NFK Guidelines Released To Clarify Which Kidney Disease Patients Should Undergo Genetic Testing

In recent years, the number of patients with chronic kidney disease (CKD) has increased year by year worldwide. According to surveys, the cause of about ≥10% of CKD adult patients and about 70% of CKD children is closely related to genetic mutations. Although genetic testing technology continues to advance and people have a better understanding of the genetic basis of certain kidney diseases, genetic testing in nephrology still lags behind other medical fields.

Therefore, the National Kidney Foundation (NFK) of the United States has made corresponding recommendations on the clinical practice of genetic testing in kidney disease. This guideline aims to make recommendations for genetic testing of monogenic diseases and identify genetic risk factors for oligogenic and polygenic causes of kidney disease.

Click to Cistanche for kidney disease

Recently, this guideline was announced at the AJKD, involving 4 major aspects of genetic testing for kidney disease, with a total of 56 recommendations. It shows that the expert working group on genetic testing for kidney disease established by NFK will vote on each recommendation, which is divided into three items: agree, neutral, and disagree. The three percentages in brackets correspond to the proportion of experts who agree, neutral, and disagree.

How should patients who undergo genetic testing to diagnose the cause of kidney disease be stratified?

1. Nephrologists should be involved in explaining the rationale, ordering, and interpreting genetic testing for patients with kidney disease (86.7%, 8.9%, 4.4%).

2. Genetic counseling that best meets the patient's needs and expectations should be provided before and after testing, while providing information on specific types of testing, possible results, and potential outcomes before testing, and explaining the results and impact after testing (95.6%, 4.44%, 0%).

3. When discussing genetic testing patterns with patients, factors that need to be considered include gene content, technical limitations, costs and reimbursement, and incidental findings and variants of uncertain significance (VUS) (97.7%, 0%, 2.3%).

4. Patients undergoing genetic testing and kidney donors should have access to genetic counseling before and after testing (100%, 0%, 0%).

5. Indications for asymptomatic genetic testing in children and adults include a first-degree family history of renal disease that suggests dominant disease or suspected familial X-linked or recessive disease (75.5%, 8.9%, 15.5%).

6. Indications for asymptomatic genetic testing include situations where genetic testing can guide proactive/preventive management and/or kidney donation (97.8%, 2.2%, 0%).

7. If management interventions to prevent/slow disease progression were taken during childhood, asymptomatic testing should be offered to children (98%, 2%, 0%).

8. To guide asymptomatic genetic testing in adults and children, clinicians should first perform genetic testing in relatives whenever possible (83.7%, 4.7%, 11.7%).

9. Genetic testing is indicated for people with a first-degree family history of related renal disease or for people with a family history more distant than the first-degree if the blood-relative phenotype is similar to the patient's phenotype (86.7%, 11.1%, 2.2%).

10. If multi-organ syndrome with unknown renal phenotype is present or suspected, genetic testing is necessary (91.1%, 8.9%, 0%).

11. Genetic testing is suitable for patients with early-onset renal disease and/or recurrent electrolyte/mineral abnormalities including kidney stones (88.9%, 6.7%, 4.4%).

12. All kidney-related abnormalities, such as cystic, glomerular, tubulointerstitial, or vascular abnormalities, or electrolyte/acid-base/blood pressure/structural abnormalities, including congenital anomalies of the kidney and urinary tract (CAKUT), require genetic testing after an appropriate clinical evaluation (88.9%, 4.4%, 6.7%).

13. If genetic diagnosis helps to clarify atypical phenotypes (such as cystic kidney disease) or guide treatment (such as nephrotic syndrome), genetic testing is necessary (97.8%, 2.2%, 0%).

14. Genetic testing can be offered if requested by the patient for prognostic prediction, family planning, inclusion in clinical trials, or other reasons deemed important by the patient (84.4%, 11.1%, 4.4%).

15. Genetic testing is indicated for patients with CKD/ESKD of unknown etiology, and after completion of standard renal workup, genetic testing may be helpful for disease management, transplant planning, or extrarenal manifestations (84.4%, 11.1%, 4.4%).

16. APOL1 should be included in the genetic testing panel for chronic kidney disease and offered to patients with clinical manifestations or biopsy results suspected to be related to APOL1, regardless of race and ethnicity (81%, 14.3%, 4.8%).

17. APOL1 genetic testing should not be restricted or recommended based on the patient's race or ethnicity (78.6%, 7.1%, 14.3%).

18. A consensus nomenclature for APOL1-related renal diseases should be developed, in which standard biopsy diagnostic classifications and APOL1 genotypes are used to accurately describe an individual's renal disease. (e.g., "FSGS, APOL1-associated") (75.6%, 13.3%, 11.1%).

19. The medical community should be educated on the indications for APOL1 genetic testing, the impact on kidney disease and its progression, family counseling, and other legal/ethnic considerations (98.8%, 2.2%, 0%).

