treated with chronic dialysis and detailedd information about these patients could not be obtained. Therefore we includedd only patients who started RRT after 1971. Patients who started RRT afterr 1991 were excluded in order to have at least a (potential) follow up period off 6 years. We were interested in the effects of end-stage renal disease obtained duringg childhood on adult life. We therefore formed a cohort of patients, who had,, or in case they were deceased, should have reached adulthood, defined as agedd older than 18 years, at the time of the study. Thus the LERIC cohort comprisedd all Dutch patients who had started chronic RRT between 1972 and 19922 at age less than 15 years, and who were born before 1979. Patients in whomm renal function recovered within four months after commencing dialysis weree excluded. Preemptive transplanted patients were included. Data on gender,, date of birth, initiation of RRT, and date of death of all the patients who fulfille dd the inclusion criteria were provided by the National Dutch Registry of patientss on RRT (RENINE, Rotterdam, The Netherlands). RENINE, founded in 1985,, is the Dutch source of the European Dialysis and Transplantation Association.. The completeness approaches 100%, as registration is compulsory forr reimbursement of RRT.

Too estimate unbiased mortality rates for all age groups, we enlarged the LERIC cohortt with those patients, who were excluded in the LERIC-study, because theyy were to young, i.e. those born after 1979. The list of these patients was also providedd by RENINE. This extended cohort was called "the total cohort" and consequentlyy consisted of all Dutch patients, who had started RRT between 19722 and 1992 at age 0-14 years.

Whenn we checked the RENINE data on the LERIC-cohort with data of all medicall centers, it turned out that the RENINE data on date of birth, start RRT andd death were very accurate, but that information about cause of death was lacking.. For this reason we used the total cohort only to describe mortality and thee LERIC cohort to describe cause of death and the relation between mortality ratess and determinants.

43 3


Thee health statistics of the Health and Welfare Department of Statistics Netherlandss (Centraal Bureau voor Statistiek, Voorburg, The Netherlands) were usedd to calculate Standardized Mortality rates.

2.. Data collection. Logistics. Patients who started RRT before 1985 are registered retrospectivelyy in the RENINE database. We checked the accuracy of data on thesee patients by comparing RENINE data with the databases of all four Dutch centerss for pediatric dialysis and kidney transplantation, and with the databasess of all centers for adult dialysis and transplantation.

Memberss of the LERIC team <JWG, MPG, JH, HC, BD, JvdM, AvdG) visited 37 hospitalss in the Netherlands in order to collect all available information on the causee of death in all LERIC patients. To achieve this all medical charts were reviewed.. We performed this review between the 1st of November 1998 and the 1stt of August 2000. In living patients the day of review was considered the day off the end of the study for that particular patient. We attempted to localize all emigratedd patients, and requested medical information from their current physician. .

CategorizationCategorization of causes of death. We used 4 classification systems for categorizationn of causes of death: the American Health Care Financing Administrationn and the European Dialysis and Transplantation lists, a list used byy Tozawa et al., and our own LERIC classification system [4,10,11]. Causes of deathh were categorized independently by three reviewers (JWG, MPG, MO). Afterr assessment of interobserver variability for each classification system, resultss were compared and consensus was achieved. For this latter purpose we usedd the guidelines of the International Classification of Diseases of the World Healthh Organization [12].

Peritonitiss without preceding intestinal pathology is a complication, which in ESRDD patients almost exclusively appears in patients on peritoneal dialysis. Theree is enough evidence that the open connection to the peritoneal cavity is thee most important factor leading to peritonitis. Therefore we categorized death byy peritonitis was categorized as a "complication of treatment", and not as an "infection". .

DeterminantsDeterminants of mortality. We collected data on total duration of hemodialysis, peritoneall dialysis and transplantation, primary renal disease, year and age at initiationn of first RRT, age at death, modality of RRT at time of death, the burdenn of hypertension and the use of EPO and immunosuppressive therapy. Thee observation period for all variable determinants lasted from the first day of RRTT until the day of chart-review. The total duration of RRT, hemodialysis, peritoneall dialysis and transplantation was expressed in days. Hypertension wass scored as follows: the mean blood pressure per 3 months was calculated fromm all documented blood pressures and recorded on file. In hemodialysis

44 4


patientss the mean of pre- and post dialysis blood pressure was used to calculate thee three month-period mean value. Over periods of uneventful follow up after transplantationn in which patients were less frequently controlled than once per threee months, the mean value of two subsequently recorded blood pressures wass presumed to represent the mean blood pressure of the three-months period lyingg in between these measured blood pressures. All eventful periods since onsett of RRT over which data could not be obtained were excluded from evaluationn and recorded as missing patient-years. Hypertension was defined as bothh systolic and diastolic blood pressure above the 95th percentile for age, in accordancee with the Task Force on Blood Pressure in Children [13]. The total numberr of periods of hypertension and normal blood pressure was recorded.

