149 first donor. The difference in the success-rate between these two groups of recipients is highly significant (P=0.01, Fisher’s
exact-probability test). Although preliminary, our results suggest that a second transplant is more likely to fail if a mismatched HLA-DR antigen present in the first donor is repeated in the second donor. Thus this may represent another important application of HLA-DR matching. Nuffield Department of Surgery,
University of Oxford, Radcliffe Infirmary,
ALAN TING PETER J. MORRIS
Oxford OX2 6HE
FROM KIDNEY DONOR TO KIDNEY RECIPIENT a 57-year-old man offered a kidney for his grafting 36-year-old son who was in chronic renal failure due to chronic glomerulonephritis. The father was in good health with normal urinary chemistry, cytology and bacteriology, normal renal function (creatinine clearance 104 ml/min, urinary specific gravity 1.026), and normal pyelogram and renal angiogram. The transplantation was done in July, 1971. The postoperative course was uneventful and the father was discharged after a month. 6 weeks later he had no proteinuria, normal Addis count, a creatinine clearance of 114 ml/min, plasma-creatinine 1.1mg/dl, urinary specific gravity 1.024 and blood-pressure 140/80 mm Hg. He was put under care of his local physician, and nothing was heard of him for 16 months. In March, 1973, he started to have headaches and gastrointestinal symptoms with progressive loss of weight, muscular weakness, and dyspnoea on effort, and was found to have insufficient renal function. In January, 1974, he was admitted to our centre with systolic hypertension, anxmia, decreased tactile perception on lower limbs and cachexia. His creatinine clearance was 9 ml/min, plasma-creatinine 5.6 mg/dl, there was proteinuria of 3 g/day, and an Addis count of 73 million red blood-cells, 1 million of white blood-cells, and 700 000 cylinders. Urine cultures were repeatedly negative. Despite thorough investigation, including intravenous and retrograde pyelography and renal angiography, the cause of his kidney failure was not found; at open biopsy only medullary tissue with non-characteristic morphology was obtained. In August, 1974, regular dialysis treatment was started, and in June, 1975 a cadaver donor kidney was transplanted without autologous nephrectomy. His post-transplant course was difficult but 2 months later he was discharged in good condition and with
SIR,-In 1971 to
good graft function. In June, 1978 (3 years post-transplant) he weighed 30 kg more than with his worst weight shortly after transplantation; his only complaint was intermittent claudication, and his blood-pressure was 140/90 mm Hg. There was no proteinuria, negative urine culture, normal Addis count, and a creatinine clearance of 94 ml/min with 0.8 mg/dl plasmacreatinine. In this case Shakespeare’s "To give away Yourself Yourself still’ (sonnet xvi) takes on a new meaning.
Keeps
T. TIRKA J. HEJNAL I. RENELTOVÁ
a day. Physical signs and straight X-ray of the abdomen confirmed small-bowel obstruction, and an emergency barium enema revealed a normal colon. Blood-tests showed a hxmoglobin of 15.99
Medicine,
VL. KOČCANDRLE P. MÁLEK
SCLEROSING PERITONITIS IN PATIENT ON TIMOLOL SrtR,-The association of sclerosing peritonitis with the 2-blocker practolol has been clearly established.’ Second-generation 3-blockers have lately appeared and are reputed to have higher cardioselectivity. We report here a case of scleros-
