Materiały źródłowe

• #1 Acquired Cystic Kidney Disease: Practice Essentials, Pathophysiology, Etiology

  https://emedicine.medscape.com/article/246888-overview

  Cystic kidney disease is a term that represents a wide spectrum of diseases that may be hereditary, developmental, or acquired; these diseases share the feature of renal cysts. […] Acquired cystic kidney disease (ACKD) was previously thought to be a consequence of hemodialysis. Studies have shown that although the association of dialysis and ACKD is indisputable, it is the uremic state that promotes the development of ACKD. The exact mechanism and pathogenesis is incompletely understood. The postulates are as follows: Tubule block: The development of cysts results from tubular obstruction due to oxalate crystals, fibrosis, or micropolyps; and tubular fluid accumulation due to glomerular filtrate and tubular fluid excretion. […] Compensatory growth: The profound loss of renal tissue in end-stage kidney disease promotes tubular cell hypertrophy and hyperplasia. Hypertrophy and hyperplasia, together with transepithelial secretion of fluid by the tubular epithelium, result in the development of cysts. Many factors may influence the process, but most important among them are growth factors and activation of oncogenes.

• #1 Mechanisms of Cyst Development in PKD

  https://pmc.ncbi.nlm.nih.gov/articles/PMC10289784/

  Autosomal dominant polycystic kidney disease is the most common inherited cause of end stage kidney disease worldwide. […] Studies suggest that a loss of function of the complex below an indeterminate threshold triggers cyst initiation, which ultimately results in dysregulation of multiple metabolic processes and downstream pathways and subsequent cyst growth. […] Cystic disease is the result of two distinct processes: an initiating event in which the function of either PKD1 or PKD2 falls below a critical threshold, which then triggers a switch that initiates a cascade of signaling events that result in cellular proliferation, fluid secretion and fibrosis. […] In ADPKD, there is evidence that more than one of these mechanisms may contribute to cystogenesis. […] The overwhelming majority of the data, however, points to a two-hit process affecting PKD1 or PKD2 as the underlying mechanism initiating kidney and liver cysts in most cases.

• #1 Autosomal dominant polycystic kidney disease (ADPKD): Genetics of the disease and mechanisms of cyst growth – UpToDate

  https://www.uptodate.com/contents/autosomal-dominant-polycystic-kidney-disease-adpkd-genetics-of-the-disease-and-mechanisms-of-cyst-growth

  Early cysts begin as dilatations of intact tubules that are in contact with the nephron and fill by glomerular filtration. In contrast, enlarging cysts lose their connection to functioning nephrons as they reach a size of more than 2 to 3 mm. Cyst growth in this setting results from secretion of fluid into the cysts (not glomerular filtration) and is associated with hyperplasia of the cyst epithelium that may reflect underlying maturational arrest. […] A notable feature of ADPKD is variable phenotypic disease expression. Even though the germline (inherited) genetic defect is present in all cells, cysts form in <10 percent of tubules, and, within tubules, cystic dilatation is focal. This observation led to a "second-hit" hypothesis of cystogenesis for both PKD1 and PKD2. Under the "second hit" hypothesis, cysts form in the presence of an inherited PKD1 or PKD2 mutation only if the remaining normal copy of PKD1 or PKD2 develops a somatic (acquired not inherited) mutation. Accordingly, studies of individual PKD1 kidney cysts, which are monoclonal and derived from a single cell, show both loss of heterozygosity and somatic PKD1 mutations.

• #1 ADPKD – How do Cysts form? – Renal Fellow Network

  https://www.renalfellow.org/2019/05/13/adpkd-how-do-cysts-form/

  Autosomal dominant polycystic kidney disease (ADPKD) is one of the most common genetic kidney disorders with a reported incidence ranging from 1:500 to 1:1000. […] Even though the disorder is inherited in an autosomal dominant manner, it is to be emphasized that a single mutated gene may not be sufficient for cystogenesis. Rather, the cellular defect is most likely recessive because it is not without a second hit that the tubules produce a cyst. Additionally, though all the tubular cells carry at least one allele of the gene mutation, only a few of them develop cysts (about 1-3%). […] For the formation of a cyst, the intracellular pathways need to converge and promote two processes epithelial proliferation and fluid secretion. In ADPKD, the common link is cyclic adenosine monophosphate (cAMP).

• #1 SciELO Brazil – Molecular and cellular pathogenesis of autosomal dominant polycystic kidney disease Molecular and cellular pathogenesis of autosomal dominant polycystic kidney disease

  https://www.scielo.br/j/bjmbr/a/qhSjRbXk6rH6f7ZHMLTfgcD/

  Autosomal dominant polycystic kidney disease (ADPKD) is characterized by bilateral, progressive renal cystogenesis and cyst and kidney enlargement, often leading to end-stage renal disease. […] The two-hit model for cyst formation has been recently extended by the demonstration that early gene inactivation leads to rapid and diffuse development of renal cysts, while inactivation in adult life is followed by focal and late cyst formation. […] Renal ischemia/reperfusion, however, can function as a third hit, triggering rapid cyst development in kidneys with Pkd1 inactivation induced in adult life. […] The intracellular Ca2+ homeostasis is impaired in ADPKD, being apparently responsible for the cAMP accumulation and abnormal cell proliferative response to cAMP. […] The mechanism of cyst formation in ADPKD, however, has been comprehensively analyzed in recent years, improving the originally proposed two-hit model.

