GENETICS and KIDNEY DISEASES /

The connection between genetics and kidney disease lies in the role of inherited genetic factors that can increase the risk of developing various kidney diseases.
Certain kidney diseases, such as Polycystic Kidney Disease (PKD) and Alport Syndrome, have a clear genetic component where mutations in specific genes contribute to the development of these conditions.
Understanding these genetic basis is vital for assessing the risk of kidney disease in individuals with family history and for advancing personalized medicine approaches in prevention, diagnosis and treatment.
Genetic testing plays a significant role in identifying these predispositions and guiding healthcare strategies.

1. GENETICS And Kidney Disease Presenting Intern: Affifa Maqbool Hussain

2. INTRODUCTION The connection between genetics and kidney disease lies in the role of inherited genetic factors that can increase the risk of developing various kidney diseases. Certain kidney diseases, such as Polycystic Kidney Disease (PKD) and Alport Syndrome, have a clear genetic component where mutations in specific genes contribute to the development of these conditions. Understanding these genetic basis is vital for assessing the risk of kidney disease in individuals with family history and for advancing personalized medicine approaches in prevention, diagnosis and treatment. Genetic testing plays a significant role in identifying these predispositions and guiding healthcare strategies.

3. BASICS OF GENETICS DNA is a double-stranded molecule forming a helical structure. It contains the genetic code that determines an individual’s traits. Genes are segments of DNA, the hereditary material in cells. Each gene carries instructions for building and maintaining the body. DNA is organized into structures called Chromosomes. Humans have 23 pairs of chromosomes, with one set inherited from each parent. Different forms of genes are called Alleles. Alleles contribute to variations in traits. Mutations are changes in the DNA sequence and can lead to genetic variations.

4. BASICS OF GENETICS Inheritance Patterns Autosomal Dominant Inheritance A person affected by an autosomal dominant disorder has a 50 percent chance of passing the altered gene to each child. The chance that a child will not inherit the altered gene is also 50 percent. However, in some cases an autosomal dominant disorder results from a new variant that occurs during the formation of egg or sperm cells. In these cases, the child’s parents maybe unaffected, but the child may pass on the condition to his or her own children.

5. Autosomal Recessive Inheritance: Two unaffected people who each carry one copy of the altered gene for an autosomal recessive disorder (carriers) have 25% chance with each pregnancy of having a child affected by the disorder. The chance with each pregnancy of having an unaffected child who is a carrier of the disorder is 50% , and the chance that a child will not have the disorder and will not be a carrier is 25% . If only one parent is a carrier of the altered gene and the other parent does not carry the variant, none of their children will develop the condition, and the chance with each pregnancy of having an unaffected child who is a carrier is 50%

6. X-linked dominant inheritance: The chance of passing on an X-linked dominant condition differs between males and females because females have two X chromosomes (XX), while males have one X and one Y (XY). If the father is affected by a condition caused by an X-linked dominant gene variant: None of their  sons   can inherit the X-linked dominant gene variant since the son only inherits the Y chromosome from the father, but all of his daughters will inherit the condition. If the mother is affected by a condition caused by an X-linked dominant gene variant then there is 50% chance of having an affected daughter or son with each pregnancy.

7. X-linked recessive inheritance: Because of the difference in sex chromosomes, the probability of passing on an X-linked recessive disorder also differs between men and women. The sons of a man with an X-lined recessive disorder will not be affected, and his daughters will carry one copy of altered gene. With each pregnancy, a woman who carries an altered gene for X-linked recessive has a 50% chance of having sons who are affected and a 50% chance of having daughters who carry one copy of the altered gene.

8. TYPES OF INHERITED KIDNEY DISEASE Inherited Cystic Kidney Disease Disease Gene Protein Renal Abnormality Autosomal Dominant Polycystic Kidney Disease AD PKD1 PKD2 Polycystin-1 Polycystin-2 Cortical and medullary cysts Autosomal Recessive Polycystic Kidney Disease AR PKHD1 Fibrocystin (polyductin) Distal tubule and collecting duct cysts Nephronophthisis I (juvenile/ adolesent ) AR NPHP1 Nephrocystin Small fibrotic kidneys, medullary cysts Nephronophthisis II (infantile) AR NPHP2 (INVS) Inversin Large kidneys, widespread cysts Nephronophthisis III (juvenile/ adolesent ) AR NPHP3 Nephrocystin-3 Small fibrotic kidneys; medullary cysts

