NEPHROTOXICITY OF CYCLOSPORIN A

663

&ggr;-GLUTAMYLTRANSPEPTIDASE AND ALCOHOL PROBLEMS

SIR,-In your editorial (Nov. 22, p. 1117) on the detection of alcoholism you suggest that screening tests, including biochemical

populations such as hospital patients. Since serum y-glutamyltranspeptidase (GGTP) determination has been suggested as a screening test for alcoholism we reviewed our data on GGTP activities in patients in our hospital. 28% (101/356) of the hospital inpatients we studied had abnormal I serum GGTP levels (30 IU/1). After clinical examination, detailed questioning, and analysis of the case histories only 4 of these patients were found to have an alcohol problem. This high number of false positives was due to the effects of drugs, surgery, and radiotherapy received while in hospital and of other diseases such as pancreatitis which can cause increases in serum GGTP. Thus great care is needed in the interpretation of serum GGTP levels because of the high rate of false positives and factors other than alcohol abuse which cause abnormal results. Some of these problems might be overcome if screening was carried out nearer the time of presentation-e.g., at the general practitioner’s surgery or on admission rather than during a stay in hospital. tests, might be of value in selected

Wolfson Research Laboratories, Queen Elizabeth Medical Centre,

Birmingham B152TH

T. P. WHITEHEAD H. PANDOV P. M. CLARK

NEPHROTOXICITY OF CYCLOSPORIN A

SIR,-Studies on patients receiving cyclosporin A (CyA) for bone marrow2 and renal transplants3,4 have suggested that the drug is nephrotoxic. What is not clear is how this effect is produced and whether or not it leads to long-term irreversible structural damage. We have studied six patients who were converted from CyA to conventional immunosuppression (prednisolone and azathioprine) about 6 months after,successful renal transplantation (table). PaCHANGES IN PLASMA CREATININE AFTER CHANGE FROM

CyA

THERAPY TO PREDNISOLONE AND AZATHIOPRINE

Such evidence as exists suggest that the nephrotoxicity of CyA is due to a tubular effect. Transplant kidney biopsy studies have shown no significant glomerular or tubular lesions to account for impaired graft function.3,4 We have been unable to reverse the nephrotoxic effect with dopamine infusions in out transplant patients. The protective effect of a mannitol induced diuresis given before CyA therapy has been commented on by Calne et al.and is compatible with a toxic effect of CyA on tubules. We have pretreated six patients with CyA (25 mg/kg 4 h before operation) and found that early non-function (less than 5 days) with a creatinine clearance of less than 5 ml/min occurred in all patients. None of six patients given CyA after a mannitol induced diuresis had early loss of graft function.4 We have further studied the nephrotoxic effects of CyA in patients receiving CyA for relapsing polyneuritis. Renal biopsy in one patient (plasma creatinine 309 mol/1) revealed no significant abnormality while he was taking CyA. Urine N-acetyl-glucosaminidase (NAG):creatinine ratios are a useful indicator of tubular damage5 (normal range 9-64). Two patients with this condition treated with CyA showed a rise in urinary NAG:creatinine ratios from pretreatment values of 55 and 75 to peaks of 286 and 643, respectively. At this time the creatinine clearances had fallen from 105 and 95 to 22 and 67 ml/min, respectively. On withdrawal of CyA therapy creatinine clearance and urinary NAG excretion rapidly returned to pretreatment levels. CyA would appear to be toxic to the renal tubules in a dose dependent and reversible fashion. In the short-term mannitol diuresis can protect the kidney but it is not yet clear whether long-term administration of CyA could lead to structural and therefore possibly irreversible renal damage. PAUL SWENY Department of Nephrology, and Transplantation, Royal Free Hospital, London NW32QG

tients 1 and 2 underwent a mild episode of rejection which was con. trolled by increasing the dose of steroids. In the four other patients renal function improved markedly over the first month. Only pa. tient 5 has shown any progressive impairment of graft function aftel changing from CyA. We agree with Dr Klintmalm and colleague! (Feb. 28, p. 470) that rejection may follow conversion to conven tional therapy but in our experience it usually responds well to extr: steroid therapy.

MICHAEL GROSS ZACHARIAH VARGHESE

SIR,-Dr Klintmalm and colleagues report easily reversible

nephrotoxicity of cyclosporin A (CyA) after 13-22 days’ treatment in transplant patients. Calne et al.l have raised the question of CyA nephrotoxicity in recipients of renal transplants, but Klintmalm’s study in liver transplant recipients facilitates evaluation of the nephrotoxic effect of CyA. We have studied renal function over a similar period (21 days) in normal rats given oral CyA 25-100 mg/kg in 48 h; at lower, immunotherapeutic doses (25-50 mg/kg in 48 h) small but significant increases in serum urea and creatinine were observed.2In animals given 100 mg/kg in 48 h impairment of renal function was more pronounced, the animals showing a 3-fold inurea, increased serum creatinine, and increased This enzymuria. nephrotoxic effect was accompanied by impaired weight gain, mild hair loss, significant lymphopenia, and minor alterations in liver function. These changes were totally reversed within 3 weeks of cessation of CyA. Our results in animals support those of Klintmalm et al. and of Marbet et a1.,3 who reported reversible CyA induced nephrotoxicity in patients with rheumatoid arthritis and in recipients of bone marrow transplants. Although both groups suggest, on the basis of renal scan procedures or histological examination, that CyA causes tubular cell necrosis, we have found no histological evidence to support this finding from our studies in the rat. Similarly, Calnehas crease

