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INTRODUCTION
Amino glycosides antibiotics are the most common nephrotoxic
antimicrobial drugs [1]. They are usually evacuated from the body
through the kidneys; therefore the main condition for a precise dose is
the renal sufficiency. In the case of kidney failure, with a decrease of
glomerural filtration rate a decrease of drug evacuation occurs, whereas
the free fraction, i.e. drug concentration in plasma increases, which is
manifested in symptoms and signs of overdose and intoxication. Toxic
concentration of gentamicin in plasma is 10 and more µg per ml. Higher
gentamicin concentration in plasma should be determined: if high doses
are given, in case of kidney failure, or if the therapy lasts for more
than 7 days.
The incident of nephrotoxicity in patients treated with gentamicin
varies from 0,5 to 32%. The metabolic acidosis increases nephrotoxicity
of this group of drugs, with the risks being even higher in patients
with existing renal dysfunction, treated with either high daily doses of
amino glycosides or during over a longer period of time [1,2]. The risks
being also: genetic predisposition, older age, recent therapy with amino
glycosides, liver dysfunction, high temperature, presence of other
nephrotoxic drug and a state of shock. These drugs tend to cumulate in
the cells of proximal tubules, thus leading to aminoglycoside
nephropathy (acute nephrotoxic nephrosis) and further on to acute renal
insufficiency, with kidney function recovery 1-3 weeks after the therapy
had been stopped. Also, kidney damage in the shape of diabetic
nephropathy is quite often during long-term diabetes mellitus [3]. The
occurance of glomerural changes in the shape of diffuse or nodular
glomerural sclerosis is almost inevitable during 15 to 20 years history
of diabetes. When the nodular glomerural sclerosis takes place, damage
to glomerural basement membrane follows, thus leading to the nephrotic
syndrome.
Below is an example of an insulin dependent long-term diabetic patient
with irregular kidney function check-up, who has developed acute renal
insufficiency (ARI) after a three-day amino glycoside therapy.
PATIENT DESCRIPTION
A 55-years old patient is admitted at EN department due to the
condition of developed anuria. A week prior to the admission, a therapy
of penicillin 1.600.000 i.u./day and gentamicin was prescribed due to
the phlegm changes on the small toe of the left foot, in the local
outpatient clinic. During the third day of the therapy, the patient
displays gastrointestinal symptoms (nausea, vomiting), followed with
haematuria (without pain during urination) and anuria on the fifth day.
The patient is given cephalosporin therapy.
Pursuant to the personal anamnesis we find out that the patient has been
insulin dependent for over 20 years, and that he suffers from
hypertensia. He has not been treated at nephrologists and there are no
existing data on diminished kidney function. He denies drug allergies.
He confirms the family history of diabetes.
Objectively, the patient is conscious, well orientated, febrile (up to
38.5º), with dyspnea, pale skin and visible mucous membrane. Head and
neck without abnormalities. Thorax cylindrical, and symmetrical in
respiratory movement. Auscultatory gap with late inspirium in both
basement parts. Heart activity rhythmical, with clear tones, systolic
bruit over Erbe EM 2/6. Hypertensia (220/130 mmHg), normotensive
frequency (80 per min). Abdomen within the thorax range, soft, not
sensitive when touched and without ascites. Liver and spleen cannot be
felt. Lumbar seats insensitive even under hard percussion. Trophic
changes on skin of both lower legs with discrete swellings, weaker
palpable pulses over aa.dorsalis pedis. Signs of inflammation on the
small toe of the left foot.
X-ray shows obstructing changes in the lung parenchyma including hilus
voluminous.
Lab analysis: faster sedimentation (160/110) leukocyte formulae to the
left, hyper fibrinogen test (8,6 g/l), hyperchromatic anaemia
(erythrocytes 2,6 x 10¹²; haemoglobin 73 g/l), high azotemia (urea 20,5
mmol/l, creatinine up to 657 umol/l, creatinine clearance 8,8 ml/min)
with maximal values noted during the sixth day of the therapy in the
hospital (urea 32 mmol/l, creatinine 1146 μmol/l, creatinine clearance
12,6 ml/min), hyperglycemia (9,3 mmol/l) hyperkalemia (7,7 mmol/l),
hyponatremia (129 mmol/l), hypoalbuminemia (40 g/l) and hyperlipidaemia
(total amount of lipids 15 g/l).