Sincee follow up time varied between individual patients, the effects of hypertensionn and dialysis on outcome were analyzed as follows. For each patientt a ratio of total number of blood pressures with values above the 95th percentilee divided by the total number of blood pressures with values below thee 95th percentile was calculated. Patients with a ratio of more than one were categorizedd as patients with a "relatively long standing" hypertension. Thus, a patientt with "a relatively long standing" hypertension had a more days of RRT withh a blood pressure above the 95th percentile than days with a blood pressure beloww the 95th percentile. We compared the mean mortality rate of these patientss with those with a ratio of less than one. The same technique was used forr analysis of the relationship with mortality of dialysis versus transplantation andd hemodialysis versus peritoneal dialysis. Thus, patients with a "relatively longg standing" period of dialysis were considered those, who had more days of RRTT on dialysis, than days living with a functioning renal graft. In the same wayy we defined "a relatively long standing period" of hemodialysis by the ratio off total hemodialysis time over total peritoneal dialysis of more than one. The medicall ethics committees of all participating centers approved the study design. .

3.. Statistical analysis. The Mortality Rate (MR) was expressed as the number of deathss per 100 patient years on renal replacement therapy. The Standardized Mortalityy Rate (SMR) was defined as the MR for a certain age group in a certain yearr divided by the expected mortality for the same age group and year. MR wass calculated separately for different age groups during two different periods off initiation of RRT, before and after 1982. We used Kaplan-Meier analysis to calculatee survival probabilities.

Thee effect of change in dialysis techniques, transplant protocols and supportive therapyy over time on causes of death was analyzed by comparing the death ratess of patients who started renal replacement therapy between 1982 and 1991 andd of those who started RRT between 1972 and 1981.The associations of, gender,, age at initiation of renal replacement therapy, and the time period of

45 5


Tablee 1. Characteristics of the total cohort and the LERIC-cohort.

TotalTotal cohort LERIC cohort

Numberr of patients 381 249

Male/femalee 216/165 136/113

Numberr of deaths 85 (22.3%) 63 (25.3%)

Numberr of deaths/total numbers starting RRT< 1.1.82 45/151 45/151

Numberr of deaths/ total numbers starting RRT> 1.1.82 40/230 18/98

Meann age start RRT, yr. (range) 8.6 (0.5-14.9) 10.6 (1.9-14.9)

Meann age of death, yr. (range) 17.3 (0.1-36.4) 17.5 (4.2-36.4)

Meann time between first RRT & death, yr. (range) 6.5 (0.1-25.9) 7.3 (0.3-25.9)

Mediann time between first RRT & death, yr. (range) 3.7 (0.1-25.9) 4.3 (0.3-25.9)

Diedd while on peritoneal dialysis No data 7 (11.1%)

Diedd while on hemodialysis No data 31 (49.2%)

Diedd with a functioning renal graft No data 25 (39.7%)

RRTRRT - renal replacement therapy

Tablee 2. Mortality Rates (MR) per 100 patient years and Standardized Mortality Ratess (SMR)1 wi th 95% confidence interval in the total cohort.

Time-PeriodTime-Period MR SMR MR age MR age MR age MR age CohortCohort Cohort 0-5 years2 6-10 years2 11-15 years2 16-20 years2

1972-1999 9

1972-1981 1

1982-1991 1

1992-1999 9

1.5 5 (1.2-1.9p p

3.6 6 (2.2-5.0) )

1.6 6 (1,1-2,1) )

1.2 2 (0.7-1.6) )

31.0 0 (24.7-38.3) )

72.4 4 (46-109) )

29.4 4 (20.6-40.7) )

21.0 0 (13.7-30.7) )

3.5 5 (1.5-5.5) )

7.0 0 (0-14.9) )

3.9 9 (1.2-6.7) )

1.0 0 (0-3.0) )

2.1 1 (1.1-3.1) )

4.3 3 (1.1-7.5) )

1.6 6 (0.3-2.8) )

1.5 5 (0-2,9) )

1.8 8 (1.1-2.5) )

2.1 1 (0.9-3.3) )

2.0 0 (0.8-3.1) )

0.8 8 (0-1.8) )

1.3 3 (0.6-1.9) )

1.4 4 (0-3.3) )

1.3 3 (0.3-2.2) )

1.3 3 (0.3-2.3) )

'' Standardized Mortality Rate (SMR) = observed age-specific mortality rate divided by the expectedexpected mortality rate in the general Dutch population; 2 age at death; 3 95% Confidence InIn terval.

