Acute renal failure due to diltiazem

1337 times previously, with satisfactory control of vomiting. If the deaths due to the antiemetic treatment it is difficult to tell which agent was the cause. However, unexpected sudden deaths have not previously been reported for intermittent high-dose corticosteroids, while there has been one sudden death in a patient on high-dose metoclopramide.Domperidone is bound to plasma proteins and is metabolised by the liver: toxicity can be suspected on the grounds of hypoalbuminaemia at the time of chemotherapy (2 - 8 and 2 - 2 g/dl); moreover, in the second patient the liver was extensively replaced by tumour. This report suggests caution in using domperidone alone or in combination at high doses. were

Division of Medical

Ospedale

S

10123 Turin,

GIUSEPPE GIACCONE OSCAR BERTETTO ALESSANDRO CALCIATI

Oncology,

Giovanni,

Italy

NB, Marit G, Hoerni B High-dose metoclopramide in cancer chemotherapynausea and vomiting. Cancer Treat Rep 1982; 66: 2107-08. 2 Gralla RJ, Itri LM, Pisko SE, et al. Antiemetic efficacy of high-dose metoclopramide: 1 Bui

induced

3 4

5.

6

Randomized trials with placebo and prochlorperazine in patients with chemotherapy-induced nausea and vomiting. N Engl J Med 1981; 305: 905-1009. Swann IL, Thompson EN, Qureshi K. Domperidone or metoclopramide in preventing chemotherapeutically induced nausea and vomiting. Br Med J 1979; ii 1188. Carreca I, Cupido G, Zerillo G, Frazio L, Sutherland JRJ. High-doses (HD) of domperidone (DPRD) as antiemetic treatment in cisplatinum combination chemotherapy of head and neck tumours. 2nd European Conference on Clinical Oncology and Cancer Nursing, 1983; abstr 04-35, 39 Giaccone G, Donadio M, Musella R, et al. Comparison of methylprednisolone and metoclopramide in the prophylactic treatment of cis-platin-induced nausea and vomiting. Tumori 1984; 70: 237-41. Pollera CF, Cognetti F, Nardi M, Malla D. Sudden death after acute dystonic reaction to high-dose metoclopramide. Lancet 1984; ii: 460-61.

CYCLOSPORIN-INDUCED HAEMOLYTIC URAEMIC SYNDROME IN LIVER ALLOGRAFT RECIPIENT

SIR,-Haemolytic uraemic syndrome (HUS) has been reported in bone-marrow transplant recipients treated with cyclosporin.I,2 HUS has also been noted to recur after renal transplantation in recipients whose original renal failure was due to this disorder. 3,4 However, HUS de novohas not been reported in recipients of solid organ allografts. We therefore wish to report such a case and the response to conversion from cyclosporin to conventional

immunosuppression. In May, 1982, a 39-year-old man had an orthotopic liver transplant for a primary hepatocellular carcinoma. Preoperative -

-

renal function (serum creatinine 62 mol/1, serum urea 5 - 6 mmol/1) and haematology (Hb 14-1g/dl, platelet count 357 x 109/1) were normal. The postoperative course was uneventful and his initial immunosuppression consisted of cyclosporin 10 mg/kg daily and prednisolone 20 mg daily. He remained well for the next 3 months apart from a single unexplained grand mal convulsion which was treated with phenytoin 100 mg daily. 3 months post-transplant he

readmitted with encephalopathy and mildly deranged liver function tests: bilirubin 50 mol/1 (normal 3-21 mol/1), aspartate transaminase 38 VII (10-40), alkaline phosphatase 249 U/1 (70-350), plasma ammonia 40 mol/1 (10-28). He was hyperglycaemic (blood glucose 20 mmolll) and hypertensive (150/110 mm Hg), and had a Klebsiella urinary tract infection. His encephalopathy and hyperglycaemia improved with dietary protein and carbohydrate restriction and oral lactulose. He received a betablocker for hypertension. His serum creatinine rose from 55 J-lmolll immediately post-transplant to 389 mol/1 and the platelet count fell from 400 to 39x 109/1 (figure). Other investigations indicated haemolysis and intravascular coagulation: Hb 10-00 g/dl, reticulocyte count 5%, prothrombin time 15/12 s, partial thromboplastin time 40/38 s, fibrinogen 3’ 96 g/1 (normal 1-5-4-0), fibrin degradation products 40 mg/1 (0-10), haptoglobulin 0 - 22 g/1 (0 - 6-1 - 5), peripheral blood film helmet cells and fragmented red cells, bilirubin 35 mol/1 (3-21), aspartate transaminase 26 VII (10-40), alkaline phosphatase 198 U/1 (70-350). A renal biopsy was not done because of the low platelet count. Reduction of the cyclosporin dosage to 5 mg/kg daily resulted in only a transient improvement of renal function. The drug was then stopped and the patient was started on azathioprine 2 mg/kg daily and continued on prednisolone. He was given fresh frozen plasma (FFP), two units per day for 3 days. His serum creatinine fell and his was

platelet

count

progressively rose.

