It has been known since the reports by
Mates (1975) that there is a relative risk in those undergoing dialysis to
develop a neoplasm, especially for some tumor types over
others.
Studies carried out in the Piedmont region of northern Italy since
the 1980s have demonstrated that, among such patients, it is the younger
ones who are most exposed to the risk of neoplasia. It has also been found
that the majority of hemodialysed patients that present with neoplasms can
correlate to basic disorders such as polycystic kidney and interstitial
nephropathies. However, the causes of this morbid situation are aspecific
so that careful clinical monitoring is necessary, aimed at the early
diagnosis of the tumor in these subjects, who are divided into two
groups:
1) immune deficiency due to uremic toxicity on the lymph nodal
cell lines and to vitamin deficiencies, so that phenotype anomalies in the
macrophagic monocytes and granulocytes result;
2) chronic infections, often
of viral etiology, such as viral hepatitis B and C, papovavirus and
Epstein-Barr virus, correlating to hepatic carcinoma, cancer of the uterus
and lymphoproliferative neoplasms, respectively.
On the other hand, the
neoplasms described in the various case-reports are somewhat manifold.
Studays conducted by Jacobs in 1981 on 5,700 patients describe, out of all
the hemodialysed patients affected by neoplasms, an incidence of 25% for
breast cancer, 25% for broncopulmonary carcinomas, 16% for cancer in the
large intestine, and 12% for uterine cancers. Acquired renal cysts, that
is to say the cystic lesions that develop in the native kidneys even some
years after the start of the terminal chronic uremia, independently of the
basic nephropathy are considered at risk of cancerous degeneration in
10-20% of cases. Such data is even more significant if we consider that
these benign acquired renal cysts are found in 8-50% of the total dialysis
population. Periodic, accurate ultrasound assessments are therefore
indicated for such patients. Resorting to the search and determination of
serum levels of the more common diagnostic tumoral markers, like CEA,
alpha-fetoprotein and CA19-9, is of limited value in such cases.
Significant serum titer increases (400-500% over standard values)
correlatable to the effective presence of a neoplasm, are those of CA19-9
and only partly those of alpha-fetoprotein, while serum titer changes in
CEA are aspecific and thus have little clinical significance due to the
possibility of frequent cases of false positives. The clinical worth of
such markers is limited at the follow-up checks, when the serum changes
indicate a greater or lesser response to treatment. Survival varies
according to the case reports. Ten years ago, Jacol had a 60% survival
rate at one year from the clinical diagnosis of neoplasia. In 1990, Ragni
did not report a significant variation; though it has to be said that the
greater clinical survival of hemodialysis patients compared to the total
patient population is linked to the stricter clinical monitoring that the
former group receives. In any case, the utmost attention by the
nephrologist is required since the clinical symptoms of a neoplastic
condition, such as asthenia, weight-loss, menometrorrhagia,
macro/micro-hematuria, feveret, recurring opportunistic infections, skin
dyschromia, anomalies of the alvus, mammary noduli or lymphocytic changes,
may be disregarded in a typical dialysis ward or be sometimes mistakingly
attributed to the uremic disease.
The early diagnosis principle is thus
neglected. Ragni's case histories (1990) report that the incidence of
neoplasia does not differ much between uremic and non-uremic patients,
exceptions being neoplasms of the digestive tract, intestinal tumors (6%
non-uremic versus 18% uremic), stomach tumors (9% non-uremic versus 13%
uremic), the digestive system generally, especially in women (12%
non-uremic versus 30% uremic), and female urinary tract tumors (2%
non-uremic versus 18% uremic).
Acquired cystic kidney disease (ACKD)
presents a separate problem. The onset of this condition in the native
kidneys of dialysis patients, even after years of substitutive treatment,
may be connected with: tubule obstructions by ectogenous or endogenous
toxicants; alterations in basement membrane turnover; abnormal epithelial
and vascular hyperplasia of the tubular and/or peritubular structures. The
neoplastic development of these acquired cysts shows forms characterized
by endo-cystic vegetant masses or by solid tumors that are formed within
the cysts deriving from aspecific tubule cells, often with hemorrhagic
and/or necrotic zones. In 1984 Mickrisch affirmed that the differentiation
between the benign and malignant forms is very much a gray area, and that
the latter would often be recognized because of the presence of
metastasis. ACKD may be detected in a range of 8-50% of the total dialysis
population, but only 10-20% of the cysts evolve in a carcinamatous
direction (Gardner et al). Frequent ultrasound monitoring of these cysts
therefore remains essential, especially for those having a diameter
greater than 3 cm.
Kidney
transplants
and neoplastic
conditions
Immunodepressive drug treatment based on prednisone or
methylprednisolone, cyclosporins, azathioprine and anti-lymphocytic and
anti-CD3 receptor sera (these latter being in routine use in the immediate
post-transplant period and/or used in treating acute rejection, also
long-term), as well as the use, still partly experimental, of new
molecules such as FK506, rapamycin, dihydroxyspergualine, mycophenolic
acid, etc., always and anyhow involves a real neoplastic risk factor in
kidney transplanted patients. This is because a depressive effect is
established on the lymphocytic systems and on the activities of the
interleukins and their receptors.
