pituitrin and Polycystic-Kidney--Autosomal-Dominant

Autosomal dominant polycystic kidney disease (ADPKD) is characterized by the formation of numerous kidney cysts which leads to kidney failure. ADPKD is responsible for approximately 10% of patients with kidney failure. Overwhelming evidence supports that vasopressin and its downstream cyclic adenosine monophosphate signaling promote cystogenesis, and targeting vasopressin 2 receptor with tolvaptan and other antagonists ameliorates cyst growth in preclinical studies. Tolvaptan is the only drug approved by Food and Drug Administration to treat ADPKD patients at the risk of rapid disease progression. A major limitation of the widespread use of tolvaptan is aquaretic events. This review discusses the potential strategies to improve the tolerability of tolvaptan, the progress on the use of an alternative vasopressin 2 receptor antagonist lixivaptan, and somatostatin analogs. Recent advances in understanding the pathophysiology of PKD have led to new approaches of treatment via targeting different signaling pathways. We review the new pharmacotherapies and dietary interventions of ADPKD that are promising in the preclinical studies and investigated in clinical trials.

Topics: Antidiuretic Hormone Receptor Antagonists; Humans; Polycystic Kidney, Autosomal Dominant; Receptors, Vasopressin; Renal Insufficiency; Tolvaptan; United States; Vasopressins

Polycystic kidney disease (PKD) encompasses a group of genetic disorders that are common causes of renal failure. The two classic forms of PKD are autosomal recessive polycystic kidney disease (ARPKD) and autosomal dominant polycystic kidney disease (ADPKD). Despite their clinical differences, ARPKD and ADPKD share many similarities. Altered intracellular Ca

Topics: Adult; Animals; Antidiuretic Hormone Receptor Antagonists; Child; Cyclic AMP; Humans; Kidney; Polycystic Kidney, Autosomal Dominant; Signal Transduction; Tolvaptan; Vasopressins

ADH is a hormone secreted by neurohypophysis that plays different roles based on the target organ. At the renal level, this peptide is capable of causing electrolyte-free water absorption, thus playing a key role in the hydro-electrolytic balance. There are pathologies and disorders that jeopardize this balance and, in this field, ADH receptor inhibitors such as Vaptans could play a key role. By inhibiting the activation pathway of vasopressin, they are potentially useful in euvolemic and hypervolemic hypotonic hyponatremia. However, clinical trials in heart failure have not given favourable results on clinical outcomes. Even in SIADH, despite their wide use, there is no agreement by experts on their use. Since vaptans inhibit the cAMP pathway in tubular cells, their use has been proposed to inhibit cystogenesis. A clinical trial has shown favourable effects on ADPKD progression. Because vaptans have been shown to be effective in models of renal cysts disorders other than ADPKD, their use has been proposed in diseases such as nephronophthisis and recessive autosomal polycystic disease. Other possible uses of vaptans could be in kidney transplantation and cardiorenal syndrome. Due to the activity of ADH in coagulation and haemostasis, ADH's activation pathway by Desmopressin Acetate could be a useful strategy to reduce the risk of bleeding in biopsies in patients with haemorrhagic risk.

Topics: Antidiuretic Hormone Receptor Antagonists; Cadaver; Cyclic AMP; Forecasting; Humans; Hyponatremia; Kidney Diseases; Kidney Diseases, Cystic; Kidney Transplantation; Kidney Tubules, Collecting; Molecular Targeted Therapy; Neurophysins; Polycystic Kidney, Autosomal Dominant; Protein Precursors; Receptors, Vasopressin; Second Messenger Systems; Tissue Donors; Vasopressins; Water-Electrolyte Imbalance

Vasopressin, also known as arginine vasopressin or antidiuretic hormone, plays a pivotal role in maintaining body homeostasis. Increased vasopressin concentrations, measured by its surrogate copeptin, have been associated with disease severity as well as disease progression in polycystic kidney disease (PKD), and in experimental studies vasopressin has been shown to directly regulate cyst growth. Blocking vasopressin effects on the kidney via the vasopressin V2-receptor and lower circulating vasopressin concentration are potential treatment opportunities that have been the subject of study in PKD in recent years. Treatment with vasopressin V2-receptor antagonist tolvaptan has been shown to inhibit disease progression in experimental studies, as well as in a large randomized controlled trial involving 1,445 patients with autosomal dominant PKD, lowering total kidney volume growth from 5.5 to 2.8%, and the slope of the reciprocal of the serum creatinine level from -3.81 to -2.61 mg per mL-1/year. Alternatively, lowering circulating vasopressin could delay disease progression. Vasopressin is secreted in response to an increased plasma osmolality, which in turn is caused by a low fluid or high osmolar intake. Other lifestyle factors, like smoking, increase vasopressin concentration. Here, we provide a comprehensive review of the physiology as well as pathophysiology of vasopressin in PKD, the promising effects of tolvaptan treatment, and potential synergistic or additive treatments in combination with tolvaptan. In this study, we also review current evidence regarding the effect of influencing disease progression in PKD by lifestyle changes, especially by fluid intake.

Topics: Antidiuretic Hormone Receptor Antagonists; Benzazepines; Disease Progression; Humans; Polycystic Kidney, Autosomal Dominant; Tolvaptan; Vasopressins

People with chronic kidney disease (CKD) are at risk of severe outcomes, such as end-stage renal disease or cardiovascular disease, and CKD is a globally increasing health burden with a high personal and economic cost. Despite major progresses in prevention and therapeutics in last decades, research is still needed to reverse this epidemic trend. The regulation of water balance and the state of activation of the vasopressin system have emerged as factors tightly associated with kidney health, in the general population but also in specific conditions; among them, various stages of CKD, diabetes and autosomal dominant polycystic kidney disease (ADPKD). Basic science findings and also epidemiological evidence have justified important efforts towards interventional studies supporting causality, and opening therapeutic avenues. On the basis of recent clinical data, the blockade of V2 vasopressin receptors using tolvaptan in patients with rapidly progressing ADPKD has been granted in several countries, and a long-term randomized trial evaluating the effect of an increase in water intake in patients with CKD is on-going.

