645

stone in the common bileduct, and a false-positiveresult was admitted. At operation, however, the headof the pancreas was hard, a biopsy was done, andcarcinoma of the pancreas was diagnosed together withthe stone in the common bileduct. This anecdote ofthe false false-positive will, we suspect, be followedin due course by a true false-positive, but the pre-liminary score is encouraging us to develop the test.

We thank our colleagues in many histopathology departments,especially that of Prof. A. D. Morgan, Westminster MedicalSchool, and in many hospitals (especially Westminster and Prof.J. H. Louw of Groote Schuur Hospital, Cape Town) for pro-viding material; and our American colleagues who, through DrT. A. Waldmann of the National Cancer Institute, Bethesda,have kindly supplied 20 sera from known patients with pancreaticcancer.

REFERENCES

1. Hobbs, J. R. Br. J. Hœmat. 1969, 16, 607.2. Feinleib, M., MacMahon, B. J. natn. Cancer Inst. 1960, 24, 1259.3. Galton, D. A. G., Peto, R. Br. J. Hœmat. 1968, 15, 319.4. Bagshawe, K. D. Adv. Cancer Res. 1973, 18, 231.5. Abelev, G. I. Acta Un. int. Contr. Cancr. 1963, 19, 80.6. Alexander, P. Nature, 1972, 235, 137.7. Gold, P., Freedman, S. O. J. exp. Med. 1965, 122, 467.8. Thomson, D. M. P., Krupey, J., Freedman, S. O., Gold, P. Proc.

natn. Acad. Sci. U.S.A. 1969, 64, 161.9. Moore, T. L., Kupchik, H. Z., Marcon, N., Zamcheck, N. Am. J.

dig. Dis. 1971, 16, 1.10. Kleist, S. V., Burtin, P. Int. J. Cancer, 1969, 4, 874.11. Versey, J. Protides biol. Fluids, 1971, 19, 565.

SCREENING POTENTIAL RELATED

TRANSPLANT DONORS FOR RENAL DISEASE

PANAYIOTIS K. SPANOSCARL M. KJELLSTRAND

RICHARD L. SIMMONSTHEODORE J. BUSELMEIER

JOHN S. NAJARIANDepartment of Surgery, University of Minnesota,

Minneapolis, Minnesota 55455, U.S.A.

Summary The families of two hundred potentialrenal-transplant recipients were studied

for evidence of renal disease. Eighteen of the twohundred families had other members with familialrenal disease (polycystic, medullary cystic, hereditarynephritis, Fabry’s disease). Thirty of the one hun-dred and eighty-two remaining families had had at

least one member die of renal disease or require a

renal transplant, hæmodialysis, or nephrectomy.Thus, a total of 22% of the families of patients withrenal failure had a history of renal failure in othermembers. 209 potential related donors were studied.10.5% of the women and 5% of the men had per-sistent bacteriuria; 12 had hypertension and 47 hadabnormal intravenous pyelograms, 41 of these hadassociated urinary abnormalities. 82 of 193 arterio-grams were abnormal, and 17 of the abnormal arterio-grams revealed other renal abnormalities. Medicalcontraindications ultimately excluded 40 relativesfrom donation. It is suggested that apparently healthysymptom-free relatives of patients with terminal renalfailure will have an extremely high frequency of

underlying renal disease. Such persons might com-prise a suitable population for intensive screeningfor asymptomatic renal disease within the popula-tion. This group might also be a suitable study

group for evaluating techniques for the preventionof progressive renal disease.

