Monogenic Kidney Diseases in Adults With Chronic Kidney Disease (CKD)

Background: According to current evidence, every 10^th to 11^th adult with chronic kidney disease (CKD) has a monogenic disease of the kidney.

Methods: This review is based on reported studies in which molecular genetic diagnostic techniques were used to investigate monogenic kidney diseases in adults with CKD. The studies were identified by a selective literature search using predefined criteria.

Results: In 12 selected studies, diagnostic variants of 179 different genes were identified in 1467 out of 6607 study participants with CKD (22.2%). More than 60% of these variants affected 8 genes (PKD1, PKD2, COL4A3, COL4A4, COL4A5, UMOD, MUC1, HNF1B). Three diseases are associated with these genes: autosomal dominant polycystic kidney disease (ADPKD), Alport syndrome, and autosomal dominant tubulo-interstitial kidney disease (ADTKD). Physicians treating patients with CKD should be alert to the presence of any red flags, such as onset at a young age, a positive family history, or hematuria of unknown cause. When a genetic etiology is suspected, a specialized work-up is indicated, often including a molecular genetic investigation. A positive genetic finding usually leads to a modification of the patient’s specific diagnosis and/or treatment.

Conclusion: Awareness of the high prevalence of monogenic kidney diseases in adults with CKD and alertness to their suggestive clinical features are crucial for the timely initiation of targeted diagnostic testing. The molecular genetic identification of these diseases is a prerequisite for appropriate patient management.

According to the KDIGO criteria (KDIGO, Kidney Disease: Improving Global Outcomes), approximately 13% of the adult population in Germany suffers from chronic kidney disease (CKD) (1, 2). The etiology of CKD can be attributed, to a relevant extent, to pathogenic alterations (variants) in genetic material (DNA). According to current evidence, the prevalence of monogenic kidney diseases in adults with CKD is approximately 9.3% (3). Monogenic diseases of the kidney are caused by DNA changes in a single gene (monogenic). Today, monogenic kidney diseases caused by pathogenic variants in > 400 genes are known (4). Specific warning signs (red flags), such as a positive family history and onset at a young age, can point to a monogenic kidney disease (5). Having said that, the absence of red flags of this kind does not rule out the presence of a monogenic kidney disease (5, 6). The implementation of molecular genetic testing in clinical nephrology is helpful in the case of clinical red flags or suspicion of a monogenic kidney disease. Knowledge regarding the prevalence of the underlying genes and the phenotypical expression of monogenic kidney diseases is essential for the diagnostic work-up (7). Thanks to sequencing and molecular genetic testing, disease-causing variants can be identified in the corresponding genes (6). Early recognition of a monogenic kidney disease can be of vital importance to those affected and their families, for example, with regard to treatment implications, prognosis, genetic counseling, and the screening of family members at risk (6, 8). This article provides a comprehensive overview of the most important genes associated with monogenic kidney diseases in adults as well as their relative frequency and manifestations. Clinical red flags as well as the diagnostic work-up and clinical implications of monogenic kidney diseases will also be discussed.

Materials and methods

Inclusion criteria for the selection of suitable studies

The aim of the literature search was to identify observational studies in which molecular genetic techniques were used to investigate monogenic kidney diseases in adults with any form of CKD. A total of 12 suitable observational studies were identified and evaluated for the occurrence of monogenic kidney diseases (3, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19). Details of the search strategy, how the search was conducted in PubMed (Supplementary Figure 1), data extraction, and the characteristics of the individual studies analyzed are described in eTable 1.

Figure

Clinical diagnostic pathway for an individual exhibiting signs of a monogenic kidney disease.

Results

Genes with disease-causing variants (“diagnostic variants”)

A total of 1520 diagnostic variants were identified in 179 different genes in 1467 of 6607 (22.2%) study participants (eTable 2). Diagnostic variants were identified in 69 genes in at least two different studies (Supplementary Figure 2). It should be noted that most study cohorts included “pre-filtered” participants with an increased likelihood for a monogenic kidney disease. Around two-thirds of all diagnostic variants (~61%) were described in genes associated with ADPKD (PKD1, PKD2), Alport syndrome spectrum (COL4A3, COL4A4, COL4A5), and ADTKD (UMOD, MUC1, HNF1B); in approximately 50% of cases, the variants occurred in only five genes: PKD1, PKD2, COL4A3, COL4A4, and COL4A5 (Supplementary Table 1, Supplementary Figure 3). At the same time, around one-third of monogenic kidney diseases are genetically and clinically extremely heterogeneous (Supplementary Figure 3, eTable 3).

