Nephrol Dial Transplant (1996) 11: Editorial Comments
bolites has been shown in heart-transplant recipients,
where this regime prevented bone loss. The addition
of monofluorophosphate was also markedly effective
in increasing trabecular bone density of vertebral
bodies. I would hesitate, however, to advocate calcidiol
and fluoride to recipients of renal grafts. Calcidiol may
cause uncontrolled hypercalcaemia [14] and fluoride
may accumulate unless serum fluoride concentrations
are carefully monitored.
Is there a role for oestrogens and thiazides?
Particularly in postmenopausal women oestrogens [15]
and thiazides [16] are of undoubted efficacy in preventing osteopenia. It appears logical to give them at
least in postmenopausal graft recipients. Is it possible
to identify patients at risk? The risk of bone problems
is the greater the lower bone mass is at the time of
transplantation. The risk is also higher in postmenopausal and elderly patients. Whether the risk can
be predicted by assessing the vitamin D receptor genotype [17] will require further study.
It is obvious from the above that many problems in
this field are still unresolved and require scientific
investigation. There is no doubt, however, that the
limited information available permits a rational
approach to the prevention. Although this is not a
panacea, use of the lowest steroid dose possible is the
cornerstone of prevention.
569
4.
5.
6.
7.
8.
9.
10.
11.
12.
Acknowledgement. The study has been supported by funds of 13.
MURST 40%.
References
1. Julian BA, Quarles LD, Nicmann KMW. Musculoskeletal complications after renal transplantation: pathogenesis and treatment. Am J Kidney Dis 1992; 19: 99-120
2. Felson DT, Anderson JJ. A cross-sectional study evaluation of
association between steroid dose and bolus steroids and avascular necrosis of bone. Lancet 1987; 1: 902-906
3. Grotz WH, Mundinger FA, Gugel B, Exner V, Kirste G,
14.
15.
16.
17.
Schollmeyer P. Bone fracture and osteodensitometry with dual
energy X-ray absorptiometry in kidney transplant recipients.
Transplantation 1994; 58: 912-915
Julian BA, Laskow DA, Dubovsky J, Dubovsky E, Curtis JJ,
Quarles LD. Rapid loss of vertebral mineral density after renal
transplantation. N Engl J Med 1991; 325: 544-550
Horber FF, Casez JP, Steiger U, Czerniak A, Montandon A,
Jaeger Ph. Changes in bone mass early after kidney transplantation. J Bone Miner Res 1994; 9: 1-9
Almond MK, Kwan JTC, Evans K, Cummingham J. Loss of
regional bone mineral density in the first 12 months following
renal transplantation. Nephron 1994; 66: 52-57
Nordal KP, Dahl E, Halse J, Aksnes L, Thomassen Y,
Flatmark A. Aluminium metabolism and bone histology after
kidney transplantation: a one-year follow-up study. / Clin
Endocrinol Metab 1992; 74: 1140-1145
Movsowitz C, Epstein S, Fallon M, Ismail F, Thomas S.
Cyclosporine A in vivo produces severe osteopenia in the rat:
effect of dose and duration of administration. Endocrinology
1988; 123: 2571-2577
Olgaard K, Storm T, Wowern v.N et al. Glucocorticoid-induced
osteoporosis in the lumbar spine, forearm, and mandible of
nephrotic patients: a double-blind study on the high-dose, longterm effects of prednisone versus deflazacort. Calcif Tissue Int
1992; 50: 490-497
Reid IR, Ibbertson HK. Calcium supplements in the prevention
of steroid induced osteoporosis. Am J Clin Nutr 1986; 44:
287-290
Hahn TJ, Halstead LR, Teitelbaum SL, Hahn BH. Altered
mineral metabolism in glucocorticoid induced osteopenia: effect
of 25-hydroxyvitamin D administration. J Clin Invest 1979;
64: 655-665
Reid IR, Schooler BA, Stewart AW. Prevention of glucocorticoid-induced osteoporosis. J Bone Miner Res 1990; 5: 619-623
Nordal KP, Halse J, Dahl E. The effect of nasal calcitonin on
bone mineral density in renal transplant recipients. Renal Bone
Disease, Parathyroid Hormone and Vitamin D, Seville, 7-10 July,
1995, (Abstract)
Lucas PA, Woodhead JS, Brown RC. Vitamin D3 metabolites
in chronic renal failure and after renal transplantation. Nephrol
Dial Transplant 1988; 3: 70-76
Lindsay R. Sex steroids in the pathogenesis and prevention of
osteoporosis. In: Riggs BL, ed, Osteoporosis: Etiology, Diagnosis
and Management. Raven Press, New York, 1988; 333-358
Wasnich RD, Benfante RJ, Yanko K et al. Thiazide effect on
the mineral content of bone. N Engl J Med 1983; 309: 344-347
Morrison NA, Qi JC, Tokita A et al. Prediction of bone density
from vitamin D receptor alleles. Nature 1994; 367: 284-287
Weekly duration of dialysis treatment—does it matter for survival?
