Scientific Papers

Exploring the clinical and genetical spectrum of ADPKD in Chile to assess ProPKD score as a risk prediction tool | Translational Medicine Communications


This study represents the first report providing insights into the clinical and genetic characteristics of ADPKD in a Latin American population, specifically in Chile. Among the patients included in the study, we identified a total of 21 novel variants, with the majority of them located within the PKD1 gene. This finding highlights a high mutability of the PKD1 gene in this population. The data obtained from this study can serve as a valuable resource to support the diagnosis of ADPKD in specific cases and contribute to early and personalized clinical management. Additionally, the findings may have implications for decision-making regarding transplantation, in accordance with the laws and regulations in Chile.

In our cohort of probands, the median age at which ADPKD was clinically diagnosed was 35 years. It is noteworthy that 60% of these individuals had already progressed to ESRD at the time of recruitment and required RRT at a median age of 49 years. This observation of relatively early disease progression, compared to other reported cohorts, suggests the presence of rapid disease progression in our study population. It is important to acknowledge that there might be additional factors contributing to the more pronounced symptoms that led these individuals to seek medical attention earlier. However, it is essential to note that our initial pilot study conducted between 2014 and 2017 exhibited certain biases. ADPKD patients were predominantly recruited from local dialysis and transplant registries, which might have influenced the higher detection rate of PKD1 variants compared to PKD2 variants.

The majority of our ADPKD probands had a positive family history, and genetic analysis successfully identified a pathogenic, likely pathogenic variant, or VUS in 95% of them. Similar to other studies, a small subgroup of individuals did not have a family history, but genetic analysis revealed the presence of de novo PKD1 variants [30]. One such case involved a 19-year-old patient who had been diagnosed with ADPKD two years prior and exhibited multiple risk factors, including being a male carrier of a PKD1-truncating variant, hypertension, and urological events.

The genetic analysis identified heterozygous variants dispersed in or adjacent to the 22/46 PKD1 exons and 2/15 PKD2 exons. According to public databases and reports, variants have not been localized at particular loci, but have been identified in untranslated regions, exons and introns. Four variants were found to be shared by two families: c.7126 C > T and c.11379_11380insG in PKD1, and c.1781delC and c.2465delA in PKD2. While some of these variants may have arisen independently because increased mutability has been described for PKD1, it is worth considering the possibility of a founder effect for PKD1 c.7126 C > T and the two novel PKD2 variants, as the families were geographically close (within 100 km) [31, 32]. Founder variants have been previously described in ADPKD, suggesting that variants that are unexpectedly frequent in specific geographic areas may have originated from a founder effect.

In this study, we observed that a significant portion of the PKD1 variants identified were concentrated in specific segments of the protein, which are predicted to have functional relevance. Based on this finding, we suggest considering the development of an algorithm for direct sequencing or bioinformatic analysis following NGS that prioritizes this segment. This approach could help optimize cost, time, and labor in genetic analysis. However, it is important to exercise caution and consider the potential recruitment bias in this study, as the cohort was not randomly selected.

As of January 2023, the PKDB has registered more than 2500 unique pedigrees with (likely) pathogenic variants or VUS. Earlier studies on ADPKD reported a high percentage (60% to 70%) of novel variants reflecting the limited comprehensiveness of genetic databases at the time. As these databases have expanded with the progressive incorporation of NGS sequencing, it is expected that the rate of novel variants may decrease. However, the rate of new variants identified in ADPKD is also influenced by the methods used for variant identification and the specific study population. In our cohort, we identified a total of 21 (62%) novel variants. No associations were found between novel variants and phenotype features; however, this may change over time as more patients and more clinical data are collected.

While our dataset is still limited, it serves as a valuable starting point for improving our understanding of the clinical phenotypes and genetic profiles of ADPKD in our country. This database will contribute to expanding our knowledge and prompt further research on ADPKD. Targeted NGS approaches have proven to be effective in identifying variants not only in the primary causative gene but also in other genes known to be associated with ADPKD. In addition to targeted NGS, whole-exome sequencing (WES) and whole-genome sequencing (WGS) are alternative approaches that offer a broader perspective on the genetic landscape of ADPKD. WES examines the protein-coding regions of the genome, while WGS encompasses the entire genome, including both coding and non-coding regions. These unbiased sequencing methods have the potential to identify novel genes associated with ADPKD or other genes that may play a role in the response to specific therapies, as described in other clinical contexts [4, 33]. It is worth noting that WES and WGS require more extensive sequencing and data analysis compared to targeted NGS, making them more resource-intensive. However, as technology advances and costs decrease, these comprehensive sequencing approaches might become increasingly accessible and may hold promise for further understanding the genetic complexities of ADPKD and related conditions.

Assessing the genetic profile of ADPKD in a broad manner can lead to the identification of various variants across the genome. One emerging concept in genetic research is the study of Total Mutational Burden (TMB), which refers to the total number of mutations present in a given sample. TMB has gained attention as a potential predictor of clinical outcomes and has demonstrated its utility in predicting cancer metastasis and treatment response. For example, a study focused on lung cancer utilized machine learning models to evaluate the predictive power of TMB [34]. The results showed that TMB was a significant predictor of metastasis, with the classification models demonstrating high-performance measures. Moreover, clinical studies have shown that tumors with high TMB tend to respond better to immunotherapy [35]. This suggests that TMB could be a relevant factor in predicting treatment outcomes and tailoring therapeutic approaches not only in cancer research. Consequently, it is plausible to estimate TMB in ADPKD patients to gain insights into disease progression and response to interventions.