• #1 SciELO Brazil – Molecular and cellular pathogenesis of autosomal dominant polycystic kidney disease Molecular and cellular pathogenesis of autosomal dominant polycystic kidney disease

  https://www.scielo.br/j/bjmbr/a/qhSjRbXk6rH6f7ZHMLTfgcD/

  These findings suggest that the biological consequences of Pkd1 inactivation are determined by a developmental switch that signals the end of the kidney maturation process. […] These data led the investigators to propose that the rapid development of cysts in the mature kidney might require a third hit in addition to the inactivation of both Pkd1 alleles. […] A subsequent study from the same group was able to prove this point, showing that renal ischemia/reperfusion (IR) can behave as a third hit for cyst formation in adult kidneys. […] It is currently admitted that PC2 in the ER participates in intracellular Ca2+ homeostasis. […] The reduced activity of the polycystin complex and consequent decrease in intracellular Ca2+ concentration, in fact, stimulates Ca2+-inhibitable adenylyl cyclase 6 and inhibits Ca2+/calmodulin-dependent phosphodiesterase 1, favoring the intracellular generation and accumulation of cAMP. […] The process of lowering intracellular Ca2+ in wild-type cells, in addition, triggers the abnormal proliferative response to cAMP. […] The fact that the polycystins participate in several cell signaling pathways makes the process of elucidating these molecular mechanisms a complex task.

• #1 Pathophysiology of PKD – CORE Kidney | UCLA Health

  https://www.uclahealth.org/programs/core-kidney/pathophysiology-pkd

  Recent evidence suggests that the primary abnormality leading to cyst formation in both the autosomal dominant and recessive forms of PKD is related to defects in cilia-mediated signaling activity. […] Specifically, PKD is thought to result from defects in the primary cilium, an immotile, hair-like cellular organelle present on the surface of most cells in the body, anchored in the cell body by the basal body. […] In a 2009 review of the pathogenesis of PKD, Patel et al discuss the accumulating evidence supporting the role of the primary cilium in PKD. […] They note the identification of polycystin-1, polycystin-2, and fibrocystin, the proteins associated with ADPKD and ARPKD, within the primary cilia and basal body of renal tubular epithelia, suggesting that defects in these proteins and subsequent cilia formation may lead to PKD.

• #1 ADPKD – How do Cysts form? – Renal Fellow Network

  https://www.renalfellow.org/2019/05/13/adpkd-how-do-cysts-form/

  Though the exact mechanism leading to increased cAMP levels is unknown, it has been attributed to increased levels of circulating vasopressin. […] While the cysts can arise from all nephron segments in ADPKD (including the glomerulus), microdissection studies done by O.Heggo revealed that the cysts derived from collecting ducts tend to be more numerous and larger. […] The complex of polycystin-1 and polycystin-2 acts either as a mechanosensor or a chemosensor which normally translates the extracellular signals into intracellular increase in calcium. […] In ADPKD, as a result of the mutation in the genes encoding the aforementioned proteins, intracellular calcium levels are decreased. […] A defective PC1 or PC2 function, therefore, may hinder this process leading to uninhibited cell multiplication.

• #1 Pathophysiology of PKD – CORE Kidney | UCLA Health

  https://www.uclahealth.org/programs/core-kidney/pathophysiology-pkd

  While it is not known how defects in the primary cilium lead to cyst development, it is thought to possibly be related to disruption of one of the many signaling pathways regulated by the primary cilium, including intracellular calcium, Hedgehog, Wnt/-catenin, cyclic adenosine monophosphate (cAMP), or planar cell polarity (PCP). […] The role of PCP in the etiology of PKD was originally demonstrated by Fischer et al who found that PCK rats (carrying mutations in PKHD1), had randomized patterns of cell division, contributing to tubular dilation and cyst formation. […] This polarity is thought to be regulated by the primary cilium, as mice with the inactivated Kif3a gene have also been found to display disorganized cell division, suggesting disrupted PCP. […] Recent evidence suggests that disrupted PCP may play a role solely in the pathogenesis of ARPKD, as mouse models of PKD1 and PKD2 mutations have been found to lose cell-oriented division only after cyst formation has begun, unlike models of PKHD1.

• #1 Autosomal dominant polycystic kidney disease (ADPKD): Genetics of the disease and mechanisms of cyst growth – UpToDate

  https://www.uptodate.com/contents/autosomal-dominant-polycystic-kidney-disease-adpkd-genetics-of-the-disease-and-mechanisms-of-cyst-growth

  The above findings, along with reports of cystic disease in patients with homozygous hypomorphic (reduced level of activity) PKD1 mutations or with a heterozygous hypomorphic PKD1 mutation associated with a second inactivating PKD1 mutation, suggest a „threshold mechanism of cystogenesis” model of disease. As an example, a dose of functional polycystin that falls below a critical threshold (approximately 10 to 30 percent of normal) within a tubular epithelial cell may be sufficient to initiate cyst formation. It has been proposed that falling below this threshold leads to abnormal fluid secretion, dysregulated cell proliferation, and apoptosis, which promote cyst growth via multiple signaling pathways. […] Increased fluid secretion into cysts, possibly mediated by the CFTR, appears to play a role in cyst growth. Fluid accumulation within ADPKD cysts is thought to be driven primarily by 3′,5′-cyclic adenosine monophosphate (cAMP)-dependent chloride secretion. One hypothesis is that chloride transport across the apical membrane occurs via the CFTR. CFTR has the appropriate characteristics since it functions as a cAMP-dependent chloride channel and has been localized to the apical membranes of ADPKD cyst lining cells. Therefore, CFTR has been postulated to contribute to cyst growth.

• #1 ADPKD – How do Cysts form? – Renal Fellow Network

  https://www.renalfellow.org/2019/05/13/adpkd-how-do-cysts-form/

  The C-terminal PC1 also has been demonstrated to interact with tuberin encoded by TSC2. […] The polycystin-tuberin interaction also explains the occurrence of renal cysts in tuberous sclerosis. […] The activity of CFTR channel is upregulated in the setting of elevated intracellular cAMP levels. Cl secretion is accompanied by movement of Na and water into the cyst lumen. […] The diagram below summarises all the known pathways till date.