*Normal range 60-120 mot/L

JULIA HOPPER

in

serum

5. Tucker

1 Szasz G, Weimann G, Stahler F, Wahlefeld AW, Persijn JP. New substrates for measuring &ggr;-glutamyl transpeptidase activity. Z Klin Chem Klin Biochem 1974; 12: 228. 2. Powles RL, Clink HM, Spence D, et al. Cyclosporin A to prevent graft-versus-host disease in man after allogeneic bone marrow transplantation. Lancet 1980; i: 327-29. 3 Calne RY, Rolles K, White DG, et al. Cyclosporin A initially as the only immunosuppressant in 34 recipients of cadaveric organs: 32 kidneys, 2 pancreases, and 2 livers. Lancet 1979; ii: 1033-36. 4 Sweny P, Younis F, Farrington K, et al. 12 months experience with cyclosporin A in human kidney transplantation. Transplant Proc (in press).

SM, Boyd PJR, Thompson AE, et al. Automated assay of NAG in normal and pathological human urine. Chn Chim Acta 1975; 62: 333-39. 1. Calne RY, White DJG, Thiru S, Evans DB, McMaster P, Dunn DC, Craddock GN, Pentlow BD, Rolles K. Cyclosporin A in patients receiving renal allografts from

cadaver donors. Lancet 1978; ii: 1323. AW, Whiting PH, Cameron ID, Lessels SE, Simpson JG. A toxicological study in rats receiving immunotherapeutic doses of cyclosporin A. Transplantation 1981; 31: 121-24. 3. Marbet UA, Graf U, Mihatsch MJ, Gratwohl A, Müller W, Thiel G. Renale Nebenwirkungen der Therapie mit Cyclosporin A bei chronischer Polyarthritis und nach Knochenmarktransplantation. Schweiz Med Wschr 1980; 110: 2017-20. 4. Calne RY. Cyclosporin. Nephron 1980; 26: 57-63.

2. Thomson

664

CyA nephrotoxicity in man is not associated with morphological changes on light or electron microscopy. Further investigation is required to elucidate the nephrotoxicity associated stated that

with CvA. P. H. WHITING Departments of Chemical Pathology and Pathology, University Medical Buildings

J. T. BLAIR J. G. SIMPSON R. J. L. DAVIDSON

Aberdeen AB9 2ZD

A. W. THOMSON

PARVOVIRUS INFECTIONS AND HYPOPLASTIC CRISIS IN SICKLE-CELL ANAEMIA

SIR,-During routine screening of sera from children aged 2-15 by counter-current immunoelectroosmophoresis (CIE) a specimen giving a precipitin line with an antibody to parvovirus

years

B191,2

was found. The serum was from a child with sickle-cell anaemia suffering a hypoplastic crisis. Five other patients with sickle-cell anaemia presented to King’s College Hospital with hypoplastic crises during 1980 and stored sera from these patients were therefore investigated for evidence of parvovirus infection. The six cases occurred in four families, cases 3 and 4 and cases 5 and 6 being siblings (table). All cases were unwell except case 4, who

