Bri/i.di Journol o / U r o / o g y (1985). 57. 370-374 i' 19x5 Rr~ t i sh Journal of Urology

Family History of Renal Stones in Recurrent Stone Patients

S. LJUNGHALL, B. G. DANIELSON, 6. FELLSTROM, K. HOLMGREN, G. JOHANSSON and 6 . WI KSTROM

Departments of internal Medicine and Urology, University Hospital, Uppsala, Sweden

Summary-A survey was carried out on the family history of renal stones among 380 patients in an out-patient stone clinic, most of whom had experienced frequent recurrences.

In 55.4% of patients at least one first-degree relative had experienced renal stones. A positive family history was more common in females (64.7%) than in males (51 .O%) and was particularly apparent in those who had multiple recurrences. It was also significantly more common in female patients with evidence of renal tubular defects (incomplete forms of renal tubular acidosis). Among the ordinary stone patients 18% of the fathers and 8% of the mothers had also formed renal stones. The corresponding figures for female stone patients with renal tubular defects were 40 and 33% respectively. These findings indicate that tubular dysfunction could be an inherited trait that predisposes to the formation of renal stones.

family history. Hypercalciuria or hyperuricosuria was not over-represented among stone formers with a positive

The risk of forming renal stones appears to be in- creased in individuals with a family history of nephrolithiasis (McGeown, 1960; Resnick et al., 1968; Ljunghall, 1979; Churchill rt al., 1980; Marya rt al., 1981). This information largely stems from studies of large, unselected populations (Resnick et al., 1968; Ljunghall, 1979; Churchill et al., 1980). Such a design is necessary when the pur- pose is to establish the true prevalence of the dis- ease, since many of these patients are never admitted to hospital (Ljunghall, 1977). However, in population-based surveys the patients generally have mild to moderate stone disease and for obvious reasons it is not possible to perform detailed clinical or laboratory examinations. The formation of a stone is generally considered to be a multifactorial event but the nature, in biochemical terms, of the possible inherited predisposition is not known.

Against this background we have extended our

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Accepted for publication 14 January 1985

previous studies of the unselected male populatiori (Ljunghall, 1979) to patients with more severe dis- ease admitted to a stone clinic.

Patients and Methods

The study comprised 380 consecutive patients who attended our out-patient stone clinic. There were 253 males and I27 females; 26.3% had a history of multiple (more than 10) stone recurrences. The age and sex distribution are shown in Figure I . All patients were investigated according to our general protocol, which included measurement of serum and urinary electrolytes and uric acid, a quantita- tive test for cystinuria, urine culture and X-ray of the urinary tracts. Hypercalciuria, defined as a 24-h urinary calcium b 7.5 mmol, was found in 130 patients (34.2'/0), whereas hyperuricosuria (urinary urate 24 .5 mmo1/24 h) appeared in 86 patients (23.7%). Urinary tract infection of clinical impor- tance was considered to have been present in 98 patients (28%). A short-term ammonium chloride test (Backman et al., 1980) was performed on 223

370

F.I \MILY HISTORY OF RENAL STONES IN RECURRENT STONE PATIENTS 371

Table I Number of Stones

Frequency (%) of Abnormal Laboratory Findings in Stone Patients Separated with Regard to Sex and

Number of patients 253 71 I27 29 380 I00 Hypercalcuria 39.5* 38.0* 18.9 13.8 34.2 31.0 Eiyperuricosuria 28.5t 21.1 14.2 13.7 23.8 19.0 Defectivc renal acidification 19.4* 29.6* 49.6 69.0 30.0 40.0** Urinary tract infection 14.3* 15.7: 43.3 37.9 28.0 22.0

* P iO.001. t P <0.01. P ~ 0 . 0 5 L'S females. **P <0.05 1's patients with < 10 stones

Table 2 Family History (%) of Renal Stones among Stone Formers Separated with Regard to Sex, Multiple (2 10) Stones and Laboratory Findings

Lohiiru~or~ finding, Mu1i.c Female F -~ ~ _ _

2 10 rtona All 3 10 ,toriec All

Urine cdlcium 2 7 5 m m o l 2 4 h 50 7 59 2 66 0 ND (414) <7 5 mmol24 h 51 2 59 I 63 1 80 0

2 4 5 mmol24 h 50 0 53 3 75 0 ND(3/4) Urine ur'ite

1 4 5 mmol 24 h 51 4 60 7 62 7 84

defective 56 0 50 0 83 3 t , ** 84 6* normdl 53 7 64 7 48 5 ND(4/6) no( \tudied 46 I 56 5 60 6 ND(9/10)

Ren'il dcidificdtion

Urin'iry trdct infection 29 36 3 571 63 6 All pntlcnts 51 0 59 2 64 7* 82 8*

* P<O.OS. t P <O.OI . $ Pi0.001 compared with males. ** PiO.001 compared with female stone formers with normal renal acidification h'D = Not determined because the group constituted less than 10 patients.

patients, primarily on those with early onset of stones and/or frequent recurrences. No patient had complete renal tubular acidosis (RTA) but the urinary acidification capacity was impaired in 67 patients (30%). The test discloses the incomplete forms of both proximal and distal RTA. Since these types were equally common and no particular features separated them in this study, they have been considered together.

