- Email: [email protected]
SCREENING POTENTIAL RELATED TRANSPLANT DONORS FOR RENAL DISEASE
645 in the common bileduct, and a false-positive result was admitted. At operation, however, the head of the pancreas was hard, a biopsy was done, and carcinoma of the pancreas was diagnosed together with the stone in the common bileduct. This anecdote of the false false-positive will, we suspect, be followed in due course by a true false-positive, but the preliminary score is encouraging us to develop the test. stone
We thank our colleagues in many histopathology departments, that of Prof. A. D. Morgan, Westminster Medical School, and in many hospitals (especially Westminster and Prof. J. H. Louw of Groote Schuur Hospital, Cape Town) for providing material; and our American colleagues who, through Dr T. A. Waldmann of the National Cancer Institute, Bethesda, have kindly supplied 20 sera from known patients with pancreatic
especially
cancer.
REFERENCES 1. 2. 3. 4.
5. 6. 7. 8.
9.
10. 11.
R. Br. J. Hœmat.
Hobbs, J. 1969, 16, 607. Feinleib, M., MacMahon, B. J. natn. Cancer Inst. 1960, 24, 1259. Galton, D. A. G., Peto, R. Br. J. Hœmat. 1968, 15, 319. Bagshawe, K. D. Adv. Cancer Res. 1973, 18, 231. Abelev, G. I. Acta Un. int. Contr. Cancr. 1963, 19, 80. Alexander, P. Nature, 1972, 235, 137. Gold, P., Freedman, S. O. J. exp. Med. 1965, 122, 467. Thomson, D. M. P., Krupey, J., Freedman, S. O., Gold, P. Proc. natn. Acad. Sci. U.S.A. 1969, 64, 161. Moore, T. L., Kupchik, H. Z., Marcon, N., Zamcheck, N. Am. J. dig. Dis. 1971, 16, 1. Kleist, S. V., Burtin, P. Int. J. Cancer, 1969, 4, 874. Versey, J. Protides biol. Fluids, 1971, 19, 565.
SCREENING POTENTIAL RELATED TRANSPLANT DONORS FOR RENAL DISEASE PANAYIOTIS K. SPANOS RICHARD L. SIMMONS CARL M. KJELLSTRAND THEODORE J. BUSELMEIER JOHN S. NAJARIAN
Department of Surgery, University of Minnesota, Minneapolis, Minnesota 55455, U.S.A. The families of
two hundred potential renal-transplant recipients were studied for evidence of renal disease. Eighteen of the two
Summary
hundred families had other members with familial renal disease (polycystic, medullary cystic, hereditary nephritis, Fabry’s disease). Thirty of the one hundred and eighty-two remaining families had had at least one member die of renal disease or require a renal
transplant, hæmodialysis, or nephrectomy. total of 22% of the families of patients with renal failure had a history of renal failure in other members. 209 potential related donors were studied. 10.5% of the women and 5% of the men had persistent bacteriuria; 12 had hypertension and 47 had abnormal intravenous pyelograms, 41 of these had associated urinary abnormalities. 82 of 193 arteriograms were abnormal, and 17 of the abnormal arterioThus,
a
grams revealed other renal abnormalities.
Medical contraindications ultimately excluded 40 relatives from donation. It is suggested that apparently healthy symptom-free relatives of patients with terminal renal failure will have an extremely high frequency of underlying renal disease. Such persons might comprise a suitable population for intensive screening for asymptomatic renal disease within the population. This group might also be a suitable study
group for evaluating techniques for the prevention of progressive renal disease.
Introduction OCCULT renal disease is well known as an important cause, not only of renal failure itself, but also of hypertension and its associated cardiovascular disorders. Since the diagnostic techniques in renal disease are relatively simple and precise, it is generally agreed that progressive renal disease might be prevented if renal abnormalities were detected before the onset of symptoms. Studies of bacteriuria in the general population 1-5 and in patients deemed to be at high risk 6-9 have been promoted in the expectation that asymptomatic urinary-tract infections are correlated with progressive renal disease. Such studies have shown that hospital patients,9 neurological patients," diabetics,’," pregnant women,12-14 and schoolgirls7have a greater frequency of asymptomatic bacteriuria than control populations. The frequency of renal disease in the entire population is so low that screening is unlikely to be economically feasible. But the screening of high-risk populations may well reduce the frequency of chronic renal disease, since it has reduced the frequency of acute pyelonephritis, prematurity, and toxaemia in pregnant women with asymptomatic bacteriuria. Renal-transplant units have the opportunity to screen the relatives of patients with end-stage renal disease when such relatives offer themselves as donors. The present study was designed to determine the frequency of abnormalities of the urinary tract in potential donors who volunteered to give a kidney to a relative with terminal renal failure.