CONGENITAL (FINNISH) NEPHROSIS AS CAUSE OF ABNORMAL AMNIOTIC FLUID ALPHA-FETOPROTEIN

HAEMATOLOGICAL AND VIROLOGICAL FINDINGS IN SIX PATIENTS WITH SICKLE-CELL ANAEMIA IN HYPOPLASTIC CRISIS

SIR,-Congenital (Finnish) nephrosis is a rare but well characterised cause of raised -alpha-fetoprotein (AFP) concentrations in serum and amniotic fluid.2 We wish to report a further case and to draw attention to the importance ofbearing this possibility in mind when an aborted fetus is apparently normal. The patient, in her third pregnancy and with no personal or family history of note, had serum AFP concentrations of 240 g/1 at 17 weeks (4-8x median) and 550 g/1 at 20 weeks (6’4x median). The amniotic fluid AFP was 280 mg/1 at 21 weeks (34-11 x median) and the pregnancy was terminated. The fetus appeared normal and routine necropsy revealed no abnormalities in fetus or placenta. However, electronmicroscopy of the kidneys revealed foot process fusion and basement membrane abnormalities in the glomeruli consistent with congenital (Finnish) nephrosis. Further tests were done on the amniotic fluid in an attempt to demonstrate abnormalities which could be used in the differential diagnosis of congenital nephrosis and neural tube defects (NTDs), paying particular attention to those analytes which might be abnormal in the presence of renal disease. The tests done were acetylcholinesterase isoenzyme studies by gel electrophoresis, electrolytes, urea, osmolality, total protein, albumin, albumin/total protein ratio, two-dimensional Laurell protein electrophoresis using anti-whole-human-serum antibody, total aminoacids, and individual aminoacids. The only abnormalities were in total protein (9 - 68 g/l; normal for 19-22 weeks 2-7) and albumin (7 - 32 g/l; normal for 19-22 weeks 1-5). However, since similar increases were found in amniotic fluid from twenty-two NTD pregnancies tested at 17-22 weeks (total protein 8-53±SD 5-66 gll and mean albumin 5-72±192 g/1) these abnormalities were of no diagnostic significance. The only investigation to yield useful information was acetylcholinesterase isoenzyme electrophoresis which differentiated between NTD and congenital nephrosis by the absence of the second band (inhibited by BW 284C51) in congenital nephrosis. This test, however, will not help to differentiate between congenital nephrosis and some other non-NTD causes of raised amniotic fluid AFP such as Turner’s syndrome and oesophageal atresia and thus the diagnosis of congenital nephrosis must still rest on the postmortem electronmicroscopic examination of the kidneys. For

successful electronmicroscopy post mortem autolysis of the kidneys must be avoided. This is best done by immediate removal of the kidneys and fixation in either formaldehyde (neutral buffered) or glutaraldehyde. All obstetric units should be aware of the possibility of congenital nephrosis and make provision for the preservation of fetal kidneys for electronmicroscopy. General

Infirmary, Salisbury

G. F. BATSTONE

Department of Chemical Pathology, Southmead Hospital, Bristol BS10 5NE

Royal Hants County Hospital, Winchester Southampton General Hospital

hyperplastic. A precipitin line was found by CIE in three of the four cases from whom a specimen taken on the first or second day after the onset of symptoms was available. The accompanying figure illustrates the virus particles found by immune-electron microscopy (IBM) in the serum of case 4. Morphologically identical particles were seen by IEM in cases 1 and 6. In cases 4 and 6 specimens taken 9 and 10 days later were negative for viral antigen but the patients had seroconverted by CIE. Antibody as well as antigen was detected in the acute phase specimen of case 1, but a previous serum was negative for both antigen and antibody. All three cases (2, 3, and 5) in whom viral antigen was not found were antibody positive and in cases 3 and 5 sera taken 15 and 27 days later gave stronger precipitin lines by CIE than their first sera. All nine antibody positive sera gave precipitin lines with all three viruses and with parvovirus B19 (kindly supplied by M. Supran, Central Public Health Laboratory, Colindale). Hypoplastic crisis in sickle-cell anaemia is most common in childhood. This and the tendency for siblings to be affected at about the same time suggests that the crises may be precipitated by common

D. J. GOLDIE A. T. LETCHWORTH A. MCIVER

Kjessler B, Johansson SGO, Sherman M, Gustavon K-H, Hultquist G. Alphafetoprotein in antenatal diagnosis of congenital nephrosis. Lancet 1975; ii: 432-33. 2. Seppälä M, Aulap, Rapola J, Karjalainen O, Huttunen N-P, Ruoslahti E. Congenital nephrotic syndrome: Prenatal diagnosis and genetic counselling by estimation of amniotic fluid and maternal serum alpha-fetoprotein. Lancet 1977; ii: 123-24. 1.

investigated because a sibling (case 3) had a crisis. He became unwell 2 days later. Case 2 was previously undiagnosed. In the other five cases the haematological findings on presentation (table) were characterised by a fall in Hb of 17 - 500 g/dl compared with the last steady state reading and a reticulocyte count of< 1.0% (steady state, 8 --13&mid ot; 6°70). Examination of the bone marrow revealed red-cell hypoplasia in cases 1, 4, 5, and 6. Marrow was not examined in case 2. Case 3 did not present until the sixth day of his present illness and the marrow already showed evidence of recovery, being was

a

childhood infections. Previous reports3,4 have shown that

variety of infections may be precipitating factors. The findings in

1. Cossart YE, Field AM, Cant B, Widdows D. Parvovirus-like particles in human sera. Lancet 1975; i: 72-3. 2. Shneerson JM, Mortimer PP, Vandervelde EM. Febrile illness due to a parvovirus. Br Med J 1980; ii: 1580. 3. Serjeant GR. The clinical features of sickle cell disease. Amsterdam: North Holland

Publishing Co., 1974: 83, 4. Mann JR, Cotter KP, Walker RA, Bird GWG, Stuart J. Anaemic crisis in sickle cell disease. J Clin Path 1975; 28: 341-44.