Which CKD Patients Need Genetic Testing? Summary Of The Article (Part 2)

1. CAKUT

CAKUT is a group of disorders characterized by congenital anatomical anatomy of the urinary system with various phenotypes due to various causes, including renal abnormalities (such as renal arrest, renal dysplasia, renal hypoplasia, polycystic kidney disease, etc.) Dysplasia, ectopic kidney, horseshoe kidney), ureteral and bladder abnormalities (eg, ureteropelvic junction obstruction, ureterovesical junction obstruction or insufficiency, ectopic ureteral opening, double collecting system), urethral abnormalities (eg, posterior urethral valves) wait. It is worth noting that CAKUT is the most common cause of renal failure in children, accounting for approximately 40% of children or adolescents on dialysis, compared with less than 5% of adults on dialysis. The etiology of CAKUT is associated with abnormal development of the kidneys and urethra during embryonic development. CAKUT can present as a disease affecting only the kidneys or urinary tract, or as part of a syndrome affecting multiple organs.

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At present, the causative gene of CAKUT is not fully understood. The majority of CAKUTs are sporadic, but some patients are obviously hereditary. Therefore, some scholars speculate that the occurrence of CAKUT is closely related to heredity and environment. More than 40 genes have been identified to be associated with CAKUT, among which HNF1B and PAX2 mutations are considered to be the cause of 5%-15% of CAKUT patients.

Clinical presentation depends on the severity of the malformation, ranging from unilateral renal dysplasia/malformation to intrauterine fetal death; from structural and functional abnormalities (eg, renal dysplasia, horseshoe kidney, pelvic kidney, congenital hydronephrosis, vesicoureteral obstruction, reflux, etc.), to high blood pressure and proteinuria caused by poor kidney function, the above situations may occur. It is worth noting that compared with their peers, CAKUT patients are more prone to recurrent infection, and the risk of progression to renal failure after infection is increased. If the patient is born successfully, he/she is more likely to develop end-stage kidney disease (ESKD) before adulthood.

Obstetric ultrasound and prenatal screening are helpful for early diagnosis of CAKUT. For CAKUT patients who have been born, their treatment involves multidisciplinary and multiple treatment modalities. First, imaging and genetic testing should be used to clarify the etiology and extent of the deformity. Second, routine follow-up, surgery, and renal replacement therapy (KRT), including dialysis or kidney transplantation, are good management options for CAKUT patients. Because of their lower cardiovascular risk, pediatric patients with KRT have better survival than adult patients.

2. ADTKD

The previous names of ADTKD include medullary cystic kidney disease (MCKD), juvenile hyperuricemia nephropathy (JHN), genetic interstitial nephropathy, tubulointerstitial nephritis, etc. This situation is not conducive to clinical diagnosis and corresponding research. It was not named ADTKD by KDIGO until 2015. Currently, there is no specific report on the incidence of ADTKD. Five types of gene mutations may lead to ADTKD, UMOD, MUC1, HNF1B, REN, SEC61A1/SEC61. If no gene mutation is found in ADTKD patients, the SEC61A1/SEC61 gene mutation is the ADTKD-NOS subtype.

The clinical manifestations of each subtype are slightly different, UMOD mutations are the most common, and the clinical manifestations are CKD progression and hyperuricemia; the common clinical manifestations of MUC1 mutation patients are cortical medullary cysts or medullary cysts; HNF1B mutations can also be known as young adults with diabetes mellitus (MODY) type 5, with renal cysts and renal dysplasia, extrarenal manifestations include pancreatic hypoplasia, early-onset diabetes mellitus, uterine abnormalities, and hypomagnesemia; common clinical manifestations in patients with REN mutations for hypotension and hyperkalemia. Most of the mutations are autosomal dominant inheritance patterns, and understanding the patient's family history is helpful for the diagnosis of ADTKD-related diseases. It is worth noting that family members of ADTKD patients may have an abnormal renal function, but it has not been detected, and genetic testing can help family members of patients to determine the risk of CKD early.