1 Brow n. P., and others Lancet, 1974, ii, 1477.
g/dl,
10 800 white
cells/1
with
a
normal differential
rate of 13 mm/h. and the whole of the small bowel from the duodenojejunal flexure to the ileocaecal valve was matted together in "cocoon-like" adhesions which were responsible for the obstruction. There were no adhesions to the parietal peritoneum (except for a small area around the right lobe of the liver) and the caecum, appendix, colon, bladder, stomach, duodenum, gallbladder, and liver were visibly and palpably normal. Dissection of these adhesions showed what appeared to be two distinct layers. The outer layer was tough and required sharp dissection to divide it between adjacent loops and to peel it off the intestine. A softer inner layer, resembled loose connective tissue and could easily be separated by blunt dissection. During the course of the separation a perforation of the jejunum was found and thought to be iatrogenic. The edge of the jejunum was trimmed before suturing and sent for histology. Samples of the peritoneal adhesions and the liver were also taken for biopsy. On histology the jejunum showed an ischxmic lesion of recent duration associated with a necrotising angiitis. Epithelial regeneration indicated that the lesion was present before surgery. The adhesions showed organising fibrinous peritonitis with fibrosis and leucocyte infiltration. There was slight mesothelial cell proliferation and increased vascularity. The liver biopsy was normal. Apart from a minor wound infection the patient made a satisfactory recovery and was discharged home on the eighteenth postoperative day. The operative findings were similar to those seen after practolol therapy,2 especially since only the small bowel was affected, the other viscera and parietal peritoneum being spared. The histology of the adhesions was not typical of that described after practolol, and histology of the jejunum demonstrated angiitis and a previous perforation which could have been responsible for the organising peritonitis. However, we feel that it was improbable that such dense and localised adhesions could have developed during the 48 h that the patient experienced symptoms. D. C. BAXTER-SMITH I. J. MONYPENNY General Hospital, N. J. DORRICOTT Birmingham B4 6NH count
and
an
erythrocyte-sedimentation
Urgent laparotomy
J. BLÁHA
Transplantation
Research Centre, Institute for Clinical and Experimental 146 22 Prague 4, Czechoslovakia
in a patient taking timolol (’Blocadren’) and feel this may be a side-effect of this drug. A 50-year-old man was admitted as an emergency because of a 48 h history of increasing symptoms of small-bowel obstruction. For 8 years he had been treated for mild proctitis with salazopyrine 2-4 g daily and ’Predsol’ enemas, receiving courses on average three or four times a year. Four barium enemas between 1965 and 1971 had shown no obvious abnormality in the colon. For the 18 months immediately before admission his general practitioner had been treating mild hypertension (200/110 mm Hg) with timolol 10 mg three times
ing peritonitis
was
carried
out
SKIN-TEST ANOMALY
SIR,-Skin testing has been used as a diagnostic tool for allergy for over a hundred years, dating back to Charles Blackley. End-point titration of allergen extracts in the skin of atopics is widely practised and we were surprised when we came upon an anomaly which, we subsequently learned, was first described thirty years ago but not since. Twelve patients seen at a hayfever clinic and having positive skin responses to grass-pollen allergens were prick tested with six ten-fold serial dilutions of five different cocksfoot 2.
Cooke, A. I. M., Foy, P. Ann. R. Coll. Surg. 1976, 58, 473.
(Dactylis
150
glomerata) pollen extracts. All dilutions were prepared in 50% glycerol saline and stored at 4°C before use. The weal outlines were transferred to clear adhesive tape 20 min after application of the extract. The weal areas were measured by planimetry and expressed in arbitrary units. Although the higher concentrations generally showed the expected reduction of weal size, the lower concentrations often elicited an increasing weal area with further extract dilution. A typical series of skin responses is shown in fig. 1. Suspecting an error
dilutions
in the dilution of these extracts, we carefully did the again and repeated the skin testing, with the same
findings.
A plot of the area obtained for the 1:10’* dilution against the corresponding area obtained for the 1:101 dilution for every extract in every patient (fig. 2) showed that 71% (28/37) of the points fell above a 45 °C line drawn diagonally through the axis. In other words the weal area for the lower allergen con-
centration tended to be greater than that found for the more concentrated solutions. Similar findings were reported by Rinkel in 1949’ but have been almost completely ignored. We find these observations repeatable and believe them to reflect a real property of the reaction between allergen, IgE, and mast cell in the skin. The mechanism is difficult to explain and we are unable to suggest a concise hypothesis for the biochemical phenomena taking place at the level of the mast-cell membrane in human skin which lead to such anomalous skin responses. Department of Immunology, Middlesex Hospital Medical School, London W1P 9PG
K. G. HUGGINS* JONATHAN BROSTOFF
*Present address: Miles Laboratories Ltd., Stoke Poges,
Slough.
IMPAIRMENT OF RENAL FUNCTION IN PATIENTS ON 1&agr;-HYDROXYCHOLECALCIFEROL
Fig. I-Typical crease
series of skin tests in two patients, showing inin weal area with reduction of allergen concentration.
