Incidence and survival of end-stage kidney disease due to polycystic kidney disease in Australia and New Zealand (1963–2014)

Autosomal dominant polycystic kidney disease (ADPKD) is the most common monogenetic disorder causing end-stage kidney disease (ESKD) in adults [1‐5]. It is a slowly progressive adult-onset chronic kidney disease that is characterized by the formation and growth of numerous fluid-filled cysts in the kidneys, which cause renal enlargement and pain, hypertension, intracranial aneurysms and cardiovascular disease [4]. ADPKD is caused by heterozygous germ-line mutations in PKD1 (85% of cases) and to a lesser extent PKD2 (15% of cases) [6]. These genes encode the proteins polycystin-1 and polycystin-2, which maintain the normal geometric structure of the distal nephron in the kidney [7]. Patients with PKD2 and hypomorphic PKD1 mutations have a better renal prognosis and a delayed onset of ESKD, compared to patients with truncating PKD1 mutations [7].

Previous observational studies, predominantly of dialysis registry data, have shown that the age of onset of ESKD due to ADPKD has increased over time and that patient survival on renal replacement therapy (RRT) has also improved [3, 8‐11]. Orskov et al. reported that the survival of Danish patients with ESKD treated with RRT has steadily increased over an 18-year period from 1990 to 2007 [11]. Similarly, a single-center study from the Oxford Renal Unit showed that patient survival improved over a 40-year period (1971–2000). Lastly, dialysis registry data from Europe (1991–2010) showed that the incidence rate of ESKD due to ADPKD has increased slightly over the last two decades (1991–2009) [12].

Over the last 50 years, there have been major improvements in the management of hypertension, hyperlipidemia and the treatment of anemia due to ESKD [13]. In Australia, angiotensin-converting enzyme inhibitors were first introduced onto the national Pharmaceutical Benefits Scheme (a government subsidized program for prescription drugs) in 1983, whereas erythropoietin stimulating agents and angiotensin receptor blockers became available in 1992 and 1997 respectively. Lowering blood pressure and treatment with cholesterol-lowering agents reduces the rate of renal cyst growth in ADPKD and could potentially delay the age of onset of ESKD [2, 14, 15]. Moreover, the treatment of anemia associated with ESKD improves outcomes in patients receiving RRT [16]. The Australia and New Zealand Dialysis and Transplant Registry (ANZDATA) has been recording the incidence, prevalence and outcome of all maintenance dialysis and transplant patients in Australia and New Zealand since 1963 [17]. This registry therefore provides an extensive timeframe to determine whether improvements in medical therapy might precede changes in the incidence of ESKD due to PKD and patient survival on RRT. Thus, the aim of the study was to determine whether there have been time-specific changes in the incidence of ESKD due to PKD and survival rates on RRT in Australia and New Zealand.

The development of end-stage kidney disease is the most significant clinical complication of PKD. In this study we investigated the incidence rate, age of onset and survival of PKD patients receiving RRT in Australia and New Zealand over a 50-year period to evaluate whether time-dependent changes have occurred. To our knowledge, this is the longest longitudinal follow-up of ESKD patients with PKD. The main findings were that: (i) the median age of onset and incidence of RRT has increased but relatively stable since 1990; (ii) the proportion of patients older than 65 years starting RRT has increased since 1990, representing almost a quarter of the cohort; (iii) hemodialysis was the most common initial dialysis RRT modality and technique survival on peritoneal dialysis was not affected by PKD; (iv) the percentage of pre-emptive kidney transplantation as the initial RRT modality has increased; and (v) the 5-year survival of PKD patients on RRT has continually improved over time.

