Autosomal Dominant Polycystic Kidney Disease

Somlo, Stefan; Torres, Vicente E.; Caplan, Michael J.

doi:10.1016/b978-0-12-381462-3.00080-x

Cited by 3 publications

(4 citation statements)

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“…This form is difficult to distinguish clinically from autosomal dominant tubulointerstitial kidney disease (ADTKD) which is also characterized by tubular damage, interstitial fibrosis and corticomedullary microcysts (Devuyst et al, 2019). In contrast, autosomal dominant polycystic kidney disease (ADPKD), which is more prevalent, is typically adult-onset with slow progression to ESRD [onset from 58 to 80 years (Chebib and Torres, 2016)] and characterized by enlarged kidneys with cysts distributed throughout the renal parenchyma (Harris and Torres, 2002).…”

Section: Introductionmentioning

confidence: 99%

Renal Ciliopathies: Sorting Out Therapeutic Approaches for Nephronophthisis

Stokman

Saunier

Benmerah

2021

Front. Cell Dev. Biol.

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Nephronophthisis (NPH) is an autosomal recessive ciliopathy and a major cause of end-stage renal disease in children. The main forms, juvenile and adult NPH, are characterized by tubulointerstitial fibrosis whereas the infantile form is more severe and characterized by cysts. NPH is caused by mutations in over 20 different genes, most of which encode components of the primary cilium, an organelle in which important cellular signaling pathways converge. Ciliary signal transduction plays a critical role in kidney development and tissue homeostasis, and disruption of ciliary signaling has been associated with cyst formation, epithelial cell dedifferentiation and kidney function decline. Drugs have been identified that target specific signaling pathways (for example cAMP/PKA, Hedgehog, and mTOR pathways) and rescue NPH phenotypes in in vitro and/or in vivo models. Despite identification of numerous candidate drugs in rodent models, there has been a lack of clinical trials and there is currently no therapy that halts disease progression in NPH patients. This review covers the most important findings of therapeutic approaches in NPH model systems to date, including hypothesis-driven therapies and untargeted drug screens, approached from the pathophysiology of NPH. Importantly, most animal models used in these studies represent the cystic infantile form of NPH, which is less prevalent than the juvenile form. It appears therefore important to develop new models relevant for juvenile/adult NPH. Alternative non-orthologous animal models and developments in patient-based in vitro model systems are discussed, as well as future directions in personalized therapy for NPH.

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Section: Introductionmentioning

confidence: 99%

Renal Ciliopathies: Sorting Out Therapeutic Approaches for Nephronophthisis

Stokman

Saunier

Benmerah

2021

Front. Cell Dev. Biol.

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“…[21,22] In an excellent and recent review of genetics and pathogenetic mechanisms of cyst formation, clinical and diagnostic investigation parameters CME [20] outlined several potential therapies for ADPKD. Tolvaptan and the vasopressin V2-receptor antagonists that inhibit cyst and kidney volume growth have been shown to be of value in the treatment of ADPKD.…”

Section: Autosomal-dominant Polycystic Kidney Diseasementioning

confidence: 99%

Recent important strategies in the management of chronic kidney disease

Meyers

Davies

2017

S Afr Med J

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The burden of chronic kidney disease (CKD) is considerably higher in low-and middle-income countries, which are less able than the developed world to cope with treating advanced renal failure owing to financial constraints. Prevention, early diagnosis and implementation of existing knowledge can improve outcomes. This review presents several recent advances to assist with avoiding and slowing down CKD progression and reducing common comorbid complications. The following are discussed: the possible use of metformin in patients with type 2 diabetes-related CKD; recent inexpensive important developments in the treatment of autosomal-dominant polycystic kidney disease; prevention of acidosis and the early dietary reduction of red meat consumption; and the therapeutic lowering of uric acid in persistent hyperuricaemia. Finally, an active and monitored exercise programme should be undertaken whenever possible. All of these recommendations have been shown to significantly slow the progression of CKD and increase cardiovascular protection. CME 731September 2017, Vol. 107, No. 9 CME addition to the multiple cardiovascular and renal complications of DM, renal dysfunction in the elderly is further compounded by the slow but progressive fall in glomerular filtration rate (GFR) in persons >45 years of age (i.e. ±1 mL/min/year) and also because people live longer. For many years the US Food and Drug Administration (FDA), the Regulatory Cooperation Council (RCC) in Canada and other regulatory bodies have indicated that the use of MF is contraindicated in patients with mild and moderate CKD (stages 3a and 3b) owing to the rarely reported but life-threatening complication of lactic acidosis (LA) (serum lactate levels ≥15 mmol/L).That LA does not occur in patients who receive MF, with an estimated GFR (eGFR) of 50 -30 mL/min., has been indicated in studies conducted by Inzucchi et al. [13] They showed that MF can be safely used in these patients, provided that certain guidelines are always followed. A Coch rane meta-analysis conducted on 47 096 patients with a follow-up of 86 067 patient-years compared the incidence of LA in patients who received MF with those who did not, irrespective of the eGFR.[14] They found that for the upper limit of 95% confidence the true incidence of LA was 6.3/100 000 patient-years for the MF group and 7.8/100 000 patient-years for the non-MF group.It is important to remember that before prescribing MF for any degree of renal function, certain rules are essential and must be fully adhered to. As many practitioners are either unaware or uncertain of the predisposing conditions, these are set out in Table 4.Mechanisms of MF-associated LA are not well elucidated, but include conversion of glucose to lactate in the splanchnic bed and inhibition of hepatic gluconeogenesis (i.e. from lactate, pyruvate and adenine). [15,16] It is essential that any patient with the abovementioned precipi ta ting disorders is instructed to immediately but temporarily withdraw the use of MF and present to a doctor. Patients h...

