Download Are post-transplant lymphomas inevitable?

Nephrol Dial Transplant (1996) 11: Editorial Comments
1952
patients with different degrees of renal insufficiency
and on different renal replacement therapies to treatment with either lovastatin, simvastatin, or pravastatin
[2]. Rhabdomyolysis has not been reported as a major
complication, although a moderate rise in serum creatine kinase is observed occasionally [3,4]. However,
experience is limited particularly in patients with severe
impairment of renal function prior to initiation of
dialysis. It can be argued that drug or metabolite
accumulation and uraemia-related muscle injury
increase the risk of myositis, especially in this subset
of patients. The situation is somewhat different and
the risk of drug and metabolite accumulation probably
less severe in dialysis patients since lovastatin is cleared
by the haemodialysis procedure itself [5]. Therefore
the protocol of the US HEMO study forsees HMGCoA reductase inhibitors as drugs of first choice for
treatment of persistent elevation of serum LDL cholesterol (> 160 mg/dl) in haemodialysis patients [6].
Several large-scale intervention and regression studies (4S, WOS and CARE) have given a rationale for
using HMG-CoA reductase inhibitors in primary and
secondary prevention of coronary heart disease.
Therefore a number of patients, among them many
with impaired renal function, will be candidates for
treatment in the future. HMG-CoA reductase inhibitors are safe and valuable drugs in patients with renal
insufficiency. However, before further experience is
published, it may be prudent to limit the dose of
lovastatin and pravastatin (<20mg/day) as well as
simvastatin (<10mg/day) in patients with a GFR
below lOml/min and prior to initiation of dialysis, as
recommended by Biesenbach and collegues [1].
References
1. Biesenbacli G, Janko O, Stuby U, Zazgornik J. Myoglobinuric
renal failure due to long-standing therapy in a patient with preexisting chronic renal insufficiency. Nephrol Dial Transplant 1996;
11: 000-000 [THIS ISSUE—INSERT NOS]
2. Massy ZA, Ma JZ, Louis TA, Kasiske BL. Lipid lowering therapy
in patients with renal disease. Kidney Int 1995; 48: 188-198
3. Wanner C, H6rl WH, Luley CH, Wieland H. Effects of HMGCoA reductase inhibitors in hypercholesterolemic patients on
hemodialysis. Kidney Int 1991; 39: 754-760
4. Wanner C, Bohler J, Eckardt HG, Wieland H, Schollmeyer P.
Effects of simvastatin on lipoprotein (a) and lipoprotein composition in patients with nephrotic syndrome. Clin Nephrol 1994;
41: 138-143
5. Eckardt H, Karkas JD, Germershausen JI, Liou R, Wanner C.
Lovastatin is hemofiltrable. In: Gotto AM, Mancini M, Richter
WO, Schwandt P (eds). Treatment of Severe Dyshpoproteinemia
in the Prevention of Coronarv Heart Disease. Karger, Basel
1992; 292-295
6. Eknoyan G, Levey AS, Beck GJ et al. for the Hemo Study
Group. The hemodialysis (HEMO) study: rationale for selection
of interventions. Semin Dial 1996; 9: 24-33
Editor's note
Please see also the Case Report by Biesenbach et al. (pp. 2059-2060
in this issue).
Are post-transplant lymphomas inevitable?
G. Opelz
Department of Transplantation Immunology, Institute of Immunology, University of Heidelberg, Germany
An increased occurrence of non-Hodgkin lymphomas
in kidney transplant patients was first reported by
Penn some 25 years ago [1]. Many authors have
confirmed this finding and post-transplant lymphomas
have become a well-recognized 'complication' of
immunosuppressive treatment. The majority of posttransplant lymphomas are of B cell origin, they are
Epstein-Barr virus (EBV) induced, and it is believed
that immunosuppressive therapy interferes with the
T cell control mechanisms that prevent the uninhibited
proliferation of B cells in healthy individuals [2].
How frequent are post-transplant lymphomas?