46 6


initiationn of RRT with outcome were analyzed in the total cohort as well as the LERICC cohort. All other determinants were analyzed in the LERIC cohort.

Wee used the Cox proportional-hazards model to estimate the relative mortality riskk for several determinants. These determinants had been established at the beginningg of the observation period and included gender, age at initiation of RRT,, period of RRT onset (1972-1982 versus 1982-1992), and primary disease. Wee calculated mortality incidence rate ratios for determinants whose status couldd only be established at the end of follow up. These latter determinants includee total duration of dialysis versus transplantation, and of hypertension andd supportive therapy during the observation period. Dialysis as a risk factor comparedd to transplantation was analyzed in two ways: firstly as the RRT mode att the end of the study period (i.e. at the time of death or in August 2000) and secondlyy by comparing total duration of dialysis versus transplantation in both groupss of surviving and deceased patients. Hemodialysis and peritoneal dialysiss were analyzed separately by comparing total peritoneal dialysis- and hemodialysis-timee in surviving and deceased patients. Continuous variables weree transformed into dichotomous variables for the calculation of incidence ratee ratios: patients with a total dialysis duration that exceeded the total time withh a functioning graft were compared with those with the inverse situation. Thee same approach was used for hemodialysis versus transplantation, peritoneall dialysis versus transplantation, hemodialysis versus peritoneal dialysiss and hypertension versus normal blood pressure. The effect of the introductionn of cyclosporine, ATG and OKT3 as new immunosuppressive therapyy was analyzed in all patients who were ever transplanted, in patients withh RRT as last RRT, and in patients with at least 5 years of transplantation as RRT.. SPSS 9.0 was used for all statistical calculations.

Results. .

VieVie cohorts. The total cohort consisted of 381 patients. Formation of the LERIC cohortt revealed the following. From the RENINE database, 251 patients matchedd the inclusion criteria. Verification using the local databases of all the participatingg centers revealed that one patient was mentioned twice, and that threee patients did not match the inclusion criteria. Reviewing the databases of alll dialysis and transplantation centers elicited two additional patients. Thereforee the definite LERIC-cohort consisted of 249 subjects. According to the RENINEE registration, seven patients had been lost to follow up. On our verification,, six of these patients were still alive and one patient had died. Also, initiall yy it appeared that in 43 of 63 deceased patients, the cause of death was 'unknown',, but we were able to establish all causes of death except one.

Off all LERIC patients we recorded a total of 3870 patient years, covering the wholee period from the onset of renal RRT until august 2000 or time of death

47 7


Figuree 1. Kaplan-Meier survival rates of two subgroups of all patients of the RENINE-cohort,, starting renal replacement therapy, respectively between 1972-19811 and 1982-1991.

1.0 0

to o

> > 3 3

LT) )

I I UU ,5

"H. - , ,

periodd RRT

DD 1982-1991

1972-1981 1

10 0 20 0 30 0

renall replacement therapy in years

4S S


withh 81 patient years missing and with an average follow up of 15.5 years per patient.. Of all 249 patients 231 were transplanted at least once.

Thee mean total RRT, transplantation, hemodialysis, and peritoneal dialysis time weree 16.0 years (range 0.3-31.1), 11.7 years (range 0-29.9 years), 3.3 years (range 0-25.6),, and 0.8 years (range 0-14.7 years), respectively. Transplantation had beenn performed twice in 118 patients, three times in 38 patients, and four times inn 8 patients. Patients changed from therapy-modality (i.e. dialysis or functioningg graft) between 1 to 9 times during the study period. Of the 249 subjectss only 2 never had been treated with dialysis, while 18 patients never hadd been transplanted. Main characteristics of both total cohort and LERIC cohortt are given in table 1.

Mortality.Mortality. Of all 381 patients of the total cohort, 85 had died. The total follow up periodd was 7-28 years. The overall Mortality Rate was 1.57 per 100 patient years.. The mean Standardized Mortality Rate was 31 for the whole period and 39.22 for the period 1972-1992; it decreased from 72.4 between 1972 and 1981 to 29.44 between 1982 and 1992 (table 2). The SMR and age-group specific MR for threee time periods are summarized in table 2.0verall, five-, ten- and twenty-yearr survival after RRT onset was 87, 82 and 78%, respectively. Five- and ten-yearr survival increased from 81% and 79% in the period 1972-1981, respectively, too 89% and 85% in the period 1982-1991 (figure 1). Of all 249 patients of the LERICC cohort, 63 had died, 25 with a functioning graft, 31 while on hemodialysis,, and 7 on peritoneal dialysis. Of all 25 patients who died with a functioningg renal graft, 4 (16%) died within 31 days and 6 (24%) with 4 months afterr transplantation.

