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Letters
Table 1. PCR variations in 14 uraemic patients with a dietary protein intake constantly less than 1 g/kg per day after a Kt/V> 1.8
Kt/V
TAC (mg/dl)
nPCR (g/kg per day)
start
month 1
month 2
month 3
month 4
month 5
month 6
1.31 ±0.08
40±10
0.62±0.10
1.85+0.06**
24 + 9**
0.68 ±0.11
1.90 + 0.03**
22 + 8**
0.64 ±0.09
1.89 + 0.04**
20 + 8**
0.67 ±0.098
1.89 + 0.45**
20 + 6**
0.68 ±0.11
1.88 + 0.06**
19 + 9**
0.69 + 0.10
1.85 + 0.05**
22 + 5**
0.61 ±0.18
**/><0.001 vs start.
Table 2.PCR variations in six uraemic subjects with a dietary protein intake constantly less than 1.8 g/kg per day after Kt/V <1.3
Kt/V
TAC (mg/dl)
nPCR (g/kg per day)
start
month 1
month 2
month 3
1.90 + 0.10
1.30 + 0.12**
101 + 10**
1.88 + 0.10
1.31+0.10**
99 ±12**
1.84 + 0.11
1.32 + 0.09**
132 + 11**
1.84 + 0.09
66±11
1.90±0.10
**/><0.001 vs start.
patients (70 men, 64 women), aged (mean + SD), 55.56 +
15.06 years (range 16-82), who had been on haemodialysis
(HD) for longer than 3 months (mean±SD 48.49±39.13)
[4]. All subjects were free from acute illness and were in
steady clinical conditions with stable body-weights. If
one of these suffered a remarkable clinical problem, he/she
was withdrawn until 3 months after recovery.
Urea kinetic modelling was performed once a month, and
2 692 determinations were done.
All patients were instructed to follow a diet containing
35 kCal/kg per day and 1-1.2 g prot./kg per day, but not all
patients observed these instructions. However, Kt/V was
kept equal or higher than patient's nPCR. Our data showed
that the simple linear regression of nPCR versus Kt/V was
y = 0.23x +0.86; r = 0.22; /> = NS. Simple linear regression
of nPCR vs real age was y=-3.94x +1.36; r=-0.36;
P<0.0l. Simple linear regression of nPCR vs dialytic age
was y = 6.26x +1.14; r = 0.152; /> = NS.
We agree with Panzetta that a prospective study using
different dialysis doses in the same patients would be necessary in order to test our hypothesis. However, it is not true
that such a study has been neither carried out nor planned
so far. Our study [4] shows in 14 uraemics with dietary
protein intake constantly lower than 1 g/kg per day in the
previous 12 months, the variations of administration of
Kt/V > 1.8. Observation lasted 6 months (Table 1).
Remarkable increases of Kt/V (and consequent TAC
reduction) do not cause any nPCR variation in 6-months
observation.
Table II shows nPCR variations in 6 uraemic patients,
with a dietary protein intake constantly higher than 1.8 g/kg
per day in the twelve months before observation, after a
Kt/V< 1.4. Observation was 3 months. At the third month,
patients showed no clinical signs of underdialysis; however,
it was thought ethical to stop observation.
Remarkable reductions of Kt/V (and consequent TAC
increases) do not give nPCR modification in 3 months
observation.
In conclusion, we confirm that nPCR and Kt/V do not
show any mathematical correlation in short and medium
times of observation after variations of Kt/V administration
in the same patients.
Unita Operativa di Nefrologia e
Dialisi, Ospedali Unificati del
Lagonegrese, ASL no 3-Lauria
(Potenza), Italy
B. Di Iorio
V. Terracciano
C. Altieri
1. Panzetta G. Protein intake does not depend on the dose of
dialysis delivered—provided Kt/V is adequate. Nephroi Dialysis
Transplant 1995; 12: 2286-2289
2. Lindsay RM, Spanner E, Heidenheim RP el at. Which comes
first, Kt/V or PCR: chicken or egg? Kidnev Int 1992; 42 [Suppl
38]: S32-36
3. Movilli E, Mombelloni S, Caggiotti M, Maiorca R. Effect of age
on protein catabolic rate, morbidity and mortality in uraemic
patients with adequate dialysis. Nephroi Dial Transplant 1993;
8: 735-739
4. Di Iorio B, Terracciano V, Gaudiano G, Altieri C. Factors
affecting nPCR in hemodialysed patients. J Artif Organs 1995;
18: 131-140
Neoral in acute renal transplantation
Sir,
Routine use of cyclosporin A (Sandimmun) as a component
of background immunosuppression in renal allograft recipients has had a major impact on graft survival [1].