After these analyses intensive diuretic therapy was applied, but the
response was weak (maximal diuresis was 30 ml per day). Even in such a
small quantity of urine the hospital managed to get the results of
sedimentation, erythrocytes, rare bacteriaes, granulated cylinders and
positive proteins. Urine culture was negative.
Additional analyses consisted of:
- ultra sound check-up of the abdomen: liver, spleen, pancreas
and bladder without changes. Both kidneys show somewhat
hyperechogenic parenchyma, although with constant size and
morphology.
- Urethra cystoscopy: urethra is passable, sphincter normal,
coliculus visible, prostatic urethra around 2-3 cm, left lobulus
somewhat obstructive
- X-ray of prostate: prostate feels hard and its shape is uneven.
Prostate carcinoma suspected, but analysis shows normal PSA serum
(0,7 ng/ml);
- Colour and duplex doppler image of abdominal aorta and iliac
veins: abdominal aorta suprarenal maximal 22mm , infrarenal up to
20mm without any significant haemodynamic and morphological changes;
- X-ray of the left foot: (due to the possible gangrene of the toe)
no bone lesion
Due to the continual diuretic therapy the amount of urine available
was scarce; after all the analyses performed, the hospital consilium
decided to introduce depuration on the sixth day of the hospitalization.
Having on mind the basic illness, peritoneal dialysis was suggested to
the patient, but was refused. Therefore, after artery to vein fistulae
was placed, haemodialysis programme was started in the duration of three
hours three times a week.
Five weeks after the haemodialysis had started, the patient felt better,
volemia is normalized (central venous pressure is 7cm of water, without
obstructive lung changes and without swellings on the lower legs), and
diuresis recovered to the stadium of oliguria (700 ml per day). The
urine check-up showed clear contents with some epithelial cells and 4-6
leukocytes. The blood transfusion was necessary on two occasions, due to
the anaemic condition of the patient, while the rest of the therapy
given was symptomatic (methylxantines, insulin, ACE inhibitors,
cephalosporins). Haemodialysis is then rescheduled for two times per
week with the duration of four hours. Eight weeks after, the
satisfactory diuresis of 1200 ml per day is reached.
The last hospital lab analysis showed sedimentation of 92, normal values
of leukocytes and fibrinogen, as well as satisfactory values of
electrolytes (kalium 4,6 mmol/l, natrium 135 mmol/l) and nitrogen
materies – having on mind the haemodialysis (urea 20,9 mmol/l, creatinin
443 μmol/l).
The patient was released from the hospital, and further dialyses will be
performed only in case of the same indications.
DISCUSSION
Antibiotic therapy proves to be the causal therapy in bacterial
infections in surgery [4]. As with other acute purulent infections,
phlegmonic inflammation requires not only surgical intervention but
energetic application of high doses of antibiotics [5]. Popular in
surgical departments in Serbia today is the empirical application of
dual antibiotic therapy (gentamicin and penicillin). Since patient
number one suffered from a phlegmonic toe (caused by a puncture) with
developed inflammatory syndromes (fast sedimentation, leukocytosis and
leukocyte formula to the left), an incision was performed, followed by
administration of penicillin and gentamicin. Additional analyses (X-ray
of the left foot and Colour Duplex Doppler of the blood vessels)
excluded the possibility of the toe gangrene.
This combination of antibiotics has the effect of synergy to many types
of bacteria, with the difference that penicillin is a bit toxic, while
gentamicin may be ototoxic, or, more often, nephrotoxic [6,7]. Since
kidneys are the main excretory organs, their sufficiency is highly
important for these types of antibiotics; it is recommended to establish
markers of the renal function prior to gentamicin application, which was
not done with this patient. Particular care should be taken with the
application of gentamicin with patients suffering from urinary
infection. After the physical check-up, urine analysis and urine
culture, the possibility of urinary infection was discarded. Gentamicin
is a base, which means that metabolic acidosis increases its
nephrotoxicity [1]. In the case of this patient who is a long-term
diabetic, there was a possibility of spontaneous milk acid acidosis.