9. Disease Gene Protein Renal Abnormality Medullary Cystic Kidney Disease AD MCKD1 /2 Uromodulin Small fibrotic kidneys; medullary cysts Tuberous sclerosis AD TSC1/2 Hamartin/ Tuberin Renal cysts; angiomyolipomas; Renal cell carcinoma Von Hippel-Lindau disease AD VHL pVHL Renal cysts; Renal cell carcinoma

10. AUTOSOMAL DOMINANT POLYCYSTIC KIDNEY DISEASE ADPKD is a multisystem disorder characterized by multiple, bilateral renal cysts associated with cysts in other organs, such as liver, pancreas, and arachnoid membranes. It is a genetic disorder mediated primarily by mutations in two different genes and is expressed in an autosomal dominant pattern, with variable expression. Researchers have found two different gene mutations that cause ADPKD. Most people with ADPKD have defects in the  PKD1  gene , and 1 out of 6 or 1 out of 7 people with ADPKD have a defective  PKD2  gene . Health care providers can diagnose people with  PKD1  sooner because their symptoms appear sooner. People with  PKD1  also usually progress more quickly to kidney failure than people with  PKD2 . How quickly ADPKD progresses also differs from person to person.

11. The incidence of autosomal dominant PKD is the same in all races, occurs equally in males and females and affects about 1 in 1,000 people worldwide. About 5% of all chronic kidney disease patients requiring dialysis or kidney transplantation have PKD.

12. Inheritance Mutations in the polycystic kidney disease(PKD)1 gene:85%, located on the short arm of chromosome 16 (16p.3.3), codes for a 4,304-amino-acid protein(polycystin 1). Mutations in the PKD2 gene:15%, located on chromosome-4 (4q.21.2), codes for a 968-amino-acid protein (polycystin 2).

13. DIAGNOSIS: Positive family Hx . PEx : palpable, B/L upper abdominal masses-tender U/S : Enlarged kidneys with multiple cysts B/L varying in size– increased cortical thickness, splaying of renal calyces CT-scan if U/S unclear MRI for kidney volume measurement Genetic testing to differentiate ADPKD1 vs ADPKD2

14. Radiographic Diagnostic Criteria for ADPKD

15. MANAGEMENT: In particular, there is good evidence that lifestyle modifications (smoking cessation, weight reduction, aiming for a body mass index less than 25 kg/m2, reduction in dietary sodium intake to 80–100 mmol/day and regular physical activity) slow kidney cyst growth and the decline in kidney function. ACE inhibitors/ARBs - for hypertension   In patients with early-stage disease(eGFR >60 mL/min/1.73 m2), the recommended blood pressure target is between 120/70 mmHg and130/80 mmHg. In patients who can tolerate lower blood pressures without significant light headedness, a target of 110/75 mmHg can be specified. In patients with advanced disease (eGFR 25–60 mL/min/1.73 m2), a blood pressure target of 120/70 mmHg to 130/80 mmHg is appropriate.

16. Specific treatment- Mammalian target of Rapamycin (mTOR) inhibitors: (Sirolimus and Everolimus) Somatostatin Analogs: Octreotide and Lanreotide Disease-modifying drugs to slow disease progression- Tolvaptan

17. Lipid soluble antibiotics such as Trimethoprim-sulfamethoxazole Quinolones Chloramphenicol More than half of ADPKD patients eventually require Dialysis and Renal transplantation. Genetic counselling

18. AUTOSOMAL RECESSIVE POLYCYSTIC KIDNEY DISEASE ARPKD is a rare genetic disorder that affects 1 in 20,000 children. A fetus or baby with ARPKD has fluid filled kidney cysts that may cause enlarged kidneys. Mutations in a single gene on the short arm of chromosome 6p 21.1

19. PATHOGENSIS ARPKD is primarily caused by variants in the  PKHD1  gene that encodes for fibrocystin (also referred to as polyductin), which localizes to the primary cilia in the cortical and medullary collecting ducts and the thick ascending limb of the kidney, and in the epithelial cells of the hepatic bile duct. Variants in the  DZIP1L  gene have been reported as a rare cause of ARPKD.

20. Prenatal symptoms Diminished amniotic fluid levels during pregnancy Enlarged kidneys on fetal ultrasound Lung immaturity and functioning issues Symptoms immediately after birth Enlarged kidneys due to cysts Breathing problems due to lack of space because of enlarged kidneys and decreased urine production. Ventilation is frequently required to sustain life. Excessive urine production Hypertension Growth problems Congenital hepatic fibrosis Enlarged spleen with low red blood cell, white blood cell and platelet counts

21. DIAGNOSIS: Molecular genetic testing is the gold standard for establishing the diagnosis. If unavailable, the clinical diagnosis of ARPKD is typically made by an abdominal ultrasound that demonstrates both the characteristic findings of large echogenic kidneys with poor corticomedullary differentiation, and coexisting liver disease.  MRI frequently shows enlarged kidneys with diffusely increased T2 signal; may also show evidence of  oligohydramnios  in better detail.