Topics: Antidiuretic Hormone Receptor Antagonists; Biomarkers; Diabetic Nephropathies; Fluid Therapy; Glycopeptides; Humans; Kidney; Kidney Diseases; Polycystic Kidney, Autosomal Dominant; Renal Insufficiency, Chronic; Vasopressins

Autosomal-dominant polycystic kidney disease (ADPKD) is the most common genetic renal disease in adults, affecting one in every 1000 Australians. It is caused by loss-of-function heterozygous mutations in either PKD1 or PKD2 , which encode the proteins, polycystin-1 and polycystin-2 respectively. The disease hallmark is the development of hundreds of microscopic fluid-filled cysts in the kidney during early childhood, which grow exponentially and continuously through life at varying rates (between 2% and 10% per year), causing loss of normal renal tissue and up to a 50% lifetime risk of dialysis-dependent kidney failure. Other systemic complications include hypertensive cardiac disease, hepatic cysts, intracranial aneurysms, diverticular disease and hernias. Over the last two decades, advances in the genetics and pathogenesis of this disease have led to novel treatments that reduce the rate of renal cyst growth and may potentially delay the onset of kidney failure. New evidence indicates that conventional therapies (such as angiotensin inhibitors and statins) have mild attenuating effects on renal cyst growth and that systemic levels of vasopressin are critical for promoting renal cyst growth in the postnatal period. Identifying and integrating patient-centred perspectives in clinical trials is also being advocated. This review will provide an update on recent advances in the clinical management of ADPKD.

Topics: Angiotensin Receptor Antagonists; Disease Management; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypertension; Mutation; Polycystic Kidney, Autosomal Dominant; Randomized Controlled Trials as Topic; Renal Dialysis; Renal Insufficiency; TRPP Cation Channels; Vasopressins

Autosomal dominant polycystic kidney disease (ADPKD) is the most common monogenic kidney disease and is responsible for 5-10% of cases of end-stage renal disease worldwide. ADPKD is characterized by the relentless development and growth of cysts, which cause progressive kidney enlargement associated with hypertension, pain, reduced quality of life and eventual kidney failure. Mutations in the PKD1 or PKD2 genes, which encode polycystin-1 (PC1) and polycystin-2 (PC2), respectively, cause ADPKD. However, neither the functions of these proteins nor the molecular mechanisms of ADPKD pathogenesis are well understood. Here, we review the literature that examines how reduced levels of functional PC1 or PC2 at the primary cilia and/or the endoplasmic reticulum directly disrupts intracellular calcium signalling and indirectly disrupts calcium-regulated cAMP and purinergic signalling. We propose a hypothetical model in which dysregulated metabolism of cAMP and purinergic signalling increases the sensitivity of principal cells in collecting ducts and of tubular epithelial cells in the distal nephron to the constant tonic action of vasopressin. The resulting magnified response to vasopressin further enhances the disruption of calcium signalling that is initiated by mutations in PC1 or PC2, and activates downstream signalling pathways that cause impaired tubulogenesis, increased cell proliferation, increased fluid secretion and interstitial inflammation.

Topics: Animals; Calcium Signaling; Cyclic AMP; Disease Models, Animal; Endoplasmic Reticulum; Humans; Polycystic Kidney, Autosomal Dominant; Receptors, Purinergic; Sarcoplasmic Reticulum; TRPP Cation Channels; Vasopressins

Autosomal dominant polycystic kidney disease (ADPKD) is the commonest inherited cause of renal failure in adults, and is due to loss-of-function mutations in either the PKD1 or PKD2 genes, which encode polycystin-1 and polycystin-2, respectively. These proteins have an essential role in maintaining the geometric structure of the distal collecting duct in the kidney in adult life, and their dysfunction predisposes to renal cyst formation. The typical renal phenotype of ADPKD is the insidious development of hundreds of renal cysts, which form in childhood and grow progressively through life, causing end-stage kidney failure in the fifth decade in about half affected by the mutation. Over the past 2 decades, major advances in genetics and disease pathogenesis have led to well-conducted randomized controlled trials, and observational studies that have resulted in an accumulation of evidence-based data, and raise hope that the lifetime risk of kidney failure due to ADPKD will be progressively curtailed during this century. This review will provide a contemporary summary of the current state of the field in disease pathogenesis and therapeutics, and also briefly highlights the importance of clinical practice guidelines, patient perspectives, patient-reported outcomes, uniform trial reporting, and health-economics in ADPKD.

Topics: Age of Onset; Humans; Polycystic Kidney, Autosomal Dominant; Practice Guidelines as Topic; Renal Insufficiency; Signal Transduction; TRPP Cation Channels; Vasopressins

Autosomal dominant polycystic kidney disease (ADPKD), which frequently leads to end-stage renal disease, currently has no specific drug therapies. Better understanding of its pathogenesis and recent clinical trials have led to more accurate diagnosis of the disease and its manifestations, as well as to promising new approaches to treatment.

Topics: Drug Discovery; Humans; Hypertension; Intracranial Aneurysm; Pain; Polycystic Kidney, Autosomal Dominant; Signal Transduction; TOR Serine-Threonine Kinases; Urinary Tract Infections; Vasopressins

Autosomal dominant polycystic kidney disease (ADPKD) is the world's most common inherited kidney disease. An increasing number of animal and human studies have enhanced our understanding of the molecular and cellular pathology of ADPKD. New treatment options are being tested in clinical trials in spite of the failure of mammalian target of rapamycin inhibitor therapy. The main and most effective therapy remains control of hypertension by renin-angiotensin-aldosterone system (RAAS) blockade. This review focuses only on promising therapies, including dual inhibition of RAAS, vasopressin receptor antagonists, increased fluid intake, and blockade of certain receptors of cyclic adenosine monophosphate. Also, the paper reviews what these advances mean to patients and clinicians and elaborates on how these changes can be immediately applied to clinical practice. There is an urgent need for discovery of new therapies targeted toward ADPKD in comparison with therapeutic progress of all other renal diseases.

