Genetics and Chronic Kidney Disease

Chronic Kidney Disease (CKD) is a degenerative condition linked to multiple co-morbidities and an increased risk of cardiovascular disease. In addition, the CKD etiology is linked to conditions like Diabetes Mellitus and hypertension. However, the deterioration of kidney function is not only associated with metabolic disorders, as it can also be affected by autoimmune disease. In addition, genetic conditions such as Autosomal dominant polycystic kidney disease (ADPKD) can cause a detriment to the kidney’s function and structure. Multiple gene variants link the implicated pathways involved with CKD progression and kidney filtration markers. 

eGFR and Genetic Variants

UMOD is the genetic code for the protein uromodulin. Indeed, uromodulin is a protein produced by the kidneys and is the most abundant urinary protein. 

UMOD 

Furthermore, in animal models, the loss in UMOD has a close link with the dysfunction of transmembrane solute transporters in the loop of Henle. Another disease linked to mutations in the UMOD gene is the autosomal dominant tubulointerstitial kidney disease that could progress into CKD. 

In particular, the UMOD variant rs12917707 found in patients with CKD and European ancestry associates with lower eGFR. In addition, the literature reports multiple UMOD gene variants which seem to change within ethnicities. Variations like the rs11864909 and rs13329952 were found in the Icelandic population by a large study involving 15 594 participants. Finally, this report concluded that these variations were significantly associated with CKD.

The UMOD variant rs12917707 was the first to gain clinical significance for the detection of CKD. The main reason behind this is that it has a powerful effect on the measurement of serum creatinine, eGFR, and cystatin C. Furthermore, confirming a CKD diagnosis depends on the measure of SCr eGFRcrea and eGFRcys. However, certain patients are difficult to stage because their biochemical filtration markers are on the borderline of the normal ranges. 

Elderly patients with low muscle mass, protein-energy wasting, or bedridden can falsely report low creatinine levels, affecting the eGFRcrea equation. On the contrary, patients with a high muscle mass, highly active individuals with a high protein diet due to their repair requirements, can report a higher creatinine level, reflecting on a low eGFR. 

In this particular case, which is very common, the literature shows that UMOD is associated with renal function and not with creatinine metabolism or production. In addition, previous studies consider UMOD as a diagnostic biomarker of CKD.

SHROOM3

This is the encoding gene for the SHROOM3 protein, which has the function to coordinate the cytoskeleton assembly. With the potential to regulate cell shape, variants in the SHROOM3 gene are associated with allograft fibrosis in transplant patients. Following UMOD, SHROOM3 rs17319721 variant is the second genetic biomarker associated with low eGFR.

Besides this variant’s association with eGFR in CKD patients, a study of 3028 Caucasian patients with DMT2 showed a powerful impact on albuminuria. Finally, this finding may imply the functional role of the shroom3 protein in proteinuria.

Cystatin C rs13038305

The KDIGO recommends using an alternative filtration marker cystatin C to determine CKD staging when creatinine-based eGFR cannot be used as a reliable marker. In addition, cystatin C has proven to be a promising biomarker of renal function since it does not reflect factors such as race and muscle mass.

However, studies show that carriers of the T allele of the SNP rs13038305 report a higher level of cystatin C. Therefore, the reporter glomerular filtration rate in these patients seems higher, resulting in misdiagnosis. 

A study performed to observe how the rs13038305 affected glomerular filtration found the following results:

• Those patients with the rs13038305 had 6.4% lower cystatin levels.
• This low cystatin C level translated to 5.5-mL/min/1.73 m2 higher eGFRcys.
• The odds of suffering from CKD lowered a 36% in the T allele carriers.

These findings raised questions about the necessity to adjust the genetic bias in the eGFRcys equation. In addition, when adjusting for genetic variant, 7.7% of the participants were reclassified to a higher staging of CKD progression. 

Chronic Kidney Disease is a complex condition that requires multiple stages of assessment. As knowledge progressed, studies showed the other shortages of creatinine and eGFR. However, the combination of these markers with cystatin C seems to be promising. In addition, genetic variants that play an essential role in the kidney’s structure and function are now considered critical biomarkers to detect CKD.- Ana Paola Rodríguez Arciniega, MS.

References:

Cañadas-Garre, M et al. “Genomic approaches in the search for molecular biomarkers in chronic kidney disease.” Journal of translational medicine vol. 16,1 292. 25 Oct. 2018, doi:10.1186/s12967-018-1664-7

O’Seaghdha, Conall M et al. “Association of a cystatin C gene variant with cystatin C levels, CKD, and risk of incident cardiovascular disease and mortality.” American journal of kidney diseases: the official journal of the National Kidney Foundation vol. 63,1 (2014): 16-22. doi:10.1053/j.ajkd.2013.06.015

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