Nephrotoxicity in the acute situation can be ameliorated by
dose reduction in association with monitoring of trough
blood concentrations (200-400 ng/ml). However, there is a
poor correlation between trough values and true exposure to
the drug. Recently the new microemulsion formulation of
cyclosporin A (Neoral) has become available for clinical use
in the UK. This formulation has pharmacokinetic advantages
with more rapid and predictable absorption [2]. Since true
exposure is greater, a dose reduction is required to avoid
nephrotoxicity. We are writing to report an increased incidence of cyclosporin A nephrotoxicity in the first 4 weeks
following renal transplantation using Neoral compared to
Sandimmun, despite an appropriate dose reduction. Trough
whole blood cyclosporin concentrations were measured by
specific radioimmunoassay using a commercial kit (Syva,
UK).
Until July 1995 patients receiving a renal allograft were
commenced on Sandimmun lOmg/kg in two divided doses
from the first postoperative day. Trough plasma concentrations were measured on alternate days and maintained
between 200 and 400 ng/ml. Since July 1995, 45 renal allograft recipients were commenced on Neoral 7 mg/kg in two
divided doses with dose adjustment to maintain trough
concentrations as above. Five patients have demonstrated
increases in plasma creatinine in the 4 weeks following
transplantation, which have responded to acute reductions
in the Neoral dose. The trough values at the time of
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Letters
deteriorating renal function were 211, 318, 329, 332 and
404 ng/ml. In addition, in another four cases (three patients)
a renal biopsy was performed because of worsening renal
function which showed evidence of cyclosporin A exposure
(cytoplasmic vacuolation in tubular cells) and in one instance,
nephrotoxicity with vascular hyalinisation. Trough concentrations at biopsy were 170, 258, 272 and 273 ng/ml. On
three of these occasions, Neoral dose reduction led to improving renal function and in the other case, where vascular
abnormalities were observed, dose reduction in combination
with intravenous methylprednisolone (for moderate cellular
rejection) was successful. In the 45 patients who received
renal allografts prior to our change to Neoral and followed
for the first 4 weeks, there were no cases of deteriorating
renal function which responded to Sandimmun dose reduction, and changes attributable to cyclosporin A exposure or
nephrotoxicity were observed in only one case on renal
biopsy, with a blood cyclosporin level of 545 ng/ml.
Achievement of a therapeutic plasma cyclosporin A in the
immediate post-transplant period is essential to reduce the
risk of acute rejection. Our clinical experience with Neoral
is that nephrotoxicity can occur with lower trough plasma
concentrations than we have observed previously with
Sandimmun. Thus, our immunosuppression policy has now
changed so that all patients are commenced on Neoral
5 mg/kg in two divided doses and the dose adjusted to
maintain trough concentrations of 200-300 ng/ml. We feel
that our clinical observations are of relevance to physicians
managing renal allograft recipients and patients with glomerulonephritis receiving cyclosporin A.
P. A. Rutherford
Departments of Medicine
Transplantation Surgery and
A. Kumar
A. Davison
Histopathology
A. R. Morley
Royal Victoria Infirmary
M. Thick
Newcastle upon Tyne
T. H. J. Goodship
NE1 4LP
UK
1. European Multicentre Trial Group. Cyclosporin in cadaveric
renal transplantation: 3 year follow up of a European Multicentre
Trial. Lancet 1985; 8454: 549-553
2. Hoit DW, Mueller EA, Kovarik JM, van Bree JB, Kutz K. The
pharmacokinetics of Sandimmun Neoral: a new oral formulation
of cyclosporin. Transplant Proc 1994; 26: 2935-2939
The ophthalmological findings reported by Dr Jin et al.
