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Published on: June 23, 2015
Rationale for early treatment of polycystic kidney disease
1The Kidney Institute, University of Kansas Medical Center, 3901 Rainbow Blvd., Kansas City, KS, 66160, USA, Jgrantha@kumc.edu.
Insights
Autosomal dominant polycystic kidney disease (ADPKD) progression is driven by arginine vasopressin (AVP). Lowering AVP levels or blocking its V2 receptors can slow cyst growth in polycystic kidney disease (PKD).
Area of Science:
- Nephrology
- Genetics
- Molecular Biology
Background:
- Hereditary cystic disorders like autosomal dominant polycystic kidney disease (ADPKD) cause renal injury starting with cyst formation.
- Symptoms in ADPKD include enlarged kidneys, abdominal pain, hypertension, and hematuria, particularly in younger individuals.
- Cysts in ADPKD and autosomal recessive PKD (ARPKD) originate in collecting ducts and expand, potentially obstructing urine flow and damaging nephrons.
Purpose of the Study:
- To investigate the role of arginine vasopressin (AVP) in the pathogenesis of polycystic kidney disease (PKD).
- To explore therapeutic strategies targeting AVP signaling pathways for managing PKD.
- To establish reliable methods for monitoring disease progression and patient outcomes in ADPKD.
Main Methods:
- Utilized an autosomal recessive polycystic kidney disease (ARPKD) rat model lacking vasopressin to observe cyst development.
- Administered exogenous arginine vasopressin (AVP) to the ARPKD rat model to study its effect on cyst formation and enlargement.
- Investigated the impact of AVP-V2 receptor inhibitors and hydration on disease progression in preclinical models.
Main Results:
- Rats lacking vasopressin developed fewer cysts until AVP was administered, indicating AVP's crucial role.
- AVP stimulates cyclic AMP production in tubule cells, promoting cystogenesis and enlargement.
- AVP-V2 receptor inhibition and sustained lowering of plasma AVP levels were shown to ameliorate disease progression.
Conclusions:
- Arginine vasopressin (AVP) is a key driver of cyst formation and progression in polycystic kidney disease (PKD).
- Targeting the AVP pathway, through V2 receptor inhibition or reduced AVP levels, offers a promising therapeutic strategy for PKD.
- Renal volume measurement is a reliable prognostic indicator for ADPKD patients, and lifestyle modifications combined with potential drug therapies form a comprehensive management approach.
Abstract:
In hereditary cystic disorders, renal injury begins with the formation of the first cyst. Renal injury may manifest as large kidneys, abdominal pain, hypertension and hematuria in children and young adults with autosomal dominant polycystic kidney disease (ADPKD). In autosomal recessive PKD (ARPKD) and ADPKD, cysts form primarily in collecting ducts and expand progressively. Collecting duct cysts that block urine flow have the potential to block urine formation in large numbers of upstream nephrons. In an ARPKD rat congenitally lacking vasopressin, only a few cysts developed until exogenous arginine vasopressin (AVP) was administered. AVP elevates cyclic AMP in vulnerable tubule cells to stimulate mitogenesis and fluid secretion, thereby causing cysts to form and enlarge indefinitely. The administration of an AVP-V2 receptor inhibitor or the consumption of sufficient water to persistently lower plasma AVP levels will ameliorate disease progression. Renal volume measurements provide the most reliable way to forecast long-term outcome in individual children and adult patients with ADPKD. Many drugs that have demonstrated efficacy in small clinical trials, preclinical trials and cell-based studies are in the treatment pipeline. Counseling, regular exercise, limitation of dietary calories, salt, protein and fat, increased fluid intake throughout the day and treatment of hypertension are components of a rational treatment program that can be offered at an early age to those with, or at risk for developing PKD.
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