Introduction

OCCULT renal disease is well known as an importantpredisposing cause, not only of renal failure itself,but also of hypertension and its associated cardio-vascular disorders. Since the diagnostic techniquesin renal disease are relatively simple and precise, itis generally agreed that progressive renal disease mightbe prevented if renal abnormalities were detectedbefore the onset of symptoms. Studies of bacteriuriain the general population 1-5 and in patients deemedto be at high risk 6-9 have been promoted in the expec-tation that asymptomatic urinary-tract infections are

correlated with progressive renal disease. Suchstudies have shown that hospital patients,9 neurolo-gical patients," diabetics,’," pregnant women,12-14 andschoolgirls 7have a greater frequency of asympto-matic bacteriuria than control populations.The frequency of renal disease in the entire popu-

lation is so low that screening is unlikely to be eco-nomically feasible. But the screening of high-riskpopulations may well reduce the frequency of chronicrenal disease, since it has reduced the frequency ofacute pyelonephritis, prematurity, and toxaemia in

pregnant women with asymptomatic bacteriuria.

Renal-transplant units have the opportunity to screenthe relatives of patients with end-stage renal diseasewhen such relatives offer themselves as donors. The

present study was designed to determine the fre-

quency of abnormalities of the urinary tract in poten-tial donors who volunteered to give a kidney to a

relative with terminal renal failure.

Materials and Methods

The following studies are performed at the University ofMinnesota Hospitals on patients who volunteer to donatea 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, cal-cium, and phosphorus; and blood-urea-nitrogen, crea-

tinine, fasting blood-sugar, and glucose-tolerance test;urinalysis and 24-hour creatinine clearance; two clean-catch urine cultures; blood-type (major and minor), tissuetyping, leucocyte cross-match for recipient anti-donor andleucocyte antibodies, venereal disease research laboratories,and Australia antigen; chest X-ray (posterior/anterior andlateral), intravenous pyelogram (LV.P.), renal arteriograms;bilateral renogram; and electrocardiogram. The renal

arteriogram is performed as a last step. 209 volunteer

potential donors related to two hundred renal-transplantrecipients were studied to determine the frequency ofurinary-tract disease in this apparently normal population.152 of these potential donors were aged from eighteen toforty-five; 45 from forty-five to fifty-four; and 12 fromfifty-four to sixty-five.

Results

Familial factors.-Of two hundred recipients withend-stage renal failure, eighteen had known familialdiseases; 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

TABLE II-ABNORMALITIES FOUND IN SYMPTOM-FREE POTENTIAL

RENAL TRANSPLANT DONORS WITH HYPERTENSION

with Fabry’s disease. Thus, 9% of the recipients inthis group had known familial renal disease whichexcluded many family members as donors before theexamination of any potential donors themselves.

In addition to these eighteen families with familialrenal disease, thirty of the prospective transplantrecipients 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 renaldisease, or (d) to have died of documented renal dis-ease. Thus, in addition to the 9 % of patients whohad known familial renal disease, 15 % had relativeswith advanced renal failure. Thus, merely inter-

viewing patients with end-stage renal disease will

yield a high number of persons with potential renaldisease.

Abnormalities detected by screening techniques.-209 volunteer potential donors were studied. Of

these, 157 ultimately donated kidneys to their rela-tives and 52 were excluded-40 because of medicalcontraindications to donation and 12 for non-medicalreasons.

TABLE III-RENAL ABNORMALITIES FOUND ON INTRAVENOUS

PYELOGRAPHY IN 47 OF 209 SYMPTOM-FREE POTENTIAL RELATEDKIDNEY DONORS

Z?acteMt’ta.—Each potential donor was studied byclean-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 sameorganism per ml. on two consecutive cultures (tableI). Thus, the frequency of bacteriuria in these poten-tial donors is higher than that reported in either

pregnant women,14 women over 40 years of age,H.15working women,15 or any other group reported exceptthe diabetic and the elderly in hospital. 9,16 The 5 , Jincidence of bacteriuria in the male population is thehighest ever reported in any male population.Hypertension.-12 of 209 apparently healthy rela-

tives of patients with terminal renal failure had

unsuspected diastolic hypertension (i.e., a persistentdiastolic blood-pressure of more than 90 mm. Hgduring initial 3-day period of in-hospital study). All12 relatives with hypertension had at least one asso-ciated renal abnormality (table 11).Abnormal I.V.P.s were found in 47 of the 209

TABLE IV-ASSOCIATED ABNORMALITIES OF SYMPTOM-FREE POTENTIAL

KIDNEY DONORS WITH ABNORMAL INTRAVENOUS PYELOGRAMS

(I.V.P.)