The renal and extrarenal manifestations of the most frequent genes are presented in detail in Box 1 and Supplementary Table 2. The manifestations of the remaining 69 genes (which were identified in at least two studies) are given in eTable 4.

Box 1

Renal and extrarenal manifestations of the three most common monogenic kidney disease entities (around two-thirds) in adults with CKD

Autosomal dominant polycystic kidney disease (ADPKD)

In > 90% of cases, ADPKD is caused by pathogenic heterozygous variants in the PKD1 (chromosome 16) or PKD2 gene (chromosome 4) (e1). Compared to pathogenic variants in the PKD2 gene, pathogenic variants in the PKD1 gene are associated with a higher prevalence of more severe disease (e2). Initial symptoms do not usually develop until adulthood. End-stage renal disease develops at around the age of 56 years on average (PKD1, ~53 years, PKD2, ~69 years) (e3). The renal phenotype is characterized by the polycystic kidneys from which it gets its name. In terms of laboratory tests, the disease manifests to varying degrees in the form of proteinuria and hematuria. Affected individuals often experience kidney pain, nephrolithiasis, cyst infections, and urinary tract infections (e4). The most common extrarenal manifestations include liver cysts (up to 80%) and early-onset arterial hypertension, which develops in the majority of affected individuals before the age of 40 years (e5). In recent years, numerous other genes that can cause an ADPKD or ADPKD-like phenotype have been identified. Examples of these include GANAB, DNAJB11, ALG5, ALG9, IFT140, and HNF1B (e6).

Alport syndrome spectrum

Alport syndrome spectrum (AS spectrum) is caused by pathogenic variants in the genes COL4A3 (chromosome 2), COL4A4 (chromosome 2), and COL4A5 (X chromosome) (e7). Clinical severity is highly variable and strongly depends on, among other things, whether a male or a female has autosomal recessive (ARAS), autosomal dominant (ADAS), or X-linked Alport syndrome (XLAS: COL4A5). Individuals with ARAS generally already present with hematuria and proteinuria before the age of 10 years, with the majority developing end-stage renal disease before the age of 30 years (e8). In addition, sensorineural hearing loss often develops, and more rarely, ocular involvement (e7). The time of onset of initial symptoms or end-stage kidney disease varies greatly in ADAS patients. At the same time, those with ADAS or heterozygous COL4A3 or COL4A4 variants can remain asymptomatic for life, although hematuria may develop (e9). Males with XLAS develop the first symptoms (hematuria, proteinuria) as early as on as in childhood and terminal renal failure at an average age of 25 years. Affected (heterozygous) females, in contrast, often remain symptom-free—with the exception of microhematuria—for life (e10, e11). It is remarkable that pathogenic COL4A3–COL4A5 variants are also the most common genetic cause of focal segmental glomerulosclerosis (FSGS) (e12). Accordingly, patients may present with nephrotic proteinuria that differs from the more nephritic constellation seen in classic Alport syndrome (e12).

Autosomal dominant tubulointerstitial kidney disease (ADTKD)

ADTKD is characterized by interstitial fibrosis and renal tubular damage (e13). Those affected often experience the first symptoms in young adulthood and present with end-stage renal disease at an average age of 45 years (e14). In contrast to ADPKD, the clinical picture is more diverse and its progression more varied, thereby hampering the clinical diagnosis. Depending on the underlying genetic defect, significant variations are seen in terms of (extra-)renal manifestations and symptom onset (Box 1, Supplementary Table 2) (e15). ADTKD can be caused by mutations in a large number of genes; to date, however, the largest number of pathogenic variants has been identified in UMOD, MUC1, REN, and HNF1B (e14, e16, e17, e18). Glomerular filtration rate worsens over time in all types of ADTKD, although patterns of progression vary. Hematuria as seen in Alport syndrome spectrum is untypical, whereas (generally mild) proteinuria is possible (e15, e16). Clinical manifestations of the most common types of ADTKD often include hyperuricemia or gout symptoms (e13). ADTKD involving cystic kidney disease is also known to occur and, in such cases, can easily be mistaken for ADPKD (e19).