MortalityMortality risk factors and causes of death. The risk ratios with respect to overall mortalityy of a relatively long period of dialysis and relatively long-standing hypertensionn were 7.2 (CI 95%: 4.4-11.8) and 3.1 (CI 95%: 2.1-4.6), respectively. InIn patients with at least one transplantation episode, the use of cyclosporine wass associated with a mortality risk of 0.3 (CI 95%: 0.1-0.4). Cumulative incidencee ratios and Cox Regression hazard ratios of these and other mortality riskk factors are presented in table 3.

Tablee 4 shows the cause specific death rates among all subjects. The data of one patient,, who died in 1974, were unrecoverable. Official cause of death in two patientss was "cardiac arrest". One of them, undergoing an otherwise uncomplicatedd chronic hemodialysis treatment, died suddenly at home after a shortt moment of acute chest pain and shortness of breath. The other patient diedd of acute asystole during a hemodialysis session. No heart-threatening electrolytee disturbances were found and autopsy of the patient revealed no evidencee for embolism or cerebrovascular bleeding. Therefore, the conclusion wass that an acute arrhythmia (in one established), secondary to left ventricular

49 9

o o NOO IN ; i n THH N n

NN q n ÖÖ rH* r-i

LTll T—I ^ T-H T-H

r-ïï H \d in' iri ii i i i i

\ ÜÜ 93 00 H H ÖÖ Ö r-J t N t-H

Q O ^ ' - ^ Ö r - t Ö Ö Ö Ö r - i r - i r - i c N N ii i i i i i i i i i i I i

c o ' r H ' N ö ö ö o ö ö o o oo o

o o

tNN (N u T ii u T j " o . ^ T j " a " ' 3 T J T J T J t i T j T 3 T 3 T 3

N N

r o c o tNN t N i o r s i c o ö o o o o o o o öo

u u s s PU U _ l l a» »

-4-> >

T5 5 C C 03 3

O O X X O O

OO 'S

m o m m \DD M N nn M N

vOO M \C rHH i n O tNN rH rH

OO O OO rO r->r-> (N

ONN 00

rHH O INN CO rHH tN

INN O M DD O >* r f ON I-HH r H T t oo i n NO m

_ . _ _ . . _ ,, -. O (N N r l H H (N \ N r H i n M l T i H N v O n i n r H n * *

NOO ON COO Tt o oo

rHH T-H rH IN ON

00 0

NO O COO rH 0O CO ON tNN NO rH sO ON O

INN m CM in n

HH H M N

IN N ONN O INN r-i

INN O oo in ro IN COO rH rH 00 CO

r H C O O N - * H H T H H u - , c N r H | N r H | N N

-4-> >

O H H

Cfi i

tri i CU U

H H

« «

C4 4 BS S

CQ Q

,, . ca a r H H ON N ON N r H H

tN N

A A H H BS S BS S

ra ra

QJ J bO O

2?? «

CQ Q

ca a

Cü ü

ca a

x x

00 0

A A H H BS S BS S ÖJD D

C C

rHH >- £

CQQ < w

13 3 h h QJ J

PH H

> > < < o; ; A3 3

uu u ON N

rN N t N N ÜN N

BS S BS S i i i (0 0

>̂ ^ NO O

V V H H BS S BS S

ra ra 03 3

O O bc c

< <

"* * II I c c

o o

(-1 1

(.; ; < <

BS S

13 3 h h n> >

fc fc ui i

> > < < (l> >

00 0 (TN N r H H

<N N | N N ON N

r H H

r--BS S B, , in n j5 5 ö5 5

bO O

>> s II - — - —

SS -2 HH " > BSS "H

"oo o CU U

" OO .*H

ii * +-- tn 033 CC rara QJ

, ,

ND D V V H H BS S BS S

^^ O XX \ 3

E—ii ra r -- " H

.22 -a

11 i «« %— >> «

-—.. 'o i

1 ^ ^ j GG >H

oo .2 . 'SS <*>

o,tS S CU

<< f ^^ o

WW -TH

11 1

o--H H

ooo H AA ^

E ^^ B S

KK « BSS J2 CC ra EE X

J33 'S cc *

_cuu oi "Ï33 S

m m A A c c o o

i n n A A x x H H

§ B Ï Ï

33 X

XX S f-HH «

-££ JG

i55 cu

i n n A A X X

H H

S S

X X

-- .a M S. .5 .§ a> cu IU x ra

a.. .. H OH rara o O H T J J

33 H XJ 'SS ~ 5 ^ii ra O-cuu .. ..

"P P P o Q O O

iss U U b O H h h

XX < < o ' o ' oo o ' o ' o ' o

<< < < f r 055 O) "

UU U UU -c

oo pa ca cc co ca ca ca ca ca ca

t/2 2 .22 S cc c oo o

rara cu ^^ OH

W) ) C C O O

rara "O

^ JJ m HW H-H 4-» ^^H

m c u ^ c u c u c u c u c u c ü cu u

o o 2 o o o o o o o o C C S C c c C C H i z ; C c ; ;

rara .5

5£ £

£? £?

