Journal of Regional Section of Serbian Medical Association in Zajecar

Year 2007     Volumen 32     Number 4
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UDK 616.379-008.64-06; 615.33.035.2 ISSN 0350-2899, 32(2007) br.4 p.189-193
Case report

Genamicin nephrotoxicity in a diabetic patient

Slađana Anđelić



A patient aged 55, with a long history of diabetes and hypertension, was treated in the outpatient clinic with 240 mg/day of gentamicin, due to the phlegm which started to appear on the small toe of the left foot. On the third day of the therapy, the patient started suffering from nausea, vomiting, high temperature and haematuria, at first with signs of oliguric renal insufficiency. On the fifth day, anuric renal insufficiency started. He was admitted to the Emergency Nephrology (EN) department in a conscious state, febrile (38.5ºC), hypertensive (220/130mmHg) and hypervolemic. Laboratory analyses confirmed positive inflammation syndrome, hyperchromatic anaemia, metabolic acidosis, hyperglycemia, hyperkalemia and hypoalbuminemia. High azotemia was stated during the sixth day of hospitalization: urea 32 mmol/l, creatinine 1146 μmol/l, creatinine clearance 12.6 ml/min. Urine analysis showed haematuria, cylindruria and proteinuria. Gentamicin therapy was cancelled, and the patient started to be treated with cephalosporin group of antibiotics. Due to anaemic condition, the patient was given two blood units. The rest of the therapy was symptomatic (methylxanthines, insulin, ACE inhibitors). Intensive diuretic therapy resulted in a low quantity of urine (maximal diuresis was 30ml per day), and after all the analyses had been performed, the hospital consilium brought the decision to introduce depuration. After eight weeks of haemodialysis, satisfactory diuresis was reached and the patient was discharged from hospital in a stable condition.
Key words: gentamicin, diabetes mellitus, acute renal insufficiency, haemodialysis

: sažetak na srpskom
Note: summary in Serbian


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.


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.


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].


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.


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  13. 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.
  Corresponding Address:
Slađana Anđelić
Aleksinačkih rudara 25/4, 11000 Beograd

Paper received: 24.02.2008
Paper accepted: 27.03.2008
Published online: 24.04.2008
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