ADPKD is the most prevalent hereditary kidney disease and the fourth most common cause of end-stage kidney failure (ESKF). This genetic disorder is characterized by the development of multiple kidney cysts, leading to kidney enlargement and structural and functional alterations that progress to ESKF in most patients. ^, ADPKD history dates back over 300 years. Fig. 45.2 represents the major milestones in ADPKD history. Both sexes and all racial and ethnic backgrounds are susceptible to this condition. Epidemiologic studies estimate the prevalence of ADPKD to range from 1 in 400 to 1 in 1000 live births with annual incidence of 2.75 per 100,000 per-years, affecting up to 12.5 million people globally. ^{, ,} Data from clinical registries suggest slightly lower prevalence rates due to varying factors such as geographic distribution, population size, epidemiologic measurement methods, and health care system characteristics ( Table 45.3 ), ^, which could explain the variability in prevalence.

Timeline of the major historical milestones and trials related to autosomal dominant polycystic kidney disease.

Prevalence rates for ADPKD have been estimated through worldwide population-based studies with specific studies reporting rates of 1 in 2459 in the United Kingdom, 1 in 1111 in France, and 1 in 542 for the Seychelles. In Copenhagen, during the period 1920–1953, the incidence was recorded at 0.8 cases per 100,000 patient-years. In the United States, ADPKD incidence is observed to be higher in males than in females, with rates of 8.2 versus 6.8 cases per million, respectively. ADPKD is the cause of ESKF in about 5% of individuals who need kidney replacement therapy (KRT) each year in the United States, constituting 5% to 10% of all ESKF patients. In most patients with ADPKD, kidney function remains relatively intact in the first 3 decades of life, after which the glomerular filtration rate (GFR) progressively declines, leading to ESKF. Patients reach ESKF at various ages depending on disease severity with approximately 50% of them reaching ESKF by age 62. A French study found that 22% of patients with ADPKD reached ESKF by the age of 50, rising to 42% by the age of 58, and to a substantial 72% by the age of 73. ^, Lately, there has been a shift toward later-onset ESKF, potentially due to reduced cardiovascular mortality among older patients before reaching ESKF. ^,

ADPKD is an autosomal dominant disorder. Most PKD1 and PKD2 disease-causing gene variants have complete penetrance and almost equal sex distribution. Within the same family, affected members may show varying degrees of severity, which may reflect the influence of environmental factors, epigenetic factors, or modifying genes on disease manifestation. ^, ADPKD is mainly caused by pathogenic variants in one of two genes: PKD1, on chromosome 16, encodes polycystin-1 (PC1) and is responsible for approximately 78% of ADPKD cases, while 15% are attributed to PKD2, located on chromosome 4 and encoding polycystin-2 (PC2). Around 7% of genetic testing remains inconclusive and may account for rarer new pathogenic variants in few genes, namely IFT140, DNAJB11, GANAB, ALG5, ALG8, and ALG9, among others. ^, Some cohorts are showing a lesser percentage of PKD1 and PKD2 variants and an increased percentage of the newly discovered variants. ^, PC1 is a complex multidomain membrane protein, resembling a G-protein-coupled receptor (GPCR) ( Fig. 45.3 ). It regulates protein-protein, cell-cell, and cell-matrix interactions and participates in intracellular signaling pathways governing cell proliferation and survival. It is localized at critical sites of cyst formation including renal tubular epithelia, hepatic bile ductules, endothelial cells, and pancreatic ducts. PC2 is a member of the transient receptor potential (TRP) family of calcium-regulated cation channels. It is found in the distal tubules, collecting ducts, and thick ascending limb and is involved in cell calcium signaling. ^, PC1 and PC2 are on nonmotile primary cilia, which receive and relay external signals into the cell. Ample evidence underscores their role in inhibiting cystogenesis, with cyst formation occurring when polycystin levels dip below a certain threshold. The interaction between these two polycystins proves to be crucial for PC1 maturation, its trafficking to the primary cilia, and ultimately its stability. ^,

Structure of polycystin proteins.

Polycystin 1 (PC1) and polycystin 2 (PC2) form the polycystin complex.