predisposing
Materials and Methods The following studies are performed at the University of Minnesota Hospitals on patients who volunteer to donate a kidney to a relative: history and physical examination; hsematocrit and leucocyte, differential, and platelet count; prothrombin, partial thromboplastin, and thrombin time; serum sodium, potassium, chloride, carbon dioxide, glutamic oxaloacetic transaminase, bilirubin, uric acid, calcium, and phosphorus; and blood-urea-nitrogen, creatinine, fasting blood-sugar, and glucose-tolerance test; urinalysis and 24-hour creatinine clearance; two cleancatch urine cultures; blood-type (major and minor), tissue typing, leucocyte cross-match for recipient anti-donor and leucocyte antibodies, venereal disease research laboratories, and Australia antigen; chest X-ray (posterior/anterior and lateral), intravenous pyelogram (LV.P.), renal arteriograms; The renal bilateral renogram; and electrocardiogram. arteriogram is performed as a last step. 209 volunteer potential donors related to two hundred renal-transplant recipients were studied to determine the frequency of urinary-tract disease in this apparently normal population. 152 of these potential donors were aged from eighteen to forty-five; 45 from forty-five to fifty-four; and 12 from
fifty-four
to
sixty-five. Results
Familial factors.-Of two hundred recipients with end-stage renal failure, eighteen had known familial diseases; eleven donor families had members with polycystic disease, three with medullary cystic disease, three with hereditary interstitial nephritis, and one
646 TABLE I-ORGANISMS CULTURED FROM ASYMPTOMATIC POTENTIAL RELATED RENAL TRANSPLANT DONORS
Z?acteMt’ta.—Each potential donor was studied by clean-catch urine culture on two separate occasions. 22 (12 women and 10 men) of the 209 potential donors (10-5%) had more than 100,000 colonies of the same organism per ml. on two consecutive cultures (table I). Thus, the frequency of bacteriuria in these potential donors is higher than that reported in either pregnant women,14 women over 40 years of age,H.15 working women,15 or any other group reported except the diabetic and the elderly in hospital. 9,16 The 5 , incidence of bacteriuria in the male population is the highest ever reported in any male population. Hypertension.-12 of 209 apparently healthy relatives of patients with terminal renal failure had unsuspected diastolic hypertension (i.e., a persistent diastolic blood-pressure of more than 90 mm. Hg during initial 3-day period of in-hospital study). All 12 relatives with hypertension had at least one associated renal abnormality (table 11). Abnormal I.V.P.s were found in 47 of the 209 J
TABLE
II-ABNORMALITIES
FOUND
IN
SYMPTOM-FREE
POTENTIAL
RENAL TRANSPLANT DONORS WITH HYPERTENSION
with Fabry’s disease. Thus, 9% of the recipients in this group had known familial renal disease which excluded many family members as donors before the examination of any potential donors themselves. In addition to these eighteen families with familial renal disease, thirty of the prospective transplant recipients had immediate family members (parents, siblings, or children) who were known either to (a) require a renal transplant, (b) to be on hasmodialysis, (c) to have required nephrectomy for primary renal disease, or (d) to have died of documented renal disease. Thus, in addition to the 9 % of patients who had known familial renal disease, 15 % had relatives with advanced renal failure. Thus, merely interviewing patients with end-stage renal disease will yield a high number of persons with potential renal disease.
Abnormalities detected by
TABLE IV-ASSOCIATED ABNORMALITIES OF SYMPTOM-FREE POTENTIAL
KIDNEY DONORS
WITH
ABNORMAL
INTRAVENOUS PYELOGRAMS
(I.V.P.)
TABLE
V-82 ABNORMALITIES FOUND WITH RENAL ARTERIOGRAPHY IN 193 HEALTHY LIVING RELATED POTENTIAL DONORS
screening techniques.-
209 volunteer potential donors were studied. Of 157 donated to their relaultimately kidneys these, tives and 52 were excluded-40 because of medical contraindications to donation and 12 for non-medical reasons. FOUND ON III-RENAL ABNORMALITIES INTRAVENOUS TABLE PYELOGRAPHY IN 47 OF 209 SYMPTOM-FREE POTENTIAL RELATED KIDNEY DONORS
symptom-free volunteer donors (table ill). In 30 the abnormalities were minor, and 17 of the slightly abnormal kidneys were used for transplantation, but several associated abnormalities were found in 41 potential donors with abnormal LV.P.S (table iv)’. Arteriography.-Arteriograms were performed in only 193 of the 209 original potential donors, 16 having been excluded due to previously discovered 82 arteriograms (42 %) revealed abnormalities. abnormalities which were previously unsuspected (table 111), but 70 represented multiple renal arteries. 12 potential donors had abnormalities other than supernumerary vessels (table v) and 7 of them had associated renal abnormalities: 2 with abnormal renograms ; 2 with abnormal I.V.P.S; 2 with bacteriuria; and 1 with a history of recurrent urinary-tract infections. 10 relatives with multiple vessels were rejected as
647
I I-
G.U.I. G.T.T.
1
1 = =
I
Genitourinary infection. Glucose-tolerance
donors because of associated abnormalities: abnormal renogram (4); abnormal I.v.P. (4); history of urinary-tract infection and/or bacteriuria (5); hypertension (2); prostatic hypertrophy (1); and proteinuria (1). Causes
ofrefusal.-Several patients with minor In were regarded as suitable donors. these cases, as a rule, the abnormal kidney was used. But 40 potential donors were felt to have medical contraindications against donation. Most of these causes were due to previously unsuspected renal disabnormalities
ease. The ultimate combinations of abnormalities which led to refusal as a donor are listed in table vi.
test.