Different biomarkers have been investigated to assess the risk of disease progression in ADPKD, including clinical, molecular, genomic, and imaging markers, featuring their advantages and disadvantages [36]. Imaging techniques such as ultrasonography, computed tomography, and magnetic resonance imaging can detect renal cysts, with monitoring of total kidney volume considered the best image-based marker for ADPKD. However, access to and affordability of these imaging methods can be limited in some countries, and accurate interpretation requires trained operators and image analysts, particularly in the early stages of the disease.

On the other hand, the cost of genetic analysis has decreased significantly over the past few decades, making it a more cost-effective option. However, genetic analysis is still not widely accessible in resource-limited settings. Nevertheless, evidence suggests that early genetic analysis can lead to substantial cost savings [37]. Genetic testing in ADPKD can provide valuable information for family planning, prenatal testing options, and clinical management decisions, as well as help evaluate future scenarios [38]. Current guidelines recommend the standard method of ADPKD genetic analysis, which involves LR-PCR followed by direct sequencing [39]. In the last decade, there have been attempts to implement NGS analysis, considering that it offers the potential to detect additional variants and somatic mosaicism. However, NGS can also result in missed variants, particularly in PKD1 due to its gene complexity [40,41,42].

It is important to note that disease progression in ADPKD can vary within families, suggesting that focusing solely on the gene and type of variant may be insufficient to predict the risk of progression accurately. In our study, differences were observed in survival curves based on the type of variant and risk stratification using the ProPKD score. The ProPKD score showed better discrimination between high-, intermediate-, and low-risk groups. While the impact of genetic and clinical variables has been useful in developing the ProPKD score, until now, it has never been applied to Latin American cohorts, which might be explained by the need for genetic testing.

Latin American countries face significant disparities, including in healthcare access. Chile, located on the southwestern coast of South America and with a population of approximately 19.5 million, is classified as a high-income country by the World Bank and an Upper-middle-income country by the sociodemographic index [43]. However, like other countries in the region, it exhibits noticeable socioeconomic variability, as evidenced by a Gini index of 0.45 in 2020. The healthcare system in Chile is served by both public (FONASA) and private providers. FONASA caters to 80% of the population and bears the cost of dialysis, a significant expenditure amounting to 253 million USD for 22,000 patients. This figure corresponds to 30% of the annual FONASA budget, not accounting for other expenses such as hospitalizations, medical visits, and medications. In our perspective, timely diagnosis of ADPKD, particularly in high-risk patients, holds the potential to propose a more individualized clinical management approach aimed at slowing down the progression of CKD and delaying the onset of ESRD. This, in turn, could contribute to reducing therapeutic costs while novel therapies for ADPKD are being developed [44, 45].

In Chile, public financial coverage of genetic testing is limited to direct sequencing, and it requires a laboratory with sanitary authorization in a clinical setting. This restriction highlights the need for cost-effective and accessible diagnostic approaches for conditions like ADPKD, given the burden imposed on the national healthcare system. It should be noted that the genetic complexity of PKD1 may hinder widespread genetic testing in developing nations in addition to several factors including variant diversity, costs, scarcity of genetic counselors and experts in molecular genetics, patient data privacy as well as regulatory and ethical frameworks. The situation regarding genetic conditions varies from one country to another and may evolve over time as healthcare systems and resources change. Efforts to raise awareness about the ADPKD diagnosis and management could help address this issue in the future.

Our study is subject to several limitations that should be acknowledged. Firstly, the majority of our patients had received their diagnosis a long time ago, which limited our ability to obtain complete imaging records to correlate with the clinical course. Furthermore, the persistence of paper-based medical registries in certain healthcare centers posed challenges in data collection and retrieval. Although we achieved a high detection rate, it is important to note that we did not employ the multiplex-ligation probe-amplification technique to identify deletions/duplications in PKD1 or PKD2. Therefore, the possibility of these genetic alterations existing within our cohort cannot be definitively ruled out. Additionally, it is important to consider that our dataset was of moderate size and initially biased toward patients registered in RRT programs. These individuals typically exhibit a more severe phenotype, increasing the likelihood of identifying pathogenic variants in PKD1. Consequently, the extrapolation of our findings to other ADPKD patients needs caution. Lastly, we did not conduct haplotype analysis for the few cases of unrelated families sharing variants, which could have provided insights into the presence of a founder effect within them. Despite these constraints, our study contributes valuable clinical data and insights into ADPKD in the Chilean population. Further research addressing these limitations and expanding the scope of investigation is required to enhance our understanding of the disease in this context.

This study benefits from several factors that contribute to its strengths and advantages. Chile has implemented a formal program to train clinical geneticists who can provide counseling in both public and private healthcare centers [46]. Some laboratories in Chile perform direct sequencing, which is covered by FONASA, however, PKD1 and PKD2 genetic testing are not included. To achieve the results presented in this study, three major research initiatives were necessary, combining direct sequencing and NGS strategies to describe the genetic profile of ADPKD patients. NGS panels offer a comprehensive option in various clinical scenarios. Chilean patient samples requiring this type of analysis are often sent to international laboratories, but PKD1 is frequently excluded.

Since 2018, there has been a significant increase in awareness among Chilean nephrologists regarding the utility of genetic testing. This awareness stems from the ability to communicate to families the risk of inheritance and to consider living-related donors for transplantation. The ProPKD score, which assesses the risk of CKD progression in ADPKD, has emerged as a suitable risk prediction tool in the local setting. However, when comparing the age of ESRD onset in our patients with the GENKYST cohort, we observed that our patients reached this stage 2.4, 7.9, and 18.6 years earlier in the high-risk, intermediate-risk, and low-risk groups, respectively. Further studies involving larger cohorts are needed to explore the relevance of other biological and environmental factors that influence kidney decline during the disease’s clinical course.



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