TABLE V-82 ABNORMALITIES FOUND WITH RENAL ARTERIOGRAPHYIN 193 HEALTHY LIVING RELATED POTENTIAL DONORS

symptom-free volunteer donors (table ill). In 30 theabnormalities were minor, and 17 of the slightlyabnormal kidneys were used for transplantation, butseveral 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 discoveredabnormalities. 82 arteriograms (42 %) revealedabnormalities 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 hadassociated renal abnormalities: 2 with abnormal reno-grams ; 2 with abnormal I.V.P.S; 2 with bacteriuria;and 1 with a history of recurrent urinary-tractinfections.

10 relatives with multiple vessels were rejected as

647

I I- 1 1 I

G.U.I. = Genitourinary infection.G.T.T. = Glucose-tolerance test.

donors because of associated abnormalities: abnor-mal renogram (4); abnormal I.v.P. (4); history ofurinary-tract infection and/or bacteriuria (5); hyper-tension (2); prostatic hypertrophy (1); and protein-uria (1).

Causes of refusal.-Several patients with minorabnormalities were regarded as suitable donors. Inthese cases, as a rule, the abnormal kidney was used.But 40 potential donors were felt to have medicalcontraindications against donation. Most of thesecauses were due to previously unsuspected renal dis-ease. The ultimate combinations of abnormalitieswhich led to refusal as a donor are listed in table vi.

Discussion

Renal disease continues to be an important world-wide health problem. Epidemiological studies esti-mate that there are 4’2 million cases of genitourinarydiseases in the U.S.A.17 The non-hospital physician/patient contact for urinary diseases in 1964 was esti-mated as over 26 million cases 1’ The insidious natureof the problem has led to its relative neglect until theadvent of dramatic forms of treatment for end-stagerenal disease, such as haemodialysis and transplanta-

tion. The great cost of such treatments has led, inturn, to attempts at early detection and prevention.

Since the 1930s,18,19 urinary-tract infection has beenrecognised as a source of chronic renal disease.Bacteriuria was introduced by Kass as a screeningtest for detection of urinary-tract infections and hasbeen used by many investigators to screen high-riskpopulations. Little 20 found that acute pyelonephritisdeveloped in 25 % of a group of 141 pregnant womenwith untreated bacteriuria. The frequency of pyelo-nephritis in a control group of 124 patients withtreated bacteriuria was 3’2% and in a third groupwithout bacteriuria it was 0-4%. Whalley et allfound that bacteriuria persisted for two-twelve monthsin 90 out of 131 untreated women whose bacteriuriawas discovered during pregnancy. Bacteria were

present in urine obtained from one or both uretersin 17 of 23 patients, and pyelographic abnormalitieswere detected in 61 of 131 patients. Freedman et aJ.21found an overall frequency of bacteriuria amongyoung and middle-aged women of 1-3%. Asscheret al .2 found bacteriuria in 3% of female hospitalvisitors (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

648

1 °6 °o and 2%, respectively. Bacteriuria amongthe pregnant population generally ranges from 4-5 to10 o/ .4,20,23-26Huvos and Rocha found bacteriuria in 26% of

diabetic and 22% of non-diabetic hospital patients.Vejlsgaard 27 found bacteriuria in 18-8% of femalediabetics and 7-9% of non-diabetics. Thus thereare groups among the general population which havea higher frequency of bacteriuria-i.e., pregnantwomen, hospital patients, and diabetics.