Lanktree and colleagues conducted a study in which they examined the frequency of pathogenic variants in large, public whole-genome sequencing (WGS) and whole-exome sequencing (WES) databases. They found the lifetime genetic prevalence of ADPKD to be 9.3 per 10,000. This indicates that the true prevalence of ADPKD is often underestimated as large studies miss asymptomatic cases or variants that do not necessarily end up with a significant disease course. Pathogenic variants in PKD1 were detected in 6.8/10,000 individuals while those in PKD2 were found in 2.6/10,000. This results in a PKD1 to PKD2 ratio of 2.6. In another study by Chang and colleagues examining WES of the Geisinger population in the United States, it was found that the loss-of-function variants in PKD1 and PKD2 were predominantly associated with ADPKD, with rare variants found in other genes including IFT140, GANAB, PKHD1, HNF1B, ALG8, and ALG9. To note, the estimated prevalence of ADPKD based on genotype (8.64/1000) was higher than the estimated prevalence based on phenotype (1.35–1.74/1000). Table 45.4 and Fig. 45.4 show the differences between the ADPKD pathogenic variants.

Representative abdominal images of patients with autosomal dominant polycystic kidney disease seen on the large disease spectrum.

GFR, Glomerular filtration rate; Ht, height; MIC, Mayo Imaging Classification; NT1, nontruncating tier 1; NT2, nontruncating tier 2; T, truncating; TKV, total kidney volume.

One of the standout features of ADPKD is the remarkable phenotypic variability among individuals. This is due to the affected locus ( PKD1 vs. PKD2 ); nature of the allelic variant (truncating, nontruncating, or hypomorphic); timing of gene inactivation; presence of mosaicism; and an individual’s unique genetic background. The ADPKD pathogenic variant is the primary determinant governing the progression rate in each patient. When compared with individuals with PKD1 variants, those with PKD2 variants tend to develop fewer cysts and experience a more gradual progression. The median onset age of ESKF is around 54 and 74 years for PKD1 and PKD2 , respectively. ^, In a rare but more severe presentation, <2% of patients exhibit deletions in both the PKD1 gene and the tuberous sclerosis complex-2 ( TSC2 ) gene, which gives rise to a more severe form of cystic kidney disease, the TSC2/PKD1 contiguous gene syndrome, that typically manifests in childhood. Protein-truncating variants of PKD1 and PKD2 exhibit 100% disease penetrance while missense variants have variable manifestations and incomplete penetrance. Truncating variants in PKD1 generally yield a more severe disease phenotype compared with nontruncating missense variants. Inheriting two inactivating variants in either PKD1 or PKD2 results in different outcomes. When such variants are present in both alleles, it leads to lethality in utero. Family history can help predict whether a PKD1 or PKD2 variant is likely. The presence of at least one family member who developed ESKF before the age of 55 years strongly favors a PKD1 variant, with a PPV of 100% and a sensitivity of 72%. Conversely, if a family member reaches 70 years of age without experiencing ESKF, it is suggestive of a PKD2 variant, with a PPV of 100% and a sensitivity of 74%. ^{, ,}

Despite the germline defect being present in all cells, cysts form in less than 5% of tubules, with focal cystic dilation within each tubule. These observations, coupled with the discovery of somatic PKD1 or PKD2 mutations in kidney and liver cysts of patients with ADPKD, have led to the hypothesis of a recessive cellular mechanism for cystogenesis with inactivation of both copies of either PKD1 or PKD2 within a cell necessary for cyst formation. There is considerable clinical overlap between ADPKD and autosomal dominant polycystic liver disease (ADPLD) caused by genes, such as SEC63 and PRKCSH . PC1 localization in the primary cilia is influenced by disruptions in the endoplasmic reticulum (ER) endogenous proteins or the N-glycosylation process. Proper coordination of those events involves a wide array of genes, namely GANAB , PRKCSH , ALG8, and PMM2 for N-linked glycosylation, as well as SEC63 , SEC61A1, and SEC61B for ER translocation. ^{, ,} Genes such as SEC63, PRKCSH, GANAB, ALG5, ALG8, ALG9, and SEC61B, which encode ER proteins, play a crucial role in the maturation of PC1 to its functional site on the primary cilium’s surface membrane ( Fig. 45.5 ). However, the ADPKD genotype does not necessarily predict the growth rate or severity of polycystic liver disease (PLD) ; therefore modifiers and estrogen might affect the phenotype. Somatic mosaicism is another process implicated in ADPKD development when no overt variants are identified. Somatic mosaicism involves the presence of two distinct genetic cell populations within a single individual, stemming from a somatic variant that occurs during embryonic development. The clinical diversity seen in somatic mosaicism is tied to the type of cell affected and the specific stage of development at which the variant arises. The presence of atypical kidney imaging patterns (such as asymmetry, unilaterality, and lopsided pattern) in a patient with de novo PKD should raise suspicion of possible somatic mosaicism. ^, Deep intronic variants in PKD1 and PKD2 contribute significantly to the diagnostic challenge in ADPKD, accounting for approximately 7% of cases where standard genetic testing fails to yield a diagnosis. ^, These variants, often affecting gene splicing, necessitate more comprehensive sequencing approaches that include both protein-coding and noncoding regions. One common PKD1 deep intronic variant, rs3874648G>A, plays a crucial role in altering gene expression by influencing splicing patterns. This variant disrupts normal splicing by activating a cryptic splicing site, ultimately leading to a reduction in full-length PKD1 mRNA levels. Specifically, the variant affects the binding affinity of a splicing regulator, Tra2-β, thereby affecting PKD1 expression.