Topics: AMP-Activated Protein Kinases; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Animals; Blood Pressure; Disease Progression; Enzyme Activators; Fluid Therapy; Hormone Antagonists; Humans; Hypertension; Polycystic Kidney, Autosomal Dominant; Renin-Angiotensin System; Risk Reduction Behavior; Treatment Outcome; Vasopressins

Autosomal dominant polycystic kidney disease (ADPKD) is the most frequent inherited nephropathy. This review will focus on the vasopressin and 3'-5'-cyclic adenosine monophosphate (cAMP) signaling pathways in ADPKD and will discuss how these insights offer new possibilities for the follow-up and treatment of the disease.. Defective osmoregulation is an early manifestation of ADPKD and originates from both peripheral (renal effect of vasopressin) and central (release of vasopressin) components. Copeptin, which is released from the vasopressin precursor, may identify ADPKD patients at risk for rapid disease progression. Increased levels of cAMP in tubular cells, reflecting modifications in intracellular calcium homeostasis and abnormal stimulation of the vasopressin V2 receptor (V2R), play a central role in cystogenesis. Blocking the V2R lowers cAMP in cystic tissues, slows renal cystic progression and improves renal function in preclinical models. A phase III clinical trial investigating the effect of the V2R antagonist tolvaptan in ADPKD patients has shown that this treatment blunts kidney growth, reduces associated symptoms and slows kidney function decline when given over 3 years.. These advances open perspectives for the understanding of cystogenesis in ADPKD, the mechanisms of osmoregulation, the role of polycystins in the brain, and the pleiotropic action of vasopressin.

Topics: Animals; Antidiuretic Hormone Receptor Antagonists; Cyclic AMP; Disease Progression; Hormone Antagonists; Humans; Kidney; Osmoregulation; Polycystic Kidney, Autosomal Dominant; Receptors, Vasopressin; Second Messenger Systems; Treatment Outcome; Vasopressins

Autosomal dominant polycystic kidney disease (ADPKD) is the most frequent inherited nephropathy. The development and enlargement of cysts in ADPKD requires tubular cell proliferation, abnormalities in the extracellular matrix and transepithelial fluid secretion. Multiple studies have suggested that fluid secretion across ADPKD cyst-lining cells is driven by the transepithelial secretion of chloride, mediated by the apical CFTR channel and specific basolateral transporters. The whole secretory process is stimulated by increased levels of cAMP in the cells, probably reflecting modifications in the intracellular calcium homeostasis and abnormal stimulation of the vasopressin V2 receptor. This review will focus on the pathophysiology of fluid secretion in ADPKD cysts, starting with classic, morphological and physiological studies that were followed by investigations of the molecular mechanisms involved and therapeutic trials targeting these pathways in cellular and animal models and ADPKD patients. This article is part of a Special Issue entitled: Polycystic Kidney Disease.

Topics: Animals; Aquaporins; Biological Transport, Active; Chlorides; Cyclic AMP; Cystic Fibrosis Transmembrane Conductance Regulator; Electrophysiological Phenomena; Epithelium; Extracellular Fluid; Humans; Models, Biological; Polycystic Kidney, Autosomal Dominant; Signal Transduction; Sodium-Potassium-Exchanging ATPase; TRPP Cation Channels; Vasopressins; Water-Electrolyte Balance

The antidiuretic hormone vasopressin is crucial for regulating free water clearance in normal physiology. However, it has also been hypothesized that vasopressin has deleterious effects on the kidney. Vasopressin is elevated in animals and patients with chronic kidney disease. Suppression of vasopressin activity reduces proteinuria, renal hypertrophy, glomerulosclerosis and tubulointerstitial fibrosis in animal models. The potential detrimental influence of vasopressin is probably mediated by its effects on mesangial cell proliferation, renin secretion, renal hemodynamics, and blood pressure. In this review, we discuss the increasing body of evidence pointing towards the contribution of vasopressin to chronic kidney disease progression in general and to autosomal dominant polycystic kidney disease in particular. These data allude to the possibility that interventions directed at lowering vasopressin activity, for example by the administration of vasopressin receptor antagonists or by drinking more water, may be beneficial in chronic kidney disease.

Topics: Humans; Polycystic Kidney, Autosomal Dominant; Renal Insufficiency, Chronic; Vasopressins; Water

Vasopressin stimulates cyst growth in autosomal dominant polycystic kidney disease (ADPKD) and is a key therapeutic target. Evaluation of high water intake as an alternative to pharmacological vasopressin blockade is supported by patients. However feasibility, safety and adherence-promoting strategies required to deliver this remain unknown.. Assess the feasibility of a definitive randomized high water intake trial in ADPKD.. In this prospective open-label randomized trial, adult ADPKD patients with eGFR ≥ 20 ml/min/1.73 m2 were randomized to prescribed high water (HW) intake targeting urine osmolality (UOsm) ≤270 mOsm/kg, or ad libitum (AW) intake (UOsm >300 mOsm/kg). Self-management strategies including home-monitoring of urine-specific gravity (USG) were employed to promote adherence.. We enrolled 42 participants, baseline median eGFR (HW 68.4 [interquartile range (IQR) 35.9-107.2] vs. AW 75.8 [IQR 59.0-111.0 ml/min/1.73 m2, P = 0.22) and UOsm (HW 353 [IQR 190-438] vs. AW 350 [IQR 240-452] mOsm/kg, P = 0.71) were similar between groups. After 8 weeks, 67% in the HW vs. 24% in AW group achieved UOsm ≤270 mOsm/kg, P = 0.001. HW group achieved lower UOsm (194 [IQR 190-438] vs. 379 [IQR 235-503] mOsm/kg, P = 0.01) and higher urine volumes (3155 [IQR 2270-4295] vs. 1920 [IQR 1670-2960] ml/day, P = 0.02). Two cases of hyponatraemia occurred in HW group. No acute GFR effects were detected. In total 79% (519/672) of USG were submitted and 90% (468/519) were within target. Overall, 17% withdrew during the study.. DRINK demonstrated successful recruitment and adherence leading to separation between treatment arms in primary outcomes. These findings suggest a definitive trial assessing the impact of high water on kidney disease progression in ADPKD is feasible.