Diagnostic red flags for the presence of a monogenic kidney disease

In CKD patients, a variety of clinical findings or constellations can point to the possible presence of a monogenic kidney disease (Table). In particular, a positive family history (around two-thirds of monogenic kidney diseases in adults have an autosomal dominant pattern of inheritance) and young age at onset (for example, onset at the age of 30 years) should be seen as important red flags (3, 20). However, a monogenic kidney disease should also be considered in older CKD patients with specific constellations, since there is no upper age limit for the presence of monogenic CKD (20). This could be, for example, a specific combination of renal and extrarenal symptoms, as well as (atypical-for-age) cystic or anatomically abnormal kidneys (21, 22). Interstitial nephropathy (confirmed by biopsy), (steroid-resistant) FSGS without an identifiable cause, or persistent microhematuria may also point to the presence of a monogenic kidney disease (5, 23). Furthermore, if the etiology of CKD or end-stage renal disease is unknown, the likelihood of a genetic cause is greater (24).

Table

Clinical diagnostic red flags for the possible presence of a monogenic kidney disease

Initiating molecular genetic testing

In the case of red flags that could point to a monogenic kidney disease, specialist medical investigation is required. Where necessary, this should also include molecular genetic testing (Figure). Ideally, this should be carried out at an interdisciplinary center or in collaboration with a human genetics institute. There, the clinical picture is re-evaluated on the one hand, while on the other, the best sequential order of further diagnostic measures can be agreed upon. The appropriate method for genetic testing (often whole exome sequencing, WES), including the determination of a suitable gene panel, is defined by the genetics laboratory (ideally in close consultation with the referring hospital) based on the clinical picture of the patient. Therefore, the medical professionals at the referring hospital do not need to be familiar with all the possibly relevant genes, but instead make a clinically suspected diagnosis or describe the clinical phenotype.

Results of molecular genetic testing

The results regarding possible genetic variants generated by the human genetics laboratory are based on guidelines issued by the American College of Medical Genetics and Genomics (ACMG) and the Association of Molecular Pathology. The ACMG classification divides genetic variants of monogenic disorders into five categories based on a combination of 28 pathogenicity and/or benignity criteria (25). The five categories indicate the probability that a genetic variant is causally associated with a particular disease or clinical phenotype: probability > 99% (pathogenic: P), > 90% (likely pathogenic: LP), uncertain significance/pathogenicity (variant of uncertain significance, VUS), < 10% (likely benign: LB), and < 1% (benign: B). The evidence framework of these criteria takes into consideration population data, computational/predictive data, functional data, segregation data, de novo data, allelic data as well as other relevant information (25). Once the results of molecular genetic testing have been obtained, these results are once again clinically evaluated (ideally on an interdisciplinary basis). The focus here is on answering the question of whether and to what extent the variant(s) found explain the patient’s clinical picture (reverse phenotypic determination) (26). In some cases, additional follow-up examinations (and possibly also genetic segregation analyses of family members) may be necessary or helpful. After communicating the results to the patient, their further clinical management and treatment (in the case of positive genetic findings) are best carried out at centers with expertise in monogenic kidney diseases. Even if the genetic findings are negative (normal) or inconclusive, the human genetics laboratory will suggest a recommended course of action, for example, re-analysis after 2 years (for VUS variants), which should be taken into consideration in the follow-up counseling of the individual concerned.

Clinical implications of a positive genetic result

The clinical implications that may arise from a positive genetic result (pathogenic variant/s are identified) are manifold depending on the specific monogenic disease (Box 2) (20). In a recent study, a positive genetic result led to a change in the clinical management of patients in > 90% of cases. The genetic result led to a reclassification of the previous CKD diagnosis in approximately 50% of patients and in changes to the medication plan in around one-third (27). It is also important to note that this type of testing should be carried out even if a hereditary disease (for example, ADPKD: familial cystic kidney disease) has already been diagnosed but not yet genetically tested. This is essential for the purposes of risk stratification (the age at which end-stage renal disease is expected to develop), the targeted use of drugs (e.g., tolvaptan in rapidly progressive ADPKD), and in order to provide correspondingly sound patient information and guidance (28, 29). Being aware of the presence of a disease-causing variant also makes it possible to provide family members with targeted care, since a monogenic kidney disease affects not only the person in question but also the wider family, which can also receive appropriate care as a result. Since monogenic kidney diseases are often associated with various extrarenal manifestations, a multidisciplinary approach is usually required to ensure the best possible patient care (20).