> >

03 3

> > in in > > en n > >

03 3 > > 03 3 > > 01 1 > > 03 3 > > 03 3 > > 033 03 >> > < < < < < < < < < < <

33 3 QQ Q

33 _ QQ BS

r ï S c u c u c u i ' c u c y c u c u a i Qj j O 3 ( / 3 0 3 W O 3 0 3 O 3 O 3 O 3 O 3 3


LegendLegend Table 3:

"number"number of death divided by total number of all patients with investigated risk factor (group A); hh number of deaths divided by toal number of all patients without risk factor (group B); cc Cox Regression analysis; dd Cumulative incidence ratio; << p < 0.05; ff RRT = renal replacement therapy; sTxsTx = transplantation; hh patients with SLE, Goodpasture, oxalosis, cystinosis or autosomal recessive cystic disease (A) vs.vs. patients with an other other primary disease (B); 'patients'patients with a total dialysis/total transplantation duration ratio >1 (A) vs. patients with a ratioratio <1 (B); ii patients with a total hemodialysis/ transplantation duration ratio>l (A) vs. patients with a ratio<lratio<l (B); kk patients with a total hemodialysis/total peritoneal dialysis duration ratio >1 (A) vs. patients withwith a ratio <1 (B); 'patients'patients with a total hypertension duration/normal blood pressure duration ratio > 1 (A) vs. patientspatients with a ratio <1 (B); mm EPO = Erythropoietin; "" CsA = Cyclosporine-A; 00 patients with at least 1 transplantation-period, ever have been using cyclosporine (A) vs. patientspatients who never used cyclosporine (B) (n=231); vv patients with at least 1 transplantation-period, ever have been using cyclosporine (A) vs. patientspatients who never used cyclosporine (B), starting RRT after 1-1-1982 (n=94); ii patients with at least 1 transplantation-period, ever have been using cyclosporine (A) vs. patientspatients who never used cyclsporine (B), with Tx as last RRT (n=171); rr patients with at least 1 transplantation-period, ever have been using cyclosporine (A) vs. patientspatients who never used cyclsporine (B) (n=189)

51 1


Tablee 4. Causes of death.

CauseCause of death Number Age at time of death RRT at time ofof death

Cardiovascular Cardiovascular

Cerebrovascularr accident Congestivee heartfailure Myocardiall infarction Cardiacc arrest Pericarditis s Aortaa dissection

ComplicationComplication treatment

Peritonitis s Scleroticc peritonitis Shuntt bleeding

Infection Infection

Septicemia a Pneumocystiss carinii CMV V Fungall encephalitis Dengue e

Malignancies Malignancies

Lymphoma a Leukemia a Fibrosarcoma a

RefusalRefusal further treatment

Other Other

Hyperkalemia a Cachexia a Abdominall bleeding

Noo data

26 26

15 5 4 4 3 3 2 2 1 1 1 1

5 5

3 3 1 1 1 1

13 13

7 7 2 2 2 2 1 1 1 1

6 6 4 4 1 1 1 1

7 7

6 6

3 3 1 1 1 1

1 1

5-26 6 7-31 1 24,, 27, 36 17,28 8 6 6 25 5

5,18,, 21 27 7 34 4

4-21 1 12,13 3 20,12 2 12 2 33 3

10-28 8 27 7 15 5

12-36 12-36

6,6,16,16 16,16 9 9 13 3

16 6

HD11,, PD l ,Tx3 Txx 3, HD 1 HDD 2, Tx 1 HDD 1, Tx 1 H D 1 1 T x l l

PD3 3 PD1 1 H D 1 1

HDD 4, PD l,Tx 2 Tx2 2 Txx 1, PD 1* Tx l l Tx l l

Tx4 4 Tx l l Tx l l

HDHD 5, Tx 2

H D 3 3 PD1 1 Tx l l

H D 1 1

RRTRRT = renal replacement therapy; HD = hemodialysis; PD = peritoneal dialysis; Tx = transplantation;transplantation; * 5 days on peritoneal dialysis after years of transplantation; age in years.

52 2


hypertrophy,, would have been responsible for the death of these patients. For thiss reason we categorized these patients as "cardiovascular deaths".