tion. The great cost of such treatments has led, in turn, to attempts at early detection and prevention. Since the 1930s,18,19 urinary-tract infection has been recognised as a source of chronic renal disease. Bacteriuria was introduced by Kassas a screening test for detection of urinary-tract infections and has been used
by many investigators to screen high-risk populations. Little 20 found that acute pyelonephritis developed in 25 % of a group of 141 pregnant women with untreated bacteriuria. The frequency of pyelonephritis in a control group of 124 patients with treated bacteriuria was 3’2% and in a third group without bacteriuria it was 0-4%. Whalley et all found that bacteriuria persisted for two-twelve months out of 131 untreated women whose bacteriuria discovered during pregnancy. Bacteria were present in urine obtained from one or both ureters in 17 of 23 patients, and pyelographic abnormalities were detected in 61 of 131 patients. Freedman et aJ.21 found an overall frequency of bacteriuria among young and middle-aged women of 1-3%. Asscher et al .2 found bacteriuria in 3% of female hospital visitors (diabetics and pregnant women excluded). Kunin et al.3 found bacteriuria in 1.2 % of schoolgirls, while Pometta et a1.22 studied two groups of diabetic schoolgirls and found asymptomatic bacteriuria in
in 90 was
Discussion Renal disease continues to be an important worldwide health problem. Epidemiological studies estimate that there are 4’2 million cases of genitourinary diseases in the U.S.A.17 The non-hospital physician/ patient contact for urinary diseases in 1964 was estimated as over 26 million cases 1’ The insidious nature of the problem has led to its relative neglect until the advent of dramatic forms of treatment for end-stage renal disease, such as haemodialysis and transplanta-
648
1 °6 °o and 2%, respectively. Bacteriuria among the pregnant population generally ranges from 4-5 to 10 o/ .4,20,23-26 Huvos and Rochafound bacteriuria in 26% of diabetic and 22% of non-diabetic hospital patients. Vejlsgaard 27 found bacteriuria in 18-8% of female diabetics and 7-9% of non-diabetics. Thus there are groups among the general population which have a higher frequency of bacteriuria-i.e., pregnant women, hospital patients, and diabetics. There is some evidence that bacteriuria may lead to the development of renal failure. Whalley et al .12 found radiological evidence of chronic pyelonephritis in 27% of 131 women with asymptomatic bacteriuria who were followed for two-twelve months after pregnancy. Cobbs et a1.28 studied 15 untreated symptom-free bacteriuric women three to eighteen months after delivery and found abnormal pyelograms in 12 (80%), with changes suggestive of pyelonephritis in 4 cases (27 Hodson 29 and Smellie and Normand 30 found radiographic evidence of progression of scarring after attacks of pyelonephritis. The total frequency of bacteriuria in our study (10-5%) is probably the highest figure reported in an otherwise healthy population. The frequency of in the male populabacteriuria asymptomatic (5 %) tion of our series was also extremely high. Kass et aJ.31 studied 1515 males in the general population of Wales and Jamaica and found only 0.5 % with bacteriuria. The frequency reported by Kunin et al.3 in schoolboys is only 0-03 %, and the highest figure published was 3’5%, in men over the age of 70.6 Bacteriuria, however, proved to be a relatively insensitive test within our population of relatives of patients with renal failure. The intravenous pyelogram was abnormal in 47 of 209 (22-5 %) symptomfree potential donors. The frequency of abnormal intravenous pyelograms among healthy populations is not known, but combinations of abnormalities appear to be even more important than the isolated findings. For example, Kunin reported that 20-6 % of the i.v.p.s in schoolchildren with bacteriuria were abnormal, and among our potential donors with bacteriuria 47% had abnormal i.v.p.s. Roden et all reviewing i.v.p.s in patients who were to have elective gynaecological operations, found that 26-8% had an
unsuspected genitourinary
tract
abnormality.
The meaning of i.v.p. abnormalities is not yet clear, but Steele et al.33 reported on a group of 72 children seen between 1940 and 1950 with pyelographic changes of pyelonephritis and a urinary-tract obstruction. Re-evaluation of this group, eleven to twentyseven years later, indicated that 48 % of the patients had died (18%), had persistent infection (22%), or had developed progressive renal insufficiency (8%). 52% of these patients were living and well without any evidence of disease. We plan a similar followup of our symptom-free patients. Intravenous pyelography seems to be a valuable screening test for early detection and follow-up of renal disease. It has a high diagnostic yield, is simple and fairly inexpensive to do, and has a low complication-rate. In a series of 21,525 intravenous pyelograms reported by Hamm et al.,34 there were 4 cases with rather serious but non-fatal reactions. In our
series there was only 1 case of transient hypotension without sequel. The third most helpful test in detection of renal disease was the arteriogram. 40% of the patients with bacteriuria had abnormal arteriograms. Complications of arteriography in this series were thrombosis of the femoral artery in 1 potential donor, treated by thrombectomy, and 1 septic episode after angiography, treated successfully with systemic antibiotics. Arteriography at present is obviously a poor screening test for medical and economic reasons. 5% of the donors had diastolic hypertension, a figure that accords with the general pattern of diastolic hypertension of the U.S.A.35,36 Hypertension therefore is a less satisfactory early screening test in highrisk but symptom-free populations. We conclude that people with a familial history of end-stage renal disease will themselves have a high frequency of urinary-tract abnormalities. In addition, 90 % of these abnormalities can be detected by accurate and detailed family history, urine cultures, and intravenous pyelography. Such people will provide many examples of preclinical renal disease when investigated by standardised detection techniques, such as urine culture and intravenous pyelography. These people could then be followed to determine the natural history of such preclinical abnormalities. Many of the abnormalities could be corrected and
prophylactic
measures
instituted.
This study was supported States Public Health Service.
by
a
grant from the United
Requests for reprints should be addressed to R. L. S., Box 185, Mayo Memorial Building, University of Minnesota Hospitals, Minneapolis, Minnesota 55455, U.S.A. REFERENCES 1. Kass, E. H. Trans. Ass. Am. Physns, 1956, 18, 221. 2. Asscher, A. W., Sussman, M., Waters, W. E., Evans, J. A. S., Campbell, H., Evans, K. T., Williams, E. J. J. infect. Dis. 1969,
120, 17. 3. Kunin, C. M., Deutscher, R., Paquin, A., Jr. Medicine, Baltimore, 1964, 43, 91. 4. Kass, E. H. Trans. Ass. Am. Physns, 1959, 72, 257. 5. Switzer, S. New Engl. J. Med. 1961, 264, 7. 6. Kass, E. H. Ann. intern. Med. 1961, 56, 46. 7. Kunin, C., Southall, I., Paquin, A. New Engl. J. Med. 1960, 263, 817.
Beeson, P. B. Am. J. Med. 1958, 24, 1. Huvos, A., Rocha, H. New Engl. J. Med. 1959, 216, 1213. Dietrict, R. B., Russi, S. J. Am. med. Ass. 1958, 166, 41. Rengorts, R. T. Am. J. med. Sci. 1960, 239, 154. Whalley, P. J., Martin, F. G., Peters, P. C. J. Am. med. Ass. 1965, 193, 879. 13. Kass, E. H. Ann. intern. Med. 1962, 56, 46. 14. Norden, C. W., Kass, E. H. Ann. Rev. Med. 1968, 19, 451. 15. Kunin, C. M., McCormack, R. C. New Engl. J. Med. 1968, 278, 8. 9. 10. 11. 12.
635. 16. 17.
18. 19. 20. 21. 22.
23. 24.
25. 26.
27.