Fig. 2-Plot of weal area for 1:10’ dilution corresponding area for 1:105 dilution.
of extracts
against
SIR,-Several groups have recorded an impressive response of renal osteomalacia and rickets to treatment with 1-hydroxylated cholecalciferol compounds. With the marketing of la-hydroxycholecalciferol (I()(-H.C.C.), its use in patients with chronic renal failure will presumably increase, and you rightly emphasise the necessity for close monitoring of serum calcium and phosphate during treatment. Because children with chronic renal failure commonly have symptoms of osteodystrophy while they still have useful renal function many of them will be treated before they have reached the stage at which dialysis and transplantation are necessary. We therefore wish to draw attention to a potentially serious complication of la-H.c.c. in this group of patients and to the need for monitoring of plasma-creatinine in addition to calcium and phosphate. We have treated six children with Ix-H.c.c. (’One-Alpha’, kindly provided by Leo Laboratories Ltd) for periods of 6-24 months. Two are brothers with vitamin-D-dependent rickets and normal glomerular filtration-rates who have been treated without complications for 24 months with doses of 21-35 ng/kg/day. The other four children have chronic renal failure of varied aetiology and renal osteodystrophy which has healed with doses of 22-62 ng/kg/day. Their glomerular filtrationrates at the start of treatment were 13-41 ml/min/1-73 m2, and all had been followed for at least 18 months previously. Plasma-creatinine values were rising in all four children before treatment, but during the first six months on la-H.c.c. the rate of rise increased two to five fold (figure). Serial creatinine clearances showed that the changes in plasma-creatinine were caused by a fall of glomerular filtration-rate and not by a change in the production of creatinine or chemical interference by non-creatinine chromogens. Tougaard et al. have reported a fall in creatinine clearance during 10 weeks treatment with la-H.c.c. which was greater than but not significantly different from the fall in control patients. The cause of the fall in G.F.R. in our patients is not clear. Hypercalcxmia occurred in two patients when they were immobilised for surgery but responded within four days to temporary withdrawal of 1 a-H.C.c. There was an increase in the calcium x phosphate product in all the patients as a result of the increase in serum-calcium but it did not approach the level at which soft-tissue calcification becomes a serious risk4 nor was radiological evidence of ectopic calcification observed. 1. Rinkel, H. J. Ann. Allergy, 1949, 7, 625. 2. Lancet, 1978, i, 973. 3. Tougaard, L., Sørensen, E., Brøchnet Mortensen, J., Christensen, M. S., Rødbro, P., Sørensen, A. W. S. ibid. 1976, i, 1044. 4. Eastwood, J. B., Bordier, P. J., de Wardener, H. E. Kidney Int. 1973, 4, 128.
exact-probability test). Although preliminary, our results suggest that a second transplant is more likely to fail if a mismatched HLA-DR antigen present in the first donor is repeated in the second donor. Thus this may represent another important application of HLA-DR matching. Nuffield Department of Surgery,
University of Oxford, Radcliffe Infirmary,
ALAN TING PETER J. MORRIS
Oxford OX2 6HE
FROM KIDNEY DONOR TO KIDNEY RECIPIENT a 57-year-old man offered a kidney for his grafting 36-year-old son who was in chronic renal failure due to chronic glomerulonephritis. The father was in good health with normal urinary chemistry, cytology and bacteriology, normal renal function (creatinine clearance 104 ml/min, urinary specific gravity 1.026), and normal pyelogram and renal angiogram. The transplantation was done in July, 1971. The postoperative course was uneventful and the father was discharged after a month. 6 weeks later he had no proteinuria, normal Addis count, a creatinine clearance of 114 ml/min, plasma-creatinine 1.1mg/dl, urinary specific gravity 1.024 and blood-pressure 140/80 mm Hg. He was put under care of his local physician, and nothing was heard of him for 16 months. In March, 1973, he started to have headaches and gastrointestinal symptoms with progressive loss of weight, muscular weakness, and dyspnoea on effort, and was found to have insufficient renal function. In January, 1974, he was admitted to our centre with systolic hypertension, anxmia, decreased tactile perception on lower limbs and cachexia. His creatinine clearance was 9 ml/min, plasma-creatinine 5.6 mg/dl, there was proteinuria of 3 g/day, and an Addis count of 73 million red blood-cells, 1 million of white blood-cells, and 700 000 cylinders. Urine cultures were repeatedly negative. Despite thorough investigation, including intravenous and retrograde pyelography and renal angiography, the cause of his kidney failure was not found; at open biopsy only medullary tissue with non-characteristic morphology was obtained. In August, 1974, regular dialysis treatment was started, and in June, 1975 a cadaver donor kidney was transplanted without autologous nephrectomy. His post-transplant course was difficult but 2 months later he was discharged in good condition and with
SIR,-In 1971 to
good graft function. In June, 1978 (3 years post-transplant) he weighed 30 kg more than with his worst weight shortly after transplantation; his only complaint was intermittent claudication, and his blood-pressure was 140/90 mm Hg. There was no proteinuria, negative urine culture, normal Addis count, and a creatinine clearance of 94 ml/min with 0.8 mg/dl plasmacreatinine. In this case Shakespeare’s "To give away Yourself Yourself still’ (sonnet xvi) takes on a new meaning.