Topics: Adult; Drinking; Feasibility Studies; Female; Glomerular Filtration Rate; Humans; Male; Middle Aged; Polycystic Kidney, Autosomal Dominant; Prospective Studies; Treatment Outcome; Vasopressins; Water; Young Adult

Autosomal Dominant Polycystic Kidney Disease (ADPKD) patients have an impaired urine concentrating capacity. Increased circulating vasopressin (AVP) concentrations are supposed to play a role in the progression of ADPKD. We hypothesized that ADPKD patients have a more severely impaired urine concentrating capacity in comparison to other patients with chronic kidney disease at a similar level of kidney function, with consequently an enhanced AVP response to water deprivation with higher circulating AVP concentrations.. 15 ADPKD (eGFR<60) patients and 15 age-, sex- and eGFR-matched controls with IgA nephropathy (IgAN), underwent a water deprivation test to determine maximal urine concentrating capacity. Plasma and urine osmolality, urine aquaporin-2 (AQP2) and plasma AVP and copeptin (a surrogate marker for AVP) were measured at baseline and after water deprivation (average 16 hours). In ADPKD patients, height adjusted total kidney volume (hTKV) was measured by MRI.. Maximal achieved urine concentration was lower in ADPKD compared to IgAN controls (533±138 vs. 642±148 mOsm/kg, p = 0.046), with particularly a lower maximal achieved urine urea concentration (223±74 vs. 299±72 mmol/L, p = 0.008). After water deprivation, plasma osmolality was similar in both groups although change in plasma osmolality was more profound in ADPKD due to a lower baseline plasma osmolality in comparison to IgAN controls. Copeptin and AVP increased significantly in a similar way in both groups. AVP, copeptin and urine AQP2 were inversely associated with maximal urine concentrating in both groups.. ADPKD patients have a more severely impaired maximal urine concentrating capacity with a lower maximal achieved urine urea concentration in comparison to IgAN controls with similar endogenous copeptin and AVP responses.

Topics: Adolescent; Adult; Aged; Aquaporin 2; Female; Glomerulonephritis, IGA; Glycopeptides; Humans; Kidney Concentrating Ability; Magnetic Resonance Imaging; Male; Middle Aged; Polycystic Kidney, Autosomal Dominant; Vasopressins

Renal handling of sodium and water is abnormal in chronic kidney diseases. To study the function and regulation of the aquaporin-2 water channel (AQP2) and the epithelial sodium channel (ENaC) in autosomal dominant polycystic kidney disease (ADPKD), we measured urinary excretion of AQP2 (u-AQP2), the β-subunit of ENaC (u-ENaC(β)), cAMP (u-cAMP), and prostaglandin E(2) (u-PGE(2)); free water clearance (C(H2O)); fractional sodium excretion (FE(Na)); and plasma vasopressin (p-AVP), renin (p-Renin), angiotensin II (p-ANG II), aldosterone (p-Aldo), and atrial and brain natriuretic peptide (p-ANP, p-BNP) in patients with ADPKD and healthy controls during 24-h urine collection and after hypertonic saline infusion during high sodium intake (HS; 300 mmol sodium/day) and low sodium intake (LS; 30 mmol sodium/day). No difference in u-AQP2, u-ENaC(β), u-cAMP, u-PGE(2), C(H2O), and vasoactive hormones was found between patients and controls at baseline, but during HS the patients had higher FE(Na). The saline caused higher increases in FE(Na) in patients than controls during LS, but the changes in u-ENaC(β), p-Aldo, p-ANP, p-BNP, p-Renin, and p-ANG II were similar. Higher increases in u-AQP2 and p-AVP were seen in patients during both diets. In conclusion, u-AQP2 and u-ENaC(β) were comparable in patients with ADPKD and controls at baseline. In ADPKD, the larger increase in u-AQP2 and p-AVP in response to saline could reflect an abnormal water absorption in the distal nephron. During LS, the larger increase in FE(Na) in response to saline could reflect a defective renal sodium retaining capacity in ADPKD, unrelated to changes in u-ENaC(β).

Topics: Adolescent; Adult; Aged; Aldosterone; Angiotensin II; Aquaporin 2; Atrial Natriuretic Factor; Chronic Disease; Cross-Over Studies; Cyclic AMP; Dinoprostone; Epithelial Sodium Channels; Female; Humans; Male; Middle Aged; Natriuretic Peptide, Brain; Polycystic Kidney, Autosomal Dominant; Renin; Saline Solution, Hypertonic; Sodium; Vasopressins; Young Adult