When diagnosing kidney disease, what clinical, technical, or other factors should be used to match patients to the appropriate genetic testing modality?

20. Studies are needed to compare the diagnostic yield of targeted kidney-specific panels with exome sequencing or genome sequencing (84.4%, 6.7%, 8.9%).

21. Relatives should only be tested for specific variants if the variant causing the disease in the family is known (80%, 11.1%, 8.9%).

22. Patients with a high suspicion of a single gene disease should be considered for focused genetic testing, that is, sequencing of genes associated with the genetic disease, such as GLA gene sequencing for patients with a high suspicion of Fabry disease (88.9%, 6.7%, 4.4%). 23. Kidney-specific genetic testing is recommended for focal segmental glomerulosclerosis (FSGS) and steroid-resistant nephrotic syndrome (SRNS) (84.5%, 6.7%, 8.9%).

24. Kidney-specific genetic testing is recommended for patients with renal tubular disease (84.4%, 11.1%, 4.4%).

25. We encourage renal pathologists to make recommendations about the need for genetic testing in written reports when appropriate, inform nephrologists, and provide support for health insurance companies to provide coverage for testing (86.7%, 11.1%, 2.2%)

26. Kidney-specific genetic testing should be used when genetic diagnosis is performed for patients with atypical cystic kidney or liver disease without a family history (88.9%, 8.9%, 2.2%).

27. Kidney-specific genetic panels should be strongly considered after a comprehensive clinical evaluation of patients with renal disease of unknown etiology (86.7%, 4.4%, 8.9%). 28. For patients suspected of having inherited kidney disease and planning or awaiting kidney transplantation, kidney-specific genetic testing should be strongly considered (88.8%, 8.9%, 2.2%).

29. For elderly patients with marginal renal function decline, genetic testing is unlikely to benefit in clinical decision-making (77.8%, 20.0%, 2.2%).

30. If the results of centralized testing are negative, but a genetic cause is still suspected, exome or genome sequencing should be considered (84.5%, 11.1%, 4.4%).

31. The initial evaluation of CAKUT patients should include genetic testing for large fragments, microdeletions, and microduplications, such as CMA, SNP, or NGS technology.

32. Although large-sample genetic testing is usually a good initial choice, if a specific disease is suspected based on imaging, family history, or pathology, reference should be made to existing customized testing procedures (78.6%, 11.9%, 9.5%).

33. If the initial genetic test result is negative, regular reanalysis of the genetic test results is recommended (75.6%, 13.3%, 11.1%).

How should the genetic test results be evaluated and accurately interpreted for patients?

34. We need consensus criteria for monogenic kidney disease genes, monogenic genes with incomplete penetrance, and oligogenic/multigenic genes (i.e., APOL1) (88.9%, 8.9%, 2.2%).

35. We need to study the natural history of monogenic kidney disease to achieve the following goals: ① determine the classification of variants, ② quantify the penetrance, and ③ understand the range of phenotypic manifestations (expressivity) (95.5%, 2.2%, 2.2%).

36. Longitudinal data on the natural history of inherited kidney diseases should be collected in registries or cohort studies (95.5%, 4.6%, 0%).

37. Expert guidelines on genetic testing and reporting for monogenic kidney disease would be helpful for clinical laboratories that lack experience with hereditary kidney disease (88.1%, 9.5%, 2.4%).

38. Currently, PRS have no actionable indications for the diagnosis, treatment, or prevention of kidney disease (81%, 16.7%, 2.4%).

39. Polygenic risk scores for kidney disease prediction and diagnosis should be developed and evaluated in different populations (89.3%, 8.5%, 2.1%).

40. The development of PRS is limited by the lack of ancestral diversity in current GWAS studies, so there is a need to increase the representation of different populations (93.3%, 6.7%, 0%).

41. Clinical laboratories that perform genetic testing for kidney disease should be encouraged to share/deposit gene variants and classifications in public databases such as ClinVar (95.4%, 2.3%, 2.3%).

42. Strategies should be developed to enable secure sharing of genotype/phenotype clinical data with registered/approved users (clinicians, ClinGen experts, clinical laboratories) to help improve the diagnosis of renal genetic diseases (93.2%, 4.6%, 2.3%).

43. In the field of genetic variation that continues to develop rapidly, it is necessary to provide nephrologists with best practice guidelines for patient follow-up responsibilities (97.7%, 2.3%, 0%).

44. Medical staff should develop the skills of "case-level interpretation" (a diagnostic reasoning process that interprets a patient's genotype and phenotype) of genetic test results to determine the significance of the results and their impact on patient treatment (93.2%, 4.6%, 2.3%).

45. Academic centers need to form a genomic medicine committee composed of experts in nephrology, clinical genetics, genetic counseling, and laboratory medicine to provide expert background advice to community nephrologists (79.5%, 13.6%, 6.9%).

46. The nephrology community should provide resources (e.g., CME training modules) to nephrologists to enable them to practice best practices in all aspects of genetic testing (97.8%, 2.3%, 0%).

