Clinical Kidney Journal, 2021, vol. 14, no. 8, 1879–1885 doi: 10.1093/ckj/sfab056 Advance Access Publication Date: 12 March 2021 CKJ Review Clinical Kidney Journal CKJ REVIEW Genetic kidney diseases as an underrecognized cause of chronic kidney disease: the key role of international Downloaded from https://academic.oup.com/ckj/article/14/8/1879/6169174 by guest on 03 January 2023 registry reports 1 1 2 3 Roser Torra , Mónica Furlano , Alberto Ortiz and Elisabet Ars 1 Department of Nephrology, Inherited Kidney Diseases, Fundació Puigvert, Instituto de Investigaciones Biomédicas Sant Pau (IIB-Sant Pau), Medicine Department-Universitat Autónoma de Barcelona, REDinREN, Instituto de Investigación Carlos III, Barcelona, Spain, 2IIS-Fundación Jimenez Diaz, School of Medicine, Universidad Autónoma de Madrid, Fundación Renal In ~ igo Alvarez de Toledo-IRSIN, REDinREN, Instituto de Investigación Carlos III, Madrid, Spain and 3Molecular Biology Laboratory, Fundació Puigvert, Instituto de Investigaciones Biomédicas Sant Pau (IIB-Sant Pau), Universitat Autónoma de Barcelona, REDinREN, Instituto de Investigación Carlos III, Barcelona, Spain Correspondence to: Roser Torra; E-mail: rtorra@fundacio-puigvert.es ABSTRACT Inherited kidney diseases (IKDs) are among the leading causes of early-onset chronic kidney disease (CKD) and are responsible for at least 10–15% of cases of kidney replacement therapy (KRT) in adults. Paediatric nephrologists are very aware of the high prevalence of IKDs among their patients, but this is not the case for adult nephrologists. Recent publications have demonstrated that monogenic diseases account for a significant percentage of adult cases of CKD. A substantial number of these patients have received a non-specific/incorrect diagnosis or a diagnosis of CKD of unknown aetiology, which precludes correct treatment, follow-up and genetic counselling. There are a number of reasons why genetic kidney diseases are difficult to diagnose in adulthood: (i) adult nephrologists, in general, are not knowledgeable about IKDs; (ii) existence of atypical phenotypes; (iii) genetic testing is not universally available; (iv) family history is not always available or may be negative; (v) lack of knowledge of various genotype–phenotype relationships and (vi) conflicting interpretation of the pathogenicity of many sequence variants. Registries can contribute to visualize the burden of IKDs by regularly grouping all IKDs in their annual reports, as is done for glomerulonephritis or interstitial diseases, rather than reporting only cystic disease and hiding other IKDs under labels such as ‘miscellaneous’ or ‘other’. Any effort to reduce the percentage of patients needing KRT with a diagnosis of ‘nephropathy of unknown etiology’ or an unspecific/incorrect diagnosis should be encouraged as a step towards precision nephrology. Genetic testing may be of value in this context but should not be used indiscriminately, but rather on the basis of a deep knowledge of IKDs. Keywords: chronic kidney disease, familial, genetic, genetic testing, inherited kidney disease, registries Received: 5.3.2021; Editorial decision: 8.3.2021 C The Author(s) 2021. Published by Oxford University Press on behalf of ERA-EDTA. V This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/ licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com 1879 1880 | R. Torra et al. INTRODUCTION most common cause of KRT in both Europe, where it ties with glomerulonephritis [2], and the USA [5]. The incidence of KRT Chronic kidney disease (CKD) affects an increasing percentage due to hypertensive nephropathy is related to the incidence of of the population, reducing the quality of life and also having a other causes of end-stage kidney disease but not to the burden very significant socio-economic impact [1]. Kidney biopsy has of hypertension per country [6]; consequently, a diagnosis of hy- long been the fundamental diagnostic tool for identifying the pertensive nephropathy essentially equates to CKD of unknown cause of CKD. However, in recent years the aetiological diagno- aetiology in a patient with hypertension. Something similar sis of kidney diseases has been enhanced by the advent of bio- occurs in some cases of diabetic nephropathy in patients with markers such as anti-phospholipase A2 receptor antibodies, mild diabetes and in those labelled as having unspecific which facilitate the diagnosis of primary membranous ne- glomerulopathy. phropathy even in the absence of a kidney biopsy. Despite these Despite the rarity of each individual