Autosomal dominant polycystic kidney disease (ADPKD) is one of the most frequent autosomal dominant diseases. Apart from kidneys it also includes alimentary system, nervous system, cardiovascular system. ADPKD is associated with endocrinal disorders of the hormones regulating volume, arterial blood pressure and water and electrolyte balance such as: ARO, AVP, Aldo. 24 patients with ADPKD (12 with normal renal function-gr. III, 12 with advanced renal insufficiency-gr. IV) and 15 healthy subjects to compare with-gr. I and 16 patients with advanced renal insufficiency of other origin than ADPKD-gr. II were examined. In all groups the levels of Aldo, AVP and ARO in blood and Na+, K+ and creatinine concentrations in blood serum were examined Also an excretion of Na, K, creatinine with urine and clearances: CNa, CK, CKrea and filtration fractions: FENa and FEK were determined. Arterial blood pressure was measured in all groups. The above described parameters were studied in standard conditions in patients in supine position and fasting-survey I; directly after intravenous infusion of 1000 ml 0.16 M NaCl at 16.7 ml/min for 1 h-survey II and two hours after intravenous infusion-survey III. Isotonic intravenous infusion of natrium chloride increased central blood volume in the examined patients (induced hypervolemia). The received results were compared among groups in standard conditions (before infusion) as well as reaction of all groups to increased central volemia was compared. On the basis of the received results it was observed that the patients with ADPKD with normal renal function (gr III) show a significant increase of ARO, AVP, arterial blood pressure what differs them from healthy individuals (gr. I). The increased values of the above mentioned parameters were typical for the patients with chronic renal insufficiency regardless to a cause of the failure (gr. II). Consequently, patients with ADPKD showed some hormonal disorders typical for patients with advanced renal insufficiency despite fairly big difference in creatinine level and renal function condition among groups. Comparing the groups with advanced renal insufficiency (gr. II and gr. IV) it was shown that despite the same creatinine and electrolytes level in blood serum they exhibited different renine activity of serum and arterial blood pressure. These parameters were higher in the group with ADPKD. After volume expansion by 1000 ml 0.16 M NaCl infusion no significant differences between renal r

Topics: Adult; Body Water; Creatinine; Electrolytes; Fasting; Humans; Infusions, Intravenous; Isotonic Solutions; Polycystic Kidney, Autosomal Dominant; Renin; Supine Position; Vasopressins

Vasopressin V

Topics: Anti-Anxiety Agents; Anticonvulsants; Antidiuretic Hormone Receptor Antagonists; Benzodiazepines; Humans; Hypnotics and Sedatives; Polycystic Kidney, Autosomal Dominant; Receptors, Vasopressin; Tolvaptan; Vasopressins

Cyst formation and enlargement in autosomal dominant kidney disease (ADPKD) is mainly driven by aberrantly increased cytosolic cAMP in renal tubule epithelial cells. Because the vasopressin V

Topics: Animals; Antidiuretic Hormone Receptor Antagonists; Benzodiazepines; Cyclic AMP; Cysts; Humans; Kidney; Mice; Polycystic Kidney, Autosomal Dominant; Receptors, Vasopressin; Vasopressins

Autosomal dominant polycystic kidney disease (ADPKD) is the most common genetic kidney disease. Fluid-filled cysts develop and enlarge in both kidneys, eventually leading to kidney failure. Tolvaptan is a selective vasopressin V

Topics: Animals; Antidiuretic Hormone Receptor Antagonists; Cyclic AMP; Cysts; Polycystic Kidney, Autosomal Dominant; Tolvaptan; Vasopressins

Concentration of the urine is primarily regulated via vasopressin dependent aquaporin-2 water channels in the apical membrane of kidney principal cells. It is unclear whether urine concentration ability in ADPKD differs from other patients with similar degree of impaired renal function (non-ADPKD patients). The purpose of this case control study was to measure urine concentration ability in ADPKD patients compared to non-ADPKD patients and healthy controls.. A seventeen hour long water deprivation test was carried out in 17 ADPKD patients (CKD I-IV), 16 non-ADPKD patients (CKD I-IV), and 18 healthy controls. Urine was collected in 4 consecutive periods during water deprivation (12 h, 1 h, 2 h and 2 h, respectively) and analyzed for osmolality (u-Osm), output (UO), fractional excretion of sodium (FE. U-Osm was significantly lower and FE. Urine concentration ability was reduced to the same extent in patients with ADPKD and other chronic kidney diseases with the same level of renal function compared to healthy controls. The lower urine excretion of AQP2 and ENaC suggests that the underlying mechanism may be a reduced tubular response to vasopressin and aldosterone.. Current Controlled Trial NCT04363554 , date of registration: 20.08.2017.

Topics: Adult; Aged; Aldosterone; Aquaporin 2; Case-Control Studies; Epithelial Sodium Channels; Female; Humans; Kidney Concentrating Ability; Male; Middle Aged; Osmolar Concentration; Polycystic Kidney, Autosomal Dominant; Renal Elimination; Renal Insufficiency, Chronic; Severity of Illness Index; Sodium; Vasopressins; Water Deprivation

Excessive salt intake and vasopressin may promote cyst growth in autosomal dominant polycystic kidney disease and glomerular filtration rate (GFR) decline in chronic kidney disease. Kramers et al. confirmed the effects of salt in a large autosomal dominant polycystic kidney disease cohort. Copeptin mediated 72% and 25% of the salt effects on GFR decline and kidney growth. Kidney growth did not significantly contribute to the copeptin-mediated salt effect on GFR. Differences in kidney growth and GFR decline trajectories and factors other than cyst growth contributing to GFR decline may explain the divergent effects.