Previous studies indicate that the population prevalence of PKD ranges anywhere from 1 in 400 to 1 in 5000 [1, 18‐23]. This wide variation is probably because the true population prevalence of PKD is virtually impossible to determine accurately, as disease penetrance (diagnosed by renal ultrasound) peaks late in life (after the age of 60 years), and a high frequency of patients (up to 50% or more) have a relatively benign life-time course and do not come to medical detection and/or the develop ESKD [20]. On the other hand, the increasing detection of asymptomatic PKD due to the fact that more diagnostic tests are being performed for other reasons in developed nations, may falsely give the impression that the population-based prevalence of PKD is rising [13]. Therefore, dialysis registry data in many ways provides the most accurate method of capturing changes in the pattern of disease incidence in the subset of PKD patients at high risk of renal morbidity.

The results of the current study show that that the incidence of ESKD due to PKD has progressively increased over the past five decades. Cohort studies from Denmark and the United States have made the same observation [9, 11], and these common findings are likely to be a reflection of a global increase in the age of patients starting dialysis rather than a feature specific to PKD. For instance, the median age at starting dialysis patients in Australia and New Zealand was 59.5 years in 1998 whereas it had increased to 62.9 years for Australia and to 60.3 years for New Zealand in 2009 [17]. This rising incidence is therefore common to all types of chronic kidney disease, including increased access and availability of RRT, and increased propensity to offer RRT to older patients, as well as reductions in the competing risk of cardiovascular mortality among those with pre-dialysis chronic kidney disease [24, 25].

Recent clinical trials in PKD suggest that a lower blood pressure and the use of renin-angiotensin inhibitors reduces the growth rate of renal cysts in PKD (albeit to a small extent of ~14% over an 8 year period) but do not alter the long-term decline in renal function [15]. In the current study the median age of onset of ESKD increased in PKD patients over time but has been stable since 1990. Angiotensin-converting enzyme inhibitors were introduced in Australia in the early 1980s (captopril in 1983 and enalapril in 1986), and first reported to have renoprotective properties in diabetic kidney disease in 1992 [26]. However, the real-world utilisation of renin-angiotensin inhibitors in CKD patients varies between 58 and 64% [27‐29], and hence a longer period of registry follow-up is required to evaluate their impact on the incidence of ESKD in ADPKD. Low birth weight has been also linked to an earlier onset of ESKD but has not been specifically addressed in the current study [30]. Therefore, the increasing age of onset of ESKD prior to 1990 is more likely due to factors discussed earlier (that is, improved access to RRT and reductions in cardiovascular death prior to RRT) [13]. Assessment of renal function by eGFR was incrementally introduced 2005 onwards [31] but it is too premature to determine the impact (if any) this could have on the incidence of ESKD. In this regard, one caveat to these conclusions is that the rate of renal disease progression in PKD occurs slowly over many decades [32]. For example, a recent analysis suggested that the time taken to transition from the early stage chronic kidney disease to final phase of ESKD, is up to seven times slower in PKD than in that due to other causes (e.g., 17.1 years in PKD vs. 2.5 years in non-PKD diseases) [33]. Thus, there may be a significant lag-time for subtle improvements in pre-dialysis medical management to be discerned, even with long-term registry data. Additionally, in this study it is not possible to model potential factors that may influence the changes in incidence using registry data because relevant risk factors (such as the use of ACE inhibitors) are not part of routine ANZDATA data collection. Instead, in the present study we have analyzed temporal changes in the incidence of the EKSD due to PKD and then associated them with changes in therapeutics in the Australia and New Zealand. Future and ongoing prospective studies, such as the CRISP cohort [34], are more likely to elucidate mechanisms for the underlying changes in incidence.