This patient had unequivocal evidence of disseminated intravascular coagulation and renal impairment whilst on cyclosporin, and recovery coincident with cyclosporin withdrawal suggests an aetiological role. Neild et al have reported striking glomerular thromboses in rabbits treated with cyclosporin associated with a decrease in a plasma factor which stimulated vascular prostacyclin synthesis.5A similar deficiency has been noted in some patients with idiopathic HUS and this provided the rationale for treating patients with this disorder with FFP.6 Cyclosporin may cause HUS when used for solid organ allografts, and this possibility should be borne in mind in patients who show evidence of nephrotoxicity on this drug. Departments of Surgery, Nephrology, and Haematology, Queen Elizabeth Hospital,

Birmingham B15 2TH 1. Shulman

R. S. BONSER D. ADU I. FRANKLIN P. MCMASTER

H, Striker G, Deeg HJ, Kennedy M, Storb R,Thomas ED Nephrotoxicity of

cyclosporin A

after allogenic bone marrow transplantation.

N Engl J Med 1981; 303:

1392-95 2. Atkinson K, first 100 3.

4.

5. 6.

Biggs JC, Hayes J, et al. Cyclosponn A associated nephrotoxicity in the days after allogenetic bone marrow transplantation Three distinct syndrome. Br J Haematol 1983; 54: 59-67. Folman R, Arbus GS, Churchill B, Gaum L, Huber J. Recurrence of haemolytic uraemic syndrome in a 3½ year old child, 4 months after second renal transplantation. Clin Nephrol 1978; 10: 121-27. Leithner C, Sinzinger H, Pohanka E, Schwarz M, Kietschmer G, Syre G Recurrence of haemolytic uraemic syndrome triggered by cyclosporin A after renal transplantation. Lancet 1982; i: 1470-71. Neild GH, Rocchi G, Imberti F, et al. Effect of cyclosporin on prostacyclin synthesis by vascular tissue in rabbits. Transplant Proc 1983; 15 (suppl 1): 2398-400. Remuzzi G, Marchesi D, Mecca G, et al. Haemolytic uraemic syndrome: Deficiency of plasma factor(s) regulating prostacyclin activity? Lancet 1978, i. 871-72.

ACUTE RENAL FAILURE DUE TO DILTIAZEM

Serum creatinine concentration and platelet

allograft recipient.

counts

in

a

liver

SIR,-Calcium antagonists are widely used, especially in cases of angina pectoris due to coronary artery spasm.l,2 Of the three commonly prescribed calcium antagonists (verapamil, nifedipine, and diltiazem) Opie3recommended diltiazem because it has few side-effects and only a slight negative inotropic effect. We have seen a case of acute renal failure due to this drug. A 77-year-old man was admitted with severe retrosternal pain, nausea, and vomiting. He was taking beclomethasone dipropionate, ipratropium bromide, theophylline, and prednisolone because of chronic obstructive lung disease. His blood pressure was 160/90 mm Hg, heart rate 60/min, and there were no signs of heart failure. ECG revealed a sinus rhythm (70/min), few ventricular extrasystoles, biphasic T waves, no conduction disturbances, and no signs of acute myocardial infarction.

