Autosomal Dominant Polycystic Kidney Disease: From Pathophysiology of Cystogenesis to Advances in the Treatment

Abstract

Autosomal dominant polycystic kidney disease (ADPKD) is the most common genetic renal disease, with an estimated prevalence between 1:1000 and 1:2500. It is mostly caused by mutations of the PKD1 and PKD2 genes encoding polycystin 1 (PC1) and polycystin 2 (PC2) that regulate cellular processes such as fluid transport, differentiation, proliferation, apoptosis and cell adhesion. Reduction of calcium ions and induction of cyclic adenosine monophosphate (sAMP) promote cyst enlargement by transepithelial fluid secretion and cell proliferation. Abnormal activation of MAPK/ERK pathway, dysregulated signaling of heterotrimeric G proteins, mTOR, phosphoinositide 3-kinase, AMPK, JAK/STAT activator of transcription and nuclear factor kB (NF-kB) are involved in cystogenesis. Another feature of cystic tissue is increased extracellular production and recruitment of inflammatory cells and abnormal connections among cells. Moreover, metabolic alterations in cystic cells including defective glucose metabolism, impaired beta-oxidation and abnormal mitochondrial activity were shown to be associated with cyst expansion. Although tolvaptan has been recently approved as a drug that slows ADPKD progression, some patients do not tolerate tolvaptan because of frequent aquaretic. The advances in the knowledge of multiple molecular pathways involved in cystogenesis led to the development of animal and cellular studies, followed by the development of several ongoing randomized controlled trials with promising drugs. Our review is aimed at pathophysiological mechanisms in cystogenesis in connection with the most promising drugs in animal and clinical studies.

Atypical Polycystic Kidney Disease in Individuals Heterozygous for ALG8 Protein-truncating variants

“…21,22 Advances in the understanding of the genetic basis of PKD have led to the investigation of various upstream targets of cystogenesis, including vasopressin-2 receptor (AVPR2), EGFR/ErB2, Beta-1 integrin receptor, and c-SRC. [23][24][25] It is unknown whether heterozygotes of ALG8 PTVs would benefit from tolvaptan although tolvaptan is typically indicated only for patients with elevated total kidney volume using the Mayo imaging classification (Mayo Class 1C, 1D, 1E). 22,26,27 While we did not have uniform imaging to calculate Mayo imaging classification on patients, we found that kidneys were not enlarged for the vast majority of the ALG8 PTV heterozygotes so most in our study would not qualify from tolvaptan.…”

Proteomic Approaches and Potential Applications in Autosomal Dominant Polycystic Kidney Disease and Fabry Disease

“…With a high penetrant state, affecting between 1:400 and 1:1000 live births, ADPKD is the most common inherited kidney disease. The bilateral kidney cysts that characterize ADPKD continuously grow and develop, inducing progressive renal enlargement and increasing the total kidney volume (TKV), frequently complicated by hypertension, polyuria, nocturia, discomfort, nephrolithiasis, hematuria, infections, kidney function loss, and ESRD which typically manifests at age 55 [ 27 , 28 ]. Even within families, disease severity and course might vary considerably.…”

Aberrant centrosome biogenesis disrupts nephron progenitor cell renewal and fate resulting in fibrocystic kidney disease

“…There was a total of 1,550 DEGs including 786 upregulated and 764 downregulated genes in Pkd1-KO kidneys compared with wildtype (Figure 7E). Hallmark analysis identified several signaling pathways known to be involved in cystogenesis and fibrosis in ADPKD (Figure 7F), including TNFα-NF-κB, TGFβ, JAK-STAT, and KRAS signaling 67,68 . Subsequently, we compared the DEGs from the Cep120-KO and Pkd1-KO mice at P15 (Figure 7G).…”