Gentamicin, as well as other aminoglycoside, damages kidney proximal
tubule cells by creating small myeloma-like bodies within, thus causing
the decrease in glomerural capillary filtration [7]. Clinical
manifestations are visible usually from the third to the tenth day of
the therapy. Our patient developed tubulo-interstitial nephropathy
during the third day of gentamicin therapy, manifested by high
temperature and macrohaematuria with signs of oliguric (fifth day) and
anuric renal insufficiency. As is the case with already existing or
threatening renal disfunctions, gentamicin doses should be lowered in
accordance to the level of the insufficiency, or even discarded (aminoglycoside
was in this case swaped with cephalosporin) (8). Urine analysis is of
major importance in the case of intoxication, since mioglobinuria with
rhabdomyolysis or haemoglobinuria with massive haemolysis can be
registered this way. The lethality in patients suffering from some other
primary illness which is contributing development of the acute tubular
necrosis is 50% [7].
Due to the cumulative nature of toxicity which occurs after application
of therapy doses, it is necessary to control the renal function as of
day four of the therapy [9,10]. Upon development of acute parenchyma
renal insufficiency, the patient in question was hospitalized. The
markers of kidney functions were checked up regularly, as is recommended
in the literature. This is of particular importance for those patients
suspected of reduced kidney function at the beginning of the therapy
(e.g. diabetic patients), or for those with initially normal kidney
function at the beginning, but suffering from the renal dysfunctions in
the course of the therapy. Our patient has been insulin dependent
diabetic with a high risk of diabetic nephropathy development, for over
20 years. The incident of gentamicin nephrotoxicity was most probable.
Diabetes mellitus as a systemic illness, damages primarily glomerural
cappilaries and their base membrane (by thickening them), especially in
the central part of glomerulus [3,11]. Since gentamicin can be
accumulated in extra-cellular space, the excretion of gentamicin is
slowed down with patients suffering from damaged renal parenchyma.
Therefore, in cases of long-term diabetic patients, the therapy should
be commenced with smaller than usual doses, until its effects are
visible. The proper dose differs from patient to patient, since the
average time for elimination of gentamicin differs, and it is in direct
proportion to creatinin clearance. We have to bear on mind the
physiological fall of kindney function caused by aging. The speed of
filtration in glomerural cells between 50-60 years of age is decreasing
up to 30%. The time needed for elimination of drugs (digoxin, gentamicin)
in spite of normal creatinin values in plasma, is extended.
Clinical sign in the phase of oligoanuria is exceptional decrease of
diuresis to several tenths of ml during 24 hours, [7,11] – with the
patient in question it was 30 ml/day. Proteinuria is present (in this
example ++) and significant increase of nitrogen in blood (maximal
values: urea 32 mmol/l, kreatinine 1146 μmol/l – recorded during the
sixth day of the hospitalization). Due to the decreased discharge of
H-plus ion the metabolic renal acidosis develops [7]. Hyperkalemia is in
this case followed by hyponatremia, which is connected to the surplus of
water. By reason of pathologicaly increased catabolism the creation of
endogenous water is intensified, thus increasing the cubic capacity of
extra-cellular liquid. The presence of hypervolemia is confirmed by
swellings on the legs, central vein pressure of 15 cm of water, and
X-ray showing numerous obstructive changes in the thorax tissue and a
number of voluminous hiluses [11]. Hyperkalemia and hypervolemia present
a life threatening situation. The hypochromatic anaemia registered is
caused by the hemolysis and also partly by the refractory nature of the
haematopoietic tissue, which is the result of the uremic toxins impact.
Cylinders similar to those in tubules can be visible in urea [8].