Keeps
T. TIRKA J. HEJNAL I. RENELTOVÁ
a day. Physical signs and straight X-ray of the abdomen confirmed small-bowel obstruction, and an emergency barium enema revealed a normal colon. Blood-tests showed a hxmoglobin of 15.99
Medicine,
VL. KOČCANDRLE P. MÁLEK
SCLEROSING PERITONITIS IN PATIENT ON TIMOLOL SrtR,-The association of sclerosing peritonitis with the 2-blocker practolol has been clearly established.’ Second-generation 3-blockers have lately appeared and are reputed to have higher cardioselectivity. We report here a case of scleros-
1 Brow n. P., and others Lancet, 1974, ii, 1477.
g/dl,
10 800 white
cells/1
with
a
normal differential
rate of 13 mm/h. and the whole of the small bowel from the duodenojejunal flexure to the ileocaecal valve was matted together in "cocoon-like" adhesions which were responsible for the obstruction. There were no adhesions to the parietal peritoneum (except for a small area around the right lobe of the liver) and the caecum, appendix, colon, bladder, stomach, duodenum, gallbladder, and liver were visibly and palpably normal. Dissection of these adhesions showed what appeared to be two distinct layers. The outer layer was tough and required sharp dissection to divide it between adjacent loops and to peel it off the intestine. A softer inner layer, resembled loose connective tissue and could easily be separated by blunt dissection. During the course of the separation a perforation of the jejunum was found and thought to be iatrogenic. The edge of the jejunum was trimmed before suturing and sent for histology. Samples of the peritoneal adhesions and the liver were also taken for biopsy. On histology the jejunum showed an ischxmic lesion of recent duration associated with a necrotising angiitis. Epithelial regeneration indicated that the lesion was present before surgery. The adhesions showed organising fibrinous peritonitis with fibrosis and leucocyte infiltration. There was slight mesothelial cell proliferation and increased vascularity. The liver biopsy was normal. Apart from a minor wound infection the patient made a satisfactory recovery and was discharged home on the eighteenth postoperative day. The operative findings were similar to those seen after practolol therapy,2 especially since only the small bowel was affected, the other viscera and parietal peritoneum being spared. The histology of the adhesions was not typical of that described after practolol, and histology of the jejunum demonstrated angiitis and a previous perforation which could have been responsible for the organising peritonitis. However, we feel that it was improbable that such dense and localised adhesions could have developed during the 48 h that the patient experienced symptoms. D. C. BAXTER-SMITH I. J. MONYPENNY General Hospital, N. J. DORRICOTT Birmingham B4 6NH count
and
an
erythrocyte-sedimentation
Urgent laparotomy
J. BLÁHA
Transplantation
Research Centre, Institute for Clinical and Experimental 146 22 Prague 4, Czechoslovakia
in a patient taking timolol (’Blocadren’) and feel this may be a side-effect of this drug. A 50-year-old man was admitted as an emergency because of a 48 h history of increasing symptoms of small-bowel obstruction. For 8 years he had been treated for mild proctitis with salazopyrine 2-4 g daily and ’Predsol’ enemas, receiving courses on average three or four times a year. Four barium enemas between 1965 and 1971 had shown no obvious abnormality in the colon. For the 18 months immediately before admission his general practitioner had been treating mild hypertension (200/110 mm Hg) with timolol 10 mg three times
ing peritonitis
was
carried
out
SKIN-TEST ANOMALY
SIR,-Skin testing has been used as a diagnostic tool for allergy for over a hundred years, dating back to Charles Blackley. End-point titration of allergen extracts in the skin of atopics is widely practised and we were surprised when we came upon an anomaly which, we subsequently learned, was first described thirty years ago but not since. Twelve patients seen at a hayfever clinic and having positive skin responses to grass-pollen allergens were prick tested with six ten-fold serial dilutions of five different cocksfoot 2.
Cooke, A. I. M., Foy, P. Ann. R. Coll. Surg. 1976, 58, 473.