Cardiovascularr diseases, infections, cessation of treatment, malignancies and complicationn of treatment accounted for 41%, 21%, 11%, 10% and 8% of all deaths,, respectively. Of all 15 patients who died of a cerebrovascular accident, 111 (73.3%) were treated with hemodialysis, one (6.7%) with peritoneal dialysis, andd three (20%) had a functioning renal graft at time of death. Of all six patients withh a renal graft who died within four months after transplantation, five died off infection and one of intestinal hemorrhage. Within the first 10 years of RRT, 422 patients, followed for 2177.7 years at risk (=1.93/100 patients years) died, comparedd to 21 patients in the period after 10 years of RRT, followed for 1660.766 patient (= 1.26/100 patient years). In the former group cerebrovascular accidentss and infection (both 11/42 = 26%) were the most prominent causes of death.. In patients who died after 10 years of renal replacement therapy, cardiac deathh (7/21 =33%) was most common. Of all patients with a relatively long periodd of hypertension 11.1% died of cerebrovascular disease, compared to 4.4%% in the group of patients with a relatively short period of hypertension (RR 2.5;; CI 95% 1.0-6.7). Of all patients with a relatively long period of dialysis 17.8%% died of cerebrovascular accidents, compared to 1.1% (RR 15.7; CI 95% 3.6-67.7)) of those with a relatively short period of dialysis. There was a decline in thee relative number of deaths by cardiovascular disease and by complication of treatmentt over time. The risk of cardiovascular death among the group who commencedd RRT after 1981 was 0.4 (0.2-1), relative to the group who commencedd treatment between 1972 and 1981. Twenty out of 144 patients (13.4%),, who started between 1972 and 1981, died of cardiovascular disease, comparedd to 6 out of 100 patients, who started RRT after 1981. No differences weree in mean age at start of RRT or median time on RRT between both groups. Noo deaths due to complication of treatment or "other causes" were seen in the groupp who commenced RRT after 1981 (table 5). In 38 patients who died under chronicc dialysis treatment, death was caused by cardiovascular disease in 45%, andd by infection, cessation of treatment, and complication of treatment each in 13%.. Cardiovascular diseases (36%), infection (28%) and malignancies (20%) weree the most common cause of death in patients who died with a functioning renall graft.

Discussion. .

Inn this cohort study all Dutch patients with juvenile ESRD were followed for at leastt 8 years. Overall mortality in this group with chronic RRT was more than 300 times higher than in age- and gender- matched Dutch youngsters. Half of all thee deceased patients died within 4 years after initiation of RRT. Although overalll survival was higher in patients, who started with RRT after 1981, this

53 3


Tablee 5. Mortality and causes of death in the LERIC cohort by calendar period off RRT initiation.

Al ll causes

Cardiovascular r

Infection n

Complicationn treatment

Malignancy y

Stopp treatment

Other r

N/pt.years N/pt.years 1972-1981 1972-1981

45/1558.1 1

20/1558.1 1

6/1558.1 1

5/1558.1 1

4/1558.1 1

3/1558.1 1

6/1558.1 1

N/pt.years N/pt.years 1982-1992 1982-1992

18/1168.6 6

6/1168.6 6

7/1168.6 6

0/1168.6 6

2/1168.6 6

4/1168.6 6

0/1168.6 6

RR RR 1972-1981 1972-1981

1 1

1 1

1 1

1 1

1 1

1 1

1 1

RRRR (95%CI) 1982-1992 1982-1992

0.544 (0.3-0.9)

0.44 (0.2-1.0)

1.66 (0.5-4.6)

0i i

0.677 (0.1-3.6)

1.788 (0.4-7.9)

01 1

11 p<0.05; RRT = renal replacement therapy; N = number of patients; pt.years = patient years; RRRR = relative mortality risk, related to the mortality rate in the period 1972-1981; 95%CI = 95%95% confidence interval.

54 4


countedd only for patients with onset of RRT under the age of ten. Onset of RRT att young age, a relatively long dialysis period, systemic and metabolic primary diseasess and a relatively long period of hypertension were associated with an increasedd mortality. The introduction of cyclosporine was associated with a significantt reduction in mortality rate in all transplanted patients. Cardiovascularr diseases, especially cerebrovascular accidents, accounted for moree than 40% of all deaths, as well in dialysis-patients as in transplanted patients.. Improvement of treatment over time resulted in a reduction of cardiovascularr deaths and death caused by direct complications of treatment.

Wee used the RENINE data of the total cohort to calculate the mortality rate, sincee the accuracy of the RENINE data on the mortality of the LERIC data was 97%.. The observed overall mortality rate of 1.57 per 100 patient years is somewhatt lower than reported in the early nineties by Reiss et al [7], and by the Americann USRDS in children, namely 2.0 per 100 patient years in children on renall replacement therapy between 0-19 years [2,14]. This difference could be explainedd by the longer follow-up period in the current study, since the median off time between initiation of RRT and death is only 3.7 years. The cumulative survivall of 82% is comparable with other reports [6,9,15,16]. Ass far as we know, untill now no data on Standardized Morality Rate in patients with juvenile end-stagee renal disease have been reported.