Maturation process in the tubular epithelium.

The maturation process of ADPKD-associated proteins, primarily polycystin 1 (PC1) and polycystin 2 (PC2), from gene expression to functional integration within the primary cilium. Initiated within the nucleus, genes encoding PC1 and PC2 undergo transcription, producing mRNA transcripts. Subsequently, these transcripts are transported to the endoplasmic reticulum (ER), where translation takes place, leading to the synthesis of PC1 and PC2 proteins. Crucial proteins in this maturation cascade, including SEC61 and SEC63 (involved in ER translocation) and DNAJB11, ALG8, GANAB, PMM2, and PRKCSH (involved in N-linked glycosylation), play important roles in guiding proper folding, post-translational modifications, and trafficking of PC1 and PC2. Notably, DNAJB11 emerges as a key facilitator in ensuring the maturation and correct trafficking of PKD1 . Additionally, the figure underscores the significance of various proteins in the accurate placement of PC1 and PC2 within the ciliary structure, where their functional roles are realized.

Achieving a definitive genetic diagnosis of ADPKD is needed to inform clinical care and facilitate cascade testing within affected families. However, the classification of variants of uncertain significance (VUS) remains a challenge, particularly in cases where variants are unique to individual families. Despite these challenges, expanding diagnostic approaches to include analysis of noncoding regions and advanced sequencing methodologies offer promising avenues for improving diagnostic rates in ADPKD. ^, For further discussion on genetics in kidney diseases, see Chapter 44 .

During the past few years, there have been significant advancements in our understanding of the pathogenesis of ADPKD. However, the precise roles of polycystins and the molecular mechanisms governing the development of the disease remain areas of ongoing investigation. Polycystins are believed to play a crucial role in regulating intracellular calcium signaling. Initially, it was thought that the polycystin complex localized in the primary cilium transduced shear stress generated by extracellular fluid flow into a cellular calcium signal. However, subsequent studies have indicated that while polycystin proteins can induce localized changes in ciliary calcium concentration, they do not substantially alter global cytoplasmic calcium levels. Polycystin proteins are also functional at other subcellular locations as PC1 may repress signaling pathways that regulate the interaction between the extracellular matrix and integrins. ^{, , ,} The precise mechanism underlying cystogenesis remains unclear. In the early stages, cysts originate as dilatations within intact tubules. However, as cysts grow by the secretion of fluid into the cysts, accompanied by hyperplasia of the cyst epithelium, they lose their connection to functional nephrons. Cystogenesis occurs when functional polycystin levels drop below a certain threshold level, rather than requiring complete loss of function. ^{, , ,}