22. MANAGEMENT: There is no known curative intervention for ARPKD. The management of ARPKD consists of supportive therapy including the management of respiratory distress in affected neonates, and KRT for patients who progress to ESKD. Genetic counseling includes prenatal genetic testing for interested family members and for siblings of affected patients who may be carriers of a  PKHD1  variant.

23. NEPHRONOPHTISIS Nephronophthisis (NPHP) is a clinical condition caused by a group of autosomal recessive cystic kidney disorders that typically progresses to end-stage kidney disease (ESKD) before the age of 25 years. Among the identified NPHP genes, four of them account for 75% of identified disease-causing variants: NPHP1, NPHP3, NPHP4 and NPHP11. Nephronophthisis can be classified by the approximate age at which ESRD begins: around age 1 (infantile), around age 13 (juvenile), and around age 19 (adolescent).

24. Polyuria Polydipsia Anaemia Growth retardation Bland urinalysis ESRF SIGNS & SYMPTOMS:

25. DIAGNOSIS : The diagnosis of NPHP is suspected by characteristic clinical findings and confirmed by genetic testing . Molecular genetic screening allows gene identification in 50 to 70% of NPHP cases. In absence of positive gene test, a kidney biopsy demonstrating chronic tubulointerstitial changes with a thickening of tubular basement membrane is suggestive of diagnosis.

26. Kidney survival was significantly associated with the underlying variant type for  NPHP1 ,  NPHP3 , and  NPHP4 .  Multivariate analysis  for the  NPHP1  cohort revealed  growth retardation  (hazard ratio 3.5) and angiotensin-converting enzyme inhibitor (ACEI)  treatment  (hazard ratio 2.8) as 2 independent factors associated with an earlier onset of ESKD, whereas arterial hypertension was linked to an accelerated  glomerular filtration rate  (GFR) decline.

27. MANAGEMENT: There is no specific treatment for NPHP. Management of children in the early stage of the disease without kidney function impairment is supportive focused on maintaining fluid and electrolyte balance. Administration of Erythropoietin and iron to patients with anaemia. Administration of growth hormone in patients with growth retardation. Kidney transplantation is the preferred replacement therapy because the disease does not recur in a replacement.

28. ALPORT SYNDROME Alport syndrome is a rare inherited disorder that damages the tiny blood vessels in the kidneys. It can also cause hearing loss and eye problems. Genetics: Alport’s may arise from a number of mutations to genes responsible for type IV collagen. It may occur due to mutations to alpha-3, alpha-4 and alpha-5 chains of type IV collagen. Type IV collagen is important to basement membranes and mutations lead to impaired function. This affects basement membranes in the kidneys (GBM), eyes and ears. Inheritance may be X-linked (most common), autosomal dominant or autosomal recessive . Rarely autosomal digenic inheritance is seen.

29. X-linked Alport Syndrome: The majority of patients are affected by the X-linked form. It occurs due to mutations of COL4A5. Female carriers (i.e. heterozygotes) of the X-linked form are not unaffected due to lyonization, they have an increased risk of hypertension and renal impairment. Up to 20% will be affected by sensorineural hearing loss. Autosomal dominant Accounts for around 20-30% of cases. Occurs due to mutations to COL4A3 or COL4A4. Autosomal recessive  Accounts for around 15% of cases. Occurs due to mutations to COL4A3 or COL4A4, may be associated with parental consanguinity.

30. DIAGNOSIS The diagnosis of Alport’s can be confirmed with genetic testing or biopsy (of the skin or kidneys). Genetic testing Molecular genetic testing can confirm the diagnosis of Alport’s syndrome and the underlying mutation type.  Biopsy There are two tissue types that may be biopsied: Skin: has the advantage of being less invasive but is primarily of use for suspected X-linked disease. Kidney: review of the GBM can show changes characteristic of Alport's syndrome.