(Dactylis
150
glomerata) pollen extracts. All dilutions were prepared in 50% glycerol saline and stored at 4°C before use. The weal outlines were transferred to clear adhesive tape 20 min after application of the extract. The weal areas were measured by planimetry and expressed in arbitrary units. Although the higher concentrations generally showed the expected reduction of weal size, the lower concentrations often elicited an increasing weal area with further extract dilution. A typical series of skin responses is shown in fig. 1. Suspecting an error
dilutions
in the dilution of these extracts, we carefully did the again and repeated the skin testing, with the same
findings.
A plot of the area obtained for the 1:10’* dilution against the corresponding area obtained for the 1:101 dilution for every extract in every patient (fig. 2) showed that 71% (28/37) of the points fell above a 45 °C line drawn diagonally through the axis. In other words the weal area for the lower allergen con-
centration tended to be greater than that found for the more concentrated solutions. Similar findings were reported by Rinkel in 1949’ but have been almost completely ignored. We find these observations repeatable and believe them to reflect a real property of the reaction between allergen, IgE, and mast cell in the skin. The mechanism is difficult to explain and we are unable to suggest a concise hypothesis for the biochemical phenomena taking place at the level of the mast-cell membrane in human skin which lead to such anomalous skin responses. Department of Immunology, Middlesex Hospital Medical School, London W1P 9PG
K. G. HUGGINS* JONATHAN BROSTOFF
*Present address: Miles Laboratories Ltd., Stoke Poges,
Slough.
IMPAIRMENT OF RENAL FUNCTION IN PATIENTS ON 1&agr;-HYDROXYCHOLECALCIFEROL
Fig. I-Typical crease
series of skin tests in two patients, showing inin weal area with reduction of allergen concentration.
Fig. 2-Plot of weal area for 1:10’ dilution corresponding area for 1:105 dilution.
of extracts
against
SIR,-Several groups have recorded an impressive response of renal osteomalacia and rickets to treatment with 1-hydroxylated cholecalciferol compounds. With the marketing of la-hydroxycholecalciferol (I()(-H.C.C.), its use in patients with chronic renal failure will presumably increase, and you rightly emphasise the necessity for close monitoring of serum calcium and phosphate during treatment. Because children with chronic renal failure commonly have symptoms of osteodystrophy while they still have useful renal function many of them will be treated before they have reached the stage at which dialysis and transplantation are necessary. We therefore wish to draw attention to a potentially serious complication of la-H.c.c. in this group of patients and to the need for monitoring of plasma-creatinine in addition to calcium and phosphate. We have treated six children with Ix-H.c.c. (’One-Alpha’, kindly provided by Leo Laboratories Ltd) for periods of 6-24 months. Two are brothers with vitamin-D-dependent rickets and normal glomerular filtration-rates who have been treated without complications for 24 months with doses of 21-35 ng/kg/day. The other four children have chronic renal failure of varied aetiology and renal osteodystrophy which has healed with doses of 22-62 ng/kg/day. Their glomerular filtrationrates at the start of treatment were 13-41 ml/min/1-73 m2, and all had been followed for at least 18 months previously. Plasma-creatinine values were rising in all four children before treatment, but during the first six months on la-H.c.c. the rate of rise increased two to five fold (figure). Serial creatinine clearances showed that the changes in plasma-creatinine were caused by a fall of glomerular filtration-rate and not by a change in the production of creatinine or chemical interference by non-creatinine chromogens. Tougaard et al. have reported a fall in creatinine clearance during 10 weeks treatment with la-H.c.c. which was greater than but not significantly different from the fall in control patients. The cause of the fall in G.F.R. in our patients is not clear. Hypercalcxmia occurred in two patients when they were immobilised for surgery but responded within four days to temporary withdrawal of 1 a-H.C.c. There was an increase in the calcium x phosphate product in all the patients as a result of the increase in serum-calcium but it did not approach the level at which soft-tissue calcification becomes a serious risk4 nor was radiological evidence of ectopic calcification observed. 1. Rinkel, H. J. Ann. Allergy, 1949, 7, 625. 2. Lancet, 1978, i, 973. 3. Tougaard, L., Sørensen, E., Brøchnet Mortensen, J., Christensen, M. S., Rødbro, P., Sørensen, A. W. S. ibid. 1976, i, 1044. 4. Eastwood, J. B., Bordier, P. J., de Wardener, H. E. Kidney Int. 1973, 4, 128.