• #1 Autosomal dominant polycystic kidney disease (ADPKD): Genetics of the disease and mechanisms of cyst growth – UpToDate

  https://www.uptodate.com/contents/autosomal-dominant-polycystic-kidney-disease-adpkd-genetics-of-the-disease-and-mechanisms-of-cyst-growth

  Derangements in cAMP related to decreased intracellular calcium signaling may underlie the development of cysts via increased fluid secretion and cell proliferation. […] Activation of the mTOR protein may contribute to cyst growth in ADPKD. In contrast, inhibition of mTOR with rapamycin (sirolimus) preserved kidney function and inhibited epithelial cell proliferation and fibrosis in a mouse model of ADPKD in which the PKD1 gene was conditionally deleted. […] Abnormalities of kidney cilia function may contribute to kidney cyst formation. The potential causes and consequences of cilia dysfunction in ADPKD remain unclear.

• #1 Cystic Diseases of the Kidney: Practice Essentials, Pathophysiology, Etiology

  https://emedicine.medscape.com/article/453831-overview

  Biochemical analyses have identified a protein (mammalian target of rapamycin [mTOR]) that may be part of a common pathway in several of the genetic forms of cystic disease. Activity of mTOR is related to cell growth, proliferation, apoptosis, and differentiation. Increased levels of mTOR have been found in cyst epithelium. Under normal conditions, PC1 (mutated in ADPKD) and TSC2 (mutated in TS) suppress or inactivate mTOR. Mutations in these genes, as well as in others that relate to the primary cilia, result in dysregulation of mTOR activity, possibly allowing cyst formation. […] One theory suggests that the development of cysts in acquired renal cystic disease (ARCD) is secondary to obstruction of the tubules by fibrosis or oxalate crystals. Another hypothesis invokes the accumulation of growth factors and stimulatory chemicals (uremia), including EGF, which leads to the development of cysts.

• #1

  https://www.frontiersin.org/journals/physiology/articles/10.3389/fphys.2023.1289388/text

  Tuberous Sclerosis Complex (TSC) is an autosomal dominant genetic disease caused by mutations in either TSC1 or TSC2 genes. […] The factors promoting cyst formation and tumor growth in TSC are poorly understood. Recent studies on kidney cysts in various mouse models of TSC, including mice with principal cell-or pericyte-specific inactivation of TSC1 or TSC2, have identified a unique cystogenic mechanism. These studies demonstrate the development of numerous cortical cysts that are predominantly comprised of hyperproliferating A-intercalated (A-IC) cells that express both TSC1 and TSC2. […] An analogous cellular phenotype in cystic epithelium is observed in both humans with TSC and in TSC2 +/-mice, confirming a similar kidney cystogenesis mechanism in TSC. […] RNA sequencing (RNA-Seq) and confirmatory expression studies demonstrate robust expression of Forkhead Box I1 (FOXI1) transcription factor and its downstream targets, including apical H + -ATPase and cytoplasmic carbonic anhydrase 2 (CAII), in the cyst epithelia of Tsc1 (or Tsc2) knockout (KO) mice, but not in Polycystic Kidney Disease (Pkd1) mutant mice.

• #1 Pathogenesis of Cysts and Cystic Kidneys | SpringerLink

  https://link.springer.com/chapter/10.1007/978-94-009-0457-6_5

  Although the formation of fluid-filled renal cysts is a fairly common event that has received attention for more than a century, the mechanisms involved in their development are not well understood. […] It is agreed that renal cysts develop in pre-existing nephrons and collecting ducts, and that they can develop in the absence of distal tubule obstruction, large transmural pressure or solute gradients, abnormally stretchable basement membranes, or permanent connection to their tubule of origin. […] It is decided, however, that there is an absolute requirement for diffuse hyperplasia of the lining epithelium that keeps pace exactly with the enlarging surface area of the cyst cavity. […] At the same time, the cyst cavity is always filled with fluid, and that probably requires the new development of a net secretory mechanism. […] As to the question of which comes first, the cellular proliferation or the accumulation of fluid, the two in fact must occur simultaneously and are perhaps consequences of the same cause.

• #1 Autosomal Dominant Polycystic Kidney Disease – Genetics and Cyst Formation

  https://www.gavinpublishers.com/article/view/autosomal-dominant-polycystic-kidney-disease-genetics-and-cyst-formation

  Autosomal Dominant Polycystic Kidney Disease (ADPKD) is the most common hereditary renal disorder with an incidence rate of 1: 400-1000 individuals. […] There are multiple postulates as to the specifics regarding cyst formation in polycystic kidney disease, second-hit, cAMP and epithelial proliferation. […] The idea of marked hyperplasia of epithelia of nephrons and collecting tubules being responsible for cyst formation, is one such hypothesis. […] A recent study by Grantham, et al suggests that if a 1mm cyst develops and thus grows to 8cm over 20 years. The cell numbers will increase to 118 million, a 102,000-fold increase. […] It suggests that early cysts begin as dilations of tubules, constantly being filled by glomerular filtration. […] Once the cysts grow to a size of 2-3cm, the cysts lose their connection to the functional nephron, and then being filling from secretion of fluid into the cysts.

• #1

  https://insight.jci.org/articles/view/135700

  Metalloproteinase PAPP-A regulation of IGF-1 contributes to polycystic kidney disease pathogenesis. […] Pregnancy-associated plasma protein A (PAPP-A), a metalloproteinase that cleaves inhibitory IGF binding proteins (IGFBPs), increasing the local bioactivity of IGF-1, was highly induced in the kidney of ADPKD mice. […] Our studies further showed that PAPP-A transcription in ADPKD was mainly regulated through the cAMP/CREB/CBP/p300 pathway. […] The role of PAPP-A in cystic disease appears to be regulation of the IGF-1 pathway and cellular proliferation in the kidney. […] These data indicated that the PAPP-A/IGF-1 pathway plays an important role in the growth and expansion of cysts in ADPKD. […] Cystogenesis in ADPKD has been proposed to include 2 phases, cyst initiation and cyst expansion.

