Sandbox:Genetics in CKD

Genetics in CKD

• The CKD poses a major public health challenge that affects roughly 800 million people globally.But many a times the cause for CKD is difficult to identify just based on clinical diagnosis. With the emerging idea that genetics play a significant role in the causation of CKD the KIDGO  The (Kidney Disease: Improving Global Outcomes organization  is advising physicians to consider genetic testing for patients with CKD to pinpoint the diagnosis and to tailor their management accordingly.

• The first gene connected with kidney disease was the locus for APCKD. Since then hundreds of genes have been identified.Several factors like the pattern in which the CKD cluster in certain racial and ethnic groups suggests genetic contributions.
• Even when a clinical phenotype based diagnosis supports a genetic cause ,it is suggested to get a variant-based diagnosis because it establishes precise cause which further can help personalised monitoring and treatment and for effective genetic family counselling.
• The genetic risk of CKD can be viewed as a spectrum of low penetrance to high penetrance variants.
• The diseases at the high end of the spectrum, the Mendelian diseases have tight genotype-phenotype correlations.
• In contrast the low penetrance variants are influenced by environmental factors.

Nephropathies with single genetic cause:

Cystic Kidney Disease:

Cystic kidney diseases are mostly due to ciliopathies, caused by alterations in the cilium-centrosome complex.Clinical phenotypes include

• • Multiple renal cysts as in ADPKD
  • Normal size or small echogenic kidneys as in Nephronophthisis.

ADPKD:

• Genotype-phenotype correlation studies show that truncated PKD1 variants are associated with more severe disease when compared to PKD1 missense and PKD2 variants.
• Recently several genes have been implicated in rare cases of ADPKD.These include  IFT140, GANAB, NEK8, and DNAJB11 .

Nephronopthisis:

• Nephronophthisis is a group of genetically heterogeneous autosomal recessive diseases characterized by nonspecific, progressive deterioration in kidney function. 
• It can occur at any age like in childhood, adolescence or adulthood with symptoms like polyuria, growth retardation kids, and anemia. But the urine is generally bland.
• Homozygous variants in NPHP1 account upto 50% of cases ,remaining cases are caused by variants in 90 different genes involved in molecular pathways regulating cell polarity, sonic hedgehog signaling, the DNA damage response, or cyclic AMP signaling.
• Genotype-phenotype studies show that null variants are associated with younger age at presentation and more severe disease phenotypes.

1. Genetic Glomerular Diseases:

• Genetic glomerular diseases often involve mutant gene products that normally maintain podocyte function or pathogenic variants of proteins that make up the glomerular basement membrane (e.g., collagen type IV)
• Clinical presentations include the steroid-resistant nephrotic syndrome (SRNS) with focal segmental glomerulosclerosis (FSGS) on kidney biopsy or chronic proteinuria with or without hematuria.
• FSGS is a nonspecific lesion that represents a pattern of podocyte injury rather than a defined disease entity. Genetic forms of FSGS may be familial or sporadic. Extrarenal features may be present, depending on the involved gene.

CKD Related to Type IV Collagen

• Variants in the genes encoding the α3, α4, and α5 chains of type IV collagen (COL4A3, COL4A4, and COL4A5, respectively) are the second most common genetic cause of CKD after ADPKD accounting for 2-3% of adults with advanced CKD.
• Over 30 years ago changes in type  IV collagen a major component of GBM (glomerular basement membrane) was found to be seen in patients with Alport syndrome a.k.a Familial nephritis.
• Further studies showed that the phenotypic variations are associated with difference in the modes of variation and the location and types of variant within the genes encoding type IV collagen.
• In Cases of CKD due to aport syndrome without its classical features studies shows that under-appreciated variants in genes encoding type IV collagen are responsible for it.
• X-linked disease is caused by pathogenic variants in COL4A5 .
• Autosomal recessive or autosomal dominant inheritance of pathogenic variants in COL4A3 or COL4A4 are identified.
• Highest risk of renal failure is associated with X-linked and Autosomal Recessive inheritance.
• Disease resulting from pathogenic variants in two different genes encoding type IV collagen (digenic inheritance) may have worse clinical outcomes than disease due to a single-gene heterozygous variant.
• Truncated variants have worse outcome when compared to missense variants.

Missense variants affect glycine residues there by altering the assembly of collagen heterotrimer structure.

Monogenic Forms of SRNS and FSGS:

Identification of variants in the podocyte-associated genes encoding nephrin (NPHS1)and podocin (NPHS2) established podocyte disease as a cause of chronic proteinuria and progressive kidney failure.