Loopuyt, L. Acta med. scand. 1946, 125, 245. Kidney Disease: Prevention and Control. U.S. Public Health Service, 1969. Longcope, W. T. Ann. intern. Med. 1937, 11, 149. Weiss, S., Parker, F. J. Medicine, Baltimore, 1939, 18, 221. Little, P. J. Lancet, 1966, ii, 925. Freedman, L. R., Phair, J. P., Seki, M., Hamilton, H. B., Nefzen, M. D., Hirata, M. Yale J. Biol. Med. 1965, 37, 262. Pometta, D., Rees, S. B., Younger, D., Kass, E. H. New Engl. J. Med. 1967, 276, 1118. Carleton, H. G., Baker, T. H., Richards, H. C. Am. J. Obstet. Gynec. 1965, 92, 227. Constable, P. J. Lancet, 1966, ii, 195. Kincaid-Smith, P., Bullen, M. ibid. 1965, i, 395. Low, J., Johnston, E., McBride, T., Tuffneld, P. Am. J. Obstet. Gynec. 1964, 90, 897. Vejlsgaard, T. in Progress in Pyelonephritis (edited by E. H. Kass); p. 478. Philadelphia, 1965.
649 HYPOKALÆMIC MUSCULAR PARESIS IN MIGRATORY PAPUA/NEW GUINEANS G. G. DUGGIN*
Royal Prince Alfred Hospita., Sydney, Australia M. A. PRICE Department of Clinical Sciences,
University of Papua/New Guinea, Moresby, Papua/New Guinea
Port
Seventeen patients with generalised muscular paresis associated with hypokalæmia are described. The disorder occurs in highlanders of Papua/New Guinea migrating to the coast and is associated with a pronounced decrease in dietary potassium intake and a pronounced increase in dietary sodium intake. Summary
Introduction
BETWEEN 1964 and 1970, seventeen patients preat the Port Moresby General Hospital on 23 occasions with transient generalised muscular paresis associated with hypokalaemia. The disorder seems to have a unique and characteristic clinical picture; it occurs in Melanesians migrating from highland and hinterland regions to the coastal areas of Papua/New Guinea. We have retrospectively analysed all case-reports of these patients. In some information was incomplete and investigations were limited because of the lack of biochemical services available in the territory over that
sented
period.
occasion, six presented
on 2 occasions, and Three 3 occasions. patients who prepresented sented more than once had returned to the highlands and then returned to Port Moresby. All patients were completely disabled by their symptoms;
disorder
1
on
on
one
The were completely paretic on presentation. proximal limb musculature was affected more severely than the distal and the legs were more severely affected most
than the
arms.
Trunk musculature
was
affected in all
patients, but respiratory musculature and muscles supplied by the cranial nerves were relatively spared. Three patients had no deep-tendon reflexes, in eleven the reflexes were reduced, and in three patients they were considered to be normal. Muscle tone was reduced in eleven patients and normal in the remainder. Nine patients complained of a minor degree of diffuse muscle discomfort, usually in the most paralysed muscle groups. Blood-pressure of 140/90 mm. Hg or greater was found in five patients on admission the remainder were within normal limits. was marked by a steady increase in muscle power over a mean of 3-6 days (range 1-11), thus making the mean duration of an attack 6-8 days. A family history of a similar disorder was not obtained from any patient, but there had been no follow-up of relatives. No patients were known to take laxatives or liquorice and there was no clinical evidence of thyrotoxicosis. No information was available about carbohydrate intake before the onset of the disorder.
hospital;
to
Recovery from paresis
Methods Serum and urinary sodium and potassium were measured by flame photometry. Serum calcium and magnesium were estimated with a Perkin Elmer double-beam atomicabsorption spectrophotometer 303. Thyroxine (T4) and T3 resin were estimated using an Armour kit. Results
The was
Patients and Methods Patients All seventeen patients were adult Melanesian males (mean age 25 years [range 18-40]). They had all recently migrated to the coastal city of Port Moresby from the highlands or hinterland regions of Papua/New Guinea. The onset of the disease usually came within 2 months of migrating to Port Moresby (mean 3 weeks). Symptoms were present for a mean of 3 days before presentation (range 1-7 days). Ten of the patients presented with the
mean
serum-potassium level on presentation This rose progressively over the
2-6 meq. per 1.
’
,
’ Present address: Department of Pharmacology and Toxicology, Dartmouth Medical School, Hanover, New Hampshire 03755, U.S.A.
Cobbs, C. G., Strickler, J. C., McGovern, J. H., Kaye, D. Am. J. Obstet. Gynec. 1967, 99, 221. 29. Hodson, C. J. in Urinary Tract Infection (edited by F. O’Grady and W. Brumfitt); p. 108. London, 1968. 30. Smellie, J. M., Normand, I. C. S. in Urinary Tract Infection (edited by F. O’Grady and W. Brumfitt); p. 123. London, 1968. 31. Kass, E. H., Savage, W., Santamarina, B. A. G. in Progress in Pyelonephritis (edited by E. H. Kass); p. 3. Philadelphia, 1965. 32. Roden, J. S., Haugen, H. M., Hall, D. G., Greenberg, P. A. Am. J. Obstet. Gynec. 1971, 82, 568. 33. Steele, E., Jr., Leadbetter, G. W., Crawford, J. D. New Engl. J. Med. 1963, 269, 883. 34. Hamm, F. C., Waterhouse, K., Weinberg, S. R. J. Am. med. Ass. 1960, 172, 542. 35. Paul, O., Ostfeld, A. M. Prog. Card. Dis. 1965/66, 8, 106. 36. Gordon, T., Devine, B. in Hypertension and Hypertensive Heart
28.
Fig. 1-Mean serum-electrolytes ± S.E.M.
Disease in Adults in the United States 1960-1962. Vital and Health Statistics Data from the National Health Survey National Center for Health Statistics, series II, no. 13. U.S. Government
Serum-potassium: day 1 v. day 2, P=0.013; day 2 v. day 3, p=0.175; day 3 v. day 4, p=0.075; day 2 v. day 4, r=0.0035; day 4 v. day 5, p =0 12; day 5 v. day 6, p =0083. Serum-sodium: day 1 v. day 2, P=0-186; day 2 v. day 3, p=0.002; day 3 v. day 4, P=0.606; day 4 v. day 5, P=0.96; day 5 v. day 6, P =0.095; day 1 v. day 3, P =0.329; day 3 v. day 6, P=0.009. p=sign.i6cance probability for two-sided alternative
Printing Office,
on
1965.
groups of unpaired data
t test.