inherited kidney disease advances, a significant percentage of patients without a diagno- (IKD), taken together the IKDs account for 10–15% of adult sis still reach CKD category G5. The latest published European patients and most paediatric patients on KRT [7–10]. The only Renal Association–European Dialysis and Transplant IKD clearly reflected in national and international registries is Downloaded from https://academic.oup.com/ckj/article/14/8/1879/6169174 by guest on 03 January 2023 Association (ERA-EDTA) registry data [2, 3] indicate that this autosomal dominant polycystic kidney disease (ADPKD). While percentage is as high as 27% among patients who are on kidney ADPKD has a similar prevalence in different regions of the replacement therapy (KRT) (Figure 1A). According to the US world, its relative frequency among the causes of CKD varies Renal Data System (USRDS) Annual Report 2017 (https://www. depending on the prevalence of other nephropathies such as di- usrds.org/), 22% of paediatric patients and 18% of adult patients abetic and hypertensive kidney disease, which are more closely who start KRT do so without a certain diagnosis (Figure 1B). related to lifestyle. The other IKDs are grouped in the ‘miscella- It also needs to be emphasized that apart from the alarm- neous’ category of the ERA-EDTA registry and in the unknown/ ingly high and ever-increasing percentage of adult patients who other sections in the USRDS. This generates a problem of invisi- start KRT without a precise diagnosis, some of those diagnosed bility: out of sight, out of mind. as having hypertensive nephropathy, diabetic nephropathy or A key point to note is that a non-negligible percentage of unspecified glomerulopathy subsequently prove to have an in- patients who need KRT without a specific diagnosis suffer correct diagnosis [4]. Hypertensive nephropathy is the second undiagnosed genetic kidney conditions, as has been A Glomerulonephritis B Unknown/other Pyelonephritis 11% 14% Cystic kidney 5% ADPKD 27% Unknown 3% 5% Glomerulo- nephritis 7% 47% Diabetes Diabetes 20% mellitus 17% Miscellaneous Hypertension 29% 12% 2% Renal vascular Hypertension disease C Other Systemic Glomerulonephritis Glomerulonephritis 3% 3% Diabetes 10% 13% 25% 13% Vascular 20% Vascular Diabetes 43% 12% 17% IKD Other 14% 8% IKD 6% 6% 7% Interstitial Unknown Interstitial Systemic FIGURE 1: (A) Percentage of incident patients receiving KRT according to the primary cause of kidney disease: ERA-EDTA registry 2018 as presented in the annual report [2, 3]. (B) Percentage of incident patients receiving KRT according to the primary cause of kidney disease: USRDS 2017, as presented in the annual report [5]. (C) Percentage of incident patients receiving KRT according to the primary cause of kidney disease when IKDs (cystic and non-cystic) are presented as a single category: left panel, data from Madrid renal registry, right panel: data from Catalan renal registry (Manuel Aparicio, personal communication for Registro Madrilen ~ o de Enfermedades Renales and http://trasplantaments.gencat.cat/web/.content/minisite/trasplantament/registres_activitat/registre_de_malalts_renals/arxius/Informe- RMRC-2018.pdf for the Catalan Society of Nephrology). Genetic kidney diseases in chronic kidney disease | 1881 demonstrated in a large cohort of adult patients with CKD [4]. In sequencing reactions in parallel and at the same time. They en- this study, genomic analysis using whole-exome sequencing able the detection of all types of genetic variants, from single- (WES) revealed that among 3315 adult patients with CKD, 9.1% nucleotide variants to large structural variants [copy number had a monogenic kidney disease. It is particularly noteworthy variations (CNVs)], although the sensitivity for CNV detection is that a precise diagnosis was achieved in 17.1% of the 281 lower. There are three NGS approaches, applied for different patients labelled as having kidney disease of unknown aetiol- purposes: targeted gene panels, in which a panel of genes spe- ogy. In another study, Connaughton et al. [11] identified the ge- cific for a disease is examined simultaneously; WES, which tar- netic cause of 34% of kidney diseases of unknown aetiology. gets all protein-coding genes in the human genome; and whole- These data highlight the prevalence of IKDs among CKD cases genome sequencing, which is used to determine the complete as a whole. In addition, the fact that 30% of patients with CKD DNA sequence of the genome. All three approaches have their have a family member with