Thee observed 24% cumulative incidence of lethal cerebrovascular accidents in thee LERIC cohort was much higher than that reported by the USRDS (6%) and Reisss et al (2%) [3,8]. The discrepancy with the American data could partly be explainedd by the high percentage of missing causes in the USRDS database [2,3,10].. As was to be expected from data from studies in adults with ESRD, in ourr study the balance tended towards an increase in cardiac deaths after ten yearss of RRT. The fact that no reduction in lethal infections was seen over time iss compatible with other recent reports [2,3,7], and is a continuing concern for thee future.

AA relatively long duration of hypertension was associated with a 3-fold death rate.. The percentage of cerebrovascular deaths was more than twice as high in thee hypertension-group, compared to patients with a relatively short period of hypertension.. As far as we know, there are no data on the impact of hypertensionn on survival in children with end-stage renal disease. It seems obviouss that hypertension is a predictor of cardiac death in patients with ESRD, sincee it is well established that left ventricular hypertrophy correlates with cardiacc mortality, as well as with the severity of hypertension [24]. Nevertheless,, most studies in adults show no or only a weak direct relationship betweenn malignant hypertension and mortality in dialyzed patients [20-22]. Charraa et al found, that the survival of dialyzed patients with a mean arterial pressuree above 99 mm Hg, was inferior to the survival of those with a mean

55 5


arteriall pressure below 99 mm Hg [23]. Yet other data from studies in adult hemodialysiss patients suggest that abnormal high (> 180 mm HG) as well as abnormall low systolic blood pressures (< 110 mmHg) are associated with decreasedd survival [11,25]. Low systolic blood pressures in older dialysis patientss could reflect the poor ventricular function in advanced cardiac disease andd might therefore be related to cardiac mortality, whereas in younger patientss the impact of hypertension on fluid overload and ventricular hypertrophyy might prevail [24.26]. Our data are consistent with this latter theory,, and would imply that a more vigorous therapeutic approach to hypertensionn may be mandatory in children with end-stage renal disease.

Ourr study emphasizes the burden of long lasting chronic dialysis. Although the absolutee number of deaths was lower than reported in elderly ESRD patients, wee found a higher standardized cardiovascular death rate [10,14,15]. Patients withh a relatively long period of dialysis had a more than 15 times increased risk off cerebrovascular death, compared to those living relatively long with a renal graft. . Peritoneall dialysis was introduced in the late seventies. During the first years onlyy patients in a relatively good condition were accepted for this therapy. Graduallyy in most Dutch centers peritoneal dialysis became the first choice of dialysiss modality in children, leaving hemodialysis to the more complicated patients.. We therefore think that patient and period selection, probably bias the slightlyy higher mortality risk of long standing hemodialysis over long-standing peritoneall dialysis.

Thee beneficial effect of the introduction of cyclosporine on short-term survival inn transplanted children has been established previously [17], and is confirmed inn our study. Given these results it would seem that this effect is persistent on thee long run, which is, again, compatible with long term outcome studies in adultss [18,19].

Likee in most pediatric studies, our total number of patients was relatively small, despitee the nation-wide character of the study. A potential bias of the study couldd derive from the fact, that children with ESRD, who were not accepted for chronicc RRT, were not included in our study. Since we know that in the eighties moree children under the age of 10 years were accepted for RRT (personal communicationn from Dutch pediatric nephrologists) than in the seventies, a correctionn on the mortality would lead to a higher mortality in the period 1972-1982,, reinforcing our findings with respect to the declining mortality over time inn this age group. It would however not influence the stabilization of the mortalityy we found in the age group 11-15 years, nor would it change the persistentt high SMR we found.

Thereforee we believe, that this long-term study provides a complete and rather accuratee picture on mortality and causes of death in children on renal

56 6


replacementt therapy. No patients were lost to follow up, and data about the causee of death were lacking for only one patient, who died in the early seventies. . InIn conclusion we think that, although the survival in children with end-stage renall disease has increased over the last 20 years, the Standardized Mortality Ratee remains high. Early transplantation and a more aggressive approach towardss hypertension and infection may be mandatory in order to reduce mortality. .

References: : 1.. Ledermann SE, Scanes ME, Fernando ON, et al.\ Long-term outcome of peritoneal dialysis

inn infants, J Pediatr 136:24-9, 2000 2.. Anonymous: Pediatric end-stage renal disease. USRDS. United States Renal Data System.