We thank our colleagues in many histopathology departments, that of Prof. A. D. Morgan, Westminster Medical School, and in many hospitals (especially Westminster and Prof. J. H. Louw of Groote Schuur Hospital, Cape Town) for providing material; and our American colleagues who, through Dr T. A. Waldmann of the National Cancer Institute, Bethesda, have kindly supplied 20 sera from known patients with pancreatic
especially
cancer.
REFERENCES 1. 2. 3. 4.
5. 6. 7. 8.
9.
10. 11.
R. Br. J. Hœmat.
Hobbs, J. 1969, 16, 607. Feinleib, M., MacMahon, B. J. natn. Cancer Inst. 1960, 24, 1259. Galton, D. A. G., Peto, R. Br. J. Hœmat. 1968, 15, 319. Bagshawe, K. D. Adv. Cancer Res. 1973, 18, 231. Abelev, G. I. Acta Un. int. Contr. Cancr. 1963, 19, 80. Alexander, P. Nature, 1972, 235, 137. Gold, P., Freedman, S. O. J. exp. Med. 1965, 122, 467. Thomson, D. M. P., Krupey, J., Freedman, S. O., Gold, P. Proc. natn. Acad. Sci. U.S.A. 1969, 64, 161. Moore, T. L., Kupchik, H. Z., Marcon, N., Zamcheck, N. Am. J. dig. Dis. 1971, 16, 1. Kleist, S. V., Burtin, P. Int. J. Cancer, 1969, 4, 874. Versey, J. Protides biol. Fluids, 1971, 19, 565.
SCREENING POTENTIAL RELATED TRANSPLANT DONORS FOR RENAL DISEASE PANAYIOTIS K. SPANOS RICHARD L. SIMMONS CARL M. KJELLSTRAND THEODORE J. BUSELMEIER JOHN S. NAJARIAN
Department of Surgery, University of Minnesota, Minneapolis, Minnesota 55455, U.S.A. The families of
two hundred potential renal-transplant recipients were studied for evidence of renal disease. Eighteen of the two
Summary
hundred families had other members with familial renal disease (polycystic, medullary cystic, hereditary nephritis, Fabry’s disease). Thirty of the one hundred and eighty-two remaining families had had at least one member die of renal disease or require a renal
transplant, hæmodialysis, or nephrectomy. total of 22% of the families of patients with renal failure had a history of renal failure in other members. 209 potential related donors were studied. 10.5% of the women and 5% of the men had persistent bacteriuria; 12 had hypertension and 47 had abnormal intravenous pyelograms, 41 of these had associated urinary abnormalities. 82 of 193 arteriograms were abnormal, and 17 of the abnormal arterioThus,
a
grams revealed other renal abnormalities.
Medical contraindications ultimately excluded 40 relatives from donation. It is suggested that apparently healthy symptom-free relatives of patients with terminal renal failure will have an extremely high frequency of underlying renal disease. Such persons might comprise a suitable population for intensive screening for asymptomatic renal disease within the population. This group might also be a suitable study
group for evaluating techniques for the prevention of progressive renal disease.
Introduction OCCULT renal disease is well known as an important cause, not only of renal failure itself, but also of hypertension and its associated cardiovascular disorders. Since the diagnostic techniques in renal disease are relatively simple and precise, it is generally agreed that progressive renal disease might be prevented if renal abnormalities were detected before the onset of symptoms. Studies of bacteriuria in the general population 1-5 and in patients deemed to be at high risk 6-9 have been promoted in the expectation that asymptomatic urinary-tract infections are correlated with progressive renal disease. Such studies have shown that hospital patients,9 neurological patients," diabetics,’," pregnant women,12-14 and schoolgirls7have a greater frequency of asymptomatic bacteriuria than control populations. The frequency of renal disease in the entire population is so low that screening is unlikely to be economically feasible. But the screening of high-risk populations may well reduce the frequency of chronic renal disease, since it has reduced the frequency of acute pyelonephritis, prematurity, and toxaemia in pregnant women with asymptomatic bacteriuria. Renal-transplant units have the opportunity to screen the relatives of patients with end-stage renal disease when such relatives offer themselves as donors. The present study was designed to determine the frequency of abnormalities of the urinary tract in potential donors who volunteered to give a kidney to a relative with terminal renal failure.