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“…Autosomal dominant polycystic kidney disease (ADPKD) is the most common hereditary renal disease, affecting approximately 1 in 1000 people (1). Although it was previously termed "adult" polycystic kidney disease, clinical manifestations may be evident in childhood and even in utero (2,3).…”

Section: Introductionmentioning

confidence: 99%

“…ADPKD is characterized by progressive kidney enlargement as a result of tubular cyst expansion and associated compression of adjacent parenchyma. Approximately half of patients with ADPKD manifest ESRD by age 60 years (1). Because ADPKD is genetic, earlier intervention in childhood may have the greatest long-term effect on the natural course of this disease.…”

Section: Introductionmentioning

confidence: 99%

Effect of Pravastatin on Total Kidney Volume, Left Ventricular Mass Index, and Microalbuminuria in Pediatric Autosomal Dominant Polycystic Kidney Disease

Cadnapaphornchai

George

McFann

et al. 2014

Clinical Journal of the American Society of Nephrology

150

101

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Background and objectives In autosomal dominant polycystic kidney disease (ADPKD), progressive kidney cyst formation commonly leads to ESRD. Because important manifestations of ADPKD may be evident in childhood, early intervention may have the largest effect on long-term outcome. Statins are known to slow progressive nephropathy in animal models of ADPKD. This randomized double-blind placebo-controlled phase III clinical trial was conducted from 2007 to 2012 to assess the effect of pravastatin on height-corrected total kidney volume (HtTKV) and left ventricular mass index (LVMI) by magnetic resonance imaging (MRI) and urine microalbumin excretion (UAE) in children and young adults with ADPKD.Designs, setting, participants, & measurements There were 110 pediatric participants with ADPKD and normal kidney function receiving lisinopril who were randomized to treatment with pravastatin or placebo for a 3-year period with evaluation at 0, 18, and 36 months. The primary outcome variable was a $20% change in HtTKV, LVMI, or UAE over the study period.Results Ninety-one participants completed the 3-year study (83%). Fewer participants receiving pravastatin achieved the primary endpoint compared with participants receiving placebo (69% versus 88%; P=0.03). This was due primarily to a lower proportion reaching the increase in HtTKV (46% versus 68%; P=0.03), with similar findings observed between study groups for LVMI (25% versus 38%; P=0.18) and UAE (47% versus 39%; P=0.50). The percent change in HtTKV adjusted for age, sex, and hypertension status over the 3-year period was significantly decreased with pravastatin (23%63% versus 31%63%; P=0.02).Conclusions Pravastatin is an effective agent to slow progression of structural kidney disease in children and young adults with ADPKD. These findings support a role for early intervention with pravastatin in this condition.

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Autosomal Dominant Polycystic Kidney Disease

Cited by 3 publications

References 473 publications

Renal Ciliopathies: Sorting Out Therapeutic Approaches for Nephronophthisis

Renal Ciliopathies: Sorting Out Therapeutic Approaches for Nephronophthisis

Recent important strategies in the management of chronic kidney disease

Effect of Pravastatin on Total Kidney Volume, Left Ventricular Mass Index, and Microalbuminuria in Pediatric Autosomal Dominant Polycystic Kidney Disease

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