ANTICIPATION OF END STAGE RENAL DISEASE IN PATIENTS WITH AUTOSOMAL DOMINANT POLYCYSTIC KIDNEY DISEASE IN SUCCESSIVE GENERATIONS

Abstract

Autosomal dominant polycystic kidney disease is a disorder, which is inherited in 50% of offspring, irrelevant the sex and it has a variable clinical expressivity. Initially it was noticed that the clinical expression was interfamilial, but some studies found out that it was different. The aim of this study was to evaluate the age of onset of end-stage renal disease (ESRD) in affected parents in comparison with their offspring in successive generations. We studied 60 families of patients with autosomal dominant polycystic kidney disease (ADPKD). The diagnosis was done by echo criteria and we included only the patients for whom we knew precisely the onset of ESRD (affected parent and offspring), the sex of the parent who suffered from the disease, and offspring. We found out that the ESRD in ADPKD appears at the same age in affected parents and offspring (49,3 ± 7,9 Vs 51,8 ± 9,2, p = NS) irrelevant of the sex of the offspring. Patients with paternal inheritance (n = 38) were diagnosed to have ESRD earlier than their affected parents (47,9 ± 8,3 Vs 52,2 ± 9,2 p < 0,05), but patients with maternal inheritance had no difference (n = 22) (51,9 ± 6,8 Vs 51,2 ± 9,4, p = NS). In all the patients (60 couples) the survival rate was the same between affected parents and offspring (p = NS, Kaplan-Meier test), but significant differences were noticed between offspring with paternal inheritance in comparison with their parents (p < 0,05). In conclusion, we have detected that the onset of ESRD between patients with ADPKD in successive generations: a) Occurs in offspring as in their ancestors, b) anticipation was observed in 55% of couples, c) the sex of offspring does not have any relation with the renal death and d) the ESRD in patients with paternal inheritance occurs earlier in offspring than in their ancestors but not with maternal.

• Anticipation
• Polycystic kidney disease
• Chronic renal failure
• Hemodialysis
• Renal failure
• End stage renal disease

INTRODUCTION

Nowadays, in a hereditary disease, as the autosomal dominant polycystic kidney disease (ADPKD), the renal death would be expected to occur later in offspring than in their parents. That is because during the last 40 years many antibiotic and antihypertensive agents have been available to treat the upper urinary tract infections and the hypertension, respectively. These complications are very common in these patients and can affect the renal function [[1]] if they are not properly treated [[2]]. Contrary to that belief, many articles have been published within the last decade, which demonstrate controversial results over the expected endstage of renal failure in offspring in comparison with their parents [3-6]. The purpose of this study was to investigate the age at renal death in the parent – offspring pairs of ADPKD patients as well as any sex relation.

PATIENTS AND METHODS

The endstage renal failure was studied in 60 offspring-parent pairs (in three renal units in our country) with ADPKD patients. The diagnosis of the disease was based on the known ultrasound criteria [[7]]. For all the patients who were included in the study, there was precise information on age at renal death at which parents or offspring started renal replacement therapy, as well as the gender of the parent who was carrier of the ADPKD trait.

Only the patients who met the above criteria were included. Excluded from the study were the pairs in which parents or offspring died before the onset of ESRD because of other reasons (accident, cardiac infraction, stroke etc). In 38 out of 60 pairs, the ADPKD gene was inherited from the father and in 22 from the mother.

Renal death was defined as the start of renal replacement therapy or a three month period after the serum creatinine levels were more than 900 μ1mol/L. Patients who were included in the study and lived before the existence of hemodialysis or peritoneal dialysis, as renal death was defined as the age at which they died from uremia.

Data are presented as mean and standard deviations. The comparison of age at renal death between the two groups was carried out using Long-Rank test and the survival rate by Kaplan–Meier method. As statistically significant differences we regarded those with significant level p < 0,05.

RESULTS

Dividing the patients in two groups (offspring-parents) with no other distinctions, we observed that offspring reached at the ESRD in a earlier age than their parents, even though this difference was not statistically significant (49,3 ± 7,9 Vs 51,8 ± 9,2, p = 0,076). Regarding the gender, the males offspring, reached at ESRD in corresponding ages with females (Table 1) (p = NS). The renal death in patients who had paternal inheritance occurred significantly earlier than in their ancestors (p < 0,05), but we observed that this fact did not occur in those who had maternal inheritance (p = NS) (Table 2). Anticipation was observed in thirty three-out of 60 couples (55%), 25 offspring patients reached at ESRD later than their parents (41,6%) and two at the same age (3,4%), but the cumulative survival rate between the two groups (offspring–parents) was the same (Kaplan–Meier, p = NS). The only significant difference in the survival rate was between offspring who had paternal inheritance in comparison with their parents (p < 0,05).