F. Valderrabano
Chairman of the EDTA-ERA Registry, Hospital General Universitario Gregorio Marafion, Madrid, Spain
Key words: age; cardiac cause of death; dialysis dose;
duration of dialysis treatment; EDTA Registry; gross
mortality rate; hypertension; Kt/V; survival
Introduction
The duration of haemodialysis sessions has shown a
tendency to decrease over the last decade. In effect, in
the 80s the use of high-flux membranes and haemodiafiltration techniques seemed to show that in spite of
reducing haemodialysis time, efficient dialysis could be
done. In the 90s, however, reduction of the time of
dialysis sessions is no longer a primary objective. What
must be aimed for is optimization of dialysis [1,2].
The EDTA Registry has observed that the tendency
persists to reduce hours of dialysis per week.
Information on the number of hours of haemodialysis
per week was collected in the 1988 and 1992 Patient
570
Questionnaires. The percentage of patients treated with
less than 12 h per week increased over this period [3].
Curiously, this trend was more marked in elderly
patients, to the point that between the ages of 65 and
74 more than 30% of the patients were treated with
less than 12 h per week and in patients over 75, more
than 40% were treated with less than 12 h per week.
Is survival less with shorter duration of dialysis?
Numerous studies, mostly in the US, showed that
treatment with fewer hours of dialysis is accompanied
by higher mortality rates [4-10]. This is considered to
be an important novel insight, but it is less well known
that the relationship between short dialysis and mortality was first described in the 1981 EDTA Registry
Report [11]. This report documented that in the former
Federal Republic of Germany, patients who were
treated for less than 12 h per week had a higher
mortality than those treated for more than 12 h.
Various factors may be implicated to account for such
higher mortality. One of these is an insufficient 'dose
of dialysis'. Studies were made to compare dialysis
prescription in Europe (EDTA Registry) with that in
the US. They came to the conclusion that the dialysers
used in Europe have 20% more surface area and that
the duration of haemodialysis is 23.5% longer than in
the US [12]. These differences in haemodialysis prescription could also explain the better results obtained
in Europe (EDTA Registry) compared with those in
the US.
Nephrol Dial Transplant (1996) 11: Editorial Comments
Table 1. Gross mortality rate (GMR) and weekly duration of haemodialysis treatment during 1992
Hours
All patients
12
9-11
<9
Patients starting RRT at any time
n
13721
38695
15586
5783
GMR (%)
8.3
11.1
11.8
10.9
GMR (%) By age groups
<35
4.1
3.2
2.8
4.1
35-49
4.4
5.1
5.4
5.6
50-64
8.5
10.2
9.35
10.2
65-74
13.4
15.4
14.6
13.8
>75
18.6
24.6
23.6
20.8
Patients starting RRT from 1986 to 1992
n
10625
28362
12499
GMR(%)
6.3
9.8
10.4
73785
10.7
3.4
5.1
9.7
14.8
23.3
5316
9.1
54770
9.6
Patients starting RRT in 1990, 1991 & 1992
n
4870
18390
8586
4341
GMR (%)
7.1
9.3
9.7
9.1
36187
9.1
n = patients at risk.
to 11.1% in those treated for 12 h per week, 11.8% in
those treated for between 9 and 11 h, and 10.9% in
those treated for less than 9 h per week. We repeated
this analysis in other patient populations shown in the
same Table, first restricting the study to those patients
who started RRT between 1986 and 1992 and then to
those who started RRT between 1990 and 1992. The
idea was to confirm the data in a more homogeneous
patient population. Again the findings were similar: a
lower gross mortality rate was found in patients treated
for more than 12 h of haemodialysis per week.
