Chronic Kidney Disease of unexplained cause (CKDx): a consensus statement by the Genes & Kidney Working Group of the ERA
ERA · 2025 · Europe
Source and licence
- Authors
- Jan Halbritter, Lucile Figueres, Albertien M Van Eerde et al.
- Title
- Chronic Kidney Disease of unexplained cause (CKDx): a consensus statement by the Genes & Kidney Working Group of the ERA
- Journal
- Nephrology Dialysis Transplantation, 2025
- Licence
- CC BY 4.0
- Changes
- Verbatim excerpts; formatting adapted
Full text retrieved 2026-10-27 from Europe PMC · PMC12709129
Licence statement of the original publication
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.
This page reproduces excerpts of the original publication; the original is authoritative. It has not been reviewed by a physician, does not state a recommendation of Medelix and does not replace medical advice. The guideline may have been updated since.
Open the original publication →Full text on Europe PMC
Recommendations
Verbatim, with grade of recommendation or strength of consensus where given.
‘The greatest enemy of knowledge is not ignorance, it is the illusion of knowledge’, (Stephen Hawking)
- The ‘cause’-component of the KDIGO CGA-classification of CKD deserves special attention considering its impact on patient counselling, prognosis, cardiovascular risk stratification and therapeutic strategies.
- CKDx is a diagnosis of exclusion. We suggest classifying the cause of CKD as CKDx in all cases in which a specific cause cannot be defined in a given healthcare system after reasonable diagnostic workup; taking into account potential limitations in access to and availability of modern diagnostic technologies.
- Naming causes with low diagnostic certainty or unspecific terms, including histological injury patterns, may lead to unnecessary, potentially harmful or missed therapies and is likely to discourage further diagnostic workup, even as additional diagnostic approaches become available. If the diagnostic processes do not identify a clear cause, the condition should be classified as CKDx.
- Nephrology should evolve to a cause-directed approach in all cases of CKD.
WORKUP OF CKDx
- A systematic diagnostic approach to CKD and standardized reporting of findings helps to secure full use of all diagnostic opportunities required to reach the diagnosis of exclusion CKDx.
- A structured family history should be obtained for all patients with CKD and specific extension of the information (e.g. towards extrarenal manifestations) should be considered depending on individual case characteristics.
REPORTING OF CKDx
- In cases of CKDx, we suggest extending usual reporting of the diagnosis (based on the KDIGO CGA-classification) by providing structured information on the availability of genetic and histological results including the year when the test was performed. In this regard, ‘h’ represents histology and ‘g’ genetic testing, with a ± sign indicating whether the respective test was performed and the performing date mentioned (Fig. 1).
- In addition to the h/g-extension of CKDx reporting, information crucial to interpreting the workup should be provided. It includes the genetic testing modality used (e.g. gene panel, WES), year when it was performed and biopsy evaluation (e.g. electron microscopy) (Fig. 1).
- Although this consensus statement specifically provides guidance for CKDx, reporting the availability of genetic and biopsy results may also be considered for other CKD cases.
Post-test considerations: negative or inconclusive results
- Genetic testing should be considered in all cases of CKDx. The expected diagnostic rate of genetic testing depends on the presence of several factors in the patient history. In individuals under 60 years of age, it is increasingly regarded as a standard diagnostic approach; omission of testing in this population should be supported by a clear clinical rationale.
- The genetic testing modality and genetic care infrastructure may vary between healthcare systems. The minimum required selection of genes to test in CKDx is a comprehensive kidney disease gene panel consisting of genes with moderate to definitive evidence for gene–disease association, as curated in standardized resources (e.g. ClinGen, PanelApp, see Supplementary data, Table S2).
- An inconclusive or negative genetic test does not exclude a genetic cause.
- Identification of a pathogenic or likely pathogenic variant does not necessarily indicate that the variant is causal for the patient's kidney disease. Interpretation must take into account the clinical phenotype and inheritance pattern.
- VUS should not be considered as conclusive diagnostic findings and require further discussions. Contact with expert centres is key. Reverse phenotyping, cosegregation analysis, and/or functional assays can help to reclassify such variants as likely pathogenic (or likely benign)
- If genetic testing does not identify a causal variant, patients should be informed that a genetic cause has not been definitively excluded. Further interpretation may include referral to an expert centre, expansion of testing, or re-evaluation of previous findings. Periodic re-assessment is recommended as new clinical or genetic information may emerge over time.
Abstract
Chronic kidney disease of unexplained cause (CKDx) is a diagnosis of exclusion. With an estimated global prevalence of at least 16–20% among CKD patients, CKDx poses a significant challenge to the field. To date, there is no established consensus on the definition of CKDx. Additionally, guidance on the diagnosis and reporting of CKDx remains lacking. CKDx is characterized by the inability to identify a specific etiology after comprehensive diagnostic evaluation, including laboratory tests, imaging, and histological or genetic analyses. This condition encompasses diverse clinical scenarios, which vary depending on the availability of diagnostic resources across healthcare systems. Notably, as the diagnostic yield of genetic testing in CKDx ranges from 11 to over 30% in the literature, it has become an integral part of the diagnostic armamentarium for patients with CKDx. This consensus statement of the working group ‘Genes&Kidney’ of the European Renal Association proposes a definition of CKDx, along with recommendations for the diagnostic approach and diagnostic reporting standards, including guidance on genetic workup as a key tool in a large proportion of such cases. Improved reporting standards, including the systematic documentation of diagnostic tests performed, are essential
to avoid the negative therapeutic consequences of misdiagnoses, address the diagnostic gap in CKDx, and inform future research. By fostering a cause-directed approach, this work aims to enhance patient care and lay the foundation for further advancements in nephrology.
Contents of the original publication
The section headings of the original.
- DEFINITION OF CKDx
- ‘The greatest enemy of knowledge is not ignorance, it is the illusion of knowledge’, (Stephen Hawking)
- WORKUP OF CKDx
- REPORTING OF CKDx
- GENETIC TESTING IN KIDNEY DISEASE: CLINICAL CONCEPTS
- Indications for genetic testing
- How to genetically test patients with CKDx
- Post-test considerations: Understanding variant classification
- Post-test considerations: negative or inconclusive results
- CONCLUSION
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