AmAm J Kidney Dis 30:S128-S144,1997 3.. Anonymous: VIII . Pediatric end-stage renal disease. Am J Kidney Dis 34:S102-S113,1999 4.. Broyer M, Chantler C, Donckerwolcke R, et al: The paediatric registry of the European

Dialysiss and Transplant Association: 20 years' experience. Pediatr Nephrol Nephrol 7:758-68,1993. 5.. Ehrich JH, Rizzoni G, Brunner FP, et al.; Renal replacement therapy for end-stage renal

failuree before 2 years of age. Neplirol Dial Transplant 7:1171-7, 1992 6.. Goh D, Evans JH, Houston IB, et al.: The changing pattern of children's dialysis and

transplantationn over 20 years. Clin Nephrol 42:227-31, 1994 7.. Reiss U, Wingen AM, Scharer K.: Mortality trends in pediatric patients with chronic renal

failure.. PediatrNephrol!0:41-5, 1996 8.. Scharer K, Reiss U, Mehls O, et al,: Changing pattern of chronic renal failure and renal

replacementt therapy in children and adolescents: a 20-year single centre study. Eur J Pediatr 152:166-71,, 1993

9.. Offner G, Rodeck B, Ringe B. Niertransplantation bei kindern. Zentralbl Chir 117:653-7,1992 10.. Anonymous: VI. Causes of death in ESRD. Am } Kidney Dis 34:S87-S94,1999 11.. Tozawa M, Iseki K, Yoshi S, Fukiyama K: Blood pressure variability as an adverse

prognosticc risk factor in end-stage renal disease. Nephrol Dial Transplant 14:1976-81,1999 12.. Lindahl BI, Glattre E, Lahti R, et al: The WHO principles for registering causes of death:

suggestionss for improvement, ƒ Clin Epidemiol 43:467-74,1990. 13.. Update on the 1987 Task Force Report on High Blood Pressure in Children and

Adolescents:: a working group report from the National High Blood Pressure Education Program.. National High Blood Pressure Education Program Working Group on Hypertensionn Control in Children and Adolescents. Pediatrics 98:649-58, 1996

14.. Anonymous: Morbidity and mortality of dialysis. N1H Consens Statement 11:1-33, 1993 15.. Mallick NP, Jones E, Selwood N: The European (European Dialysis and Transplantation

Association-Europeann Renal Association) Registry. Am J Kidney Dis 25:176-87, 1995 16.. Wiesel M, Weber C, Mehls O, et al.: Organ transplantation im kinderaltern. Urologe A 33:422-7,

1994 4 17.. Najarian JS, Almond PS, Mauer M, et al.: Renal transplantation in the first year of life: the

treatmentt of choice for infants with end-stage renal disease, J Am Soc Nephrol 2:S228-S233, 1992 2

18.. Rizzolo M, Puggia R, Maresca MC, et al.: Long-term results of kidney grafts surviving beyondd the first year: comparison of cyclosporine-based regimens with the azathioprine andd steroid regimen. Transplant Proc 30:1751-2, 1998

19.. Montagnino G, Tarantino A, Maccario M, et al: Long-term results with cyclosporine monotherapyy in renal transplant patients: a multivariate analysis of risk factors. Am } Kidney DisDis 35:1135-43, 2000

20.. Salem MM: Hypertension in the haemodialysis population: any relationship to 2-years survival?? Nephrol Dial Transp 14:125-8,1999

57 7


21.. De Lima J J, da Fonseca J A, Godoy A, et al.\ Outcome of patients with malignant hypertensionn and end-stage renal failure treated by long-term haemodialysis. Cardiology 92:93-8,, 1999

22.. Delgoulet P, Legrain M, Reach I, et al:. Mortality risk factors in patients treated by chronic hemodialysis.. Nephron 31:103-110, 1982

23.. Charra B, Calemard E, Ruffet M, et al.: Survival as an index of adequacy of dialysis. Kidney IntInt 41:1286-1291, 1992

24.. Foley RN, Parfey PS, Harnett JD, et al: Impact of hypertension on cardiomyopathy, morbidityy and mortality in end-stage renal disease. Kidney Int 49:1379-1385, 1996

25.. Lowry EG, Lew NL: Death risk in hemodialysis: The predictive value of commonly measuredd variables and an evaluation of death rate differences between facilities. Am ƒ KidneyKidney Dis 15:458-482, 1990

26.. Kimura G, Tomiat J, Nakamura S, et al.: Interaction between hypertension and other cardiovascularr risk factors in survival of hemodialyzed patients. Am J Hi/pertens 9: 1006-1012,, 1996

58 8

60 0

Date post:	04-Oct-2020
Category:	Documents
Upload:	others
View:	0 times
Download:	0 times

UvA-DARE (Digital Academic Repository) Late effects of renal … · Denguee...

Documents