kidney disease suggests that ge- advantages and disadvantages, as well summarized elsewhere netic variants can explain a significant proportion of CKD cases [25, 26]. The clinical interpretation of the thousands of variants [12]. Alport syndrome is now considered to be almost as fre- identified in each individual with respect to the reference se- quent as ADPKD [4], the latter being a difficult-to-miss diagnosis quence genome represents a bottleneck in all NGS approaches. Downloaded from https://academic.oup.com/ckj/article/14/8/1879/6169174 by guest on 03 January 2023 that accounts for ~5% of patients on KRT. Genetic forms of inter- While the number of gene–disease relationships reported stitial kidney diseases, including autosomal dominant tubuloin- within the field of nephrology has rapidly expanded, the evi- terstitial kidney disease (ADTKD) and nephronophthisis, may dence to support these relationships is frequently very limited, also be more frequent than anticipated among patients with which precludes precise evaluation of genomic variation in clin- CKD of unknown aetiology or misdiagnosed [4, 13]. ical settings. The National Institutes of Health–funded Clinical In many cases, inaccurate diagnoses serve to disguise a sub- Genome Resource has developed a framework for the definition optimal diagnostic workup. As part of that workup, genetic test- and evaluation of the clinical validity of gene–disease pairs ing should be considered to rule out an IKD. There are two across a wide range of Mendelian disorders [27]. Moreover, in re- fundamental ways in which genetics can explain the family ag- cent years, laboratories across the world have implemented gregation of CKD. Pathogenic variants in Mendelian genes are standardized guidelines for the clinical interpretation of se- rare, but they exert an enormous disease-causing effect; exam- quence variants associated with Mendelian diseases [28]. These ples include IKDs such as ADPKD, Alport syndrome, ADTKD and guidelines allow the classification of sequence variants accord- ing to a five-tier nomenclature system: pathogenic, likely patho- tubulopathies. On the other hand, common genetic variants ex- genic, uncertain significance, likely benign and benign. The ert a very slight effect on the phenotype but are very frequent. largest category is variants of unknown significance, which The CKDgen consortium attempts to discover genetic loci asso- makes genetic testing difficult in many patients. ciated with CKD-classifying quantitative traits that influence The availability of larger and more diverse reference datasets the evolution and even the presentation of many kidney dis- has shown that many previously reported pathogenic variants in eases [14]. The heritability of the estimated glomerular filtration fact have an allele frequency that exceeds the disease prevalence rate has been suggested to be somewhere between 6% and 30% and can be reclassified as benign. As a general rule, clinicians in the general population [15–17], and several loci have been should only act on variants that are classified as either patho- reported to be associated with kidney function [18, 19]. Genetic genic or likely pathogenic and should also consider reassessing variants related to the presence and degree of microalbuminuria old genetic results in the light of newly available data. It is evi- and proteinuria have also been identified [20] and a meta-analy- dent that post-sequencing data analysis is becoming the key sis revealed variants of significance for rapid decline in kidney step in NGS. While the cost of sequencing has been declining function [21]. DNA variants in APOL1 have been shown to be as- rapidly, the amount of sequence data generated is expanding, as sociated with non-diabetic CKD in individuals of African origin a consequence of which data analysis and storage are accounting [22]. In addition, genome-wide association studies (GWASs) have for larger fractions of the real cost of sequencing [29]. led to the discovery of a significant number of loci that cause NGS has facilitated identification of the genetic basis of sev- small to moderate effects in immunoglobulin A nephropathy, eral IKDs and improved the diagnosis and management of membranous nephropathy and steroid-sensitive nephrotic syn- patients with these nephropathies. It should be noted that other drome [23]. All of these GWAS findings reveal a genetic back- genetic techniques must be used for the diagnosis of ADTKD- ground in non-commonly IKDs. The utility of these findings lies