Which CKD Patients Need Genetic Testing? Summary Of The Article (Part 1)

Common causes of chronic kidney disease (CKD) include hypertension, diabetes, glomerulonephritis, and polycystic kidney disease (PKD). Unlike most etiologies, PKD is a hereditary kidney disease. Similar to PKD are hereditary nephrotic syndrome, focal segmental glomerulosclerosis (FSGS), Alport syndrome, atypical hemolytic uremia Syndrome (aHUS), etc. With the enhancement of genetic testing and analysis capabilities, it is no longer difficult to diagnose and identify the etiology of CKD through genetic testing. Clinicians must understand the clinical manifestations, risks, and management of patients with hereditary CKD, screen patients and their families who should receive genetic testing, and provide them with comprehensive management.

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On January 5, 2023, nephrology experts from the Cleveland Clinic in the United States released a review on patients with hereditary CKD, focusing on which diseases should receive genetic testing and clarifying the management priorities of patients. This article summarizes cystic kidney disease and hereditary glomerulonephritis for the convenience of the reader.

Congenital anomalies of the kidney and urinary tract (CAKUT), autosomal tubulointerstitial kidney disease (ADTKD), kidney stones, and renal calcium deposits will be discussed in "Which CKD Patients Need Genetic Testing?"

cystic kidney disease

ADPKD and ARPKD

Autosomal dominant polycystic kidney disease (ADPKD) is an autosomal dominant (or recessive) and relatively common hereditary kidney disease, accounting for about 5% to 10% of end-stage kidney disease (ESKD). In most cases, ADPKD is caused by mutations in the PKD1 and PKD2 genes. PKD1 mutations account for approximately 85% of ADPKD cases. Kidney function in patients with PKD1 mutations is usually normal in youth and they do not develop other symptoms, but kidney function becomes abnormal around age 40 and progresses to ESKD around age 60. Patients with PKD2 mutations are more likely to develop abnormal renal function in childhood (around 7 years old). ADPKD can be hereditary, so it is necessary to carry out a genetic examination on family members of patients, which is helpful for early detection, early intervention, and early treatment.

Autosomal recessive polycystic kidney disease (ARPKD) is a rare fibrocystic kidney-liver hereditary disease. The main patients are infants and young children. The main gene mutation is PKHD1, which can lead to hepatic and renal cysts. Unlike ADPKD, ARPKD mainly affects the renal tubules and liver and does not affect nephrons. About half of the pediatric patients progress to ESKD relatively quickly.

Imaging tools such as ultrasound, CT, and magnetic resonance (MRI) can assess the number and size of cysts for diagnosis and measurement of total kidney volume (TKV). After the above data are corrected by the patient's height, it can be judged whether the patient responds to the treatment. Because intracranial aneurysms are common in ADPKD patients, some clinical studies suggest that ADPKD patients and their families should be screened universally.

Treatment goals for patients with ADPKD and ARPKD are similar in that both angiotensin-converting enzyme inhibitors (ACEi) and angiotensin receptor blockers (ARBs) can be used to control blood pressure, reduce sodium, and increase fluid intake. Tolvaptan is an oral V2 receptor antagonist that can be used in the treatment of ADPKD, reducing the rate of decline in a patient's glomerular filtration rate (GFR), improving blood pressure, and reducing pain caused by cysts. However, once patients progress to ESKD patients require dialysis or kidney transplantation.

Nephron tuberculosis

Nephron tuberculosis (NPHP), an autosomal recessive cystic kidney disease, is one of the most common causes of genetically induced ESKD in children and adolescents. Patients usually progress to ESKD before the age of 30. Unlike PKD, the tubulointerstitial fibrosis and cysts in NPHP patients are only concentrated at the junction of the cortex and medulla, and the volume of the patient’s kidneys is usually normal or small, so ultrasound or Imaging is more difficult to detect NPHP. At present, more than 20 gene mutations have been found to cause NPHP, and about 25% of NPHP is caused by mutations in the NPHP1 gene. The clinical manifestations of extrarenal involvement include bone defects, visual impairment, and liver fibrosis. The clinical symptoms were early-onset polyuria, severe hypertension, and ESKD.

Genetic testing can confirm the diagnosis of NPHP in more than 70% of cases, but for the remaining patients, renal biopsy is the most accurate examination method. Tubular changes and basement membrane thickening are common biopsy findings. Unfortunately, other than controlling hypertension and increasing fluid intake, there are currently no specific treatment options for patients with NPHP.

hereditary glomerulonephritis

hereditary nephrotic syndrome

The population with hereditary nephrotic syndrome includes children and adults. Typically, nephrotic syndrome is idiopathic or autoimmune-mediated. Steroid therapy is the usual treatment modality for patients with immune-mediated glomerulonephritis or nephrotic syndrome, however, some patients have steroid-resistant nephrotic syndrome (SRNS). Currently, there is evidence that SRNS may be genetically related, manifesting as isolated glomerular involvement or with extrarenal clinical manifestations due to mutations in genes affecting podocytes. Doctors should provide patients with genetic testing services at an appropriate time. Genetic testing results can help doctors predict and evaluate the possibility of successful hormone therapy, as well as assess the risk of renal disease recurrence after kidney transplantation.