3. Kidney stones and renal calcium deposition

Although most kidney stones are caused by multiple factors, such as genetics, environment, etc., single gene mutations cause up to 15% of patients. For kidney stone patients with onset at a young age and a positive family history, genetic testing should be performed on the patient and their family members. In addition, extrarenal factors, such as hearing, vision, and nervous system abnormalities are also important hints of single-gene mutations. This summary will summarize primary hyperoxaluria (PH), cystinuria, urinary calculi caused by purine metabolism disorders, Dent disease, Bartter syndrome, single nucleotide polymorphisms (SNPs), and kidney stones.

01 PH

PH is a recessive genetic disease associated with three groups of autosomal mutations. The mechanism is that mutations lead to enzyme deficiency, which in turn leads to increased calcium oxalate production or decreased metabolism, which in turn causes kidney stones or calcinosis. PH1~3 types can all lead to increased oxalate levels, and the cause is all due to enzyme deficiency, but the specific enzymes lacking are different. PH1 is the most common form of PH, affecting about 70% to 80% of patients, but it is also the most severe, with about 50% of PH1 patients progressing to ESKD at a younger age.

The disease may be diagnosed during childhood, but some patients are not found to have abnormal kidney function or calcium oxalate stones until they are adults. Timely diagnosis and intervention can help slow down the progression of the disease. The most common clinical manifestation of PH is elevated urinary oxalate levels, and specific urinary metabolites can be used to distinguish the subtypes initially, but genetic testing is required for the diagnosis. Doctors should intervene according to the subtype. If the subtype is not distinguished, the intervention may not be effective. For specific intervention methods and subtype distinctions, please refer to "Guideline Consensus 丨 The latest consensus on primary hyperoxaluria publishes 48 recommendations for diagnosis and management".

02 Cystinuria

Cystinuria is an autosomal recessive disorder in which cystine levels in the urine are elevated due to a defect in the renal tubular cystine transporter, which results in decreased cystine reabsorption in the proximal tubule. Cystine is less soluble in normal pH urine, which promotes the formation of cystine stones. SLC3A1 or SLC7A9 are gene mutations that cause cystinuria. Stones, usually staghorn crystals, are often discovered in childhood and often recur. Urinalysis may reveal hexagonal cystine crystals, or stone analysis may reveal 100% cystine stones. Cystinuria can be basically diagnosed through the above clinical features, while genetic testing can confirm cystinuria, but it is not necessary to check.

Once diagnosed, all patients should undergo a 24-hour urinary cystine quantitative examination. Most patients will excrete more than 400 mg of cystine in 24 hours, while normal people excrete 30 mg. Conservative treatment consists of drinking plenty of water, alkalizing the urine, and reducing the intake of sodium and animal protein in the drinking water. For patients with severe conditions, thiol-containing compounds can be taken, but such compounds (such as tiopronin, note: off-label use) have serious adverse reactions, so they need to be used with caution.

There is no doubt that molecular genetics may change the treatment of kidney stones. As more genetic mutations and mutants are discovered, the secrets of kidney stones and nephrocalcinosis may be revealed by us. However, kidney stones and nephrocalcinosis are not only related to genetic factors, but also related to complex environmental and genetic factors. Identifying these factors can help reduce the risk of kidney stone-related disease and reduce the likelihood that patients will develop ESKD.

Generally speaking, the previous concept believed that kidney disease was related to other modifiable factors of patients, such as diet, exercise, etc.. Still, current research shows that genetic factors also have a greater impact on the occurrence and development of kidney disease. With the popularization of genetic testing technology and the improvement of basic research, our knowledge and understanding of this disease will continue to grow, and eventually individualized, patient-centered CKD management methods and new treatment methods can be established.

Remarks: ADPKD is autosomal dominant polycystic kidney disease, ARPKD is autosomal recessive polycystic kidney disease, aHUS is an atypical hemolytic uremic syndrome, CAKUT is congenital kidney and urinary tract malformations, ADTKD is autosomal dominant polycystic kidney disease Genetic tubulointerstitial nephropathy, PH is primary hyperoxaluria.

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