MUC1, which is not possible on the basis of NGS [30–32]. Thus above all in the development of prognostic scores for these ne- comprehensive exclusion of other nephropathies requires both phropathies. GWAS findings have less direct impact, at least indi- NGS and a search for specific genetic variants that are known to vidually, than the pathogenic variants found in genes causing be relatively common but are missed by NGS. In addition to var- Mendelian diseases, which are the leading cause of a given phe- iants in a single gene, chromosomal abnormalities contribute to notype. The present article focuses on the latter. It is of great im- IKDs, and this is especially true in children with neurodevelop- portance that nephrologists can access the tools to diagnose mental and/or multiorgan syndromes [33, 34]. Such chromo- IKDs. It has been estimated that across a wide spectrum of disor- somal anomalies can be identified by karyotyping or by ders, up to 50% of individuals with rare genetic conditions remain ‘comparative genomic hybridization’, which is a molecular cyto- undiagnosed, and IKDs are no exception [24]. genetic method for the analysis of CNVs. Clinicians should be aware of the potential psychosocial impli- AVAILABLE TECHNIQUES FOR THE DIAGNOSIS cations that a genetic diagnosis has for patients. There is a need for a multidisciplinary approach to genetic testing for IKDs. It does OF IKDS not seem feasible that all nephrologists requesting a genetic test The implementation of next-generation sequencing (NGS) tech- will be sufficiently proficient to interpret any kind of genetic report nologies (also known as massively parallel sequencing) in rou- appropriately. For example, many nephrologists do not know tine genetic testing has hugely improved the diagnostic yield in about the very common finding of variant of unknown signifi- patients with IKDs. NGS technologies process millions of cance. A multidisciplinary team comprising molecular geneticists, 1882 | R. Torra et al. nephrologists, psychologists and genetic counselors should help milder clinical presentations. This is a frequent finding in in delivering this kind of genetic result to patients. mildly affected tuberous sclerosis patients. These patients have limited organ involvement, as most cells in their body do not carry the pathogenic tuberous sclerosis complex OBSTACLES TO SUSPECTING AN IKD variant. However, they may have extremely severely af- Patients often spend years visiting multiple healthcare pro- fected offspring, as in the progeny without mosaicism, viders before they receive an accurate diagnosis of an IKD. For where all cells throughout the body harbour the pathogenic some diseases, such as ADPKD, clinical suspicion of the disease variant [46]. combined with information acquired by means of clinical imag- v. Epigenetic regulation: These are modifications to the ge- ing studies is usually sufficient for diagnosis; however, this nome that are not encoded in the DNA sequence but do does not hold true for the vast majority of IKDs. Genetic testing form a part of the cellular memory and impact on the phe- has led to the reclassification of IKDs and has also broadened notype. Environmental insults such as hyperglycaemia or the phenotypic spectrum of many classic IKDs. uraemia can lead to an altered metabolic situation, which There are several reasons why a nephrologist may never in turn can trigger changes in chromatin modifications and Downloaded from https://academic.oup.com/ckj/article/14/8/1879/6169174 by guest on 03 January 2023 suspect a genetic disease in a patient with a kidney condition. gene expression. Among these, lack of knowledge on IKDs in conjunction with vi. X inactivation: This is a physiologic process in which one the presence of an unexpected phenotype is probably the main of the copies of the two X chromosomes present in every obstacle to diagnosis. A family history of kidney disease is fre- female cell is inactivated. The inactive X chromosome is si- quently not obtained in adults with kidney disease. Questions lenced through epigenetic modifications and is transcrip- on the existence of kidney disease among family members tionally inactive. In humans, X chromosome inactivation is should be asked periodically, as individuals may not initially be a random process, but in certain cases it is skewed towards aware of health issues in family members but may become in- the wild-type or the mutated allele. When a very high per- terested in them when asked. Additionally, the family history centage of cells with