What are the remaining issues in the implementation of genetic testing? How can they be addressed?

47. Genetics should be included in the core curriculum of all nephrologists (97.8%, 2.3%, 0%).

48. The nephrology community should develop an optional advanced fellowship in renal genetics (in collaboration with clinical genetics), similar to fellowship training in transplant nephrology or glomerular diseases, for one year (95.5%, 4.6%, 0%).

49. Nephrologists should have the skills to inform/counseling patients about the potential benefits, risks, and interpretation of genetic testing (95.5%, 4.6%, 0%).

50. Nephrologists should understand the policy regarding the return of unexpected test results and the impact on life/disability insurance, etc. (95.5%, 4.6%, 0%).

51. Nephrologists should inform patients and the general renal community of the limitations of the Genetic Information Nondiscrimination Act (GINA), which protects workplaces and health insurance from genetic discrimination, but not life and disability insurance (95.5%, 4.6%, 0%)

52. Living donors who are related to patients with known genetic kidney diseases must undergo genetic testing (77.3%, 11.4%, 11.4%).

53. Unrelated living donors with a clear family history, renal cell carcinoma of unknown etiology, early-onset CKD, cystic kidney disease, congenital diseases with extrarenal signs, atypical hemolytic uremic syndrome (aHUS), etc. should be offered kidney transplants.

54. Given the current practice of paired donation and exchange, the kidney transplant team should encourage living donors with monogenic kidney disease to share recent genetic test results with the donor evaluation team so that targeted genetic testing can be performed on the donor (76.2%, 16.7%, 7.1%).

55. Genetic testing should be considered for living donors who are related to patients with high-risk APOL1 variants (93.2%, 4.6%, 2.3%).

56. There is insufficient evidence to make a clear recommendation for or against APOL1 testing to predict which donors are at increased risk of developing CKD after kidney donation (71.2%, 11.1%, 17.8%).

How Does Cistanche Treat Kidney Disease?

Cistanche is a traditional Chinese herbal medicine used for centuries to treat various health conditions, including kidney disease. It is derived from the dried stems of Cistanche deserticola, a plant native to the deserts of China and Mongolia. The main active components of cistanche are phenylethanoid glycosides, echinacoside, and acteoside, which have been found to have beneficial effects on kidney health.

Kidney disease, also known as renal disease, refers to a condition in which the kidneys are not functioning properly. This can result in a buildup of waste products and toxins in the body, leading to various symptoms and complications. Cistanche may help treat kidney disease ase through several mechanisms.

Firstly, cistanche has been found to have diuretic properties, meaning it can increase urine production and help eliminate waste products from the body. This can help relieve the burden on the kidneys and prevent the buildup of toxins. By promoting diuresis, cistanche may also help Reduce high blood pressure, a common complication of kidney disease.

Moreover, cistanche has been shown to have antioxidant effects. Oxidative stress, caused by an imbalance between the production of free radicals and the body's antioxidant defenses, plays a key role in the progression of kidney disease. ies help neutralize free radicals and reduce Oxidative stress, thereby protecting the kidneys from damage. The phenylethanoid glycosides found in cistanche have been particularly effective in scavenging free radicals and inhibiting lipid peroxidation.

Additionally, cistanche has been found to have anti-inflammatory effects. Inflammation is another key factor in the development and progression of kidney disease. Cistanche's anti-inflammatory properties help reduce the production of pro-inflammatory cytokines and inhibit the activation of mandatory pathways for inflammation, thus alleviating inflammation in the kidneys.

Furthermore, cistanche has been shown to have immunomodulatory effects. In kidney disease, the immune system can be dysregulated, leading to excessive inflammation and tissue damage. Cistanche helps regulate the immune response by modulating the production and activity of immune cells, such as T cells and macrophages. This immune regulation helps reduce inflammation and prevent further damage to the kidneys.

Moreover, cistanche has been found to improve renal function by promoting the regeneration of renal tubes with cells. Renal tubular epithelial cells play a crucial role in the filtration and reabsorption of waste products and electrolytes. In kidney disease, these cells can be damaged, leading to damaged renal function. Cistanche's ability to promote the regeneration of these cells helps restore proper renal function and improve overall kidney health.

In addition to these direct effects on the kidneys, cistanche has been found to have beneficial effects on other organs and systems in the body. This holistic approach to health is particularly important in kidney disease, as the condition often affects multiple organs and systems. che has been shown to have protective effects on the liver, heart, and blood vessels, which are commonly affected by kidney disease. By promoting the health of these organs, cistanche helps improve overall kidney function and prevent further complications.

In conclusion, cistanche is a traditional Chinese herbal medicine used for centuries to treat kidney disease. Its active components have diuretic, antioxidant, anti-inflammatory, immunomodulatory, and regenerative effects, which help improve renal function and protect the kidneys from further damage. , cistanche has beneficial effects on other organs and systems, making it a holistic approach to treating kidney disease.