Table 1. Mean Age of Patients with ESRD (Offspring and Parents), in Relation to the Sex of Offspring

	Age
	Offsping	Parents	p
Female (n = 27)	49,7 ± 6,7 (35–67)	52,9 ± 9,9 (33–80)	NS
Male (n = 33)	49,1 ± 8,9 (31–74)	50,9 ± 8,8 (42–71)	NS
All (n = 60)	49,3 ± 7,9 (31–74)	51,8 ± 9,2 (33–80)	NS

Table 2. Age at Renal Death in Parents and Offspring in Relation to Paternal or Maternal Inheritance

	Age
	Offspring	Parents	p
Paternal inheritance (n = 38)	47,9 ± 8,3 (31–71)	52,2 ± 9,2(40–80)	<0,05
Maternal inheritance (n = 22)	51,9 ± 6,8 (43–74)	51,2 ± 9,4 (33–70)	= NS

DISCUSSION

The expression of ADPKD is varied among different families, while it was considered to be fairly homogenous within the same family [[8]]. However, recently it has been used again the term “anticipation” [[9]], that is the earlier onset of ESRD in successive generations of patients with inherited diseases, as ADPKD. The concept of this term was defined at first, early in this century, as a progressively earlier age of onset of ESRD from generation to generation [[10]] in patients suffered from ADPKD.

It must be emphasized that in most studies, the ESRD in patients with ADPKD seem to occur at the end of the 5th and at the beginning of the 6th decade of life as we noticed [3-4], [[6]], but some authors demonstrated that it occurs later than the above [[11]]. Also, during the last years, many articles demonstrated that the age at renal death in offspring was the same as their parents [3-4], [[9]].

Our results in this study are in accordance with others [[3]], [[9]], that is, the age of renal death is not different between offspring and parents. Especially, in some families the renal death occurred earlier in offspring (anticipation) and in others later than their parents. That means, that it is unlikely for the renal death to occur in all offspring earlier than their parents [[12]]. However, bibliography demonstrates that in a great percentage of patients (38–50%) there is anticipation (renal death occurred earlier in offspring) [[3]], [[9]], [[13]], as we also observed (55%), but others show less percentage of anticipation [[14]]. The renal death in our patients was not correlated with the gender as demonstrated in some studies [[13]], however, some authors have demonstrated more adverse prognosis in males (both offspring and parents) than in females [[3]], [[11]].

Regarding the gender of the parent who transmitted the ADPKD gene, we found that in case of paternal transmission, the renal prognosis in offspring was adverse in a statistically significant level (p < 0,05), as showed by others [[13]]. Some authors have demonstrated worse prognosis in case of maternal transmission [[9]] and others did not find such differences [[4]], [[6]]. In order to explain this phenomenon (earlier occurrence of renal death in offspring), some authors suggested the simple hypothesis, that patients with less severe manifestations of an inherent disease (mild expression of the disease) is more likely to give birth to children than those with severe manifestations. So, according to these authors who are mainly geneticists, it is de facto wrong to discuss earlier renal death in offspring, since the “bad” material of these patients is not included in the studies (because they do not give birth to children, so they do not exist as pairs) [[5]]. Other authors suggested that environmental or genetic factors influence the age at renal death in offspring, probably randomly. Specifically, they estimate that the earlier onset of ESRD in offspring is due to a molecular mechanism and moreover they suggest the presence of an unstable DNA, a fact that can explain the differences in the clinical manifestations of ADPKD [[9]].

But how can the anticipation be useful? It would be of great importance indeed, because offspring should be routinely checked, for their clinical manifestations (e.g. hypertension, upper urinary tract infections) as well as for special laboratory findings (e.g. glomerular filtration rate, kidney ultrasonography), because in a great percentage of children with ADPKD (∼ 30%), many treatable complications can be found [15-16].

In conclusion, this study shows that in successive generations of patients with ADPKD: a) the renal survival rate does not differ between offspring and parents, b) there is anticipation at 55% couples, c) the renal death does not have any relation with the sex of offspring, and d) the ESRD in patients with paternal inheritance occurs earlier in offspring than in their parents but not with maternal.