People with nephrotic syndrome who have:

①Primary nephrotic syndrome or SRNS occurred at <1 year old;

② Nephrotic syndrome occurs in adult patients <25 years old;

③No response to immunosuppressant/therapy;

④ There are extrarenal features consistent with the etiology of nephrotic syndrome;

⑤Specific ethnicity (such as APOL1 nephropathy in the African-American population).

There are a variety of genes associated with the development of nephrotic syndrome, which can be distinguished by affecting the location, such as affecting the nucleus, lysosomes, mitochondria, cytoskeleton, etc.,

Genetic mutations can lead to multiple injury patterns such as minimal change disease (MCD), FSGS, collapsing glomerulopathy, and diffuse mesangial sclerosis. Most cases of FSGS in adults are autosomal dominant and involve mutations in the INF2, TRPC6, ACTN4, SCARB2, and PAX2 genes. Of note, not all patients with FSGS develop proteinuria. Diffuse mesangial sclerosis is usually accompanied by mutations in genes such as LAMB2, PLCE1, and NPHS1/2. Finally, DGKE and INF2 mutations may be associated with membranous nephropathy, FSGS, and thrombotic microangiopathy (TMA).

At present, there is no definite treatment for hereditary nephrotic syndrome, and only conservative treatment strategies such as ACEi or ARB can be adopted. In some cases, indomethacin may reduce resistance to immunosuppressants. CoQ supplementation may be beneficial in cases of CoQ2 or CoQ6 gene mutations. For ARHGDIA gene mutations, eplerenone may be considered.

 HUS

Hemolytic uremic syndrome (HUS) is a life-threatening disorder that can cause anemia, thrombocytopenia, and acute renal failure due to uncontrolled activation of the complement pathway. In the vast majority of cases, HUS is associated with Shiga toxin-producing E. coli infection, however, HUS unrelated to Shiga toxin-producing E. coli infection, ie aHUS, is occasionally seen. Unlike HUS, gene mutations are the main cause of abnormal complement activation in aHUS patients. Specifically, gene mutations can cause loss of function of regulatory proteins such as CFH, CFI, C3, and CD46, resulting in abnormal activation of the complement pathway in patients. Currently, eculizumab is a drug for the treatment of aHUS and has been marketed in China2.

Alport syndrome

Alport syndrome is a type IV collagen disorder dating back to the 19th century, yet its prevalence and incidence have been debated. Alport syndrome is mainly associated with COL4A3, COL4A4, and COL4A5 gene mutations, of which COL4A3 and COL4A4 are distributed on autosomes, while COL4A5 is on the X chromosome. Therefore, Alport syndrome is also divided into X-linked dominant inheritance and non-X-linked dominant inheritance.

Alport syndrome is characterized by glomerular basement membrane (GBM) lesions. Under the electron microscope, compared with the normal population, the GBM of early patients is thinner, and GBM split or layered lesions can be found in advanced patients. The manifestations under the light microscope were glomerular abnormalities, GBM hyperplasia, and glomerulosclerosis. After immunofluorescent staining, negative staining can be found, and non-specific positive stainings such as IgG, IgA, IgM, C3, or C1q can also be found. The clinical symptoms are most severe proteinuria.

There have been some developments in the diagnosis of Alport syndrome. In particular, genetic testing can classify patients, which is beneficial to clarify the genetic type of the disease. However, progress in the treatment of Alport syndrome has been slow. Currently, the treatment basis for Alport syndrome is the maximum tolerated dose of ACEi or ARB. However, preliminary clinical studies have shown that sodium-glucose cotransporter 2 inhibitors (SGLT-2i) seem to be beneficial, but large-scale clinical studies are still needed for verification. Therapies in preclinical and preliminary clinical research include paricalcitol, stem cell therapy, epidermal growth factor receptor inhibitors, etc.

Fabry disease

Fabry disease is a rare disease with a prevalence of about 1/100,000 in the general population and 0.12% of ESKD patients. my country has included it in the first batch of rare disease catalogs in 2018. The etiology is caused by the deficiency of α-galactosidase (α-gala) caused by gene mutation Xq21.3-q22. The disease affects not only the kidneys but the whole body, and people of all ages can be diagnosed with Fabry disease.

The nephropathy in Fabry disease is characterized by mild to severe proteinuria and microscopic hematuria. In the early stage, the patient's GFR is usually relatively normal or does not decrease significantly. However, as the disease progresses, the patient's renal function will gradually decline and cause high blood pressure. Podocytes can be seen under an electron microscope to be filled with laminar granules, resembling zebra stripes, and this phenomenon is often referred to as "zebra body".

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