• #1 Glucose Absorption May Drive Cyst Formation in Polycystic Kidney Disease in: Kidney News Volume 15 Issue 3 (2023)

  https://www.kidneynews.org/view/journals/kidney-news/15/3/article-p1_2.xml

  Researchers have identified many of the genes that cause autosomal-dominant polycystic kidney disease (ADPKD) and other forms of PKD, which are characterized by fluid-filled cysts that arise from tubules in kidneys and other organs. […] very little is known about the mechanisms underlying cyst formation in affected patients. […] the work, which is published in Nature Communications, points to the importance of aberrant glucose absorption in cyst formation. […] In organoids that had been genetically edited to mimic PKD, the process of cyst swelling involved the absorption of fluid inward through cells from outside the cyst. […] it revealed that absorption also appears to play a critical role. […] increasing the levels of glucose in dish cultures augmented cyst swelling, which was blocked in the presence of the sodium-glucose co-transporter inhibitors phloridzin or dapagliflozin.

• #1 Pathogenesis of renal cyst expansion: opportunities for therapy – PubMed

  https://pubmed.ncbi.nlm.nih.gov/8311077/

  Renal epithelial cysts are caused by hereditary or acquired etiologies of undetermined molecular mechanisms. […] The cysts develop within renal tubules by pathogenetic processes that involve cellular proliferation, accumulation of tubule fluid within distended cavities, and remodelling of extracellular matrix. […] Evidence is accumulating to support the view that renal cysts are composed of moderately dedifferentiated, immature epithelial cells that proliferate abnormally and transport solute and fluid by secretion, in contrast to the usual absorptive movement of liquid in normal renal tubules. […] The formation and expansion of renal cysts occurs in conjunction with alterations in the extracellular matrix, including thickening of the tubule basement membrane, infiltration of the interstitium with mononuclear inflammatory cells, and interstitial fibrosis. […] The pathogenetic elements of cyst formation are understood well enough that it is reasonable, and of considerable importance, to examine in animal models treatment strategies that may be hypothesized to allay the progression of cystic disease to end-stage renal failure.

• #1 Pathophysiology of PKD – CORE Kidney | UCLA Health

  https://www.uclahealth.org/programs/core-kidney/pathophysiology-pkd

  Accordingly, with mutations in PKD1, PKD2, or PKHD1, function of the primary cilium is impaired, resulting in disruption of a number of intracellular signaling cascades that produce dedifferentiation of cystic epithelium, increased cell division, increased apoptosis, and loss of resorptive capacity. […] These signaling pathways have been found to include cAMP-activated, Wnt signaling, and mammalian target of rapamycin (mTOR) pathways, the discoveries of which have greatly expanded the number of potential therapeutic targets for the disease. […] Ultimately, cyst growth and expansion compresses renal vessels and leads to intrarenal ischemia and activation of the renin-angiotensin-aldosterone system (RAAS), in turn producing progressive cyst expansion, increased systemic vascular resistance, sodium retention, and renal fibrosis.

• #1 MECHANISMS OF CYST GROWTH AND FIBROSIS IN CONGENITAL HEPATIC FIBROSIS IN AUTOSOMAL RECESSIVE POLYCYSTIC KIDNEY DISEASE

  https://kuscholarworks.ku.edu/entities/publication/fc6ee485-e34f-4be9-a35b-4aa39733b0ae

  Autosomal recessive polycystic kidney disease (ARPKD) is a rare genetic disorder that occurs in 1:20,000 live births. Patients present with a broad spectrum of symptoms involving the kidneys, liver, and pancreas. Renal manifestations are characterized by the presence of cysts that are derived from dilated collecting ducts. All patients with ARPKD develop some degree of congenital hepatic fibrosis (CHF) at birth. CHF is characterized by bile duct dilation resulting in eventual development of cysts and pericystic fibrosis in the liver. Accompanying cyst growth and fibrosis, recent reports suggest that inflammation is also present, and likely contributes to disease pathogenesis and/or progression. Therefore, three interrelated processes form a ‘pathogenic triumvirate’ in CHF/ARPKD: cell proliferation (cyst growth), fibrosis, and inflammation.

• #1 Simple Kidney Cyst – Kidney Cysts – Nephrology – Diseases – McMaster Textbook of Internal Medicine

  https://empendium.com/mcmtextbook/chapter/B31.II.14.9.1.

  Simple kidney cysts are found in 10% of adults aged 50 years, more commonly in men, with prevalence increasing with age. […] Possible complications of simple kidney cysts include hematuria and infection. […] Polycystic kidney disease should be considered in those with kidney enlargement, multiple cysts, bilateral cysts, and positive family history.

• #1 📃 Kidney, cyst

  https://thefetus.net/content/kidney-cyst/

  The pathogenesis of renal cyst is not entirely known. […] It has been suggested that cyst formation is acquired a result of the aging process. […] Vascular changes associated with age affect blood flow to the kidneys. This decreased blood flow causes areas of ischemia or infarct and obstruction of the renal tubules which leads to cyst formation. […] Another theory suggests that cysts are developmental in origin. During renal organogenesis, the second to fourth generations of uriniferous tubules do not coalesce or unite with later generations of collecting tubules, resulting in cyst formation. […] Other possible causes of cyst formation in children and adults are liquefied hematomas, sterilized abscess, or calyceal diverticula that have lost their communication with the renal pelvis.

