The subfornical organ drives hypertension in polycystic kidney disease via the hypothalamic paraventricular nucleus

2021 ◽  
Author(s):  
Conor F Underwood ◽  
Simon McMullan ◽  
Ann K Goodchild ◽  
Jacqueline K Phillips ◽  
Cara M Hildreth
Keyword(s):  
Blood Pressure ◽  
Angiotensin Ii ◽  
Kidney Disease ◽  
Polycystic Kidney Disease ◽  
Paraventricular Nucleus ◽  
Subfornical Organ ◽  
Ionotropic Glutamate Receptors ◽  
Type I ◽  
Lamina Terminalis ◽  
Polycystic Kidney

AbstractAimsHypertension is a prevalent yet poorly understood feature of polycystic kidney disease. Previously, we demonstrated that increased glutamatergic neurotransmission within the hypothalamic paraventricular nucleus produces hypertension in the Lewis Polycystic Kidney (LPK) rat model of polycystic kidney disease. Here, we tested the hypothesis that augmented glutamatergic drive to the paraventricular nucleus in Lewis polycystic kidney rats originates from the forebrain lamina terminalis, a sensory structure that relays blood-borne information throughout the brain.Methods and resultsAnatomical experiments revealed that 38% of paraventricular nucleus-projecting neurons in the subfornical organ of the lamina terminalis expressed Fos/Fra, an activation marker, in LPK rats while <1% of neurons were Fos/Fra+ in Lewis control rats (P = 0.01, n = 8). In anaesthetized rats, subfornical organ neuronal inhibition using isoguvacine produced a greater reduction in systolic blood pressure in LPK vs. Lewis rats (−21±4 vs. −7±2 mmHg, P < 0.01; n = 10), which could be prevented by prior blockade of paraventricular nucleus ionotropic glutamate receptors using kynurenic acid. Blockade of ionotropic glutamate receptors in the paraventricular nucleus produced an exaggerated depressor response in LPK relative to Lewis rats (−23±4 vs. −2±3 mmHg, P < 0.001; n = 13), which was corrected by prior inhibition of the subfornical organ with muscimol but unaffected by chronic systemic angiotensin II type I receptor antagonism or lowering of plasma hyperosmolality through high-water intake (P > 0.05); treatments that both nevertheless lowered blood pressure in LPK rats (P < 0.0001).ConclusionOur data reveal multiple independent mechanisms contribute to hypertension in polycystic kidney disease, and identify high plasma osmolality, angiotensin II type I receptor activation and, importantly, a hyperactive subfornical organ to paraventricular nucleus glutamatergic pathway as potential therapeutic targets.

Autosomal dominant polycystic kidney disease management

2018 ◽  
Author(s):  
Young-Hwan Hwang ◽  
York Pei
Keyword(s):  
Blood Pressure ◽  
Kidney Disease ◽  
Polycystic Kidney Disease ◽  
Autosomal Dominant ◽  
Kidney Volume ◽  
Polycystic Kidney ◽  
Renal Disease Progression ◽  
Kidney Size ◽  
Autosomal Dominant Polycystic Kidney ◽  
Cyst Growth

Management of patients with autosomal dominant polycystic kidney disease (ADPKD) currently comprises non-specific measures including promotion of healthy lifestyle, optimization of blood pressure control, and modification of cardiovascular risk factors. A high water intake of 3–4 L per day in patients with glomerular filtration rate greater than 30 mL/min/1.73 m2 may decrease the risk of kidney stones, but its potential benefit in reducing renal cyst growth is presently unproven. Maintenance of a target blood pressure of 130/80 mmHg is recommended by expert clinical guidelines though this is unlikely to slow cyst growth. It is unclear whether pharmacological blockade of the renin–angiotensin axis confers an extrarenal protective effect. Recognition of the variable clinical presentations of cyst infection, cyst haemorrhage, or nephrolithiasis is important for early diagnosis and optimal management of these complications. Most patients with ADPKD do well on dialysis and after transplantation. Nephrectomy may be needed to make space for a donor kidney, or if kidney size or infection is an issue after end-stage renal failure is reached. Recent advances in ADPKD have led to the identification of multiple potential therapeutic targets with more than 10 clinical trials completed or currently in progress. Given the promising results of the TEMPO trial, tolvaptan may well be the first disease-modifying drug to be approved for clinical use. Several other classes of drugs (e.g. somatostatin analogues, triptolide, metformin, and glucosylceramide synthase inhibitors) with good long-term safety profiles are promising candidates which may be repurposed for this disease. In the future, identifying patients with different risks of renal disease progression by their genotype and/or kidney volume will likely assume an important role for the clinical management of ADPKD.

