Autosomal recessive polycystic kidney disease in adulthood

Catherine Fonck1,3, Dominique Chauveau1,, Marie-France Gagnadoux2, Yves Pirson3 and Jean-Pierre Grünfeld1

1 Service de Néphrologie and Inserm U 507, 2 Service de Néphrologie Pédiatrique, Hôpital Necker–Enfants Malades, Paris, France and 3 Service de Néphrologie, Cliniques Universitaires Saint-Luc, Brussels, Belgium



   Abstract
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
Background. Renal cysts arising from collecting ducts, congenital hepatic fibrosis, and recessive inheritance characterize autosomal recessive polycystic kidney disease (ARPKD). The disorder usually manifests in infancy, with a high mortality rate in the first year of life. For the patients who survive the neonatal period, the probability of being alive at 15 years of age ranges from 50 to 80%, with 56–67% of them not requiring renal replacement therapy at that stage. Some develop portal hypertension. Long-term outcome of adults escaping renal insufficiency above age 18 is largely unknown.

Method. In consecutive patients with ARPKD and autonomous renal function at age 18, clinical course of kidney and liver disease in adulthood and status at last follow-up were evaluated. Progression of renal insufficiency was assessed by the rate of decline of creatinine clearance, according to Schwartz's formula before age 18 and Cockcroft and Gault formula thereafter. Severity of liver involvement was estimated by imaging techniques, liver function tests, and endoscopy.

Results. Sixteen patients from 15 families were included. ARPKD was diagnosed between 1 day and 13 years of age. From diagnosis, mean follow-up period lasted 24±9 years. Before age 18, nine patients (56%) were hypertensive, nine (56%) had renal failure, and four (25%) had portal hypertension. Beyond age 18, no additional patient became hypertensive, and another five developed progressive renal insufficiency; altogether, the mean yearly decline of creatinine clearance was 2.9±1.6 ml/min. Portal hypertension was recognized in two additional patients. Four patients experienced gastro-oesophageal bleeding, while recurrent cholangitis or cholangiocarcinoma developed in one case each. At the end of follow-up, 15/16 patients (94%) were alive at a mean age of 27 (18–55) years. Two patients had a normal renal function, 11 had chronic renal insufficiency, one was on regular dialysis, and two had functioning kidney grafts. Four patients had required a porto-systemic shunt.

Conclusions. A subset of ARPKD patients with autonomous renal function at age 18 experiences slowly progressive renal insufficiency. With prolonged renal survival, complications related to portal hypertension are not rare, requiring careful surveillance and appropriate management.

Keywords: adulthood; autosomal recessive polycystic kidney disease; congenital hepatic fibrosis; portal hypertension; renal failure



   Introduction
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
Autosomal recessive polycystic kidney disease (ARPKD) is characterized by the association of renal cysts arising from dilated collecting ducts, and biliary dysgenesis known as congenital hepatic fibrosis. Its incidence has been estimated at about 1/10 000 to 1/40 000 individuals. The disease usually manifests first in infancy but it may present later, with predominant renal or hepatic manifestations and a wide range of clinical severity. ARPKD is caused by mutations in a single gene locus localized in the 6p21.1-p12 region (the locus PKHD1–polycystic kidney and hepatic disease) [1].

The survival of patients with ARPKD is not as bleak as previously thought. The mortality rate is high during the first year of life, but for children who survive the neonatal period, the probability of being alive at 15 years ranges from 50 to 80% [2,3]. Heterogeneity of renal outcome in childhood has been demonstrated as well. Fifty-six to 67% of the patients who survive the first months of life reach 15 years of age without requiring dialysis [3,4].

Long-term outcome of children escaping early renal failure is largely unknown. To the best of our knowledge, only 21 ARPKD patients reaching adulthood without end-stage renal disease (ESRD) have been reported [3,514]. In this subset of patients the rate of progression of the renal disease, and the course of hepatic complications have not been comprehensively documented. This prompted us to review the outcome of ARPKD patients who reached age 18 with autonomous renal function, to characterize better the course of kidney function and liver involvement in adulthood.