Topics: Biomarkers; Disease Progression; Glomerular Filtration Rate; Glycopeptides; Humans; Kidney; Polycystic Kidney, Autosomal Dominant; Sodium Chloride, Dietary; Vasopressins; Water

Patients with autosomal dominant polycystic kidney disease (ADPKD) are treated with a vasopressin V2 receptor antagonist (V2RA) to slow disease progression. This drug increases vasopressin considerably in these patients with already elevated baseline levels. Vasopressin is known to stimulate the hypothalamic-pituitary-adrenal (HPA) axis through V1 and V3 receptor activation. It is unknown whether this increase in vasopressin during V2RA treatment affects glucocorticoid production.. Twenty-seven ADPKD patients were studied on and off treatment with a V2RA and compared to age- and sex-matched healthy controls and IgA nephropathy patients, the latter also matched for kidney function. Vasopressin was measured by its surrogate copeptin. Twenty-four-hour urinary excretions of cortisol, cortisone, tetrahydrocortisone, tetrahydrocortisol, allotetrahydrocortisol, and the total glucocorticoid pool were measured.. At baseline, ADPKD patients demonstrated a higher copeptin concentration in comparison with healthy controls, while urinary excretion of cortisol and cortisone was lower (medians of 0.23 vs. 0.34 μmol/24 h, p = 0.007, and 0.29 vs. 0.53 μmol/24 h, p < 0.001, respectively). There were no differences in cortisol and cortisone excretion compared to IgA nephropathy patients. Cortisol, cortisone, and total glucocorticoid excretions correlated with kidney function (R = 0.37, 0.58, and 0.19, respectively; all p < 0.05). Despite that V2RA treatment resulted in a 3-fold increase in copeptin, only cortisone excretion increased (median of 0.44 vs. baseline 0.29 μmol/24 h, p < 0.001), whereas no changes in cortisol or total glucocorticoid excretion were observed.. Increased concentration of vasopressin in ADPKD patients at baseline and during V2RA treatment does not result in activation of the HPA axis. The impaired glucocorticoid production in these patients is related to their degree of kidney function impairment.

Topics: Adult; Aged; Antidiuretic Hormone Receptor Antagonists; Case-Control Studies; Cortisone; Female; Glomerular Filtration Rate; Glomerulonephritis, IGA; Glycopeptides; Humans; Hydrocortisone; Hypothalamo-Hypophyseal System; Male; Middle Aged; Pituitary-Adrenal System; Polycystic Kidney, Autosomal Dominant; Receptors, Vasopressin; Renal Elimination; Severity of Illness Index; Vasopressins

Autosomal dominant polycystic kidney disease (ADPKD) is a common genetic disorder characterized by the relentless growth of numerous fluid-filled cysts in the kidneys. Mutations in PKD1 and PKD2, genes that encode polycystin 1 and 2, respectively, are responsible for most cases of ADPKD. Currently, the cellular mechanisms responsible for cyst formation remain poorly understood. In vitro models have been used by researchers to investigate cellular processes for cyst formation in carefully controlled experimental conditions. Madin-Darby canine kidney (MDCK) cells, a distal tubule epithelial cell line, were first used to form 3-dimensional (3-D) cysts within a hydrated collagen gel. This method was applied to epithelial cells cultured from cysts of human ADPKD kidneys, allowing investigators to study cellular mechanisms for cyst growth using cells that harbor the genetic mutations responsible for ADPKD in humans. Studies using ADPKD in vitro cysts have provided insight into cellular processes regulating cell proliferation, fluid secretion, and cell polarity. These assays were used to demonstrate the central role of cAMP agonists, such as arginine vasopressin, on cyst growth; and to test the effectiveness of potential therapeutic agents, including tolvaptan. Results obtained from in vitro cyst experiments demonstrate the translational value of cell model systems for investigating the mechanisms for cyst formation in human ADPKD. In this chapter, we describe protocols for growing ADPKD cells in a 3-D in vitro cyst assay and measuring total cyst volume by microscopy and image analysis.

Topics: Animals; Collagen; Culture Media; Cyclic AMP; Dogs; Epithelial Cells; Humans; Intravital Microscopy; Madin Darby Canine Kidney Cells; Neurophysins; Polycystic Kidney, Autosomal Dominant; Primary Cell Culture; Protein Precursors; Vasopressins

Vasopressin plays an essential role in osmoregulation, but has deleterious effects in patients with ADPKD. Increased water intake to suppress vasopressin activity has been suggested as a potential renoprotective strategy. This study investigated whether urine and plasma osmolality can be used as reflection of vasopressin activity in ADPKD patients.. We measured urine and plasma osmolality, plasma copeptin concentration, total kidney volume (TKV, by MRI) and GFR ((125)I-iothalamate). In addition, change in estimated GFR (eGFR) during follow-up was assessed.. Ninety-four patients with ADPKD were included (56 males, age 40 ± 10, mGFR 77 ± 32 ml/min/1.73 m(2), TKV 1.55 (0.99-2.40) l. Urine osmolality, plasma osmolality and copeptin concentration were 420 ± 195, 289 ± 7 mOsmol/l and 7.3 (3.2-14.6) pmol/l, respectively. Plasma osmolality was associated with copeptin concentration (R = 0.54, p < 0.001), whereas urine osmolality was not (p = 0.4). In addition, urine osmolality was not associated with TKV (p = 0.3), in contrast to plasma osmolality (R = 0.52, p < 0.001) and copeptin concentration (R = 0.61, p < 0.001). Fifty-five patients were followed for 2.8 ± 0.8 years. Baseline plasma and urine osmolality were not associated with change in eGFR (p = 0.6 and p = 0.3, respectively), whereas baseline copeptin concentration did show an association with change in eGFR, in a crude analysis (St. β = -0.41, p = 0.003) and also after adjustment for age, sex and TKV (St. β = -0.23, p = 0.05).. These data suggest that neither urine nor plasma osmolality are valid measures to identify ADPKD patients that may benefit from increasing water intake. Copeptin appears a better alternative for this purpose.