Reliable figures on the incidence of post-transplant
lymphomas have been difficult to obtain because the
Correspondence and offprint requests to: Gerhard Opelz, MD,
Institute of Immunology, Im Neuenheimer Feld 305, D-69120
Heidelberg, Germany.
absolute numbers of cases occurring at individual
transplant centres are small. A large multicentre analysis of the Collaborative Transplant Study arrived at
an incidence in cadaver kidney recipients of approximately 0.2% during the first post-transplant year [3].
The yearly incidence decreased during subsequent years
and remained fairly stable at approximately 0.04% per
year. Compared with the general population, the first
year incidence is about 20-fold increased. Interestingly,
post-transplant lymphomas occur approximately twice
as often in North America than in Europe [3].
Lymphomas are seen at a much higher rate in heart
transplant recipients than in kidney transplant recipients. This observation provides important clues with
respect to the nature of promoting factors. Figure 1
illustrates an update of the Collaborative Transplant
Study analysis on the cumulative incidence of posttransplant lymphomas in kidney and heart transplant
recipients.
1953
Nephrol Dial Transplant (1996) 11: Editorial Comments
FIRST HEART TX
100
o
o
o
FIRST CADAVER KIDNEY TX
o
o
i
*
4000
4000
•
CD
a.
CD
Q.
!
8 3000-
g
CD
T3
_C
y*
2000
3
o
2000
y*
*
CD
*
1000-
•2 1000E
3
j
00 1
3000
CD
/
CD
>
co
5000
o
2 3 4 5 6
Years
7 8 9
10
0
1 2 3 4 5 6 7 8 9
Years
10
n=72360
HEART n=14284
Fig. 1. Cumulative incidence of non-Hodgldn lymphomas in recipients of heart transplants (left) or cadaver kidney transplants (right). The
numbers of patients studied are indicated at the bottom of each graph.
Factors that influence the occurrence of lymphomas
It is widely believed that the strength of immunosuppressive treatment is directly related to the incidence
of post-transplant lymphomas. The differential incidence in kidney and heart transplant recipients supports
this notion. Heart recipients are known to receive more
aggressive immunosuppressive treatment during the
early post-transplant period than kidney recipients.
Moreover, evidence was found for higher immunosuppressive maintenance doses in heart than in kidney
recipients (as well as in kidney and heart recipients
treated in North America compared to patients treated
in Europe) [3]. Unquestionably, induction therapy
with monoclonal or polyclonal antilymphocyte antibodies increases the risk of lymphoma. The risk associated with antibody induction is moderate [4], although
the massive administration of antilymphocyte antibodies was associated with an excessive rate of lymphomas
in one series of heart transplant patients [5]. There
has been speculation that the cumulative dose of
immunosuppressive drugs and antibodies administered
may be a key variable. The case report published in
this issue, in which a patient developed a lymphoma
after receiving antibody induction as treatment for a
kidney graft, having had a previous heart transplant,
would seem to fit the 'cumulative dose' hypothesis [6].
There are intriguing data, however, indicating that
the occurrence of lymphoma is not completely
explained by the effect of potent immunosuppression.
When the locations at which the lymphomas occurred
were analysed, there was a striking prevalence of
lymphomas of the kidney in renal transplant recipients,
and of lymphomas of the lung or heart in heart
transplant recipients [3], These highly significant associations indicate that the local immune response against
the transplanted organ must play an important role in
the cellular deregulation process that results in
lymphomas. Another interesting observation is that
lymphomas of the CNS occur at a relatively high
frequency in organ transplant recipients, whereas they
are extremely rare among lymphoma patients in the
non-transplant population [4].
Prognosis of lymphomas
There are a number of anecdotal reports in the literature showing that lymphomas regressed or disappeared
in patients when immunosuppressive treatment was
reduced or discontinued [7]. Therefore, it is nowadays
common practice to decrease or, if deemed permissible,
discontinue immunosuppressive treatment in patients
developing a lymphoma. Unfortunately, this strategy
does not uniformly result in permanent regression of
the tumour. The survival statistics following the diagnosis of post-transplant lymphoma show a sobering
50% death rate within a year of diagnosis (Fig. 2).
Patients with CNS lymphoma appear to do particularly
poorly [4].
What can be done?