Hypercalciuria was more common in males and defective renal acidification in the females. Patients with multiple recurrences (of both sexes) more often had incomplete RTA than had those with fewer stones (Table 1).

Patients were asked during a routine visit to the clinic about the occurrence of stones in their first- degree relatives. Since previous studies (Ljunghall, 1979) showed that this type of information was usually accurate, i.e. there was no over-reporting of stones, the patients' history was not further

verified, nor were any attempts made to obtain di- rect information from the 241 2 first-degree rela- tives of the 380 patients in this study.

A positive family history was considered to be present when at least one of the first-degree rela- tives had experienced a renal stone. On the other hand, a negative history was accepted only if the patients did possess information about their first- degree relatives. Twenty-five female and 57 male patients (21.5%) either had no siblings or did not have information about the possible occurrence of stones in their other first-degree relatives.

The chi-square test was used for comparison of proportions.

Results

Of the 380 stone patients 55.4% reported that at least one of their first-degree relatives had a history of renal stones.

372

Pts

701

BRITISH JOURNAL OF CJROLOGY

50

40

30

20

10

n

30 40 50 60 70 Age

Fig. I Agc and sex distribution

c i

?

(253)

( 1 27)

A positive family history was more common in female stone patients (64.7%) than in males ( 5 1 .go/") and was more common in those with fre- quent recurrences (Fig. 2).

The family history of stones in the males appeared to be unrelated to laboratory findings, i.e. there was no over-representation in those with hypercalciuria, hyperuricosuria and impairment of renal acidification (Table 2 ) . In the female stone patients, however, a positive family history was sig- nificantly more common in those with the incom- plete forms of renal tubular acidosis (Table 2).

When the prevalence of stones was calculated in the relatives, no differences were found among the relatives of male stone patients when divided according to laboratory findings, i.r. approxi- mately 17% of their fathers, 8% of their mothers, 15% of their brothers, 6% of their sisters and 2% of their children had also experienced renal stones regardless of the underlying biochemical abnor- mality in the probands (Fig. 3). In the relatives of female stone patients a different picture emerged. A markedly higher figure was reported from those females with impaired renal acidification, where more than 40% of the fathers and 33% of the mothers had also formed renal stones (Fig. 3).

Discussion

A family history of stones was obtained in more than half of the patients. I t was more common in

Pts

'0°1

-

50-

2-3 4-9 10- 1

No of stones

Fig. 2 positive family history of stones (lower part of bars).

Patients divided according to sex. number of stones and

% 20

10

10

20

30

40

Fathers Mothers Brothers Sisters Children

1

Fig. 3 Occurrence of renal stones i

No abnormality / Hypercalciuria b<,ti;y r ur i c o su r i a

first-degree relatives of stone patients divided according to underlying biochemical abnormalities.

females than in males, particularly in those with many stones.

Churchill et al. (1980) reported similar sex differ- ences in an epidemiological survey. They found

FAMILY HISTORY OF RENAL STONES IN RECURRENT STONE PATIENTS 373

that in an unselected population of stone formers a positive family history was reported by 39% of all patients. The prevalence of renal stones in the parents of male stone formers was not higher than expected from studies of the stone-free population. The female stone formers, however, had an affected parent significantly more often than their stone-free counterparts.

The fact that renal stone formation runs in cer- tain families does not necessarily imply that i t is inherited. Members of the family share not only genetic information but also tend to adopt similar ways of living, 4.g. as regards dietary habits. We have previously reported that the spouses of such families also appear to have an increased risk of stones (Ljunghall, 1979). Hence we prefer the term family history to inheritance.

Among female stone formers, in the present study. a family history of stones was obtained from almost two-thirds and was even more common in those who had evidence of renal tubular dysfunc- tion. Complete distal renal tubular acidosis can be inherited and is known to cause renal stones or nephrocalcinosis (Feest and Wrong, 1975). We have previously reported that renal tubular defects (either tubular proteinuria or incomplete defects in urinary acidification) are common among recur- rent renal stone formers (Backman rt al., 1980). The incomplete forms of RTA can only be detected by an ammonium chloride load (Backman et al., 1976). Among our stone patients those with incom- plete RTA tended to have more severe stone dis- ease than the idiopathic stone formers and there was also an over-representation of young females in this group ( Backman r t ul., 1980).