the wild-type allele is inactivated, the may evolve over time, as subclinically affected individuals may disease will be much more severe than would normally be eventually develop manifestations of kidney disease. On the expected in a female [45, 47, 48]. This phenomenon is very other hand, patients may display a phenotype very different important for certain IKDs, including X-linked Alport syn- from that described initially for the disease in question, making drome and Fabry disease. While one would expect females it very unlikely that the nephrologist will consider this disease. to be much less severely affected than males with these There are a number of explanations for the existence of pheno- diseases, the skewed X inactivation means that in these types that differ greatly from those classically described. pedigrees some females will be affected to the same extent, impeding identification of an X-linked pattern of inheri- i. Allelic heterogeneity: Different pathogenic variants in a tance [49]. particular gene give rise to different phenotypes [35–37]. vii. Environmental factors: Both during embryonic develop- For example, some missense variants in Fabry patients al- ment and throughout life, phenotype is influenced by envi- low the production of a certain amount of -galactosidase ronmental factors. For exxample, a lifestyle not in accord and give rise to a late and predominantly cardiac pheno- with cardiovascular health will worsen the course of al- type [38]. most any IKD. ii. Incomplete penetrance: Some individuals who carry a given pathogenic variant do not develop the disease phe- notype [39–41]. This has been shown to occur for certain TIPS ON HOW TO SUSPECT AN IKD IKDs, including ADTKD, in which intrafamilial variability Although, as previously pointed out, a significant percentage of may be so pronounced that the nephrologist will not sus- patients with kidney disease of unknown aetiology may have pect an IKD [31]. an IKD and genetic testing allows a diagnosis to be made, one iii. Oligogenic inheritance and modifier genes: The disease must not make the mistake of requesting unsubstantiated ge- phenotype is determined by pathogenic variants in more netic studies. While the cost of NGS has decreased, it is still suf- than one gene. For example, patients with mutations in a ficiently high that it must not be used in a non-cost-effective steroid-resistant nephrotic syndrome/focal segmental glo- way. merulosclerosis (FSGS) gene and COL4A3 present a more The following circumstances may arouse suspicion of an severe phenotype than family members with a mutation in IKD, in descending order of importance (Figure 2): only one of these genes [42]. On the other hand, a sequence variant in a modifier gene that is not a disease-causing var- i. a family history of kidney disease or a patient from an area iant acts as a genetic modifier of the disease phenotype. with a high level of inbreeding, which may make one think For example, it has been suggested that heterozygous dele- of an autosomal recessive disease terious TTC21B variants act as genetic modifiers of the se- ii. patients with cystic kidney diseases, tubulopathies or sus- verity of glomerular and cystic kidney diseases [43]. Also, pected monogenic glomerulopathies have a likely mono- hypomorphic alleles, which are sequence variants that by genic cause of the disease [50] themselves give rise to no phenotype or only a very mild iii. a syndromic disease in which organs besides the kidney one, together with another hypomorphic allele or a patho- are affected genic variant in trans, worsen the phenotype [44]. This has iv. congenital kidney anomalies been shown in, for exxample, ADPKD, where almost v. kidney disease of unknown aetiology in patients <25– asymptomatic parents who carry a hypomorphic allele 30 years of age; at least 20% of CKD patients under the age have severely affected children [45]. of 25 years have an IKD [9, 50] iv. Mosaicism: The coexistence of mutated and wild-type cells vi. haematuric (and proteinuric) kidney disease without a de- in a patient who is a de novo case for an IKD can explain finitive diagnosis by kidney biopsy or with a diagnosis of Genetic kidney diseases in chronic kidney disease | 1883 Hematuric and Interstitial nephropathy proteinuric nephropathy of unknown origin +/– FSGS CKD < 25–30 years – Probability of IKD Downloaded from https://academic.oup.com/ckj/article/14/8/1879/6169174 by guest on 03 January 2023 Congenital kidney anomalies + Cystic disease Family history Syndromic disease of CKD