predisposing
Materials and Methods The following studies are performed at the University of Minnesota Hospitals on patients who volunteer to donate a kidney to a relative: history and physical examination; hsematocrit and leucocyte, differential, and platelet count; prothrombin, partial thromboplastin, and thrombin time; serum sodium, potassium, chloride, carbon dioxide, glutamic oxaloacetic transaminase, bilirubin, uric acid, calcium, and phosphorus; and blood-urea-nitrogen, creatinine, fasting blood-sugar, and glucose-tolerance test; urinalysis and 24-hour creatinine clearance; two cleancatch urine cultures; blood-type (major and minor), tissue typing, leucocyte cross-match for recipient anti-donor and leucocyte antibodies, venereal disease research laboratories, and Australia antigen; chest X-ray (posterior/anterior and lateral), intravenous pyelogram (LV.P.), renal arteriograms; The renal bilateral renogram; and electrocardiogram. arteriogram is performed as a last step. 209 volunteer potential donors related to two hundred renal-transplant recipients were studied to determine the frequency of urinary-tract disease in this apparently normal population. 152 of these potential donors were aged from eighteen to forty-five; 45 from forty-five to fifty-four; and 12 from
fifty-four
to
sixty-five. Results
Familial factors.-Of two hundred recipients with end-stage renal failure, eighteen had known familial diseases; eleven donor families had members with polycystic disease, three with medullary cystic disease, three with hereditary interstitial nephritis, and one
646 TABLE I-ORGANISMS CULTURED FROM ASYMPTOMATIC POTENTIAL RELATED RENAL TRANSPLANT DONORS
Z?acteMt’ta.—Each potential donor was studied by clean-catch urine culture on two separate occasions. 22 (12 women and 10 men) of the 209 potential donors (10-5%) had more than 100,000 colonies of the same organism per ml. on two consecutive cultures (table I). Thus, the frequency of bacteriuria in these potential donors is higher than that reported in either pregnant women,14 women over 40 years of age,H.15 working women,15 or any other group reported except the diabetic and the elderly in hospital. 9,16 The 5 , incidence of bacteriuria in the male population is the highest ever reported in any male population. Hypertension.-12 of 209 apparently healthy relatives of patients with terminal renal failure had unsuspected diastolic hypertension (i.e., a persistent diastolic blood-pressure of more than 90 mm. Hg during initial 3-day period of in-hospital study). All 12 relatives with hypertension had at least one associated renal abnormality (table 11). Abnormal I.V.P.s were found in 47 of the 209 J
TABLE
II-ABNORMALITIES
FOUND
IN
SYMPTOM-FREE
POTENTIAL
RENAL TRANSPLANT DONORS WITH HYPERTENSION
with Fabry’s disease. Thus, 9% of the recipients in this group had known familial renal disease which excluded many family members as donors before the examination of any potential donors themselves. In addition to these eighteen families with familial renal disease, thirty of the prospective transplant recipients had immediate family members (parents, siblings, or children) who were known either to (a) require a renal transplant, (b) to be on hasmodialysis, (c) to have required nephrectomy for primary renal disease, or (d) to have died of documented renal disease. Thus, in addition to the 9 % of patients who had known familial renal disease, 15 % had relatives with advanced renal failure. Thus, merely interviewing patients with end-stage renal disease will yield a high number of persons with potential renal disease.
Abnormalities detected by
TABLE IV-ASSOCIATED ABNORMALITIES OF SYMPTOM-FREE POTENTIAL
KIDNEY DONORS
WITH
ABNORMAL
INTRAVENOUS PYELOGRAMS
(I.V.P.)
TABLE
V-82 ABNORMALITIES FOUND WITH RENAL ARTERIOGRAPHY IN 193 HEALTHY LIVING RELATED POTENTIAL DONORS
screening techniques.-
209 volunteer potential donors were studied. Of 157 donated to their relaultimately kidneys these, tives and 52 were excluded-40 because of medical contraindications to donation and 12 for non-medical reasons. FOUND ON III-RENAL ABNORMALITIES INTRAVENOUS TABLE PYELOGRAPHY IN 47 OF 209 SYMPTOM-FREE POTENTIAL RELATED KIDNEY DONORS
symptom-free volunteer donors (table ill). In 30 the abnormalities were minor, and 17 of the slightly abnormal kidneys were used for transplantation, but several associated abnormalities were found in 41 potential donors with abnormal LV.P.S (table iv)’. Arteriography.-Arteriograms were performed in only 193 of the 209 original potential donors, 16 having been excluded due to previously discovered 82 arteriograms (42 %) revealed abnormalities. abnormalities which were previously unsuspected (table 111), but 70 represented multiple renal arteries. 12 potential donors had abnormalities other than supernumerary vessels (table v) and 7 of them had associated renal abnormalities: 2 with abnormal renograms ; 2 with abnormal I.V.P.S; 2 with bacteriuria; and 1 with a history of recurrent urinary-tract infections. 10 relatives with multiple vessels were rejected as
647
I I-
G.U.I. G.T.T.
1
1 = =
I
Genitourinary infection. Glucose-tolerance
donors because of associated abnormalities: abnormal renogram (4); abnormal I.v.P. (4); history of urinary-tract infection and/or bacteriuria (5); hypertension (2); prostatic hypertrophy (1); and proteinuria (1). Causes
ofrefusal.-Several patients with minor In were regarded as suitable donors. these cases, as a rule, the abnormal kidney was used. But 40 potential donors were felt to have medical contraindications against donation. Most of these causes were due to previously unsuspected renal disabnormalities
ease. The ultimate combinations of abnormalities which led to refusal as a donor are listed in table vi.
test.
tion. The great cost of such treatments has led, in turn, to attempts at early detection and prevention. Since the 1930s,18,19 urinary-tract infection has been recognised as a source of chronic renal disease. Bacteriuria was introduced by Kassas a screening test for detection of urinary-tract infections and has been used
by many investigators to screen high-risk populations. Little 20 found that acute pyelonephritis developed in 25 % of a group of 141 pregnant women with untreated bacteriuria. The frequency of pyelonephritis in a control group of 124 patients with treated bacteriuria was 3’2% and in a third group without bacteriuria it was 0-4%. Whalley et all found that bacteriuria persisted for two-twelve months out of 131 untreated women whose bacteriuria discovered during pregnancy. Bacteria were present in urine obtained from one or both ureters in 17 of 23 patients, and pyelographic abnormalities were detected in 61 of 131 patients. Freedman et aJ.21 found an overall frequency of bacteriuria among young and middle-aged women of 1-3%. Asscher et al .2 found bacteriuria in 3% of female hospital visitors (diabetics and pregnant women excluded). Kunin et al.3 found bacteriuria in 1.2 % of schoolgirls, while Pometta et a1.22 studied two groups of diabetic schoolgirls and found asymptomatic bacteriuria in
in 90 was
Discussion Renal disease continues to be an important worldwide health problem. Epidemiological studies estimate that there are 4’2 million cases of genitourinary diseases in the U.S.A.17 The non-hospital physician/ patient contact for urinary diseases in 1964 was estimated as over 26 million cases 1’ The insidious nature of the problem has led to its relative neglect until the advent of dramatic forms of treatment for end-stage renal disease, such as haemodialysis and transplanta-
648
1 °6 °o and 2%, respectively. Bacteriuria among the pregnant population generally ranges from 4-5 to 10 o/ .4,20,23-26 Huvos and Rochafound bacteriuria in 26% of diabetic and 22% of non-diabetic hospital patients. Vejlsgaard 27 found bacteriuria in 18-8% of female diabetics and 7-9% of non-diabetics. Thus there are groups among the general population which have a higher frequency of bacteriuria-i.e., pregnant women, hospital patients, and diabetics. There is some evidence that bacteriuria may lead to the development of renal failure. Whalley et al .12 found radiological evidence of chronic pyelonephritis in 27% of 131 women with asymptomatic bacteriuria who were followed for two-twelve months after pregnancy. Cobbs et a1.28 studied 15 untreated symptom-free bacteriuric women three to eighteen months after delivery and found abnormal pyelograms in 12 (80%), with changes suggestive of pyelonephritis in 4 cases (27 Hodson 29 and Smellie and Normand 30 found radiographic evidence of progression of scarring after attacks of pyelonephritis. The total frequency of bacteriuria in our study (10-5%) is probably the highest figure reported in an otherwise healthy population. The frequency of in the male populabacteriuria asymptomatic (5 %) tion of our series was also extremely high. Kass et aJ.31 studied 1515 males in the general population of Wales and Jamaica and found only 0.5 % with bacteriuria. The frequency reported by Kunin et al.3 in schoolboys is only 0-03 %, and the highest figure published was 3’5%, in men over the age of 70.6 Bacteriuria, however, proved to be a relatively insensitive test within our population of relatives of patients with renal failure. The intravenous pyelogram was abnormal in 47 of 209 (22-5 %) symptomfree potential donors. The frequency of abnormal intravenous pyelograms among healthy populations is not known, but combinations of abnormalities appear to be even more important than the isolated findings. For example, Kunin reported that 20-6 % of the i.v.p.s in schoolchildren with bacteriuria were abnormal, and among our potential donors with bacteriuria 47% had abnormal i.v.p.s. Roden et all reviewing i.v.p.s in patients who were to have elective gynaecological operations, found that 26-8% had an
unsuspected genitourinary
tract
abnormality.