• Autosomal dominant and recessive inherited alterations in more than 50 different gene products that maintain podocyte ultrastructure, mediate signal transduction, or control podocyte cytoskeletal rearrangements have been reported as genetic causes of nephrotic syndrome or chronic proteinuria.
• These variants often seen in children can sometime result in adult disease like FSGS.

R229Q is associated with increased risk of adult-onset FSGS.

• Single-gene causes of adult-onset proteinuria and FSGS include autosomal dominant variants in the cytoskeletal genes ACTN4 and INF2 and the cation channel protein encoded by TRPC6.

TUBULOINTERSTITIAL DISEASES

• Genetic conditions affecting renal tubular function (tubulopathies) involve ion channels or transporters.
• Autosomal dominant disease due to gain-of-function variants in UMOD is one of the most prevalent monogenic causes of adult CKD worldwide.
• Uromodulin (also known as Tamm–Horsfall protein) is a kidney-specific protein that is synthesized by the thick ascending limb of the loop of Henle and autosomal dominant disease due to gain-of-function variants in UMOD is one of the most prevalent monogenic causes of adult CKD worldwide.
• UMOD variants cause a spectrum of disorders that have been termed UMOD-related autosomal dominant tubulointerstitial kidney disease (ADTKD).
• ADTKD is characterized by insidious kidney failure between the third and sixth decades of life. Patients may also have hyperuricemia and gout related to reduced fractional excretion of urate, despite a normal GFR.
•  Most disease-causing genetic variants are missense variants, often located in exons 3 and 4; 60% involve a cysteine residue.
• Pathogenic UMOD variants cause protein misfolding, with subsequent retention of protein in the endoplasmic reticulum and mistargeting of uromodulin in the thick ascending limb of the loop of Henle.
•  Variants in MUC1 are the second most common genetic cause of ADTKD and should always be considered in UMOD-negative cases.

KIDNEY STONE DISEASE

It is a multifactorial disease with a genetic component.

• Metabolic imbalances lead to urine crystallization and defective genes that normally encode proteins that maintain metabolic balance causes heritable forms of nephrolithiasis, sometimes leading to CKD.
• Genetic forms of kidney stone disease include adenine phosphoribosyltransferase deficiency, Dent’s disease, familial hypomagnesemia with hypercalciuria and nephrocalcinosis, and primary hyperoxaluria, frequently lead to CKD and progress to kidney failure.
• These patients have the risk of recurrence after a transplantation as it doesnot address the underlying metabolic imbalance.

Syndromes like monogenic diabetes, monogenic hyperlipidemia or hypertension, and monogenic systemic lupus erythematosus are known to cause secondary kidney damage.

NEPHROPATHIES WITH A COMPLEX GENETIC BASIS

APOL1-Related CKD

APOL1 is a protein that provides protection against Trypanosomc mediated African sleeping sickness.

• Two variants of APOL1 a linked pair of missense variants, S342G and I384M, and two consecutive amino acid deletions, N388 and Y389are suspected to be major contributors for several subtypes of progressive CKD.
• They are designated as G1 and G2 ,confer protection against an extended spectrum of Trypanosoma species compared with its ancestral G0 allele.
• Although they offer protection they also contribute to an increased frequency of CKD among the Sub Saharan African ancestry.
• APOL1 is associated with broad spectrum of Nephropathies like FSGS<Hypertensive Nephropathies,HIV associated nephropathies and lupus-associated nephropathies.They define a new spectrum of APOL1 related CKD.
• Success with inaxaplin in FSGS suggests glomerular podocyte as the target of cell injury more specifically  luminal endoplasmic reticulum trafficking of the aberrant gene product is thought to result in abnormal cell-membrane cation channel activity.

Clinical and Diagnostic Evaluation from genetical aspect

• the first step in genetic diagnosis is
  • obtaining gf a comprehensive phenotyping.
  • detailed family history
  • three generation family pedigree.
• The diagnostic yield of genetic testing in CKD is variable and depends on the disease phenotype, associated coexisting conditions, ethnicity, consanguinity, family history, and age at onset.( table 1)
• Analyses of single kidney disease genes are currently being supplanted by large gene panels, exome sequencing, and whole-genome sequencing. 

Emerging Therapies

• Primary, secondary, and tertiary prevention of CKD is increasingly possible because of genetic diagnoses. 
• A recent study involving a small molecule Inaxaplin reverses the toxic gain-of-function effect of APOL1 high-risk variants, in patients with two APOL1 variants and biopsy-proven FSGS.
• A mouse model showed that gene transfer of Pkd1 trans gene lead to re expression of polycystic 1 protein thereby markedly delayed cyst development, retarded cyst progression, and postponed kidney failure in Pkd