Variants in PKD1 or PKD2 lead to reduced intracellular calcium levels, resulting in increased cAMP, and activation of protein kinase A (PKA). The pathogenesis of ADPKD is critically influenced by cyclic AMP (cAMP), which drives cyst initiation and expansion by stimulating cystic epithelial cell proliferation, fluid secretion, and downstream signaling pathways that impair tubulogenesis, promote interstitial inflammation, and enhance collecting duct principal cell sensitivity to AVP ( Fig. 45.6 ). In fact, vasopressin V2 receptor antagonists were shown to increase intracellular calcium and decrease cystogenesis. ^, One prominent hypothesis suggests that decreased calcium in PKD affects both the synthesis and hydrolysis of cAMP. Synthesis is enhanced through the activation of calcium-inhibitable Adenylyl cyclase 6 (AC6), while cAMP hydrolysis is diminished due to the inhibition of calcium-calmodulin-dependent phosphodiesterase 1 (PDE1). ^, PDE3 might also play a role in regulating cAMP signaling, as it is localized in the ER membrane and degrades pools of cAMP that control cell proliferation and chloride secretion mediated by the CFTR transporter. Consequently, abnormal epithelial chloride secretion occurs via the cAMP-dependent transporter encoded by the CFTR gene, significantly contributing to the generation and maintenance of fluid-filled cysts in ADPKD. The upregulation of PKA is crucial in CFTR-mediated chloride-driven fluid secretion. The calcium-dependent chloride channel anoctamin-1 (ANO1), also known as TMEM16A, which is notably present in ADPKD kidneys, is also implicated in fluid secretion into cysts as inhibiting this channel halts cystogenesis. The activation of PKA could result in a maladaptive response or “self-perpetuation of disruption” that further disrupts calcium signaling. With the progression of PKD, the molecular alterations in the kidneys increasingly result from secondary events that disrupt the network of signaling pathways. This sustained disruptive response eventually leads to IP3R and PC2 hyperphosphorylation, depletion of calcium stores, and the expression of the PKD phenotype. ^, Decreased Ca ²⁺ entry, increased cAMP levels, and the irregular activation of RAS–RAF–ERK pathways within renal epithelial cells contribute to cyst growth. This process is amplified by enhanced signaling from growth factors. For example, the higher levels of the epidermal growth factor receptor and its mislocalization on the apical surface of cystic epithelial cells, coupled with the existence of ligands such as epidermal growth factor and transforming growth factor–α (TGF-α) in cystic fluid, are possible drivers of tubular epithelial cell proliferation. ^,

Hypothetical pathways upregulated (green) or downregulated (red) in PKD and possible treatment targets.

The molecular cascade driving the progression of autosomal dominant polycystic kidney disease (ADPKD). Initiated by PKD variants, aberrant crosstalk between calcium (Ca) and cyclic AMP (cAMP) signaling pathways disrupts cellular homeostasis. This disruption enhances cAMP and protein kinase A (PKA) signaling through the activation of Ca-inhibitable adenylyl cyclases and inhibition of calcium-dependent phosphodiesterase 9. The ensuing PKA-induced effects include the perturbation of intracellular calcium balance, phosphorylation of endoplasmic reticulum calcium cycling proteins, and the activation of CFTR, leading to Cl and water secretion, thus enhancing fluid secretion. PKA activation exhibits contrasting effects on cell proliferation in wild-type and PKD cells. Calcium modulation, through deprivation or delivery, reverses these effects, proposing a mechanism involving PI3K inhibition and the regulation of transcription factors governing cell progression and energy metabolism. Disease progression in ADPKD is further fueled by factors such as mislocalized EGFR, overexpressed growth factors, cytokines, chemokines, and their receptors. Abnormal miRNA expression is linked to disease advancement, with miR-17 controlling various target genes in proliferative signaling pathways including PPARA and mTOR and directly repressing PKD1, PKD2, and HNF-1β transcripts, thereby contributing to reduced gene expression and cyst formation. This comprehensive illustration provides insights into the interconnected molecular events shaping the complex pathogenesis of ADPKD. AC6, Adenylate cyclase 6; AMPK, AMP-activated kinase; ATP, adenosine triphosphate; AVP, vasopressin; CaMKK, calcium/calmodulin-dependent protein kinase; CDK, cyclin-dependent kinase; EGF, epidermal growth factor; ERK, extracellular signal-regulated kinase; Gi, inhibitory G protein; Gq, a G-protein subunit; Gs, stimulatory G protein; GSK3β, glycogen synthase kinase 3β; HIF, hypoxia-inducible factor; IGF1, insulin growth factor 1; IP3R, inositol 1,4,5 triphosphate (IP3) receptor; LKB1, liver kinase B1; MEK, mitogen-activated protein kinase kinase; mTOR, mammalian target of rapamycin; PC1, polycystin-1; PC2, polycystin-2; P2R, purinergic 2 receptor; PLC, phospholipase C; Rheb, Ras Homolog enriched in brain; RSK, ribosomal s6 kinase; RYR, ryanodine receptor; Sirt1, sirtuin 1; SOC, store operated channel; STAT3, signal transducer and activator of transcription 3; STIM1, stromal interaction molecule 1; SSTR, somatostatin receptor; TKIs, tyrosine kinase inhibitors; TSC, tuberous sclerosis proteins tuberin (TSC2) and hamartin (TSC1); TZDs, thiazolidinediones; V2R, vasopressin V2 receptor.

