Genetic Diseases of the Distal Nephron

Question 1

Genetic Make Up of Polycystic Kidney Disease

Answer 1

• ADPKD – Autosomal dominant polycystic kidney disease is one of the most common life-threating genetic diseases. Fluid filled cysts in both kidneys eventually leads to kidney failure
• ARPKD – Autosomal recessive polycystic kidney disease is a rare genetic disorder occurring in 1:20,0000. Can cause death in first few months of life.

Question 2

ADPKD

Answer 2

• Autosomal-dominant polycystic kidney disease (ADPKD) is one of the most common human monogenic diseases and affects 12 million people worldwide (1: 800 births)
• Excessive proliferation of renal epithelial cells leads to cysts that eventually replace most of the normal tissue.
• ADPKD results in severe enlargement of the kidneys, and renal failure occurs
• aka Adult PKD

Question 3

ADPKD

Answer 3

• Autosomal Dominant Polycystic Kidney Disease

PKD1 (chromosome16p); polycystin-1 mutation causes renal failure by 70 yrs old

PKD2 (chromosome 4q); polycystin-2 mutation less severe, only 50% renal failure at 70 yrs old

Autosomal Dominant inheritance with variable penetrance

Only 4-6% of those with ESRD due to PKD (compare to 33% of ESRD due to Diabetes)

Question 4

Characteristics of ADPKD

Answer 4

• Renal cysts increase in size and number with age
• Enlarged kidneys
• Can get cysts in liver, pancreas and rarely other sites
• Liver cysts rarely cause liver failure, or portal HTN, and pancreatic insufficiency is rare
• Adult PKD also associated with Spontaneous Subarachnoid Hemorrhages due to saccular aneurysms in circle of Willis
• Hypertension. Increase in blood pressure can be first sign of PKD. Occurs even with normal renal function. – PKD Renal cysts can impair perfusion of glomeruli, and press on arterioles in kidney and activate RAS. – ACE inhibitors helpful in this disease, as are ARB’s – Increase renal blood flow, and reduces HTN
• Patients with high blood pressure have larger cysts. and progress to renal failure more rapidly

Question 5

ADPKD: PKD1 vs PKD2

Answer 5

Question 6

Gender differences in ADPKD

Answer 6

• Disease progresses faster in males
• These findings are consistent with the stimulating effect of testosterone on cAMP accumulation and Cl and fluid secretion by cultured renal cells.
• Females, however, have more and larger liver cysts, which are associated with number of pregnancy, suggesting that liver cyst growth is associated with estrogen exposure.

Question 7

Polycystin 1 and 2 (PKD1 and PKD2)

Answer 7

• Both PKD1 and PKD2 are proteins found in the primary cilia of epithelial cells
• PKD occurs in renal epithelial cells, origin thought to be collecting duct cells
• Loss of polycystin thought to lead to loss of intracellular calcium regulation allowing greater activation of cAMP pathways

Question 8

PKD is a ciliopathy

Answer 8

• Primary cilia are single hair like organelles that project from the surface of most mammalian cells.
• They were previously described as vestigial organelles, but recent findings suggest otherwise
• In tubular epithelial cells the cilium projects into the lumen and is thought to have a sensory role, flow across the cilium activates a Ca2+ response.
• PKD1 -/- cells have a normal appearing cilia but they lack the flow-induced Ca2+ response

Question 9

PKD: Increased Vasopressin Type 2 receptor activation increases proliferation

Answer 9

• Upregulation of V2 receptor and high circulating levels of vasopressin thought to lead to increased cAMP levels in collecting duct cells and contribute to cell proliferation
• Loss of polycystin thought to lead to loss of intracellular calcium regulation allowing greater activation of cAMP pathways

Question 10

Clinical Trials for PKD: Tolvaptan (TEMPO trial)

Answer 10

• Clinical trials examined the ability of Tolvaptan reduce cyst size in PKD
• Tolvaptan already approved by FDA for use in CHF
• TEMPO trials used 3 fold higher doses (120-90mg a day) for PKD patients (than CHF, 30mg), and trial failed due to off target effects in the liver (increased liver enzymes) and aquaresis events (discontinuation events 23% vs 14% in placebo) . FDA did not give approval after TEMPO trial
• Japan approved 30mg doses for use in PKD, 2018
• Canada approved, REPRISE study = USA in 2019 (JINARQUE/Tolvaptan), tested in 3000 patients

Question 11

Clinical Trials for PKD: Rapamycin

Answer 11

• Clinical trials are examining the ability of Rapamycin (mTOR inhibitor) to reduce proliferation in PKD
• Primary Outcome Measures: combined kidney volume
• Inclusion Criteria:

– adult ADPKD patients aged 18-70

– combined kidney volume >1200 ml

– estimated creatinine clearance >60 ml/min

Question 12

ADPKD Summary

Answer 12

• Role of primary cilia in PKD

– intracellular Ca and cAMP

– increased proliferation/apoptosis

• For ADPKD, cystogenesis is a two-step process

– cyst initiation: earlier in PKD1 than in PKD2

– cyst expansion: faster in males than females.

• Critical issues in managing PKD:

– Screening relatives at risk

– Blood pressure control

• Treatment: FDA Approved Jynarque (Tolvaptan) in 2019

– Vasopressin receptor antagonists reduce cAMP levels and slow cyst growth in animals with PKD

Drinking water suppresses vasopressin

Question 13

ARPKD

Answer 13

• Autosomal-recessive polycystic kidney disease (ARPKD) is rare disease. Both parents need to be carriers of PKHD1 (fibrocystin/polyductin) gene mutation. 25% chance of ARPKD in offspring
• Small cysts in the collecting ducts of kidney, high urine output in children as cannot retrieve water (loss of concentrating mechanism)
• Prenatal symptoms

– Diminished amniotic fluid levels during pregnancy

– Enlarged kidneys on fetal ultrasound

– Lung immaturity and functioning issues

Question 14

ARPKD Symptoms After Birth

Answer 14

• Symptoms after birth

– Enlarged kidneys due to cysts

– Breathing problems, because of enlarged kidneys and decreased urine production. Ventilation is frequently required to sustain life.

– Excessive urine production

– Hypertension

– Growth problems

– Congenital hepatic fibrosis can lead to portal HTN (not seen in Adult ADPKD)

• Neonatal death approximately 30-50%

– However, 85% of infants with ARPKD survive to 10yrs old

Question 15

Liddle’s Disease

Answer 15

• Liddle described patients with autosomal dominant Mendelian hypertension who also tended to hypokalemia
• His patients had low renin and low aldosterone values; they did not respond to spironolactone (MR blocker) while thiazides reduced the blood pressure
• This observation convinced Liddle that they probably did not have a form of mineralocorticoid excess
• Liddle speculated that they would show a distal tubular defect of enhanced sodium and chloride reabsorption.

– A renal transplant performed on a patient with Liddle’s syndrome who happened to develop renal failure cured the disease, providing strong evidence that the problem resided within the kidneys rather than in a humoral regulatory system.

• Shimkets et al. subsequently localized the responsible gene of a family with Liddle’s syndrome to chromosome 16p and were able to show that the gene encodes for the ß subunit of the epithelial sodium channel (ENaC).
• The channel is amiloride sensitive, explaining the efficacy of these potassium-sparing diuretics in the syndrome.
• The channel remains inappropriately permeable (open) even in the face of high salt intake, thereby explaining the salt sensitive hypertension.