• #1 Kidney cysts – Symptoms and causes – Mayo Clinic

  https://www.mayoclinic.org/diseases-conditions/kidney-cysts/symptoms-causes/syc-20374134

  A kidney cyst is a round or oval fluid-filled pouch with a well-defined outline. Kidney cysts typically grow on the surface of a kidney. Some may develop inside the kidney. […] It’s not clear what causes simple kidney cysts. One theory suggests that kidney cysts develop when the surface layer of the kidney weakens and forms a pouch. The pouch then fills with fluid, detaches and develops into a cyst.

• #1

  https://link.springer.com/article/10.1007/BF00256861

  The simple cyst in the adult seems to be mainly an acquired disorder. Microdissection of the nephron in the adult kidney points to the presence of diverticula on the distal tubule as the starting point of the affection. A degree of obstruction in the urinary tract together with normal involutional phenomena of the basal membrane, both typical of the aging process, are believed to be precipitating factors.

• #1 Acquired cystic kidney disease | Radiology Reference Article | Radiopaedia.org

  https://radiopaedia.org/articles/acquired-cystic-kidney-disease-1?lang=us

  Acquired cystic kidney disease (ACKD) is a condition that occurs in patients with end-stage renal disease (ESRD), especially when on dialysis treatment. They do not have a history of other cystic renal disease. […] Although uremia is associated with an eventual development of acquired cystic kidney disease, the pathogenesis is unknown. Some theories suggest that tubular epithelial hyperplasia from accumulation of growth factors, such as epidermal growth factor may play a role. […] The hyperplastic renal cysts in acquired cystic kidney disease have been considered a possible source of dialysis-associated renal cell carcinoma.

• #1 Acquired Cystic Kidney Disease: Practice Essentials, Pathophysiology, Etiology

  https://emedicine.medscape.com/article/246888-overview

  Ischemia: Kidney atrophy is a recognized consequence of ischemia that may be caused either by primary renal arterial occlusion or by the secondary arterial occlusions that develop after dialysis is begun. Parenchymal acidosis may result from chronic progressive occlusion and, if sustained just short of causing cell death, might result in renal cyst formation. […] Research into the cystic fluid and epithelium suggests that the cysts arise from proliferation of renal tubules. […] Progressive destruction of the renal parenchyma triggers several mitogenic signals (eg, azotemic products, altered concentration of sodium and potassium, activation of the renin-angiotensin-system, inflammation, local growth factors), ultimately leading to hypertrophy and hyperplasia of renal tubules. […] In addition, restricted tubular fluid flow and net fluid secretion contribute to cyst formation. […] Over a period of time, the activation of proto-oncogenes combined with additional risk factors may result in malignant transformation.

• #1 Mechanism of cystogenesis in nephrotic kidneys: a histopathological study | BMC Nephrology | Full Text

  https://bmcnephrol.biomedcentral.com/articles/10.1186/1471-2369-15-3

  Our ultrastructural and immunohistochemical analysis of CNF and FSGS kidneys disclosed that cystogenesis in proximal tubules was associated with increased cell proliferation, apoptosis and changes of primary cilia on the surfaces of tubular cells. […] Both in CNF and FSGS kidneys, deregulations of cell turnover were accompanied by apoptosis of tubular and mesenchymal cells, as also described in human kidney malformations associated with urinary tract obstruction. […] We suggest that described alteration of primary cilia number, structure or orientation might diminish the overall quality and quantity of tubular cells signaling, leading to compensatory growth of cilia in distal/collecting tubules segments in effort to increase signaling and preserve function of the damaged nephron. […] In conclusions, our study on CNF and FSGS tubular cells during cystogenesis revealed serious disturbances of cells proliferation, apoptosis and primary cilia formation, implying existence of general principle of kidney cystogenesis, independently of its cause. We suggest that cystogenesis in nephrotic kidneys starts with increased proliferation and apoptosis leading to disturbed lumen formation and damage of primary cilia.

• #1

  https://journals.lww.com/10.1681/ASN.2024bmq1pz35

  Studies have reported an elevated prevalence of renal cysts in patients with primary aldosteronism. A proposed mechanism is that chronic hypokalemia results in renal tubular cell injury and cyst expansion. […] Our case highlights the role of hyperaldosteronism on the development of renal cysts. Especially unique here is the absence of hypokalemia, suggesting an alternative mechanism by which aldosterone influences renal cyst formation and growth. […] While prior studies have postulated that chronic hypokalemia leads to cyst formation and growth, our patient’s hyperaldosteronism was without hypokalemia. One should consider alternative mechanisms, such as aldosterone inducing signaling cascades that enhance cell multiplication and modify ion transport activities in renal cells. Along with broadening the differential for cystic kidney disease to include CACNA1H mutation, further research is needed to determine mechanistic pathways by which aldosterone influences cyst growth.

• #1 A new drug candidate can shrink kidney cysts | MIT News | Massachusetts Institute of Technology

  https://news.mit.edu/2024/new-drug-candidate-can-shrink-kidney-cysts-0122

  Researchers at MIT and Yale University School of Medicine have now found that a compound originally developed as a potential cancer treatment holds promise for treating ADPKD. […] The drug works by exploiting kidney cyst cells vulnerability to oxidative stress a state of imbalance between damaging free radicals and beneficial antioxidants. […] The 11beta compounds work by disrupting the mitochondrias ability to generate ATP (the molecules that cells use to store energy), as well as a cofactor known as NADPH, which can act as an antioxidant to help cells neutralize damaging free radicals. […] A little bit of oxidative stress is OK, but the cystic cells have a low threshold for tolerating it. […] Using two different mouse models of ADPKD, the researchers showed that 11beta-dichloro could significantly reduce the size of kidney cysts and improve kidney function.