With the rather grim survival prospects of patients
who develop post-transplant lymphomas, prevention
rather than treatment would seem to deserve the high-
Nephrol Dial Transplant (1996) 11: Editorial Comments
1954
FIRST CADAVER KIDNEY TX
100-]
100-
90-
90
80-
80-
7060-
its Surviving
its Surviving
FIRST HEART TX
•
50-
40a. 3020CD
CD
CO
"ra
Q.
70- I
6050403020-
10-
10-
n
U
n
c
1
2 3 4 5 6 7 8 9
Years
10
c
HEART n=354
1
2 3 4 5 6 7 8 9
Years
10
KIDNEY n=360
Fig. 2. Survival after the time of diagnosis in heart or kidney transplant recipients with non-Hodgkin lymphomas. The numbers of patients
studied are indicated at the bottom.
est priority. This raises the dilemma of balancing too
little against too much, that is, underimmunosuppression with resulting graft rejection against overimmunosuppression and lymphoma. Clearly, some risk of
lymphoma must be accepted in organ transplant recipients. In general, because the risk of lymphoma is
infinitely smaller than that of graft rejection, there is
an understandable inclination of preserving a functioning graft even though this may carry on increased
risk of lymphoma. Nevertheless, it would seem prudent
to aim at the 'smallest necessary' cumulative immunosuppressive regimen. In this context, good HLA compatibility deserves special attention since it provides an
opportunity for getting by on less intensive immunosuppressive treatment.
More potent and more effective immunosuppressive
medication is usually associated with some increase in
the risk of lymphoma. Combination drug therapy,
which is commonly used because it allows for a reduction of other drug-related side effects, also is associated
with an increased lymphoma risk [4]. The argument
to be addressed here is that more powerful immunosuppression should not be avoided at all cost, and that
sound judgement should dictate the choice of immunosuppressive induction and maintenance regimen, as
well as the doses at which the drugs are administered.
In a 'high risk' recipient, e.g. a patient with highly
reactive lymphocytotoxic antibodies or a retransplant
recipient, induction therapy with poly- or monoclonal
antibodies may well be appropriate. Likewise, triple
drug maintenance will be necessary for some patients
but not for others. Especially when the cumulative
load of previous immunosuppression, including rejection treatment, has already been high, caution must be
exercised. Unfortunately, little information is currently
available on 'acceptable thresholds' of cumulative
immunosuppression beyond which the risk of
lymphoma becomes unacceptable. It therefore remains
a challenge for each physician to carefully weigh any
benefits of increased immunosuppression against the
potential risk of lymphoma.
A final word of caution would seem appropriate
with respect to the new, even more powerful immunosuppressive drugs which are currently being introduced.
While there is an understandable desire for stronger
and better immunosuppression, the lymphoma issue
should not be overlooked. It would be wrong to take
an alarmist position and to argue against the introduction of new immunosuppressants. Nevertheless, care
should be taken to carefully monitor the effect of any
new drug on the incidence of lymphomas, a complication which fortunately affects a very small proportion
of all transplant patients but which is associated with
a high risk of death.
References
1. Perm I, Hammond W, Brettschneider L, Strzl TE. Malignant
lymphomas in transplantation patients. Transplant Proc 1969;
1: 106-112
2. York LJ, Qualtiere LF. Cyclosporine abrogates virus-specific
T cell control of EBV-induced B-cell lympho-proliferation. Viral
Immunol 1990; 3: 127-136
3. Opelz G, Henderson R. Incidence of non-Hodgkin lymphoma in
kidney and heart transplant recipients. Lancet 1993; 1514-1516
4. Opelz G, Schwarz V, Wujciak T et al. Analysis of non-Hodgkin's
lymphomas in organ transplant recipients. Transplant Rev 1995;
231-240
5. Swinnen U A , Constanzo-Nordin MR, Fisher S el al. Increased
incidence of lymphoproliferative disorder after immunosuppres-
Nephrol Dial Transplant (1996) 11: Editorial Comments
sion with the monoclonal antibody OKT3 in cardiac transplant
recipients. N EnglJ Med 1990; 323: 1723-1728
6. Haas et at. Nephrol Dial Transplant 1996; 11: 000-000
7. Starzl TE, Nalesnik MA, Porter KA et al. Reversibility of
lymphomas and lymphoproliferative lesions developing under
cyclosporine-steroid therapy. Lancet 1984; 1: 583-587
1955
Editor's note
Please see also the Case Report by Haas et al. (pp. 2085-2087 in
this issue).