Another hypothesis sheds light on the role of decreased PC2-mediated calcium entry, which activates AC5 and/or AC6 while inhibiting PDE4C. This effect is secondary to a dysfunction in ciliary proteins within the A-kinase anchoring protein complex. ^, However, this theory has been challenged as studies have shown that primary cilia are largely impermeant to calcium. Regardless of what is initiating calcium entry, polycystin loss or dysfunction has been consistently linked to disrupted calcium signaling. ^, A final hypothesis related to cAMP signaling involves STIM1 oligomerization and translocation to the membrane due to the depletion of ER calcium stores and subsequently AC6 activation. ^,

The dysregulation of purinergic signaling may also lead to altered cAMP signaling. Under normal conditions, renal tubular epithelial cells exhibit constitutive ATP release and spontaneous calcium variations. This is the result of ligand-gated P2X receptors and G-protein-coupled P2Y receptors that interact with ATP, tightly controlling intracellular calcium levels. In ADPKD cells, there is a significant reduction in flow-sensitive ATP release, disturbing intracellular calcium regulation. This reduction in function may be linked to decreased mRNA levels of the aforementioned receptors. ^, Cyst expansion is accompanied by changes in cellular metabolism including increased glucose consumption and impaired fatty acid oxidation. Anomalous activation of the mammalian (mechanistic) target of rapamycin (mTOR) pathway has been associated with the upregulation of aerobic glycolysis, increase in ATP levels, and further inhibition of 5’-AMP-activated protein kinase. Furthermore, cysts can induce mechanical stress on nearby nephrons, leading to apoptosis of renal epithelial cells and local cyst formation. ^{, ,}

Downstream factors also play a role. The Wnt-β-Catenin pathway becomes activated downstream of PKA and may be intensified in ADPKD due to the inhibition of glycogen synthase kinase-3β and stabilization of β-catenin. This leads to the phosphorylation of PKA. Consequently, the upregulated PKA enhances the production of several transcription factors including cAMP-response element-binding protein, paired box protein Pax-2, and STAT3. ^, Both innate and adaptive immunity have been implicated in the pathogenesis of ADPKD. Monocyte chemoattractant protein 1 (MCP1), also known as CCL2, accumulates in cystic kidneys promoting cyst growth.

On the macroscopic level, ADPKD is characterized by a gradual enlargement of kidney cysts. In early stages, the kidney typically contains relatively few cysts, and most of the parenchyma remains intact. ^, The cyst epithelium secretes a significant quantity of chemokines and cytokines, which in turn trigger an inflammatory response in the surrounding tissue. In advanced stages, marked kidney enlargement is evident, accompanied by notable vascular remodeling and interstitial fibrosis. Cystic epithelial cells are characterized by increased proliferation, abnormal fluid secretion, and excessive deposition of extracellular matrix. These alterations are closely linked to changes in the blood and lymphatic microvasculature around the cysts. Most cysts are eventually independent of the originating nephron. The expansion of these cysts also exerts pressure on nearby tissue and vasculature. Obstructed nephrons progress toward forming atubular glomeruli, and proximal tubule cells undergo apoptosis. ^{, ,}

ADPKD is diagnosed clinically when both kidneys are enlarged and uniformly distributed cysts are noted on imaging. An individual’s medical history, clinical presentation, physical examination, and, in some cases, genetic studies can provide valuable insights. Additional factors that complement imaging studies include a family history of the disease, the age of presentation, and the number of kidney cysts. Therefore ADPKD should be considered in patients with a relevant medical history, such as a history of hypertension, multiorgan involvement, recurrent urinary infections, gross hematuria, kidney stones, or a family history of ADPKD or kidney failure. Physical examination findings may include palpation of masses in the upper to midabdomen or elevated blood pressure (BP). Extrarenal manifestations such as a mitral valve prolapse, murmur on auscultation, or evidence of hepatomegaly can also raise suspicion for ADPKD. Laboratory tests, primarily involving a renal profile, and urinalysis are also helpful. ^, Fig. 45.7 shows a diagnostic algorithm for cystic kidney diseases. The diagnostic approach can be categorized on the basis of the patient’s presentation:

• 1.