31. GENETICS AND TUBULAR DISORDER

32. Syndrome Genetics BP Acid base disorder and potassium Renin and Aldosterone Other features Treatment Liddle Syndrome ENaC gene Chr 16p12 Autosomal dominant HTN Metabolic alkalosis Both suppressed Salt-sensitive ENaC inhibitors Bartter Syndrome (Similar to loop diuretics) Multiple genes such as: SLC12A1 KCNJ1 CLCNKB BSND Types 1, 2, 3,4, 4b: Autosomal recessive Type 5: Autosomal dominant Normal-low Metabolic alkalosis Hypokalemia Renin and aldosterone elevated Nephrocalcinosis (types 1 & 2) Neonatal manifestation (types 1, 2, 4 and 4b) Deafness (types 4 & 4b) Hypercalciuria Increase salt intake Potassium supplementation NSAIDs K+ sparing diuretics

33. Syndrome Genetics BP Acid base disorder and potassium Renin and Aldosterone Other features Treatment Gitelman Syndrome (similar to thiazide diuretics) SLC12A3 Chr 16q13 Autosomal recessive Normal-low Metabolic alkalosis Hypokalemia Both elevated Hypomagnesemia Hypocalciuria Increased bone density Chondrocalcinosis Increase salt intake Potassium supplementation Magnesium supplementation NSAIDs K+ sparing diuretics

34. GENETIC SYNDROME ASSOCIATED WITH HYPERTENSION Syndrome Genetics Mechanism Treatment Liddle Syndrome AD ENaC gene Chr 16p12 Increased sodium reabsorption in distal nephron ENaC inhibitors Glucocorticoid-remediable Aldosteronism (GRA) AD 11 β‐ hydroxylase (CYP11B1) Aldosterone synthase (CYP11B2) Chr8q24 Overexpression of aldosterone synthase Corticosteroid therapy Apparent mineralocorticoid excess (AME) AR 11β- hydroxysteroid dehydrogenase ( 11β -HSD2) Chr 16q22 Overstimulation of mineralocorticoid receptor by cortisol Spironolactone and ENaC inhibitors

35. Syndrome Genetics Mechanism Treatment Mineralocorticoid Receptor Mutation (Geller syndrome) AD NR3C2 Chr 4q31 Increased sodium reabsorption in distal nephron ENaC inhibitors Aldosterone producing adenomas (APA) AD KCNJ5 CACNA1D ATP1A1 ATP2B3 Excess production of mineralocorticoid hormone aldosterone by the adrenal cortex Spironolactone or Eplerenone Adenectomy Gordon’s Syndrome AD WNK1 WNK4 Defects in the sodium regulatory pathway in distal nephron Thiazide diuretics

36. REFERENCES Theivendran T, Ramachandran A, Rangan G. Drug management of autosomal dominant polycystic kidney disease . Aust Prescr 2022;45:167-70. Vicente E. Torres, Ron T. Gansevoort, Ronald D. Perrone, et al; Tolvaptan in ADPKD Patients With Very Low Kidney Function ; Kidney International Reports,Volume 6, Issue 8,2021, 2171-2178. Xiaolei Zhou, Eric Davenport, John Ouyang, et al. Pooled Data Analysis of the Long-Term Treatment Effects of Tolvaptan in ADPKD . Kidney International Reports, Volume 7, Issue 5, 2022, 1037-1048. Wicher D, Obrycki Ł, Jankowska I. Autosomal Recessive Polycystic Kidney Disease-The Clinical Aspects and Diagnostic Challenges . J Pediatr Genet. 2021 Mar;10(1):1-8. Ramona Ajiri , Kathrin Burgmaier , Nurver Akinci, et al., Phenotypic Variability in Siblings With Autosomal Recessive Polycystic Kidney Disease , Kidney International Reports, Volume 7, Issue 7, 2022,1643-1652. Takuya Fujimaru , Kunio Kawanishi , Takayasu Mori, et al ; Genetic Background and Clinicopathologic Features of Adult-onset Nephronophthisis. Kidney International Reports, Volume 6, Issue 5, 2022,1346-1354.

37. Jens Christian König, Rebeka Karsay , Joachim Gerß , et al; Refining Kidney Survival in 383 Genetically Characterized Patients With Nephronophthisis , Kidney International Reports, Volume 7, Issue 9, 2022, 2016-2028. Salomon, R.; Saunier, S. & Niaudet , P. Nephronophthisis . Pediatr Nephrol,  2009 , 24 , 2333-2344. Clinical practice recommendations for the diagnosis and management of Alport syndrome in children, adolescents, and young adults-an update for 2020 , Clifford E. Kashtan & Oliver Gross Pediatric Nephrology (2021) 36:711-719 Mónica Furlano , Victor Martínez, Marc Pybus , et al; Clinical and Genetic Features of Autosomal Dominant Alport Syndrome: A Cohort Study , American Journal of Kidney Diseases, Volume 78, Issue 4, 2021, 560-570.

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