   Subjects and methods
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
Patients were consecutively identified at Necker–Enfants Malades Hospital, Paris, and Cliniques Universitaires Saint Luc, Brussels. Criteria for inclusion of each patient required (i) a well-established diagnosis of ARPKD [2] and (ii) no requirement for renal replacement therapy at the age of 18. The diagnosis of ARPKD was considered when two or more of the following criteria were met: (i) renal changes characteristic of ARPKD as documented either by ultrasonography (increased parenchymal echogenicity within large kidneys in early childhood; multiple renal cysts or medullary increased echogenicity in enlarged or normal-sized kidneys thereafter), intravenous pyelography (linear radial pattern on contrast-enhanced nephrogram), or pathology (dilated or cystic changes of collecting ducts on renal biopsy or post-mortem specimen); (ii) a typical liver involvement as assessed by ultrasonography (hepatic fibrosis and/or portal hypertension with or without intrahepatic biliary dilatation) or pathology (congenital hepatic fibrosis accompanied or not by non-obstructive dilation of intrahepatic bile ducts (Caroli disease) on liver biopsy or post-mortem specimen); (iii) a family history consistent with autosomal recessive inheritance, relying on the absence of renal cysts at ultrasound examination of both parents and/or a pathological diagnosis of ARPKD in an affected sibling. No attempt at genetic testing was made.

Clinical course and clinical and biochemical status at last follow-up were obtained by reviewing of in- and outpatient medical records. Progression of renal failure was assessed by the rate of decline of estimated creatinine clearance (Ccr), expressed in ml/min/year, until ESRD, death, or the last recorded value. Ccr was estimated using the formula of Schwartz under 18 years [15], or the formula of Cockcroft and Gault thereafter [16]. Renal insufficiency was defined by a Ccr<80 ml/min. Hypertension was defined by the need of antihypertensive treatment. Liver assessment included liver function tests and screening for portal hypertension by imaging techniques and endoscopy.

All results are expressed as mean±SD, or percentages.



   Results
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 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
Sixteen patients (12 females and 4 males) belonging to 15 families and born between 1942 and 1979 were included. Parental consanguinity was established in two families. With regard to diagnosis criteria for ARPKD, three criteria were met in 11 (69%) of the patients (see Table 1Go). Renal ultrasound examination was available in both parents for 15 of the patients. None had polycystic kidneys. In the parents of the last case, renal ultrasonography could not be obtained. Both parents were clinically healthy in their seventh decade. Their index daughter had renal changes characteristic of ARPKD, and developed portal hypertension. At last follow-up, four patients (24%) had no clinical liver involvement; however, all had typical family history and ultrasonography was suggestive of hepatic fibrosis in two cases.


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Table 1. Diagnostic criteria for ARPKD in 16 adult patients

 
Age at diagnosis, initial presentation, and observation period
Age at diagnosis of ARPKD ranged from 1 day to 13 years (mean, 2.8±4.4 years). At the time of diagnosis, 10 patients (62%) were younger than 1 year and 4 patients (25%) were older than 5 years. The main presenting features were nephromegaly (n=13), hypertension (n=6), urinary symptoms (n=5), failure to thrive (n=2), and hepatosplenomegaly or signs of portal hypertension (n=2). The mean observation period was 24±9 years (range: 13–46). At the end of follow-up, ages ranged from 18 to 55 years (mean, 27±10), and all patients but one were alive.

Renal disease
Hypertension was present at the time of diagnosis in 37% and subsequently developed in another 19% before 18 years of age. None of the patients became hypertensive above 18 during the observation period. Currently, renal function is normal in two patients (aged 18 and 21 respectively), and impaired in the 14 other patients. Renal decline started before age 18 in nine patients, between age 18 and 30 in three additional patients, and was recognized at age 30 and 45 in the last two patients. Mean age at recognition of renal insufficiency was 15.9±12 years (range, 1 day to 45 years). Among the 14 patients with renal impairment, the yearly decline of Ccr was 2.9±1.6 ml/min (range, 0.2–5.5) (Figure 1Go). At the end of follow-up, three had reached ESRD. Regular haemodialysis was started at age 20, 22, and 29 respectively (an average of 15 years after the beginning of renal decline). Kidney transplantation was subsequently performed in two patients. For the 11 others with chronic renal insufficiency, Ccr at last follow-up was 29±16 ml/min (range, 12.3–56.4).