Our finding that these patients also have a strong family history of renal stones indicates that tubular dysfunction can be inherited and that it is of patho- genelic importance in the development of renal stones. Systematic studies of renal tubular function in the stone-forming and stone-free relatives of these patients should be performed to corroborate this hypothesis.

Apart from this observation there was no appar- ent correlation between the laboratory profile and the family history of renal stones. In particular, neither hypercalciuria nor hyperuricosuria oc- curred significantly more often in those with stones in their first-degree relatives. This confirms findings from previous epidemiological studies (Ljunghall, 1979). Nevertheless, there have been reports of familial hypercalciuria (Weinberger et al., 1981). Coe ct 01. ( 1979) found increased urinary calcium in half of all investigated relatives of stone formers

with idiopathic hypercalciuria. However, there was no association between hypercalciuria and stone formation in the relatives, although a stone-form- ing tendency was much more common in the first- degree relatives of stone formers than in other rela- tives. In addition, the study by McGeown (1960) revealed no tendency for hypercalciuria to be more common in those with a positive family history of renal stones. Investigation of renal tubular func- tion was no: performed in these studies and familial factors other than the presence of hyper- calciuria could have been important.

There has been a marked increase in the inci- dence of renal stones during the last few decades (Ljunghall, 1978), presumably related to the in- creased standard of living, but the precise nature of this association has not been established. “Pure” genetic causes of stone formation are presumably rare within the large number of unselected stone formers. The tendency towards over-represen- tation of renal stones in certain families might therefore be thought to reflect an inherited predis- position to stone formation which becomes mani- fest only when other (environmental?) factors are also present. It is thus not remarkable that the majority of “idiopathic” stone formers with a family history of renal stones cannot be dis- tinguished by laboratory tests. The higher preva- lence of a positive family history in female stone formers is consistent with a multifactorial model for stone formation, where affected individuals of the sex which is less often affected will tend to be more extreme deviants in terms of genetic liability and the genetic risk to their relatives will be corres- pondingly higher.

References Backman, U., Danielson, B. G., Johansson, G., Ljunghall, S. and

Wikstrorn, B. (1980). Incidence and clinical importance of renal tubular defects among renal stone formers. Nephron, 25, 96-101.

Backman, U., Danielson, B. G. and Sohtell, M. (1976). A short term renal acidification test. Scandinuvian Journal of Uro1og.v and Nephmlogy, Supplement 35.33-48.

Churchill, D. N., Maloney, C. M., Bear, J., Bryant, D. G., Fodor, G. and Cault, M. H. (1980). Urolithiasis--a study of drinking water hardness and genetic factors. Journal qf Chronic Dis- mses, 33, 721-73 1.

Coe, F. L., Parks, J. H. and Moore, E. S. (1979). Familial idio- pathic h ypercalci uria. New Englund Journal of Medicine, 300, 337-340.

Feest, T. G. and Wrong, 0. M. (1975). Inherited defects in distal tubular acidification. Annuls of Interns/ Medicine, 82, 584- 585 .

Ljunghall, S. (1977). Renal stone disease. Studies of epidemi- ology and calcium metabolism. Scandinavian Journal of Urology and Nephrolo~y, Supplement 41.6-19.

3 74 BRlTISH JOURNAL OF UROLOGY

Ljunghall, S. ( I 978). Incidence and natural history of renal stone disease and its relationship to calcium metabolism. European

Ljunghall, S. (1979). Family history of renal stones in a popula- tion study of stone formers and healthy subjects. British Jour- nal of Urology. 51,249-252.

Marya, R. K., Dadoo, R. C. and Sharma, N. K. (1981). Genetic predisposition to renal stone disease in the first-degree rela- tives of stone formers. (lrologiu inrernurionulis, 36, 245-247.

McGeown, M. (1960). Heredity in renal stone disease. Clinical Science, 19, 465-471.

Resnick, M., Pridgen, D. B. and Coodman,H. 0. (1968). Genetic predisposition to formation of calcium oxalate renal calculi. New England Joitrnul @Medicine. 278, 1 3 13- 13 18.

Weinherger, A., Schechter, J., Pinkhas, J. and Sperling, 0. (1981). Hereditary hypercalciuric urolithiasis. A study of a family. British Journal of Urology, 53, 285-286.

C'rol~g.~, 4, 424-430.

The Authors S. Ljunghall, MD, Associate Professor and Consultant. Section

B. G. Danielson, M D , Associate Professor and Consultant, Sec-

B. Fellstrom, MD. Assistant Professor and Registrar, Section of

K . Holmgren, MD, Registrar, Department of Urology. G . Johansson, MD, Assistant Professor and Registrar, Section

B. Wikstrom, MD. Assistant Professor and Registrar, Section

of Endocrinology.

tion of Nephrology.

Nephrology .

of Nephrology.

of Nephrology.

Requests for reprints to: S. Ljunghall, Department of Internal Medicine, University Hospital, S-75 1 85 Uppsala, Sweden.