On the other hand, the classical trio of the diabetic nephropaty
consists of: arterio hypertension, oedema and proteinuria [3]. This
combination, together with hypoalbuminemia and hyperlipidemia, is
typical for nephrotic syndrome. It was all recorded in the case of our
patient. Ultra sound examination showed those kidneys are of preserved
size and morphology, with a slightly hyper-echogenic parenchyma. When
checked-up during the acute intoxication phase, the kidneys were pale
and swollen [12]. It was impossible to perform invasive analyses such as
intra-venous pielography, radio-renogram or scintigraphy, due to the
renal dysfunction.
ABI is treated with a combination of conservative therapeutic procedures
and emergency treatment with peritoneal dialysis or haemodialysis. In
cases of over-dose or toxic reaction, haemodialysis may be helpful in
removing gentamicin from blood, especially in cases of disbalanced renal
function [7]. The speed of gentamicin extraction is significantly lower
when periotoneal dialysis is performed.
Conservative therapeutic procedure consists of hypoprotein nutrition, as
well, since hyperkalemia and hypervolemia present a threat to the
patient's life, so the intake of kalium, water and kitchen salt has to
be decreased. The recommended daily intake of water is 10-15 ml/kg. In
cases of hyperkalemia above 7mmol/l, as was the case with our patient,
the therapy of intravenous 10% glycosis with 40 units of chrystal
insulin, has to be applied. If the hyperkalemia is due to the metabolic
acidosis, we should apply 100 ml 8,4% natrium-bicarbonaat solution. The
toxic effect of hyperkalemia to the heart muscle can be mitigated by
intravenous intake of 20 ml 10% calcium salt solution.
Emergency haemodialysis treatment is performed in hospitals and
specialised nephrologic centres. Acute uremia syndrome, caused by
progressive acute azotemia, quickly withdraws under the dialysis method,
and many prospective complications that could be caused by the
disturbance of acid-base balance, are thus avoided. The surplus of water
is quickly removed. Oligoanuria stadium usually lasts between 10 to 14
days (as in the case of our patient), although cases which lasted up to
two months are recorded, as well. ABI caused by drugs is usually
reversible [13], although there are notifications of its irreversible
toxicity. Although the progress in treating parenchyma ABI is
remarkable, the lethality is still over 65% [1].
CONCLUSION
After application of gentamicin, ARF can be avoided by establishing
the correct diagnosis and with the exclusion of risk factor patients
with risk factors (diabetes, hypertension, cardiovascular diseases). In
the course of illness acute stadium, the passing ARF is developed, so we
have to be cautious with drug application, since the latent
insufficiency may easily develop into manifest one.
In cases of diabetic patients with threatening or existing renal
dysfunction, gentamicin doses need to be decreased in proportion to the
insufficiency. Cumulative toxicity which occurs due to the application
of gentamicin therapy demands kidney markers check-up as of the fourth
day of the therapy. It is further more recommended for these patients to
be clinically observed.
If possible, the concentration of gentamicin should be checked with
patients that are treated for either longer period or with larger doses.
The line between therapeutic and toxic concentration is thin; a routine
check-up of gentamicin in plasma is justified, even in cases with normal
kidney function.
LITERATURE
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3C):16S-20S
- Moore RD, Smith CR, Lipsky JJ, et al: Risk factors for
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- Devečerski M: Diabetes mellitus. U: Interna medicina. Urednik:
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- Srpsko lekarsko društvo – traumatološka sekcija: Acta
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1988
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necrosis associated with gentamicin and cephalotin. JAMA
1972,222;1546-7.
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reakcije i interakcije lekova. »Novi dani«. Beograd 1991
- Stork MC: Antibiotics. In: Golfranks Toxicologic Emergencies,6th
edition. Goldfrank RL editor. Appletion&Lange. Stamford. Connecticut
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- Feinfeld AD: Renal Principles. In: Goldfranks Toxicologic
Emergencies, 6th edition. Goldfrank RL, editor. Appletion & Lange.
Stamford. Connecticut 1996:391-410
- Robbins LS: Patologijske osnove bolesti. Školska knjiga. Zagreb
1985:1176-1248.
- Anđelić S, Gojković S. Acute renal insufficiency (ARI) at the
diabetic patient treated with gentamicin. VI Mitteleurope-countries
congress of internal medicine. Igalo, June 24-27, 2001. Abstract
book Nº1, p. 71.
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