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Fig. 1. Change in estimated creatinine clearance in 16 ARPKD patients with autonomous renal function at age 18. HD, haemodialysis; KT; kidney transplantation.

 
The rate of progression of renal insufficiency was not uniform among affected siblings from a given family (Table 2Go). While the course was similar in family 3, it was strikingly different in families 1 and 2 regarding mode and age of onset, and life span. Two affected children died early in infancy, whereas index cases reached adulthood, being currently alive at 20 and 32 years of age respectively, with slowly progressive renal insufficiency.


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Table 2. Comparison of renal course between two affected sibs within three ARPKD families

 

Liver involvement
Clinical evidence for liver involvement was present at diagnosis of ARPKD in seven patients (44%), and subsequently developed in five additional cases (31%), including three before age 18. A pathological diagnosis was obtained in four patients (liver biopsy, 3; post-mortem specimen, 1). Liver function tests remained normal in all patients. Portal hypertension developed in six, including two cases above 18. In five of them it was responsible for 22 episodes of bleeding (Figure 2Go). The first rupture of gastro-oesophageal varices occurred at a mean age of 16±17.5 years (range, 6–47). In addition to beta-blockers, portal hypertension required a porto-systemic surgical shunt in four patients between 6 and 21 years of age (mean 11.6±6]; varix ligatures were performed in a single case at age 53. Dilatation of intrahepatic bile ducts (Caroli's disease) was demonstrated in two patients by ultrasonography or CT cholangiography; it was associated with recurrent cholangitis in one case. A multifocal cholangiocarcinoma was diagnosed in a 47-year-old patient, who eventually died of intractable gastrointestinal bleeding.



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Fig. 2. Details of liver complications in five ARPKD adult patients with severe hepatic involvement. R, rupture of gastro-oesophageal varices; L, ligature of gastro-oesophageal varices; C, cholangitis; S, portocaval shunt; Ch, cholangiocarcinoma; {dagger}, death.

 



   Discussion
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
This study presents the long-term follow-up, ranging from 13 to 46 years, of a series of 16 adult patients with ARPKD. The diagnosis of ARPKD was ascertained in 15 of them on strict criteria. In only one patient could parental ultrasonography not be performed, so that a diagnosis of autosomal dominant (AD) PKD, which is very rarely associated with congenital hepatic fibrosis in PKD1 families was not formally excluded [17]. In other families, a diagnosis of ADPKD could also be theoretically considered in case of illegitimate paternity or de novo ADPKD. However, none of our patients had progressive enlargement of kidneys, as expected in ADPKD. In all of them, kidney size was indeed normal or reduced (data not shown). This is in keeping with data from Zerres et al. [10] showing that in contrast to ADPKD, ARPKD kidneys do not increase in size with age and with the decline in renal function during childhood. Progressive decrease in size has even been reported [18]. Interestingly, twelve out of 16 of our patients were females, whereas in two cohorts of 170 children with ARPKD male to female ratio was 1.36, and survival probability was smaller for girls [10,19].

Notably, only 56% of our patients developed high blood pressure, whereas hypertension is the rule in children with ARPKD and was the most significant cause of morbidity and mortality among perinatal survivors before the availability of potent antihypertensive agents. Our observation is, however, in line with late regression of hypertension noted by paediatric nephrologists [2].