Tubular disease FIGURE 2: Situations warranting suspicion of an IKD. FSGS; such disease may be due to mutations in the COL4A3 including pre-symptomatic testing that may provide strategies or COL4A4 genes, giving rise to the so-called autosomal and reproductive options to prevent passage of the disease to dominant Alport syndrome with highly variable clinical ex- new generations, e.g. prenatal diagnosis or pre-implantation ge- pression [51–53] netic testing [54]. The diagnosis of a rare IKD also allows vii. interstitial nephropathy without an apparent cause, even patients to access reference centres that are used to manage in the absence of a family history, as it may show incom- their disease and can provide up-to-date information and man- plete penetrance or be a sporadic case. agement. This is one of the aims of the European Reference Network for Rare Kidney Diseases (ERKnet; https://www.erknet. org/index.php?id¼home). Genetic testing of IKDs has also BENEFITS OF DIAGNOSING AN IKD IN CKD allowed the reclassification of many conditions and improved PATIENTS disease ontology [55]. One of the drawbacks of genetic testing is The diagnosis of an IKD in a patient with CKD not only implies that, in some countries, it may have consequences for insur- the end of a diagnostic odyssey for many patients, but also has ance coverage. In addition, legal, social and ethical difficulties clear repercussions for prognosis, management and treatment. need to be addressed in some cases. Actionable findings will greatly benefit the patient’s outcome. For example, when faced with FSGS, the expectations after a CONCLUSION kidney transplant will be very different depending on whether the origin is immunological or genetic. In the latter case, the Achieving a precise diagnosis is a fundamental goal of medical likelihood of recurrence is non-existent. In the case of a protei- practice. Genetic testing has emerged as a powerful diagnostic nuric kidney disease of genetic origin, corticosteroid therapy or tool in nephrology. The evidence that at least 10% of adult immunosuppression will not be administered. Once a precise patients and most children with CKD [7, 9] suffer from an IKD diagnosis has been established, e.g. Alport syndrome, the pa- together with the accessibility of new genetic diagnostic tools tient will be able to take part in clinical trials and to benefit should allow the diagnosis of a high percentage of undiagnosed from future treatments. In the case of IKDs with systemic or IKDs and thus assist in reducing the number of patients who syndromic involvement, study of the patient will extend beyond need KRT without a certain diagnosis or with an incorrect one. the renal involvement to encompass other organs. Also, in the It is important to determine which patients will benefit from ge- context of living donor transplantation, the fact that an IKD has netic studies, and certain medical and family history data are been diagnosed will have repercussions, since there will be rela- helpful in deciding whether to order a genetic test. As indica- tives in whom nephropathy must be ruled out before they can tions for genetic testing continue to expand, better education be considered as donors. will be required for both patients and nephrologists regarding When an IKD is suspected, it seems reasonable not to per- topics such as genomic medicine, informed consent, the poten- form a kidney biopsy but to order a genetic test, which may fa- tial benefits and implications of genetic results and current lim- cilitate a precise diagnosis and prevent unnecessary use of an itations in the interpretation of genetic results. National and invasive procedure such as a kidney biopsy. international registries may promote awareness of IKDs by One of the most relevant consequences of reaching a diag- reporting them as a separate category encompassing all IKDs nosis of an IKD is the possibility of offering genetic counselling, instead of splicing the IKD category and dumping non-cystic 1884 | R. Torra et al. IKDs into the invisible ‘other’ or ‘miscellaneous’ categories 14. Köttgen A, Pattaro C. The CKDGen consortium: ten years of (Figure 1C). Any effort to reduce the percentage of patients insights into the genetic basis of kidney function. Kidney Int reaching the need for KRT with a diagnosis of nephropathy of 2020; 97: 236–242 unknown etiology or an unspecific/incorrect diagnosis should 15. Wuttke M, Li Y, Li M et al. A catalog of genetic loci associated be encouraged. 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