The onset of neoplasia differs,
depending on the immuno-suppressive treatment employed. In the course of
cyclosporin treatment the neoplasia manifest even only after twenty months
post-op., whereas in the traditional therapies with azathioprine and
methylprednisolone such conditions show up after five years. Work by Penn
(Cincinnati, Ohio, U.S.A.) reported that the non-Hodgkin lymphomas
manifested in 40% of the cases described (even after only one year
post-op.) in cyclosporin-treated patients, and in only 10% (and after more
than 42 months post-op.) in patients treated with just azathioprine and
methylprednisolone. The neoplastic forms that manifest most frequently in
kidney transplanted patients are the skin neoplasms in general (15%) and
Kaposi's disease (3-8%). Having medial frequency are the lymphomas (10%)
and carcinomas of the breast, lung, kidneys and gastrointestinal system
(4-6%). Relatively rare (1-3%) are carcinomas of the prostate, bladder,
female genital apparatus, thyroid and pancreas. As said for the
hemodialysis patients, so also for the post-kidney transplant patients, in
the current cyclosporin era, continuous interdisciplinary clinical
monitoring is the only instrument of early diagnosis, in fact not having
to be limited to the functional study of the graft and the problems of
acute and chronic rejection. It should also be said that the transplant
patients are subjected to much more assiduous check-ups and therefore
early diagnosis of neoplasia must be more easily
achieved.
The post-transplant patient does not present all the symptomology
of the hemodialysis patient, so that a suspected diagnosis of a neoplasm
in progress should be easier. According to my own clinical experience, it
can also be found that the very patient who manifests a neoplasm is the
one with better graft functioning, since he/she is surely better covered,
perhaps too much so, by the immunodepressive therapy. And in practice,
this is perhaps the patient who receives less attention by the
nephrologist, precisely because he/she is known to have good graft
function. In fact, over nine years I have personally followed-up seven
cases of various neoplasms out of a total of seventy six patients (9.2%).
At the condition's onset, five of these had serum creatinine levels
between 0.9 and 1.5 mg% and only two had a chronic rejection with
creatinine values greater than 2.5-2.8 mg%. At this point, however, we may
also state that the onset of these neoplasms, since ascertained extremely
early on, have a relatively better course compared to the general patient
population, in that it is a question of neoplasia referable to
drug-induced immunodepression.
The clinical picture of the neoplasia,
until the point of a complete remission, or in any case a full surgical
healing, in fact improves if one proceeds to interrupt the
immunosupressive therapy at once and decisively. In in situ neoplasia
clinical pictures, where there is no local spreading and without any
involvement of the lymph nodes and with the absolute absence of
metastasis, it is advisable to maintain a dosage of 5-10 mg/day of
methylprednisolone to preserve the graft, if at all possible. At this
point in these conditions, an initial drop in serum creatinine levels is
seen (the toxic effect of the cyclosporin becoming less), while in the
subsequent months and sometimes years the functioning of the graft stops
at acceptable values, as if the immune system were so depressed as to be
hypo-anergic to the graft's antigenic structures. In cases where it would
instead be prudent, for the patient's quoad vitam, to suspend the
immunosuppressive therapy, or in cases where only the steroid treatment at
5-10 mg/day would not in time be sufficient, the patient's return to
dialysis and the concomitant organ explantation do not constitute any
problem for the neoplasia. However, to retransplant the patient at this
point and thence to subject him/her to new immunosuppressive treatment
would surely reproduce the onset of neoplasia, or it would anyway
constitute an unacceptible neoplastic risk.
The presence of a neoplasm in
the pre-transplantation period, diagnosed during the time of dialysis
treatment, in theory would have to exclude the patient from any kidney
transplant program. I. Penn investigated the post-transplant recurrence of
neoplasia diagnosed and treated before renal transplantation: such
recidivations were verified in 22% of the total neoplasia cases
examined.
The least relapses (0-10%) were had in the lymphomas and in
carcinomas of the testicles, uterine cervix and thyroid. A medial
recurrence (11-25%) was found in carcinomas of the uterine body, the
colon, prostate and breasts.
Most of the recidivations (> 26%)
were verified in cases of myeloma, skin and bladder carcinomas, melanoma..
Of these relaspes, according to Penn, 53% occur within two years for
transplant, 34% within 2-5 years, 13% affer 5 years. However it is
necessary a period of two years between a complete resolution of
neoplasia and the eventual kidney transplant. In any case neoplasia is
increased by immunosuppressive therapy.
CONCLUSION
The onset of neoplasia is certainly an
important clinical aspect of kidney therapy both for the patient
undergoing hemodialysis and for the patient with a transplanted kidney.
Careful studays are therefore necessary for such patients, directed at
searching for the presence of neoplasia, also employing the help of
oncology specialists. In the case of neoplasia ascertained in the
transplanted patient, CT scans, MR and histological examinations are
necessary for accurate staging and, subsequently, the suspension or
modulation of the immunosuppressive therapy.
According to my own
experience, it is particularly useful to reduce the cyclosporin by 25 mg
per week until its elimination, the rapid elimination of azathioprine, and
the maintenance of immunosuppressive therapy with 10 mg of
methylprednisolone/day, reserving the total suspension of steroid therapy
for when a significant remission of the neoplastic lesions is
witnessed.
Maurizio Mingarelli
Coordinamento Trapianti
Casa
di Cura Santa Rita - Bari |
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