Nitric oxide (NO) in renal physiology and pathophysiology
C. Baylis and J. Bloch
Department of Physiology, West Virginia University, Morgantown, WV, USA
Renal localization of NO synthesis
Endogenous NO is synthesized by nitric oxide synthases (NOS) which use L-arginine as substrate. The
various isoforms of NOS are widely distributed within
the kidney. Brain NOS (bNOS) and endothelial NOS
(eNOS) are constitutively expressed and are both distributed in glomeruli and vasculature. In addition
bNOS is found in epithelial tissue including macula
densa and the collecting duct. Two structurally distinct
inducible NOS (iNOS) are 'constitutively expressed'
at the juxtaglomerular apparatus (JGA) and in tubules
and after immune stimulation iNOS has been located
in glomerular mesangial cells and several locations in
the tubule [1,2]
Physiological actions of NO on the kidney
NO synthesized by eNOS, and possibly bNOS, has a
major role in control of renal vascular tone, via its
vasodilatory actions. NO produces vasodilatation via
a cyclic guanosine, 3',5', monophosphate (cGMP)
mechanism and also by stimulating calcium-dependent
potassium channels [1]. Generalized systemic NO
inhibition (NOI) leads to dose dependent increases in
blood pressure (BP) and renal vascular resistance
(RVR), a large fall in renal plasma flow (RPF) and a
slight fall in glomerular nitration rate (GFR) [1]. The
kidney is particularly sensitive to NO inhibition, which
leads to increases in afferent arteriolar resistance (RA),
decreases in the ultrafiltration coefficient (K f ), possibly
via mesangial cell contraction [ 1 ] and a variable effect
on the efferent arteriolar resistance (RE)- When systemic NO inhibition leads to increased BP, RE rises
and causes marked elevation in the glomerular blood
pressure (PGc)- I n addition to directly influencing
vascular tone via eNOS, NO at the JGA controls
glomerular hemodynamics via the tubuloglomerular
feedback mechanism (TGF). JGA NO blunts the
Correspondence and offprint requests to: Chris Baylis, Department of
Physiology, PO Box 9229, West Virginia University, Morgantown,
WV 26506-9229, USA.
increase in RA seen when the macula densa is perfused
with high NaCl [3]. Also, NO plays complex roles in
control of JGA renin release [1-3] and the physiological relationship between NO and renin has not yet
been defined.
NO also influences sodium excretion and may play
a physiological role in control of sodium balance. NO
has a direct tubular effect to inhibit sodium reabsorption in the collecting duct . Also local administration
of NOI into the renal medullary interstitium selectively
decreases papillary blood flow and lowers urinary
sodium excretion with no change in GFR or BP. It is
likely that NO controls sodium excretion both by
direct tubular actions and also by regulating the vascular tone in the medullary circulation and the pressure
natriuresis. There is some evidence that increased NO
production is stimulated by increased dietary salt
intake in normal animals, and may function as a
'natriuretic hormone' although the origin of this NO
remains to be determined [2].
NO also influences growth and is generally reported
to function as an anti-growth factor, although this has
recently been disputed [1,2,4].
Deranged NO production in renal pathology
Overproduction of NO
There is increasing evidence that elevated levels of NO
play a primary pathogenic role in some forms of
immune-mediated glomerular injury. The injurious NO
in glomerular inflammation probably originates from
iNOS and may come from a variety of cell types
including infiltrating macrophages and resident glomerular cells including mesangial cells [1]. NO appears
to play a primary pathogenic role in the glomerular
injury caused by antithymocyte serum; an acute glomerulonephritis that primarily involves the glomerular
mesangial cells. Both NOI and dietary arginine
deprivation are protective, and in this model excess
NO actually promotes glomerular extracellular matrix
accumulation [5]. Excessive NO is cytotoxic by several
mechanisms, including formation of peroxynitrite and