Box 2

Clinical consequences and implications of molecular genetic testing*^1sup>

Discussion

Summary

Approximately two-thirds of all diagnostic variants (61%) were identified in only eight genes associated with the disease entities ADPKD, Alport syndrome spectrum, and ADTKD. At the same time, around one-third of monogenic kidney diseases are both genetically and clinically highly heterogeneous and are caused by a multitude of different (pathogenically altered) genes. When caring for CKD patients, attention must be paid to red flags that could point to the presence of a monogenic kidney disease. In the case of relevant warning signs, a specialist medical investigation and, where appropriate, molecular genetic testing should be initiated. A positive genetic result often changes the diagnosis and/or treatment of those affected. Furthermore, it is an essential prerequisite for adequate risk stratification, effective disease management, and the co-treatment (including testing, where necessary) of family members.

Observational studies to investigate genetic kidney diseases

The 12 observational studies considered here fulfilled all inclusion criteria described in the Methods Section. Nevertheless, significant differences were seen between the individual study designs, the specific methodology used, and documentation (eTable 1). The individual studies differed in terms of the inclusion of participants with ADPKD, the size of the gene panel analyzed (between 225 and > 625), and methodological details in the determination of diagnostic variants (eTable 1 and Supplementary Results).

In order to ensure comparability and traceability across studies, the tools, workflows, and documentation for evaluating diagnostic variants should be further standardized. It is also necessary to establish international standard reference gene lists for monogenic kidney diseases in order to further improve the quality of nephrogenetic studies (20).

Putting the results in an epidemiological context

The average percentage of participants with diagnostic variants in the studies selected here (diagnostic yield) was 22.2%, with percentages varying between 9.3% (non-preselected CKD cohort) and 65% (heavily preselected CKD cohort) (3, 11). Selection bias of this kind hampers the determination of the actual prevalence of monogenic kidney diseases (20). It is important to bear in mind that even when a monogenic kidney disease is present, there can be other etiological (concomitant) causes for CKD (1, 30). However, the figures presented here clearly show that targeted pre-selection of (adult) patients with CKD enables a very high diagnostic rate using molecular genetic testing.

Putting the results in a clinical context

Molecular genetic testing should not be used indiscriminately in adults with CKD (6). In clinical routine, one must remain vigilant to red flags in order to consider the possibility of a monogenic kidney disease. In the medium term, specific (guideline) criteria and/or scores should be established that make it possible to estimate the probability of a monogenic kidney disease and that serve as a basis for the use of suitable molecular genetic testing. An example here would be the genetic testing used in oncology for hereditary breast and ovarian cancer (HBOC) (24, 31). Recent studies show that the rigorous (early) implementation of genetic testing in cases of CKD in adults selected on the basis of appropriate criteria not only makes it possible to achieve a very high diagnostic rate but even reduces costs (11, 32). In a very high proportion of patients, these results lead directly to clinical consequences (27). In addition to the implications for the patient themselves, molecular genetic results are also highly relevant to family members and can have an impact on family planning. Therefore, additional specialist medical counseling and care (of the entire family, where necessary) provided by human genetics specialists is essential.

Conclusion

Monogenic kidney diseases account for a notable share of the etiology of CKD in adults. Knowledge of the prevalence of monogenic kidney diseases in adults with CKD and clinical awareness of their suggestive clinical features (red flags) are crucial for the timely initiation of targeted diagnostic testing. The molecular genetic identification of a monogenic kidney disease can significantly alter the diagnosis, treatment, and management of patients.

Conflict of interest statement
The work conducted by UTS was supported by funding from the German Federal Ministry of Education and Research (Bundesministerium für Bildung und Forschung, BMBF) as part of the e:Med junior consortium CKDNapp (01ZX1912B). UTS is employed by the SYNLAB MVZ Humangenetik Freiburg GmbH and has received participation fees, travel expenses, and funding from the BMBF as part of the e:Med (01ZX192B) funding concept.

The work conducted by JE and AK was supported by the Collaborative Research Center (Sonderforschungsbereich, SFB) 1453 (Nephrogenetics; project ID: 431984000.

Manuscript submitted on 25 January 2024, revised version accepted on 28 May 2024.

Translated from the original German by Christine Rye.

Corresponding author
Julian Eble, M.D., M.Sc.
Institut für Genetische Epidemiologie
Universitätsklinikum und Medizinische Fakultät der Universität Freiburg

Breisacher Straße 33
79106 Freiburg im Breisgau, Germany

Cite this as
Eble J, Köttgen A, Schultheiß UT: Monogenic kidney diseases in adults with chronic kidney disease. Dtsch Arztebl Int 2024; 121: 689–95. DOI: 10.3238/arztebl.m2024.0120

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