• #1 Novartis Drops up to $1.7B to Bolster Oligo Pipeline With Regulus Buy – BioSpace

  https://www.biospace.com/business/novartis-drops-up-to-1-7b-to-bolster-oligo-pipeline-with-regulus-buy

  The disease is caused by mutations in the Pkd1 or Pkd2 gene, leading to the accumulation of fluid-filled cysts in and across the kidneys and worsening kidney function over time. […] According to Regulus, Pkd1 or Pkd2 mutations are tied to the upregulation of miR-17, a microRNA molecule that directly leads to suppression of certain genes, ultimately dampening the production of the proteins encoded by those genes, polycystin 1 (PC1) and 2 (PC2). […] Farabursen binds to miR-17 to disrupt this pathway to correct the underlying pathology of ADPKD, according to Regulus. Through this mechanism of action, farabursen can restore PC1 and PC2 levels, in turn reducing the growth of cysts.

• #2 Simple and complex kidney cysts in adults – UpToDate

  https://www.uptodate.com/contents/simple-and-complex-kidney-cysts-in-adults/print

  Kidney cysts result from genetic or nongenetic processes and occur in a variety of diseases in adults and children. […] Other unusual causes of kidney cysts in adults are von Hippel-Lindau disease, tuberous sclerosis complex, Fabry disease, and nephronophthisis. […] Kidney cysts are categorized as simple or complex. Simple kidney cysts are commonly observed in normal kidneys, with an increasing incidence as individuals age. They are benign, asymptomatic lesions that rarely require treatment. By contrast, complex cysts may require follow-up imaging, biopsy, or surgical excision for diagnosis and management.

• #2 Mechanisms of Cyst Development in PKD

  https://pmc.ncbi.nlm.nih.gov/articles/PMC10289784/

  The two-hit model indicates that cyst initiation results from loss of PKD1 or PKD2 function. […] The overarching conclusion is that ADPKD results from a decrease in PKD gene activity below some threshold which is otherwise necessary to suppress cyst growth. […] The evidence to date suggests that PKD is a complex disease, involving both cell autonomous pathways driving cyst initiation, and an interplay with the tissue metabolic and immune milieu that modulate cystic growth.

• #2 Polycystic kidney disease – Wikipedia

  https://en.wikipedia.org/wiki/Polycystic_kidney_disease

  The disease is characterized by a 'second hit’ phenomenon, in which a mutated dominant allele is inherited from a parent, with cyst formation occurring only after the normal, wild-type gene sustains a subsequent second genetic 'hit’, resulting in renal tubular cyst formation and disease progression. […] PKD results from defects in the primary cilium, an immotile, hair-like cellular organelle present on the surface of most cells in the body, anchored in the cell body by the basal body. In the kidney, primary cilia have been found to be present on most cells of the nephron, projecting from the apical surface of the renal epithelium into the tubule lumen. The cilia were believed to bend in the urine flow, leading to changes in signalling, however this has since been shown to be an experimental error and that bending of cilia does not contribute to alterations in Ca flux. While it is not known how defects in the primary cilium lead to cyst development, it is thought to possibly be related to disruption of one of the many signaling pathways regulated by the primary cilium, including intracellular calcium, Wnt/-catenin, cyclic adenosine monophosphate (cAMP), or planar cell polarity (PCP). Function of the primary cilium is impaired, resulting in disruption of a number of intracellular signaling cascades which produce differentiation of cystic epithelium, increased cell division, increased apoptosis, and loss of resorptive capacity.

• #2 Mechanism of cystogenesis by Cd79a-driven, conditional mTOR activation in developing mouse nephrons | Scientific Reports

  https://www.nature.com/articles/s41598-023-27766-2

  Polycystic kidney disease (PKD) is a common genetic disorder arising from developmental and postnatal processes. Defects in primary cilia and their signaling (eg, mTOR) underlie the pathogenesis. […] To understand the role of mTOR in early cystogenesis, we studied an in-house mouse model, Cd79a-Cre;Tsc1ff. (Cd79a-Tsc1 KO hereafter), recapitulating human autosomal-dominant PKD histology. […] Our results indicate that mTORC1 overactivation in developing distal tubules impairs their postnatal narrowing by disrupting morphogenesis, which orients an actively proliferating cell toward the elongating axis. The interplay between mTOR and cilium signaling, which coordinate cell proliferation with PCP, may be essential for cystogenesis. […] Given that cyst formation early in life significantly contributes to cystic burden in adulthood, understanding initial cystogenesis events can have profound therapeutic benefits.

• #2 ADPKD – How do Cysts form? – Renal Fellow Network

  https://www.renalfellow.org/2019/05/13/adpkd-how-do-cysts-form/

  Though the exact mechanism leading to increased cAMP levels is unknown, it has been attributed to increased levels of circulating vasopressin. […] While the cysts can arise from all nephron segments in ADPKD (including the glomerulus), microdissection studies done by O.Heggo revealed that the cysts derived from collecting ducts tend to be more numerous and larger. […] The complex of polycystin-1 and polycystin-2 acts either as a mechanosensor or a chemosensor which normally translates the extracellular signals into intracellular increase in calcium. […] In ADPKD, as a result of the mutation in the genes encoding the aforementioned proteins, intracellular calcium levels are decreased. […] A defective PC1 or PC2 function, therefore, may hinder this process leading to uninhibited cell multiplication.

• #2 Pathophysiology of PKD – CORE Kidney | UCLA Health

  https://www.uclahealth.org/programs/core-kidney/pathophysiology-pkd

  Accordingly, with mutations in PKD1, PKD2, or PKHD1, function of the primary cilium is impaired, resulting in disruption of a number of intracellular signaling cascades that produce dedifferentiation of cystic epithelium, increased cell division, increased apoptosis, and loss of resorptive capacity. […] These signaling pathways have been found to include cAMP-activated, Wnt signaling, and mammalian target of rapamycin (mTOR) pathways, the discoveries of which have greatly expanded the number of potential therapeutic targets for the disease. […] Ultimately, cyst growth and expansion compresses renal vessels and leads to intrarenal ischemia and activation of the renin-angiotensin-aldosterone system (RAAS), in turn producing progressive cyst expansion, increased systemic vascular resistance, sodium retention, and renal fibrosis.