The meaning of i.v.p. abnormalities is not yet clear, but Steele et al.33 reported on a group of 72 children seen between 1940 and 1950 with pyelographic changes of pyelonephritis and a urinary-tract obstruction. Re-evaluation of this group, eleven to twentyseven years later, indicated that 48 % of the patients had died (18%), had persistent infection (22%), or had developed progressive renal insufficiency (8%). 52% of these patients were living and well without any evidence of disease. We plan a similar followup of our symptom-free patients. Intravenous pyelography seems to be a valuable screening test for early detection and follow-up of renal disease. It has a high diagnostic yield, is simple and fairly inexpensive to do, and has a low complication-rate. In a series of 21,525 intravenous pyelograms reported by Hamm et al.,34 there were 4 cases with rather serious but non-fatal reactions. In our
series there was only 1 case of transient hypotension without sequel. The third most helpful test in detection of renal disease was the arteriogram. 40% of the patients with bacteriuria had abnormal arteriograms. Complications of arteriography in this series were thrombosis of the femoral artery in 1 potential donor, treated by thrombectomy, and 1 septic episode after angiography, treated successfully with systemic antibiotics. Arteriography at present is obviously a poor screening test for medical and economic reasons. 5% of the donors had diastolic hypertension, a figure that accords with the general pattern of diastolic hypertension of the U.S.A.35,36 Hypertension therefore is a less satisfactory early screening test in highrisk but symptom-free populations. We conclude that people with a familial history of end-stage renal disease will themselves have a high frequency of urinary-tract abnormalities. In addition, 90 % of these abnormalities can be detected by accurate and detailed family history, urine cultures, and intravenous pyelography. Such people will provide many examples of preclinical renal disease when investigated by standardised detection techniques, such as urine culture and intravenous pyelography. These people could then be followed to determine the natural history of such preclinical abnormalities. Many of the abnormalities could be corrected and
prophylactic
measures
instituted.
This study was supported States Public Health Service.
by
a
grant from the United
Requests for reprints should be addressed to R. L. S., Box 185, Mayo Memorial Building, University of Minnesota Hospitals, Minneapolis, Minnesota 55455, U.S.A. REFERENCES 1. Kass, E. H. Trans. Ass. Am. Physns, 1956, 18, 221. 2. Asscher, A. W., Sussman, M., Waters, W. E., Evans, J. A. S., Campbell, H., Evans, K. T., Williams, E. J. J. infect. Dis. 1969,
120, 17. 3. Kunin, C. M., Deutscher, R., Paquin, A., Jr. Medicine, Baltimore, 1964, 43, 91. 4. Kass, E. H. Trans. Ass. Am. Physns, 1959, 72, 257. 5. Switzer, S. New Engl. J. Med. 1961, 264, 7. 6. Kass, E. H. Ann. intern. Med. 1961, 56, 46. 7. Kunin, C., Southall, I., Paquin, A. New Engl. J. Med. 1960, 263, 817.
Beeson, P. B. Am. J. Med. 1958, 24, 1. Huvos, A., Rocha, H. New Engl. J. Med. 1959, 216, 1213. Dietrict, R. B., Russi, S. J. Am. med. Ass. 1958, 166, 41. Rengorts, R. T. Am. J. med. Sci. 1960, 239, 154. Whalley, P. J., Martin, F. G., Peters, P. C. J. Am. med. Ass. 1965, 193, 879. 13. Kass, E. H. Ann. intern. Med. 1962, 56, 46. 14. Norden, C. W., Kass, E. H. Ann. Rev. Med. 1968, 19, 451. 15. Kunin, C. M., McCormack, R. C. New Engl. J. Med. 1968, 278, 8. 9. 10. 11. 12.
635. 16. 17.
18. 19. 20. 21. 22.
23. 24.
25. 26.
27.