scholarly journals SAT-331 RENAL DENERVATION DOES NOT REDUCE BLOOD PRESSURE IN A RODENT MODEL OF POLYCYSTIC KIDNEY DISEASE

2019 ◽  
Vol 4 (7) ◽  
pp. S146
Author(s):  
S. Li ◽  
C.M. Hildreth ◽  
A.A. Rahman ◽  
V.J. Tallapragada ◽  
P.M. Pilowsky ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Kidney Disease ◽  
Polycystic Kidney Disease ◽  
Renal Denervation ◽  
Reduce Blood Pressure ◽  
Rodent Model ◽  
Polycystic Kidney

TOLVAPTAN USE IN SEVERE NEONATAL AUTOSOMAL DOMINANT POLYCYSTIC KIDNEY DISEASE (ADPKD): THE PHARMACEUTICAL CHALLENGE

2016 ◽  
Vol 101 (9) ◽  
pp. e2.58-e2 ◽  
Author(s):  
Kazeem Olalekan ◽  
Andy Fox ◽  
Rodney Gilbert
Keyword(s):  
Blood Pressure ◽  
Kidney Disease ◽  
Polycystic Kidney Disease ◽  
Kidney Function ◽  
Hospital Pharmacist ◽  
Kidney Volume ◽  
Polycystic Kidney ◽  
Vasopressin V2 Receptor ◽  
V2 Receptor ◽  
Paediatric Formulation

BackgroundUnlicensed medications are used all the time in the management of diseases in childhood. Tolvaptan (Jinarc®) is a vasopressin V2-receptor antagonist licensed for use to slow the progression of cyst development and renal insufficiency of ADPKD in adults with CKD stage 1 to 3 with evidence of rapidly progressing disease. Studies of animal models implicate the antidiuretic hormone arginine vasopressin and its messenger cyclic adenosine monophosphate (cAMP) as promoters of kidney-cyst cell proliferation and luminal fluid secretion. The suppression of vasopressin release by means of high water intake, genetic elimination of vasopressin, and vasopressin V2-receptor blockade all reduce the cyst burden and protect kidney function1 A Phase 3 trial showed that Tolvaptan, as compared with placebo, slowed down the increase in total kidney volume and decline in kidney function in adults (average 39 yrs) with ADPKD over a 3-year period.2 ADPKD is the most common form of polycystic kidney disease (PKD) typically late in onset and results from mutation of either of two genes: PKD1 and PKD2. Autosomal recessive polycystic kidney (ARPKD), the other form of PKD, is 20 times less common, presents primarily in infancy and childhood, is typically more severe, and commonly associated with hypertension. ARPKD results from mutation of PKHD1. In spite of these differences, there is growing evidence to suggest that ADPKD and ARPKD are more related than previously suspected.3 Bilineal inheritance of PKD1 abnormalities has been reported to cause extremely severe disease resembling ARPKD.4 The use of Tolvaptan in the management of PKD in children is therefore expected to become more important.AimTo describe the first known UK use of Tolvaptan in a neonate with severe ADPKD and the role of the hospital pharmacist in facilitating the use.MethodThe role descriptor of hospital pharmacists produced by the World Health Organisation (WHO) was adapted and used to map the pharmaceutical challenges of using Tolvaptan in this child. The descriptor include: (i) Promotion of rational prescribing of drugs, (ii) Use of specialist pharmacists networks to gain greater expertise; (iii) Monitor compliance and therapeutic response and report adverse drug reactions; (iv) ensure supply of high quality products; (v) partake in planning and implementation of clinical trials.ResultsThe use of Tolvaptan for indication other than hyponatraemia and other endocrine uses are not routinely commissioned by NHS England. In view of the exceptionality of this case – a severe neonatal form of ADPKD with estimated prevalence of the order of 1 in tens of millions, an Individual Funding Request (IFR) application was made and was approved. The application was supported by financial information provided by the hospital pharmacist who facilitated the application process. Using available information and formulation knowledge, a suspension was eventually recommended and was well tolerated. This resulted in approximately 85% reduction in the cost of treatment over six months. Tolvaptan produced the expected aquaresis and blood pressure reduction. Initial dose of 0.1 mg/kg/day was used and increased according to weight and clinical response. Initial monitoring parameters, which included 4 hourly blood pressure, urine and electrolytes and hepatic function, were recommended. Electrolyte supplements were adjusted accordingly. At 2-month review point, there was no oedema of leg and face but the kidneys were still enlarged. The long term effect on cyst burden and kidney function is being evaluated and will feed into the IFR process.ConclusionThe use of unlicensed medications in children poses a number of pharmaceutical challenges and can be managed through a multidisciplinary approach to treatment intervention. It also re-enforce the paediatric formulation challenge to pharmaceutical companies in which formulation needs are prioritised and existing data are better used to facilitate paediatric formulation development.

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