There is some evidence that bacteriuria may lead tothe development of renal failure. Whalley et al .12 foundradiological evidence of chronic pyelonephritis in 27%of 131 women with asymptomatic bacteriuria whowere followed for two-twelve months after pregnancy.Cobbs et a1.28 studied 15 untreated symptom-freebacteriuric 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 afterattacks of pyelonephritis.The total frequency of bacteriuria in our study

(10-5%) is probably the highest figure reported in anotherwise healthy population. The frequency of

asymptomatic bacteriuria (5 %) in the male popula-tion of our series was also extremely high. Kass etaJ.31 studied 1515 males in the general population ofWales and Jamaica and found only 0.5 % with bac-teriuria. The frequency reported by Kunin et al.3 inschoolboys is only 0-03 %, and the highest figurepublished was 3’5%, in men over the age of 70.6

Bacteriuria, however, proved to be a relativelyinsensitive test within our population of relatives ofpatients with renal failure. The intravenous pyelo-gram was abnormal in 47 of 209 (22-5 %) symptom-free potential donors. The frequency of abnormalintravenous pyelograms among healthy populationsis not known, but combinations of abnormalities

appear to be even more important than the isolatedfindings. 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 bac-teriuria 47% had abnormal i.v.p.s. Roden et allreviewing i.v.p.s in patients who were to have elec-tive gynaecological operations, found that 26-8% hadan 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 childrenseen between 1940 and 1950 with pyelographicchanges of pyelonephritis and a urinary-tract obstruc-tion. Re-evaluation of this group, eleven to twenty-seven years later, indicated that 48 % of the patientshad died (18%), had persistent infection (22%), orhad developed progressive renal insufficiency (8%).52% of these patients were living and well withoutany evidence of disease. We plan a similar follow-up of our symptom-free patients.

Intravenous pyelography seems to be a valuable

screening test for early detection and follow-up ofrenal disease. It has a high diagnostic yield, is simpleand fairly inexpensive to do, and has a low complica-tion-rate. In a series of 21,525 intravenous pyelo-grams reported by Hamm et al.,34 there were 4 caseswith rather serious but non-fatal reactions. In our

series there was only 1 case of transient hypotensionwithout sequel.The third most helpful test in detection of renal

disease was the arteriogram. 40% of the patientswith bacteriuria had abnormal arteriograms. Compli-cations of arteriography in this series were throm-bosis of the femoral artery in 1 potential donor,treated by thrombectomy, and 1 septic episode afterangiography, treated successfully with systemic anti-biotics. Arteriography at present is obviously a poorscreening test for medical and economic reasons.5% of the donors had diastolic hypertension, a

figure that accords with the general pattern of diastolichypertension of the U.S.A.35,36 Hypertension there-fore is a less satisfactory early screening test in high-risk but symptom-free populations.We conclude that people with a familial history of

end-stage renal disease will themselves have a highfrequency of urinary-tract abnormalities. In addi-

tion, 90 % of these abnormalities can be detected byaccurate and detailed family history, urine cultures,and intravenous pyelography. Such people will pro-vide many examples of preclinical renal disease wheninvestigated by standardised detection techniques,such as urine culture and intravenous pyelography.These people could then be followed to determine thenatural history of such preclinical abnormalities.Many of the abnormalities could be corrected andprophylactic measures instituted.

This study was supported by a grant from the UnitedStates Public Health Service.

Requests for reprints should be addressed to R. L. S.,Box 185, Mayo Memorial Building, University of MinnesotaHospitals, 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,

817.8. Beeson, P. B. Am. J. Med. 1958, 24, 1.9. Huvos, A., Rocha, H. New Engl. J. Med. 1959, 216, 1213.

10. Dietrict, R. B., Russi, S. J. Am. med. Ass. 1958, 166, 41.11. Rengorts, R. T. Am. J. med. Sci. 1960, 239, 154.12. 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,

635.16. Loopuyt, L. Acta med. scand. 1946, 125, 245.17. Kidney Disease: Prevention and Control. U.S. Public Health

Service, 1969.18. Longcope, W. T. Ann. intern. Med. 1937, 11, 149.19. Weiss, S., Parker, F. J. Medicine, Baltimore, 1939, 18, 221.20. Little, P. J. Lancet, 1966, ii, 925.21. Freedman, L. R., Phair, J. P., Seki, M., Hamilton, H. B., Nefzen,

M. D., Hirata, M. Yale J. Biol. Med. 1965, 37, 262.22. Pometta, D., Rees, S. B., Younger, D., Kass, E. H. New Engl. J.

Med. 1967, 276, 1118.23. Carleton, H. G., Baker, T. H., Richards, H. C. Am. J. Obstet.

