Kidney Biopsy Does Not Determine The Cause? Or Try Genetic Testing
Aug 02, 2023
Globally, chronic kidney disease (CKD) affects more than 840 million people. Correctly identifying the etiology of CKD has always been the focus of CKD management. However, 25%, 20%, and 17.7% of CKD patients in the United States, Germany, and France could not be identified despite comprehensive physical examinations, blood tests, imaging studies, and kidney biopsies. Other data show that in most developed countries, CKD patients with unknown etiology account for more than 20% of the total CKD patients; in most developing countries, CKD patients with unknown etiology account for more than 10% of the total CKD patients. According to this ratio, there may be more CKD patients with unknown etiology in my country.
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It is worth noting that CKD and even end-stage renal disease (ESRD) patients may have familial inheritance. Therefore, genetic testing, especially exome sequencing (ES), should be considered in the diagnostic approach to CKD.
On July 21, 2023, Kidney International Reports released a study from France. This study shows that in CKD patients with unknown etiology, ES examination has very important diagnostic significance and needs to be paid attention to by doctors, and important conclusions can be seen in detail.
important conclusion
① Exome sequencing can determine the etiology of 40% of CKD patients with unknown etiology;
②For CKD patients who cannot accept renal biopsies, such as pregnancy or renal atrophy, but have a family history of renal disease, ES examination may be better than renal biopsy;
③Patients with a family history of kidney disease should receive an ES examination;
④ES examination can not only clarify the specific etiology of CKD patients with unknown etiology, but also clarify the patient's response to immunosuppressive therapy, the risk of renal disease recurrence after kidney transplantation, and the risk of lesions in extrarenal organs.
Research design
This is a single-center retrospective cohort study to explore the diagnostic ability of ES examination in patients with CKD of unknown etiology. The inclusion criteria were: ①adults; ②CKD patients whose etiology could not be identified after comprehensive physical, blood, and imaging examinations, as well as a renal biopsy. Notably, hypertension is both a risk factor and a common comorbidity of CKD. Therefore, in this study, CKD of unknown etiology included patients with essential hypertension at the time of diagnosis of CKD. In addition, patients with typical clinical symptoms of Gitelman or Bartter syndrome were excluded from this study.
The collection, testing, and evaluation of ES complied with the instructions of the gene collection kit, the American College of Medical Genetics (ACMG) guidelines, and other relevant standards.
Research result
A total of 52 patients were enrolled, of which 32 were male. The median age was 39.5 years old (IQR 25.8~49.5 years old). 6 patients were related by blood, and 2 cases were suspected to be related by blood. Family members of 37 patients had renal disease. One-third of the patients had developed ESRD at the time of renal biopsy, and 58% of patients had developed ESRD at the time of ES examination. The median interval between renal biopsy and ES examination was 1 year.
ES detected 13 monogenic variants associated with kidney disease in 21 patients (40%). Among the single gene variants, glomerular disease-related lesions were the most common, accounting for 57.1% (12/21), of which type IV collagen-related nephropathy was the most common. The remaining renal lesions were cilia disease and tubular disease. Only 1 case was found to be related to renal vascular disease.
The family history of kidney disease was significantly higher in ES-diagnosed patients than in undiagnosed patients (71.4% vs 38.7%; P = 0.026). In addition, the proportion of women with confirmed ES was significantly higher than that of undiagnosed patients (57.1% vs 25.8%, P = 0.04). However, there were no statistically significant differences in age of onset, consanguinity, and age at renal biopsy.
ES can also guide the treatment and management of renal disease. A total of 4 patients' ES examination results showed that they were not suitable for initiation/continuation of immunosuppressive therapy; family members of 12 patients were also detected to have gene mutations related to kidney disease; renal disease recurrence after kidney transplantation was identified in 6 patients Higher risk; and detection of lesions in other systems of the patient, such as eyes, ears, liver, etc.
research discussion
Previous studies have shown that the acceptance of genetic testing for CKD is low. Only 3.8% of doctors believe that genetic testing can be performed on adult patients with CKD, and more doctors believe that ES is suitable for infants rather than adults. However, a growing body of research demonstrates that genetic testing is warranted in adults with CKD of unknown etiology. It is important to emphasize that genetic testing should be offered to adults with a family history of kidney disease, regardless of known etiology.
It is worth noting that many studies have already shown that there are certain genetic factors in CKD and ESRD. Previous studies have confirmed that 25% of CKD patients have a family history of kidney disease. Freedman et al found that approximately 20% of family members of dialysis patients develop ESRD. Connaughton et al. found that in the Irish population, the most common family history of kidney disease was polycystic kidney disease, followed by CKD of unknown etiology. In clinical practice, a patient's family history can be confirmed at initial diagnosis, guiding the diagnostic process and facilitating genetic evaluation.
However, compared with other routine tests, genetic testing faces the problems of high cost and low accessibility. Therefore, how to flexibly use genetic testing, especially ES is a question worth pondering. In this study, for patients with or without hematuria/proteinuria but with a family history of kidney disease, the diagnostic rate of ES was >50%, suggesting that ES can be used as a first-line diagnostic tool for these patients. The research team believes that for CKD patients who cannot accept renal biopsy, such as pregnancy or renal atrophy, but have a family history of renal disease, ES may be superior to renal biopsy; for patients with a family history of renal disease, ES should be accepted. In addition, for patients with CKD of unknown etiology, ES and other genetic tests should also be mandatory tests.
In general, this study suggests that: ① For CKD patients who cannot accept renal biopsy, such as pregnancy or renal atrophy, but have a family history of renal disease, ES examination may be better than renal biopsy; ② Patients with a family history of renal disease, All patients should receive ES examination; ③ES examination can not only clarify the etiology of kidney disease in CKD patients with unknown etiology, but also clarify the patient's response to immunosuppressive therapy, the risk of renal disease recurrence after kidney transplantation, and the risk of lesions in extrarenal organs.
references:
1. Robert T, Greillier S, Torrents J, et al. Diagnosis of Kidney Diseases of Unknown Etiology through Biopsy-Genetic Analysis. Kidney International Reports (2023). July 03, 2023.