Topics: Adult; Biomarkers; Female; Follow-Up Studies; Glomerular Filtration Rate; Glycopeptides; Humans; Male; Middle Aged; Osmolar Concentration; Polycystic Kidney, Autosomal Dominant; Prognosis; Vasopressins

Autosomal dominant polycystic kidney disease (ADPKD) is the most prevalent hereditary renal disease, characterized by cyst formation in the kidneys leading to end stage kidney failure. It is clinically acknowledged that ADPKD patients have impaired urine concentrating capacity, but the mechanism behind this observation is unknown.. Fifteen ADPKD patients (estimated GFR ≥60 ml/min per 1.73 m(2)) and 15 age- and sex-matched healthy controls underwent a standard prolonged water deprivation test in which urine and plasma osmolality, vasopressin, and copeptin were measured. The effect of a synthetic vasopressin analog (desmopressin) injected at the moment of maximal urine concentrating capacity was also studied.. After 14 hours of water deprivation, ADPKD patients tended to have higher plasma osmolality (P=0.07) and significantly higher vasopressin and copeptin levels (both P<0.05), whereas urine osmolality was similar in ADPKD patients and controls (710 versus 742 mOsmol/kg; P=0.61). Maximal urine concentrating capacity was lower in ADPKD patients (758 versus 915 mOsmol/kg in controls; P<0.001). At maximal urine concentrating capacity, plasma osmolality, vasopressin, and copeptin levels were significantly higher in ADPKD patients. The median increase in urine osmolality after desmopressin administration in ADPKD patients was less than in healthy controls.. Already early in their disease, ADPKD patients have impaired maximal urine concentrating capacity brought out upon dehydration, with no evidence of impaired hypothalamic response. To maintain fluid balance, vasopressin concentration increases, which is hypothesized to play a role in ADPKD disease progression.

Topics: Adult; Biomarkers; Case-Control Studies; Deamino Arginine Vasopressin; Disease Progression; Female; Glycopeptides; Humans; Kidney; Kidney Concentrating Ability; Male; Middle Aged; Netherlands; Neurophysins; Osmolar Concentration; Polycystic Kidney, Autosomal Dominant; Protein Precursors; Regression Analysis; Time Factors; Vasopressins; Water Deprivation; Water-Electrolyte Balance; Young Adult

Experimental studies have suggested that vasopressin plays a detrimental role in autosomal dominant polycystic kidney disease (ADPKD). It is, however, unknown whether endogenous vasopressin concentration is associated with kidney function decline in subjects with ADPKD.. We measured plasma copeptin (a marker of vasopressin) in 79 ADPKD subjects with renal function assessed during short-term follow-up by inulin clearance measured glomerular filtration rate (mGFR) and during long-term follow-up by Modification of Diet in Renal Disease (MDRD) equation estimated GFR (eGFR).. In these subjects (43% male, age 36.8 ± 10.1 years, GFR 96.8 ± 18.2 mL/min/1.73 m(2)), median copeptin concentration at baseline was 2.71 [interquartile ranges (IQR) 1.63-5.46] pmol/L. Baseline copeptin concentration was inversely associated both with change in mGFR during follow-up for 3.3 (3.1-3.5) years, (R = -0.300, P = 0.01), as well as with change in eGFR during follow-up for 11.2 (4.5-14.3) years, (R = -0.302, P < 0.01). These associations were independent of age, gender and baseline GFR. Nine subjects started renal replacement therapy during follow-up of which eight had at baseline a copeptin concentration above the median in this population.. In ADPKD subjects, a higher copeptin concentration is associated with kidney function decline during follow-up, suggesting that copeptin may be a new marker to predict kidney outcome in ADPKD.

Topics: Adult; Biomarkers; Female; Follow-Up Studies; Glomerular Filtration Rate; Glycopeptides; Humans; Kidney; Kidney Function Tests; Male; Middle Aged; Polycystic Kidney, Autosomal Dominant; Vasopressins

Topics: Female; Glycopeptides; Humans; Kidney; Kidney Concentrating Ability; Male; Neurophysins; Polycystic Kidney, Autosomal Dominant; Protein Precursors; Vasopressins

Autosomal dominant polycystic kidney disease (ADPKD) is associated with a urine-concentrating defect attributed to renal cystic changes. As PKD genes are expressed in the brain, altered central release of arginine vasopressin could also play a role. In order to help determine this we measured central and nephrogenic components of osmoregulation in 10 adults and 10 children with ADPKD, all with normal renal function, and compared them to 20 age- and gender-matched controls. Overnight water deprivation caused a lower rise in urine osmolality in the patients with ADPKD than controls, reflecting an impaired release of vasopressin and a peripheral defect in the patients. The reactivity of plasma vasopressin to water deprivation, as found in controls, was blunted in the patients with the latter showing lower urine osmolality for the same range of plasma vasopressin. The maximal urine osmolality correlated negatively with total kidney volume. Defective osmoregulation was confirmed in the children with ADPKD but was unrelated to number of renal cysts or kidney size. Thus, patients with ADPKD have an early defect in osmoregulation, with a blunted release of arginine vasopressin. This reflects expression of polycystins in hypothalamic nuclei that synthesize vasopressin, and this should be considered when evaluating treatments targeting the vasopressin pathway in ADPKD.

Topics: Adolescent; Adult; Aged; Case-Control Studies; Chi-Square Distribution; Child; Child, Preschool; Female; Humans; Hypothalamus; Kidney; Male; Middle Aged; Neurophysins; Osmolar Concentration; Osmoregulation; Polycystic Kidney, Autosomal Dominant; Protein Precursors; Time Factors; TRPP Cation Channels; Vasopressins; Water Deprivation; Young Adult

Topics: Biomarkers; Glycopeptides; Humans; Polycystic Kidney, Autosomal Dominant; Urea; Vasopressins

Topics: Female; Glycopeptides; Humans; Kidney; Male; Polycystic Kidney, Autosomal Dominant; Vasopressins

