How important are kidney diseases in healthcare today?
About one in 10 people worldwide suffer from chronic kidney disease, i.e. around 9 million people in Germany. Approximately 90,000 people are dependent on renal replacement therapy (dialysis or transplantation), and patients who are not yet in the final stages of the disease are at high risk of cardiovascular complications such as high blood pressure and therefore of heart attack or stroke. While diabetes mellitus and high blood pressure are the most common causes of chronic kidney disease (CKD), 10% of patients have a hereditary form, rising to as much as 70% for childhood kidney disease.
How do you diagnose hereditary kidney diseases and which genetic tests are most frequently carried out for kidney diseases?
If a genetic defect in one of only a few genes is the suspected cause, we may perform a targeted test just of the relevant genes. In the case of unclear diagnosis, we carry out whole exome sequencing (WES), which involves analysing the coding regions of all human genes. The most common genetic diagnoses we find are Alport syndrome, in patients with chronic kidney disease, and polycystic kidney disease (PKD) in patients with end-stage renal disease.
What role do genetic tests play in the diagnosis of chronic kidney disease (CKD)?
Genetic tests allow an aetiological classification of the disease. Prognosis, disease progression and appropriate disease management can differ significantly between hereditary and acquired chronic kidney disease. Groopman et al (NEJM, 2019) showed that a genetic diagnosis led to a change in clinical management in 89% of cases in terms of information on prognosis and changes in decisions regarding renal replacement procedures and therapeutic approaches. The detection of a genetic cause also allows the identification of other at-risk individuals in affected families and can enable prenatal or pre-implantation diagnostics if affected persons or carriers wish to have children.
When should genetic testing or counselling be considered?
Genetic testing is particularly valuable when the cause of chronic kidney disease remains unexplained: at least 17% of patients with nephropathy of unknown cause received a genetic diagnosis through whole exome sequencing. In addition, molecular genetic testing and diagnosis also offer the possibility of personalised therapy approaches and much progress has been made in this area in recent years. Genetic counselling is valuable whenever a genetic disease is suspected, but is recommended or even required if a diagnostic genetic test is performed.
How does the identification of a genetic cause of kidney disease affect a patient's treatment?
Firstly, unnecessary immunosuppression can be avoided when a genetic diagnosis is made. Patients can also be eligible for new treatment options or clinical trials. In the case of Alport syndrome, the most common genetic cause of chronic kidney disease, numerous new therapeutic options and the use of known drugs such as SGLT2 inhibitors have demonstrated positive results in recent years. The table provides further examples (adapted with acknowledgement from Elliott, Rasouly and Gharavi 2023, Annu. Rev. Med. 2023. 74:353–67).
| Syndrome | Gene(s) | Therapy |
|---|---|---|
| Amyloidosis, hereditary, transthyretin-related | TTR | RNAi |
| COQ10 deficiency | COQ2, COQ6, ADCK2/COQ8B, PDSS2, MTTL1 | COQ10 replacement |
| Corticosteroid remediable aldosteronism | CYP11B2/CYP11B1 | Glucocorticoids |
| Fabry disease | GLA | α-Gal enzyme replacement, chaperone therapy |
| Familial hyperaldosteronism, type II and III | CLCN2 and KCNJ5 | Aldosterone antagonists |
| Liddle syndrome | SCNN1A, SCNN1B, SCNN1G | Amiloride |
| Primary hyperoxaluria 1 | AGXT | RNAi therapy |
| Pseudohyperaldosteronism, type II | KCNJ5 | Thiazide diuretics |
What role does SYNLAB Germany play in genetic counselling?
SYNLAB Germany is very active in human genetic counselling and diagnosis, including for suspected hereditary kidney diseases. We have Genetics centres in Freiburg, Jena, Mannheim, and Munich plus branches in Baden-Baden, Karlsruhe, Lörrach and Constance; teleconsultation is also available. In Freiburg notably, PD Dr med. Ulla Schultheiß collaborates closely with the Institute for Genetic Epidemiology and the Department of Nephrology at Freiburg University Hospital.
Are there any promising developments in sight for the diagnosis of genetic kidney diseases?
The use of whole genome sequencing (WGS) and of polygenic risk scores (PRS) offers hope to shed new light on chronic kidney diseases that are currently unexplained but potentially genetic in origin. For WGS, the analysis of very large quantities of data remains challenging. PRS are valuable in identifying high-risk patient groups for referral to nephrological care, even in the absence of a single causal genetic defect. In addition, single-stranded genome sequencing and optical genome mapping are new methods which can detect genetic defects that are more structural in nature, and so not identifiable with conventional sequencing techniques. Precise genetic diagnoses are required with regard to therapies, as precision medicine or gene therapy are only possible if the causative genetic defects are known.
World Kidney Day 2024
We interviewed two of our experts in nephrology, Prof. Dr med. Walter Hofmann at SYNLAB Germany and Dr Olivia Shaw at Synnovis to get insights on dialysis treatments, kidney transplantation and the importance of having guidelines for diagnosing kidney related diseases.