What is the evidence based on recent Registry
In contrast to the findings in the majority of studies
data?
carried out in the US, we did not observe a higher
mortality rate in patients treated with shorter dialysis,
but
rather a lower mortality rate in patients treated
All these reasons prompted us to study whether in the
EDTA Registry we could demonstrate a relationship with longer dialysis. This finding would favour the
between the duration of treatment and patient survival. hypothesis of some authors that longer dialysis could
We studied the gross mortality rate of all the patients have a protective effect [13]. It is interesting to note
treated with haemodialysis in 1992 and divided them that in some European countries a bimodal curve can
into four categories according to the number of hours be observed: gross mortality rate is lower in patients
of haemodialysis treatment they received in that year. dialysed for more than 12 h per week and also in those
The four groups of patients were the following: who are dialysed for less than 9 h per week [3]. The
(1) patients treated for less than 9 h; (2) patients explanation for this finding is difficult. More sophistictreated for 9-12 h; (3) patients treated for 12 h; ated analysis is required, which includes information
(4) patients treated for more than 12 h. Gross mortality on the type of dialysis used in these patients.
rates were calculated multiplying by one hundred the
number of patients who died during 1992 and dividing
by the total number of patients reported at the end of Is the effect of duration of dialysis dependant on
1992. In the first analysis we included all the patients age?
treated with haemodialysis in 1992 who started renal
replacement therapy (RRT) at any time. In this study We wanted to know whether these differences in morthe total number of patients as 73 785 and gross tality rate were similar in patients of different ages.
mortality rate was 10.7%.
Table 1 documents that the gross mortality rate
The most important finding was that the patient increased proportionally with age. It was 3.4% in
group who received more than 12 h of treatment per patients under 35 and 23.3% in patients over 75 in
week showed a lower gross mortality rate than the 1992. When we analysed the gross mortality rate in
other patient groups (Table 1). In effect, in these different age groups according to the number of hours
patients, the gross mortality rate was 8.3% compared of haemodialysis, we saw that there were no differences
Nephrol Dial Transplant (1996) 11: Editorial Comments
in patients under 35; the differences are small in
patients between 35 and 49; they are marked in patients
over 65. It is therefore in older patients that long
dialysis is accompanied by a lower mortality rate.
The practical conclusions of this observation are
important, keeping in mind the high percentage of new
patients over 65 years old. In effect, 37% of the new
patients starting RRT in 1992 were over 65.
The gross mortality rate was also analysed in the
different European countries. There are significant
differences in gross mortality rates from one country
to another, but in the majority of these countries, the
finding of lower mortality rates in patients receiving
more than 12 h of dialysis per week is confirmed [3].
Why does short dialysis kill?
571
of death were calculated in the four patient groups
according to the number of hours of dialysis per week.
It is interesting to note that cardiac causes of death
were more frequent in patients treated for more than
12 h of haemodialysis per week, i.e. in those in whom
the gross mortality rate was lower [3].
The value of our study, although preliminary, lies
in the large number of patients analysed. However, we
feel that to confirm these facts, a prospective study
must be designed which allows in-depth analysis of the
causes related to the different mortality rates according
to the weekly duration of haemodialysis treatment.
This type of prospective study carried out on samples
of well-characterized patients is one of the present
objectives of the EDTA Registry. The importance of
this topic gives it a high priority.