• #2 ADPKD – How do Cysts form? – Renal Fellow Network

  https://www.renalfellow.org/2019/05/13/adpkd-how-do-cysts-form/

  Autosomal dominant polycystic kidney disease (ADPKD) is one of the most common genetic kidney disorders with a reported incidence ranging from 1:500 to 1:1000. […] Even though the disorder is inherited in an autosomal dominant manner, it is to be emphasized that a single mutated gene may not be sufficient for cystogenesis. Rather, the cellular defect is most likely recessive because it is not without a second hit that the tubules produce a cyst. Additionally, though all the tubular cells carry at least one allele of the gene mutation, only a few of them develop cysts (about 1-3%). […] For the formation of a cyst, the intracellular pathways need to converge and promote two processes epithelial proliferation and fluid secretion. In ADPKD, the common link is cyclic adenosine monophosphate (cAMP).

• #2 Autosomal dominant polycystic kidney disease (ADPKD): Genetics of the disease and mechanisms of cyst growth – UpToDate

  https://www.uptodate.com/contents/autosomal-dominant-polycystic-kidney-disease-adpkd-genetics-of-the-disease-and-mechanisms-of-cyst-growth

  The above findings, along with reports of cystic disease in patients with homozygous hypomorphic (reduced level of activity) PKD1 mutations or with a heterozygous hypomorphic PKD1 mutation associated with a second inactivating PKD1 mutation, suggest a „threshold mechanism of cystogenesis” model of disease. As an example, a dose of functional polycystin that falls below a critical threshold (approximately 10 to 30 percent of normal) within a tubular epithelial cell may be sufficient to initiate cyst formation. It has been proposed that falling below this threshold leads to abnormal fluid secretion, dysregulated cell proliferation, and apoptosis, which promote cyst growth via multiple signaling pathways. […] Increased fluid secretion into cysts, possibly mediated by the CFTR, appears to play a role in cyst growth. Fluid accumulation within ADPKD cysts is thought to be driven primarily by 3′,5′-cyclic adenosine monophosphate (cAMP)-dependent chloride secretion. One hypothesis is that chloride transport across the apical membrane occurs via the CFTR. CFTR has the appropriate characteristics since it functions as a cAMP-dependent chloride channel and has been localized to the apical membranes of ADPKD cyst lining cells. Therefore, CFTR has been postulated to contribute to cyst growth.

• #2 Mechanism of renal cyst formation in a child with tuberous sclerosis complex: a case report | Egyptian Pediatric Association Gazette | Full Text

  https://epag.springeropen.com/articles/10.1186/s43054-024-00310-1

  Tuberous sclerosis complex (TSC) is a multisystem genetic disorder characterized by the development of benign tumors in various organs, including the brain, kidneys, heart, lungs, skin, and eyes. Herein, an infant who was followed up with a diagnosis of TSC and multiple cysts which were found in the kidneys was presented, and the mechanism of renal cyst formation in TSC was elucidated. […] TSC is caused by mutations in either the TSC1 gene (encoding hamartin) or the TSC2 gene (encoding tuberin), leading to dysregulation of the mammalian target of rapamycin (mTOR) signaling pathway. The resulting abnormal cell growth and proliferation underlie the diverse clinical manifestations of the disease. […] The dysregulation of common signaling pathways, such as the mTOR pathway, could contribute to the development and progression of renal cysts. Therefore, kidney cysts are seen in 30-50% of TSC patients.

• #2

  https://www.frontiersin.org/journals/physiology/articles/10.3389/fphys.2023.1289388/text

  Deletion of FOXI1, which is vital to H + -ATPase expression and intercalated (IC) cell viability, completely inhibited mTORC1 activation and abrogated the cyst burden in the kidneys of Tsc1 KO mice. These results unequivocally demonstrate the critical role that FOXI1 and A-IC cells, along with H + -ATPase, play in TSC kidney cystogenesis.

• #2 Mechanism of cystogenesis by Cd79a-driven, conditional mTOR activation in developing mouse nephrons | Scientific Reports

  https://www.nature.com/articles/s41598-023-27766-2

  Multiple cellular processes have been implicated in the pathogenesis of PKD. Most are cilia-related functions, such as proliferation, apoptosis, and planar cell polarity (PCP). […] Our data support the idea that the mTORC1 pathway plays a predominant role in the cystogenesis of our model. […] Our findings, together with those of others, indicate a possible link of PCP to cilia-dependent signaling and cystogenesis. […] Aberrant mTOR and cilium signaling may converge on a common mechanism triggering cystogenesis: the inability to coordinate proliferation with PCP during the tubule narrowing process.

• #2

  https://insight.jci.org/articles/view/135700

  The subsequent expansion of cysts is a key component of the pathogenesis of ADPKD. […] Several signaling molecules, including cAMP, mTOR, AMPK, and growth factors have been implicated in the pathogenesis of ADPKD. […] Recent findings have revealed that metabolic alterations play a role in ADPKD pathogenesis. […] We thus hypothesized that increased PAPP-A expression may play an active role in the pathogenesis and progression of ADPKD. […] These data suggest that Pappa expression is concomitant with the progression of cystic disease, and may be directly associated with the growth and expansion of the cysts in ADPKD at a threshold that correlates with tissues injury, inflammation, and fibrosis. […] PAPP-A deficiency effectively inhibited the development of cysts in the Pkd1RC/RC mice.