are compatible with those resulting from CMV infection
which is most common with potent immunosuppression. In
their patient, accelerated rejection on the second postoperative day was unsuccessfully treated by a 6-day course
of pulse methylprednisolone, before OKT3 was started on
the 8th post-operative day. CMV infection, for example, by
transmission from the donated organ, may well have occurred
after more than a week of high-dose steroid therapy. It is
not mentioned whether the donor was tested for anti-CMV
antibodies. Regrettably, the onset of visual disturbances was
not noticed by the transplant physicians and the exact time
course is thus not known. Their patient retrospectively
reported a 10-day period of slowly progressing ophthalmological problems 12 days after start of antibody therapy (7
days after stopping OKT3). At no time was acute CMV
infection ruled out as the underlying cause of the ophthalmological problems by investigation of direct CMV-antigen in
peripheral blood leukocytes, viral DNA by polymerase chain
reaction, or CMV-specific IgM [5].
We conclude that the occurrence of ophthalmological
problems in this particular patient cannot be clearly related
to OKT3 monoclonal antibody therapy. The underlying
cause of visual loss could as well have been an ophthalmologic manifestation of acute CMV infection.
Department of Medicine
Department of Ophthalmology
Karl Franzens University
A-8036 Graz, Austria.
Jorg H. Horina
Sabina Horn
Herwig Holzer
Gerald Langmann
1. Duker O, Barr C. Visual loss complicating OKT3 monoclonal
antibody therapy. Am J Ophthalmol 1993; 115: 781-785
2. Marks WH, Perkal M, Lorber MI. Aseptic encephalitis and
blindness complicating OKT3 therapy. Clin Transplant 1991;
5: 435
3. Bowen EF, Wilson P, Atkins M et al. Natural history of untreated
cytomegalovirus retinitis. Lancet 1995; 346: 1671-1673
4. Egbert PR, Pollard RB, Gallagher JG et al. Cytomegalovirus
retinitis in immunosuppressed hosts. II. Ocular manifestations.
Ann Intern Med 1980; 93: 664-669
5. Cohen J, Hopkin J, Kurtz J. Infections complications after renal
transplantation. In Morris PJ, ed. Kidney Transplantation:
Principles and Practice, 4th Edition, W. B. Saunders Company:
Philadelphia, 1994: 364-389
OKT3 monoclonal antibody therapy and visual loss
Sir,
In their report on visual loss complicating acute renal allograft rejection in a 30-year-old female Dr Jin et al. (Nephrol
Dial Transplant 1995; 10: 2144-2146) suggest this severe side
effect to be related to OKT3 monoclonal antibody therapy.
Although some reports on ophthalmological problems following OKT3 administration have been published recently,
we believe that the presented data do not allow this conclusion [1,2].
The authors fail to exclude acute cytomegalovirus (CMV)
infection which is well known to cause chorioretinitis with
perivascular infiltrates, exudates, and haemorrhage, and a
permanent reduction in visual acuity [3,4]. The classical
lesions are due to vasculitis and often involve both macula
and papilla. We base our argument on personal experience
with a renal transplant recipient who developed severe neuritis of both optic nerves, necrotizing retinitis and permanent
visual loss during an episode of otherwise subclinical CMV
infection. This happened 10 days post-operatively when the
patient was on high-dose steroids and cyclosporin, but had
not received OKT3.
Reply by authors
Sir,
CMV infection usually develops 4-6 months after transplantation, probably reactivation due to prolonged immunosupression. The patient preoperatively was IgG anti-CMV
antibody positive as usual transplant recipients in our centre.
We have not seen chorioretinitis in over 1000 patients including over 200 treated with pulse solumedrol therapy.
Recently we studied CMV reactivation, and the results
were presented at the 4th Congress of Asian Society of
Transplantation (Dr Wie et al., August 1995). Using an
immunohistochemical assay for CMV antigenaemia in peripheral blood, we found positive results in about 60% of
transplant recipients, but no chorioretinitis was detected in
high titre patients who also recieved solumedrol pulse therapy
or OKT3 therapy.
We did not study CMV in the reported retinitis case
because there were no other symptoms of CMV infection,
e.g. fever, leukopaenia, CMV viral pneumonia, at the time