What are the possible explanations for the above
observation? Some authors [1] have attributed the
higher mortality rate in patients exposed to short References
dialysis to an increase in cardiac complications. This
1. Shaldon S. Unanswered questions pertaining to dialysis
was thought to be a consequence of low tolerance to
adequacy in 1992. Kidney Int 1993; 43 [Suppl. 41]: S274-S277
more aggressive ultrafiltration necessitated by short
Valderrabano F, Perez-Garcia R, Junco E. How to prescribe
dialysis. This might lead to hypotensive episodes and 2. optimal
dialysis. Nephrol Dial Transplant. (In press)
myocardial ischaemia. A higher incidence of hyperten- 3. Valderrabano F, Berthoux FC, Jones EHP, Mehls O. EDTAsion as a consequence of sympathetic activation has
ERA Registry Report, XXV, 1994. End-Stage Renal Disease
been also described in ultrashort haemofiltration, parand Dialysis Report. Nephrol Dial Transplant. (In press)
ticularly in the elderly [1]. Another possible explana- 4. Lowrie EG, Lew NL. Death risk in hemodialysis patients: The
predictive value of commonly measured variables and an evalution is provision of an insufficient 'dose of dialysis'.
ation of death rate differences between facilities. Am J Kidney
Various authors suggest [2,13] that procedures to
Dis 1990; 15: 458-482
evaluate adequacy of dialysis should include not only 5. Parker TF, Husni L, Huang W, Lew N, Lowrie EG, Dallas
data on morbidity and mortality, but also information
Nephrology Associates: Survival of hemodialysis patients in the
US is improved with a greater quantity of dialysis. Am J Kidney
on the quality of life. Further information on this
Dis 1994; 23: 670-680
point is required.
6. Hakim RM, Breyer J, Ismail N, Schulman G. Effects of dose of
When relating dialysis 'dose' to survival, one should
dialysis on morbidity and mortality. Am J Kidney Dis 1994;
23: 661-669
also be aware of several studies which show an inverse
7. Hakim RM, Dopmer TA, Parker TF. Adequacy of hemodialysis.
relationship between mortality and Kt/V [14] or urea
J Kidney Dis 1992; 20: 107-123
reduction rate [15] respectively. In any case, it is 8. Am
Lowrie EG. Chronic dialysis treatment: clinical outcome and
important to note that it is not an adequate analysis
related processes of care. Am J Kidney Dis 1994; 24: 255-266
of dialysis efficiency to simply count the hours of
9. Lowrie EG, Huang WH, Lew NL, Liu Y. The relative contribudialysis per week. In fact, dialysis efficiency depends
tion of measured variables to death risk among hemodialysis
patients. In: E Friedman, ed. Death on Hemodialysis: Preventable
not only on the duration of dialysis, but also on
or Inevitable? ch. 13. KJuwer Academic Publishers, Hingham
variables such as the type of dialysis membrane and
MA, 1994; 121-141
its permeability, the surface area of the dialyser, the 10. Held
JP, Levin NW, Bobjerg JD, Pauly MD, Diamond LH.
blood flow, the dialysate flow, the use of intravenous
Mortality and duration of treatment. JAMA 1991; 265: 871-875
perfusion of fluids (haemodiafiltration), etc. The use 11. Kramer P, Broyer M, Brunner FP, Brynger H el al. Combined
Report on Regular Dialysis and Transplantation in Europe XII,
of some of the more efficient techniques may provide
1981. Proc Eur Dial Transplant Assoc 1982; 19: 4-59
an explanation why we observed a lower gross mortal12.
Held
PJ, Blagg CR, Liska DW, Port FK, Hakim R, Levin N.
ity rate in some European countries, not only in
The dose of hemodialysis according to dialysis prescription in
patients treated with longer dialysis, but also in those
Europe and the US. Kidney Int 1992; 42 [Suppl 38): S16-S21
treated for less than 9 h per week.
13. Charra B, Calemard E, Ruffet M et al. Survival as an index of
adequacy of dialysis. Kidney Int 1992; 41: 1286-1291
Some recent studies carried out in Japan also show
P, Mittman N, Antignam A et al. Predictors of
a lower gross mortality rate in patients treated for 14. Goldwasser
mortality in hemodialysis patients. J Am Soc Nephrol 1993; 3:
more than 12 h per week [16]. Recent prospective
1613-1622
studies in the US noted a relationship between higher 15. Owen WF Jr, Lew NL, Liu Y, Lowrie EG, Lazarus JM. The
urea reduction ratio and serum albumin concentration as premortality and short dialysis [17,18].