• #2 Glucose Absorption May Drive Cyst Formation in Polycystic Kidney Disease in: Kidney News Volume 15 Issue 3 (2023)

  https://www.kidneynews.org/view/journals/kidney-news/15/3/article-p1_2.xml

  we found that increasing the levels of sugar in the dish cultures caused cysts to swell. […] it is the transport of glucose which drives cystogenesis. […] this work suggests that patients with PKD are also likely to benefit from such drugs. […] verifying the importance of fluid flow in mediating cyst growth and (converse to previous understanding) that cystic cells have an absorptive phenotype.

• #2 MECHANISMS OF CYST GROWTH AND FIBROSIS IN CONGENITAL HEPATIC FIBROSIS IN AUTOSOMAL RECESSIVE POLYCYSTIC KIDNEY DISEASE

  https://kuscholarworks.ku.edu/entities/publication/fc6ee485-e34f-4be9-a35b-4aa39733b0ae

  These data indicate that increased YAP activity, possibly through dysregulation of the Hippo signaling pathway, is associated with hepatic cyst growth in CHF/ARPKD. […] Our study showed an increased HA level in livers from PCK rats and polycystic liver disease patients relative to healthy controls. HA accumulation could be due to an increased Has1 (a HA synthase) expression and decreased expression of HA degrading enzymes. Therefore, we hypothesized that HA plays a pathogenic role in progression of CHF/ARPKD. […] Taken together, CHF/ARPKD is a hepatobiliary disease that is regulated by a ‘pathogenic triumvirate’ (cell proliferation/cyst growth, inflammation, fibrosis). My studies aimed to discover novel mechanisms driving CHF/ARPKD and investigated how MC, and YAP, regulated the ‘pathogenic triumvirate’ in CHF/ARPKD.

• #2 Acquired Cystic Kidney Disease: Practice Essentials, Pathophysiology, Etiology

  https://emedicine.medscape.com/article/246888-overview

  Ischemia: Kidney atrophy is a recognized consequence of ischemia that may be caused either by primary renal arterial occlusion or by the secondary arterial occlusions that develop after dialysis is begun. Parenchymal acidosis may result from chronic progressive occlusion and, if sustained just short of causing cell death, might result in renal cyst formation. […] Research into the cystic fluid and epithelium suggests that the cysts arise from proliferation of renal tubules. […] Progressive destruction of the renal parenchyma triggers several mitogenic signals (eg, azotemic products, altered concentration of sodium and potassium, activation of the renin-angiotensin-system, inflammation, local growth factors), ultimately leading to hypertrophy and hyperplasia of renal tubules. […] In addition, restricted tubular fluid flow and net fluid secretion contribute to cyst formation. […] Over a period of time, the activation of proto-oncogenes combined with additional risk factors may result in malignant transformation.

• #2 Mechanism of cystogenesis in nephrotic kidneys: a histopathological study | BMC Nephrology | Full Text

  https://bmcnephrol.biomedcentral.com/articles/10.1186/1471-2369-15-3

  Our ultrastructural and immunohistochemical analysis of CNF and FSGS kidneys disclosed that cystogenesis in proximal tubules was associated with increased cell proliferation, apoptosis and changes of primary cilia on the surfaces of tubular cells. […] Both in CNF and FSGS kidneys, deregulations of cell turnover were accompanied by apoptosis of tubular and mesenchymal cells, as also described in human kidney malformations associated with urinary tract obstruction. […] We suggest that described alteration of primary cilia number, structure or orientation might diminish the overall quality and quantity of tubular cells signaling, leading to compensatory growth of cilia in distal/collecting tubules segments in effort to increase signaling and preserve function of the damaged nephron. […] In conclusions, our study on CNF and FSGS tubular cells during cystogenesis revealed serious disturbances of cells proliferation, apoptosis and primary cilia formation, implying existence of general principle of kidney cystogenesis, independently of its cause. We suggest that cystogenesis in nephrotic kidneys starts with increased proliferation and apoptosis leading to disturbed lumen formation and damage of primary cilia.

• #2 A new drug candidate can shrink kidney cysts – MIT Department of Chemistry

  https://chemistry.mit.edu/chemistry-news/a-new-drug-candidate-can-shrink-kidney-cysts/

  A compound originally developed to treat cancer could be repurposed to treat polycystic kidney disease, an inherited condition that can lead to kidney failure. […] The drug works by exploiting kidney cyst cells vulnerability to oxidative stress a state of imbalance between damaging free radicals and beneficial antioxidants. […] In a study employing two mouse models of the disease, the researchers found that the drug dramatically shrank kidney cysts without harming healthy kidney cells. […] The 11beta compounds work by disrupting the mitochondrias ability to generate ATP (the molecules that cells use to store energy), as well as a cofactor known as NADPH, which can act as an antioxidant to help cells neutralize damaging free radicals. […] Tumor cells and kidney cyst cells tend to produce increased levels of free radicals because of the oxidative stress theyre under.

• #3 Kidney Research and Clinical Practice

  https://www.krcp-ksn.org/journal/Figure.php?xn=KRCP-033-02-73.xml&id=

  It has been reported that abnormalities in the structure or function of primary cilia result in kidney cyst growth in animal models and human genetic diseases collectively known as ciliopathies. […] Functional defects in this complex caused by mutation of PKD1 or PKD2 result in autosomal dominant polycystic kidney disease (ADPKD). […] A two-hit model has been proposed to explain the focal nature of renal cysts and the variability in cyst size in both orthologous mouse models and in humans. […] The presence of somatic PKD2 mutations detected in cystic patients with PKD1 germline mutations and increased disease severity in patients with heterozygous germline mutation in both PKD1 and PKD2 offer further support for the two-hit model and the dosage effect hypothesis for cyst formation. […] Disruption of primary cilia or mutations in cilia-associated proteins leads to renal epithelial proliferation and cyst growth in animal models and many human genetic diseases that are classified as ciliopathies.

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