Hemodialysis was the most common mode of initial RRT in PKD patients in Australia and New Zealand, with only 25% using peritoneal dialysis. This pattern of dialysis modality utilization remained stable throughout the study period. It is not clear whether the preference for hemodialysis was due to patient-dependent and/or health-care-related biases. Certainly, it has been hypothesized that PKD patients experience greater technique failure on peritoneal dialysis due to systemic complications such as hernias, diverticular disease and reduced peritoneal surface area because of nephromegaly [35‐37]. However, this hypothesis was not been supported by others [38]. Lobbedez et al. [39] analyzed 344 French PKD and did not find evidence of a higher incidence of technique failure when compared with the non-PKD group. Similarly, Portoles et al. [40] also found that a “peritoneal dialysis first” model combined with an active transplant program has been successful in Spain. Li et al. [41] also reported peritoneal dialysis is a feasible treatment option for PKD patients despite a higher risk of abdominal wall hernia in their analysis of 126 peritoneal dialysis patients from Hong Kong. Finally, Courivad et al. also recently verified that the total kidney volume in PKD patients did not predict technique survival on peritoneal dialysis [42].

The survival of PKD patients in Australia and New Zealand improved with each decade, similar to other cohorts [43]. In our study, the magnitude of increase in the 1-year survival was most marked between the first two time periods (1963–1974 to 1975–1984). The progressive increase in survival could, in part, be explained by the rise in living kidney transplantation in the study cohort. The current data are similar to that of Orskov et al. [11] who followed 693 Danish PKD dialysis patients for 18 years (1990–2007) and found that there was a progressive improvement in survival (2-year survival increased from 80 to 86%, and 5-year survival increased from 56 to 68%). It is noteworthy that cerebrovascular disease as a cause of death has decreased in PKD dialysis patients in our study period. Presumably this is a result of increased radiological screening for cerebral aneurysms over the study period and improvements in the management of hypertension [44]. These data are also consistent with the Danish cohort of PKD dialysis patients, where it was reported that cerebrovascular declined by 69% over an 18-year period [45].

There are several limitations of our study. First, it is a retrospective registry-based analysis and therefore provides only correlative data associated with the timing of changes in medical treatments, such as the introduction of angiotensin converting enzyme inhibitors in Australia. Second, the categorization of primary renal disease used by the ANZDATA Registry has remained constant for many years. We hypothesize the vast majority of patients in the cohort are likely to have ADPKD because this is by the most common form of cystic renal disease associated with CKD and ESKD in adults, with an estimated population prevalence of ~1:2500 (as discussed earlier in the discussion) whereas the autosomal recessive variant falls into the ultra-rare category with an estimated incidence of 1:20,000 to 40,000 [46] and almost all manifest at birth or early childhood. In this regard, the latter are more likely to have been reported under the “juvenile polycystic disease” category, not included in our analysis. At present, ANZDATA does not collect information regarding genetic testing because this is not routine clinical practice in Australia (and most other countries), where the Pei-Ravine Unified Ultrasound Criteria is the standard method of diagnosis [47]. The latter has high sensitivity and specificity (validated against DNA Sanger Sequencing), and we would anticipate that the majority of cases identified as PKD in the ANZDATA Registry would be of the autosomal dominant subtype. Third, as discussed earlier, it may take a longer period of follow-up before minor changes in the incidence of ESKD due to PKD are consistently detected as a result of changes in pre-dialysis care. Finally, another limitation is the year in which the entire (100%) Australian and New Zealand population had full access to dialysis. Although an exact date cannot be provided, on reviewing the rate of expansion of the entire ESKD population (data not shown), we noted that the absolute number of patients was more stable (that is, the rate slowed) from 1970 onwards, and therefore hypothesise that this period onwards was period in which the entire population would have had full access to dialysis treatment options.

In conclusion, the results of this study show that the incidence and age of onset of ESKD in patients with PKD has increased over a 50-year period in Australia and New Zealand but have stabilized in the most recent era. These findings are important because they clearly imply that that the development of disease-specific drugs that alter renal cyst growth [48] are needed to prevent kidney failure due to PKD. Because renal cysts in PKD develop during early childhood, it does not seem unreasonable to suggest that the implementation of highly effective and safe disease-specific treatments in a young person with PKD [49] could potentially eliminate the development of ESKD due to this condition in the 21^st century. Further studies will hopefully confirm this hypothesis in the future.