Gynec. 1965, 92, 227.24. Constable, P. J. Lancet, 1966, ii, 195.25. Kincaid-Smith, P., Bullen, M. ibid. 1965, i, 395.26. Low, J., Johnston, E., McBride, T., Tuffneld, P. Am. J. Obstet.

Gynec. 1964, 90, 897.27. Vejlsgaard, T. in Progress in Pyelonephritis (edited by E. H. Kass);

p. 478. Philadelphia, 1965.

649

28. 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’Gradyand 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 inPyelonephritis (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

Disease in Adults in the United States 1960-1962. Vital andHealth Statistics Data from the National Health Survey NationalCenter for Health Statistics, series II, no. 13. U.S. GovernmentPrinting Office, 1965.

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,Port Moresby, Papua/New Guinea

Seventeen patients with generalisedSummary muscular paresis associated with hypo-

kalæmia are described. The disorder occurs in

highlanders of Papua/New Guinea migrating to thecoast and is associated with a pronounced decrease indietary potassium intake and a pronounced increasein dietary sodium intake.

Introduction

BETWEEN 1964 and 1970, seventeen patients pre-sented at the Port Moresby General Hospital on 23occasions with transient generalised muscular paresisassociated with hypokalaemia. The disorder seems tohave a unique and characteristic clinical picture; itoccurs in Melanesians migrating from highland andhinterland regions to the coastal areas of Papua/NewGuinea.We have retrospectively analysed all case-reports of

these patients. In some information was incompleteand investigations were limited because of the lack ofbiochemical services available in the territory over thatperiod.

Patients and Methods

Patients ’

All seventeen patients were adult Melanesian males(mean age 25 years [range 18-40]). They had all recentlymigrated to the coastal city of Port Moresby from thehighlands or hinterland regions of Papua/New Guinea.The onset of the disease usually came within 2 months ofmigrating 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

’ Present address: Department of Pharmacology and Toxicology,Dartmouth Medical School, Hanover, New Hampshire 03755,U.S.A.

disorder on 1 occasion, six presented on 2 occasions, andone presented on 3 occasions. Three patients who pre-sented more than once had returned to the highlands andthen returned to Port Moresby.

All patients were completely disabled by their symptoms;most were completely paretic on presentation. The

proximal limb musculature was affected more severelythan the distal and the legs were more severely affectedthan the arms. Trunk musculature was affected in all

patients, but respiratory musculature and muscles suppliedby the cranial nerves were relatively spared. Three patientshad no deep-tendon reflexes, in eleven the reflexes werereduced, and in three patients they were considered to benormal. Muscle tone was reduced in eleven patients andnormal in the remainder. Nine patients complained of aminor degree of diffuse muscle discomfort, usually in themost paralysed muscle groups. Blood-pressure of 140/90mm. Hg or greater was found in five patients on admissionto hospital; the remainder were within normal limits.Recovery from paresis was marked by a steady increase inmuscle power over a mean of 3-6 days (range 1-11), thusmaking 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 ofrelatives. No patients were known to take laxatives orliquorice and there was no clinical evidence of thyrotoxi-cosis. No information was available about carbohydrateintake before the onset of the disorder.

MethodsSerum and urinary sodium and potassium were measured

by flame photometry. Serum calcium and magnesiumwere estimated with a Perkin Elmer double-beam atomic-absorption spectrophotometer 303. Thyroxine (T4) andT3 resin were estimated using an Armour kit.

Results

The mean serum-potassium level on presentationwas 2-6 meq. per 1. This rose progressively over the

Fig. 1-Mean serum-electrolytes ± S.E.M.

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 alternativeon groups of unpaired data t test.