Experimental studies suggest a detrimental role for vasopressin in the pathogenesis of autosomal dominant polycystic kidney disease (ADPKD). However, it is unknown whether endogenous vasopressin concentration is associated with disease severity in patients with ADPKD.. Plasma copeptin concentration (a marker of endogenous vasopressin levels) was measured in 102 ADPKD patients (diagnosis based on Ravine criteria) by an immunoassay. Plasma and urinary osmolarity were also measured. To assess disease severity, GFR and effective renal blood flow were measured by continuous infusion of 125I-iothalamate and 131I-hippuran, total renal volume by magnetic resonance imaging, and 24-hour urinary albumin excretion by nephelometry.. In these ADPKD patients, copeptin was associated with the various markers of disease severity in ADPKD (positively with total renal volume [R=0.47] and albuminuria [R=0.39] and negatively with GFR [R=-0.58] and effective renal blood flow [R=-0.52], all P<0.001). These associations were independent of age, gender, and use of diuretics. Copeptin was furthermore associated with plasma osmolarity (P<0.001) but not with 24-hour urinary volume, 24-hour urinary osmolarity or fractional urea excretion (P=0.7, 0.9, and 0.3, respectively).. On cross-sectional analysis, copeptin is associated with disease severity in ADPKD patients, supporting the results of experimental studies that suggest that vasopressin antagonists have a renoprotective effect in ADPKD and offering a good prospect for clinical studies with these agents.

Topics: Adult; Albuminuria; Biomarkers; Cross-Sectional Studies; Female; Glomerular Filtration Rate; Glycopeptides; Humans; Immunoassay; Iodine Radioisotopes; Iodohippuric Acid; Iothalamic Acid; Magnetic Resonance Imaging; Male; Middle Aged; Nephelometry and Turbidimetry; Netherlands; Osmolar Concentration; Polycystic Kidney, Autosomal Dominant; Predictive Value of Tests; Regression Analysis; Renal Blood Flow, Effective; Severity of Illness Index; Urodynamics; Vasopressins

In autosomal dominant polycystic kidney disease (ADPKD), arginine vasopressin (AVP) accelerates cyst growth by stimulating cAMP-dependent ERK activity and epithelial cell proliferation and by promoting Cl(-)-dependent fluid secretion. Tolvaptan, a V2 receptor antagonist, inhibits the renal effects of AVP and slows cyst growth in PKD animals. Here, we determined the effect of graded concentrations of tolvaptan on intracellular cAMP, ERK activity, cell proliferation, and transcellular Cl(-) secretion using human ADPKD cyst epithelial cells. Incubation of ADPKD cells with 10(-9) M AVP increased intracellular cAMP and stimulated ERK and cell proliferation. Tolvaptan caused a concentration-dependent inhibition of AVP-induced cAMP production with an apparent IC(50) of ∼10(-10) M. Correspondingly, tolvaptan inhibited AVP-induced ERK signaling and cell proliferation. Basolateral application of AVP to ADPKD cell monolayers grown on permeable supports caused a sustained increase in short-circuit current that was completely blocked by the Cl(-) channel blocker CFTR(inh-172), consistent with AVP-induced transepithelial Cl(-) secretion. Tolvaptan inhibited AVP-induced Cl(-) secretion and decreased in vitro cyst growth of ADPKD cells cultured within a three-dimensional collagen matrix. These data demonstrate that relatively low concentrations of tolvaptan inhibit AVP-stimulated cell proliferation and Cl(-)-dependent fluid secretion by human ADPKD cystic cells.

Topics: Adult; Aged; Amiloride; Antidiuretic Hormone Receptor Antagonists; Benzazepines; Blotting, Western; Cell Proliferation; Cells, Cultured; Chlorides; Cyclic AMP; Cystic Fibrosis Transmembrane Conductance Regulator; Cysts; Diuretics; Extracellular Signal-Regulated MAP Kinases; Female; Humans; Male; Middle Aged; Polycystic Kidney, Autosomal Dominant; Renal Agents; Tolvaptan; Vasopressins

Topics: Arginine Vasopressin; Humans; Polycystic Kidney Diseases; Polycystic Kidney, Autosomal Dominant; Polycystic Kidney, Autosomal Recessive; Vasopressins

Topics: Adolescent; Adult; Angiotensin-Converting Enzyme Inhibitors; Cyclic AMP; Enalapril; Hematuria; Humans; Lisinopril; Magnetic Resonance Imaging; Male; Polycystic Kidney, Autosomal Dominant; Vasopressins

Topics: Animals; Blood Pressure; Disease Progression; Diuresis; Endothelins; Female; Glomerulonephritis, IGA; Humans; Kidney Failure, Chronic; Kidney Tubules; Male; Nitric Oxide; Oxidative Stress; Polycystic Kidney, Autosomal Dominant; Retrospective Studies; Risk Factors; Sex Factors; Smoking; Vasopressins

In five members of three generations in a family studied in 1972, 3 nephrological disorders occurred concurrently: distal renal tubular acidosis (dRTA), polycystic kidney and nephrogenic diabetes insipidus (with the exception of a five-year-old child in whom polycystic kidney was not detectable--yet?). Chromosoma studies revealed an increased rate of the occurrence of variations. The youngest patient was reinvestigated in 1993; the other four affected members of the family were already not alive. 7 offsprings in two generations of the 3 healthy members of the third "patient generation" were healthy. The autosomal dominant way of inheritance characteristic to both dRTA and polycystic kidney disease was obvious in this family. On the other hand the same degree of the concentrating defect found both in the patients of the familial dRTA and in 11 control patients with non familial (acquired) dRTA suggested that the nephrogenic diabetes insipidus as an acquired disorder was associated with the two congenital abnormalities. The clinical picture of the combined disease was dominated by the symptoms of polydipsia and polyuria. The vasopressin resistance with a variation in the degree interindividually seemed to be responsible for the nephrogenic diabetes insipidus. Functional insufficiency of the loop of Henle was excluded on the basis of normal responses to a "loop diuretic".

Topics: Acidosis, Renal Tubular; Adolescent; Adult; Aged; Child; Child, Preschool; Diabetes Insipidus, Nephrogenic; Drinking; Female; Humans; Male; Middle Aged; Nephrocalcinosis; Pedigree; Polycystic Kidney, Autosomal Dominant; Polyuria; Radiography; Vasopressins