Loopuyt, L. Acta med. scand. 1946, 125, 245. Kidney Disease: Prevention and Control. U.S. Public Health Service, 1969. Longcope, W. T. Ann. intern. Med. 1937, 11, 149. Weiss, S., Parker, F. J. Medicine, Baltimore, 1939, 18, 221. Little, P. J. Lancet, 1966, ii, 925. Freedman, L. R., Phair, J. P., Seki, M., Hamilton, H. B., Nefzen, M. D., Hirata, M. Yale J. Biol. Med. 1965, 37, 262. Pometta, D., Rees, S. B., Younger, D., Kass, E. H. New Engl. J. Med. 1967, 276, 1118. Carleton, H. G., Baker, T. H., Richards, H. C. Am. J. Obstet. Gynec. 1965, 92, 227. Constable, P. J. Lancet, 1966, ii, 195. Kincaid-Smith, P., Bullen, M. ibid. 1965, i, 395. Low, J., Johnston, E., McBride, T., Tuffneld, P. Am. J. Obstet. Gynec. 1964, 90, 897. Vejlsgaard, T. in Progress in Pyelonephritis (edited by E. H. Kass); p. 478. Philadelphia, 1965.
649 HYPOKALÆMIC MUSCULAR PARESIS IN MIGRATORY PAPUA/NEW GUINEANS G. G. DUGGIN*
Royal Prince Alfred Hospita., Sydney, Australia M. A. PRICE Department of Clinical Sciences,
University of Papua/New Guinea, Moresby, Papua/New Guinea
Port
Seventeen patients with generalised muscular paresis associated with hypokalæmia are described. The disorder occurs in highlanders of Papua/New Guinea migrating to the coast and is associated with a pronounced decrease in dietary potassium intake and a pronounced increase in dietary sodium intake. Summary
Introduction
BETWEEN 1964 and 1970, seventeen patients preat the Port Moresby General Hospital on 23 occasions with transient generalised muscular paresis associated with hypokalaemia. The disorder seems to have a unique and characteristic clinical picture; it occurs in Melanesians migrating from highland and hinterland regions to the coastal areas of Papua/New Guinea. We have retrospectively analysed all case-reports of these patients. In some information was incomplete and investigations were limited because of the lack of biochemical services available in the territory over that
sented
period.
occasion, six presented
on 2 occasions, and Three 3 occasions. patients who prepresented sented more than once had returned to the highlands and then returned to Port Moresby. All patients were completely disabled by their symptoms;
disorder
1
on
on
one
The were completely paretic on presentation. proximal limb musculature was affected more severely than the distal and the legs were more severely affected most
than the
arms.
Trunk musculature
was
affected in all
patients, but respiratory musculature and muscles supplied by the cranial nerves were relatively spared. Three patients had no deep-tendon reflexes, in eleven the reflexes were reduced, and in three patients they were considered to be normal. Muscle tone was reduced in eleven patients and normal in the remainder. Nine patients complained of a minor degree of diffuse muscle discomfort, usually in the most paralysed muscle groups. Blood-pressure of 140/90 mm. Hg or greater was found in five patients on admission the remainder were within normal limits. was marked by a steady increase in muscle power over a mean of 3-6 days (range 1-11), thus making the mean duration of an attack 6-8 days. A family history of a similar disorder was not obtained from any patient, but there had been no follow-up of relatives. No patients were known to take laxatives or liquorice and there was no clinical evidence of thyrotoxicosis. No information was available about carbohydrate intake before the onset of the disorder.
hospital;
to
Recovery from paresis
Methods Serum and urinary sodium and potassium were measured by flame photometry. Serum calcium and magnesium were estimated with a Perkin Elmer double-beam atomicabsorption spectrophotometer 303. Thyroxine (T4) and T3 resin were estimated using an Armour kit. Results
The was
Patients and Methods Patients All seventeen patients were adult Melanesian males (mean age 25 years [range 18-40]). They had all recently migrated to the coastal city of Port Moresby from the highlands or hinterland regions of Papua/New Guinea. The onset of the disease usually came within 2 months of migrating to Port Moresby (mean 3 weeks). Symptoms were present for a mean of 3 days before presentation (range 1-7 days). Ten of the patients presented with the
mean
serum-potassium level on presentation This rose progressively over the
2-6 meq. per 1.
’
,
’ Present address: Department of Pharmacology and Toxicology, Dartmouth Medical School, Hanover, New Hampshire 03755, U.S.A.
Cobbs, C. G., Strickler, J. C., McGovern, J. H., Kaye, D. Am. J. Obstet. Gynec. 1967, 99, 221. 29. Hodson, C. J. in Urinary Tract Infection (edited by F. O’Grady and W. Brumfitt); p. 108. London, 1968. 30. Smellie, J. M., Normand, I. C. S. in Urinary Tract Infection (edited by F. O’Grady and W. Brumfitt); p. 123. London, 1968. 31. Kass, E. H., Savage, W., Santamarina, B. A. G. in Progress in Pyelonephritis (edited by E. H. Kass); p. 3. Philadelphia, 1965. 32. Roden, J. S., Haugen, H. M., Hall, D. G., Greenberg, P. A. Am. J. Obstet. Gynec. 1971, 82, 568. 33. Steele, E., Jr., Leadbetter, G. W., Crawford, J. D. New Engl. J. Med. 1963, 269, 883. 34. Hamm, F. C., Waterhouse, K., Weinberg, S. R. J. Am. med. Ass. 1960, 172, 542. 35. Paul, O., Ostfeld, A. M. Prog. Card. Dis. 1965/66, 8, 106. 36. Gordon, T., Devine, B. in Hypertension and Hypertensive Heart
28.
Fig. 1-Mean serum-electrolytes ± S.E.M.
Disease in Adults in the United States 1960-1962. Vital and Health Statistics Data from the National Health Survey National Center for Health Statistics, series II, no. 13. U.S. Government
Serum-potassium: day 1 v. day 2, P=0.013; day 2 v. day 3, p=0.175; day 3 v. day 4, p=0.075; day 2 v. day 4, r=0.0035; day 4 v. day 5, p =0 12; day 5 v. day 6, p =0083. Serum-sodium: day 1 v. day 2, P=0-186; day 2 v. day 3, p=0.002; day 3 v. day 4, P=0.606; day 4 v. day 5, P=0.96; day 5 v. day 6, P =0.095; day 1 v. day 3, P =0.329; day 3 v. day 6, P=0.009. p=sign.i6cance probability for two-sided alternative
Printing Office,
on
1965.
groups of unpaired data
t test.