dictors
of mortality in patients undergoing hemodialysis. N Engl
In an attempt to clarify the possible explanation for
J Med 1993; 329: 1001-1006
our findings, we studied the different causes of death 16. Teraoka S, Toma H, Nihei H et al. Current status of renal
in the patients reported to the EDTA Registry who
replacement therapy in Japan. Am J Kidney Dis 1995; 25:
died in 1992. The percentages of the different causes
151-164
NephrolDial Transplant (1996) 11: Editorial Comments
572
17. Lowrie EG, Huang WH, Lew NL. Death risk predictors among
peritoneal dialysis and hemodialysis patients: a preliminary
comparison. Am J Kidney Dis 1995; 26: 220-228
18. Avram MM, Mittman N, Bonomini L, Chattopadhyay J, Fein P.
Markers for survival in dialysis: a seven-year prospective study.
Am J Kidney Dis 1995; 26: 209-219
Leukocyte-endothelial cell interactions in haemodialysis-induced
neutropenia
E. Munoz de Bustillo and V. Alvarez Chiva
Nephrology Unit, Hospital Universitario de la Princesa, Universidad Autonoma de Madrid, Madrid, Spain
Key words: adhesion; /?2 integrins; chemoattractants;
chemokines; cytokines; haemodialysis; leukocyte transmigration; neutropenia; rolling; selectin
Introduction
Haemodialysis is associated with an inflammatory
response and activation of leukocyte-endothelial adhesion molecules. During inflammation leukocytes roll
on the endothelium, then spread and adhere more
tightly and finally migrate into the underlying tissues
[1] (Figure 1).
Rolling
The selectin family of adhesion molecules contribute
greatly to leukocyte rolling, and comprises three related
proteins that interact with carbohydrate ligands [2]
(Figure 2). L-selectin is present on leukocytes and
mediates their binding to the endothelium during
lymphocyte recirculation and neutrophil migration at
inflammatory sites. Recombinant L-selectin protein and
L-selectin Abs inhibit leukocyte rolling [3]. P-selectin
is found in granules of platelets and endothelial cells
and is rapidly mobilized to the plasma membrane [4].
E-selectin is an endothelial cell surface glycoprotein
maximally expressed on cytokine-activated endothelial
cells [5]. Data obtained from antibody-blocking studies, gene-targeted mice, and 'in vivo' reconstitution
assays demonstrate that optimal leukocyte rolling is
likely to be dependent on the function of leukocyte
L-selectin in conjunction with either of the endothelial
selectins [6].
clearly mediate binding to endothelial cells. The /?2
integrins consist of three adhesion receptors (Figure 3);
LFA-1 ( ai :/? 2 )(CDlla/CD18), Mac-1 (aM:jS2)
(CDllb/CD18), and gp-150 (aX:0 2 )(CDllc/CD18).
In neutrophils and monocytes the most important
receptors are Mac-1 and gp-150. /?2 integrins bind to
ICAM-1, ICAM-2 and ICAM-3, members of the
immunoglobulin gene superfamily, which are expressed
on endothelium [7,8].
Integrins must be activated by trigger factors to
promote strong adhesion. These activating agents may
be derived from local tissue, infiltrating leukocytes, or
the endothelium, and are cytokines (e.g. GM- CSF,
11-5), chemoattractants (e.g. C5a, PAF), and chemokines (e.g. 11-8, NAP2) [9]. Binding of these agents to
leukocyte receptors transmits signals that augment /?2
integrin-dependent adhesion [1,8].
Leukocyte transmigration
After firm adhesion to endothelium, neutrophils
migrate between the endothelial cell junctions and
subendothelial extracellular matrix to accumulate at
the site of inflammatory reaction [7]. /?2 integrins are
involved in neutrophil transmigration, especially
LFA-1 and Mac-1 [1,8].
Rolling
Migration
Triggenng
CHEMOKINES
SELECTINS
INTEGRINS
BLOODFLOW
Strong adhesion
Strong adhesion is mediated by leukocyte integrins
that bind to counterreceptors on endothelium. In the
neutrophils the /?2 integrins are the molecules that
INFLAMMATORY
STIMULUS
Chcmotuis
Correspondence and offprint requests to: Vicente Alvarez Chiva,
Servicio de Nefrologia, Hospital de la Princesa, Diego de Leon 62,
28006 Madrid, Spain.
Fig. 1. Role of adhesion molecules in inflammation