_

1338 enzyme in vitro. I suggest that the methyltetrazolethiol side-chain of the antibiotics in question is liberated in vivo and oxidised to 5,5’-dithiobis(l-methyltetrazole), the disulphide subsequently reducing the activity of aldehyde dehydrogenase so that acetaldehyde accumulates during ethanol metabolism. This route is closely similar to that believed to be followed by disulfiram;upon absorbtion disulfiram is reduced to diethyldithiocarbamate, which is then presumably reoxidised later, at least in part, to disulfiram before the enzyme is modified. Department of Chemistry, Biochemistry, and

Biophysics,

Massey University, Palmerston North, New Zealand

Serum creatinine and urea concentrations before, treatment with diltiazem (’Tildiem’).

during,

and after

An infusion of nitroglycerine was started and the patient’s current drugs were continued. On the second day of the infusion nitroglycerine was replaced by oral isosorbide nitrate (4x 20 mg daily) and diltiazem (4 x 60 mg orally per day) was added because of persistent periods of retrosternal pain together with increased STsegments on the ECG without changes in myocardial enzymes. On this regimen the retrosternal pain disappeared. However, after starting diltiazem the patient became oliguric and serum creatinine and urea rose (figure). His serum level of diltiazem 2 h after an oral dose was 247 g/1 (therapeutic reference range 50-250 g/1). There had been no periods of hypotension or fever with sepsis. Renal echography revealed two normal kidneys and no signs of postrenal obstruction. It was concluded that the acute renal failure most probably was due to one of the drugs, possibly diltiazem. After withdrawal of diltiazem, while all other drugs were continued, the patient became polyuric and serum creatinine and urea fell (figure). 1 month after the patient left hospital his creatinine and urea levels had returned to pre-admission levels. We conclude that the acute renal failure in this patient was most probably caused by diltiazem since no other cause for the deterioration in renal function could be found.

TREVOR M. KITSON

1. Neu HC, Prince AS. Interaction between moxalactam and alcohol. Lancet 1980; i: 1422. 2. Portier H, Chalopin JM, Freysz M, Tanter Y Interaction between cephalosporins and alcohol. Lancet 1980; ii: 263. 3. Reeves DS, Davies AJ. Antabuse effect with cephalosporins. Lancet 1980; ii: 540. 4. Buening MK, Wold JS, Israel KS, Kammer RB. Disulfiram-like reaction to &bgr;-lactams. JAMA 1981; 245: 2027-28 5. Kitson TM. Mechanism of inactivation of sheep liver cytoplasmic aldehyde dehydrogenase by disulfiram. Biochem J 1983; 213: 551-54. 6. Kitson TM. The disulfiram-ethanol reaction: a review. I Stud Alcohol 1977; 38: 96-113.

ONCE-DAILY VERAPAMIL

SIR,-Verapamil is the parent compound for a series of drugs that block the calcium-mediated slow response in cardiac tissue.’ The drug has been used in angina, arrhythmia, and hypertension. Despite almost complete absorption from the gastrointestinal tract the bioavailability of the drug is only 10-22%, probably because of first-pass hepatic metabolism.2Large single doses produce high peak concentrations in the blood but do not prolong the duration of activity.2 One of us (J. M. D.) has designed a solid oral dosage form of verapamil (US patent 4, 461, 759) which has a constant-release rate pattern in vitro. We present here data on the first four volunteers participating in a study comparing the bioavailability of verapamil from our

P. M. TER WEE J. B. ROSMAN S. VAN DER GEEST

Intensive Care Unit, State University Hospital, 9713 EZ Groningen, Netherlands

E, Kishida H. Treatment of

variant angina with drugs: a survey of 11 Circulation 1981; 63: 844-48. 2. Schroeder JS Multiclinic controlled trial of diltiazem for Prinzmetal’s angina. Am J Med 1982; 72: 227-31. 3. Opie LH. Drugs and the heart four years on. Lancet 1984; i: 496-501.

1. Kimura

cardiology institutes in Japan.

METHYLTETRAZOLETHIOL AND THE ANTABUSE REACTION

SIR,-Several reports have mentioned an ’Antabuse’ (disulfiram) to alcohol which may be experienced by patients taking cephalosporin antibiotics with a methyltetrazolethiol side-chain. 1-4 In my work on the in-vitro chemical modification of like reaction

cytoplasmic aldehyde dehydrogenase5 I 5,5’-dithiobis(l-methyltetrazole) is a rapid

have found that inactivator of the in chemical structure, it

enzyme, and in this respect, as well as resembles disulfiram (tetraethylthiuram disulphide). A limiting residual enzyme activity of about 2507o is brought about within the time of mixing when a four to six fold excess (over enzyme concentration) of 5,5’-dithiobis(I-methyltetrazole) is added to aldehyde dehydrogenase. Under similar conditions, disulfiram reduces the activity to about 3%. The substrates, NAD+ and acetaldehyde, do not protect the enzyme against inactivation. The reduced derivative, 1-methyltetrazole-5-thiol, has no effect on the

Fig I-Verapamil and norverapamit levels.