In this subset of ARPKD patients selected on the basis of the persistence of autonomous renal function at the age of 18, it is remarkable that the decline in renal function only started beyond the third decade in five of them, and that the mean annual loss in creatinine clearance was 2.9 ml/min. This is lower than in ADPKD patients with declining renal function, in whom the rate of loss is 5–6.4 ml/min/1.73 m2/year [20]. The determinants of slow progression in this subset of ARPKD are unknown. The small number of patients did not allow us to assess a possible influence of gender. Genetic heterogeneity is not likely to play a major role. Indeed, except for the very rare patients with additional skeletal and facial anomalies [21], there is so far no evidence for genetic heterogeneity in ARPKD, since the same genetic locus was found to be involved in families with childhood presentation [1], as well as in the severe perinatal form [22]. This was confirmed in 164 families covering a broad spectrum of clinical manifestations [23]. A wide variation of phenotype may even be found with the same mutation, as exemplified in two of our families with a contrasting course of renal impairment within sibling pairs. Such a marked discordance in the progression of the disease among siblings with ARPKD has been reported by others [7,8,22,24]. This variability may be accounted for either by environmental or genetic factors. Early detection and good control of hypertension may delay ESRD in inherited polycystic kidney diseases, with more compelling evidence in the autosomal recessive [2], as compared to the dominant form [26]. Alternatively, modifying genes could modulate the expression of the disease, as demonstrated by Woo et al. [27] in pcy/pcy mice with autosomal recessive polycystic kidney disease.

Liver involvement can become symptomatic with age [10]. In accordance with earlier studies, none of our patients had impaired hepatocellular function. However, at the end of follow-up, 87% had clinical and/or imaging signs of portal hypertension and/or biliary duct ectasia. Magnetic resonance (MR) cholangiography seems to be a sensitive method of revealing biliary abnormalities associated with congenital hepatic fibrosis, even when ultrasonography is normal [28]. Combined with MR imaging of the kidneys, which enables early detection of microcystic dilatation of collecting ducts [29], it may become a valuable tool for diagnosis and follow-up of ARPKD in the future. Liver involvement may lead to life-threatening complications such as gastro-oesophageal bleeding. Thirty-one per cent of the patients with liver involvement developed haemorrhage due to portal hypertension, and one died of uncontrolled bleeding. Of note, all but two of our patients developed portal hypertension early in life, either in their first or second decade. Early detection and appropriate management of portal hypertension is mandatory. Well-known primary and secondary prevention measures should apply to patients with ARPKD, including prophylactic use of beta-blockers, and endoscopic or surgical procedures. Finally, cholangiocarcinoma complicating intrahepatic duct dilatations developed in one patient. Cholangiocarcinoma associated with Caroli disease [30] and congenital hepatic fibrosis [31] has been reported. The dismal prognosis of cholangiocarcinoma raises the issue of regular screening for this complication of adult patients with ARPKD. However, the age at first screening, the periodicity, and the most sensitive tests are not yet known [30]. Until firm guidelines are available, screening may rely on yearly or half-yearly serum carbohydrate antigen 19-9 determination, being aware that the latter may be increased in severe renal failure.

We conclude that a small subset of ARPKD patients progress slowly to ESRD, some of them reaching the 5th or even the 6th decade with autonomous renal function. Determinants and prediction of slow progression are so far unknown. With prolonged survival, portal hypertension may lead to life-threatening complications. These are, however, amenable to medical and/or surgical treatment. Along with kidney transplantation, effective management of these complications, makes this disease compatible with long-term survival in children who survive the neonatal period.



   Acknowledgments
 
The authors thank Dr Alphonse (Clermont-Ferrand, France), Dr Antignac (Paris, France), Dr Benhamou (Clichy, France), Dr Conté (Toulouse, France), Dr Cornu (Cliniques Universitaires St Luc, Brussels, Belgium), Dr Lebon (Le Mans, France) and Dr Subra (Angers, France) for providing clinical care to the patients, and Mrs Doreen Broneer for secretarial assistance.



   Notes
 
Correspondence and offprint requests to: Dominique Chauveau MD, Service de Néphrologie, Hôpital Necker, 149 rue de Sèvres, f-75015 Paris, France. Back



   References
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 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 

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Received for publication: 2. 1.01
Accepted in revised form: 12. 3.01