  In asymptomatic patients with normal kidney function and a family history of ADPKD:

• US is the imaging method of choice for presymptomatic individuals due to its accessibility and cost-effectiveness. A diagnosis of ADPKD can be established if at-risk individuals aged 15 to 39 years have three or more kidney cysts and those aged 40 to 59 years have two or more cysts in each kidney ( Table 45.5 ). If a definite diagnosis is not achieved, CT or MRI studies become valuable given their sensitivity of detecting smaller cysts. In individuals older than 40 with no cysts detected by US, the diagnosis of ADPKD can be excluded. For those younger than 40, MRI is superior to US for exclusion, as the detection of fewer than five cysts by MRI is sufficient to rule out ADPKD. MRI or CT with intravenous contrast is recommended when masses or complex cysts are incidentally discovered. ^, Asymptomatic patients can be clinically monitored by assessing BP and kidney function. Once diagnosis is confirmed, a baseline contrast-enhanced CT (CCT) or MRI, if not obtained yet, is recommended to assess the risk of rapid progression through measuring total kidney volume (TKV). ^, For individuals younger than 18, current recommendations advise against screening due to the absence of disease-modifying agents for this age group. However, it is recommended that pediatricians be informed of the family history, monitor BP regularly, and promote a healthy lifestyle within the household.

  Table 45.5

  Performance of Ultrasound-Based Unified Criteria for Diagnosis or Exclusion of ADPKD in Patients ( PKD1 or PKD2 pathogenic variants) With Positive Family History

  Adapted from Chapman AB, Devuyst O, Eckardt KU, et al. Autosomal-dominant kidney disease: executive summary from a kidney conference. Kidney Int . 2015;88:17–27).

  Age (yr)	Imaging Findings	PKD1	PKD2	Unknown Gene Type
  For Diagnostic Confirmation
  15-29	A total of ≥3 cysts∗	PPV = 100% Sensitivity = 94.3%	PPV = 100% Sensitivity = 69.5%	PPV = 100% Sensitivity = 81.7%
  30-39	A total of ≥3 cysts∗	PPV = 100% Sensitivity = 96.6%	PPV = 100% Sensitivity = 94.9%	PPV = 100% Sensitivity = 95.5%
  40-59	≥2 cysts in each kidney	PPV = 100% Sensitivity = 92.6%	PPV = 100% Sensitivity = 88.8%	PPV = 100% Sensitivity = 90%
  For Diagnostic Exclusion
  15-29	No kidney cyst	NPV = 99.1% Specificity = 97.6%	NPV = 83.5% Specificity = 96.6%	NPV = 90.8% Specificity = 97.1%
  30-39	No kidney cyst	NPV = 100% Specificity = 96.0%	NPV = 96.8% Specificity = 93.8%	NPV = 98.3% Specificity = 94.8%
  40-59	No kidney cyst	NPV = 100% Specificity = 93.9%	NPV = 100% Specificity = 93.7%	NPV = 100% Specificity = 93.9%

  ADPKD, Autosomal dominant polycystic kidney disease; PPV, positive predictive value; NPV, negative predictive value; ∗, unilateral or bilateral.

• 2.

  In patients with clinical findings suggestive of ADPKD and a positive family history of ADPKD:

• When ADPKD is highly suspected in an individual at risk of ADPKD, A CCT or MRI is preferred over an initial US ( Fig. 45.8 ). These advanced imaging methods confirm the diagnosis and also offer a baseline for future reference, help identify extrarenal complications of ADPKD, and enable the calculation of htTKV for prognosis and treatment planning. The choice between CCT and MRI depends on the patient’s kidney function, considering the risk of contrast exposure with CT. Patients with preserved kidney function (estimated glomerular filtration rate [eGFR] ≥60 mL/min/1.73 m ² ) may undergo a CCT for TKV calculation, to distinguish between cystic and noncystic tissue and assess cyst burden. Noncontrast CT helps assess stones in the collecting system. For patients with an eGFR <60 mL/min/1.73 m ² , MRI is the preferred choice due to lack of iodinated contrast and radiation exposure. MRI is effective in distinguishing between cystic and noncystic tissue but may not reliably detect intrarenal factors like kidney stones or parenchymal calcifications. ^{, ,}

  

  Abdominal Imaging representation of a 64-year-old man with autosomal dominant polycystic kidney disease.

  (A) Ultrasound. (B) Computed tomography scan transverse section. (C) Magnetic resonance imaging coronal section.

Algorithm involved in diagnosing autosomal dominant polycystic kidney disease (ADPKD) based on the location of the kidney cysts, family history, extrarenal manifestations, and congruency between cystic burden and kidney function.

Among the large differential, we emphasize how to diagnose definite, likely, and possible ADPKD. ADPLD, Autosomal dominant polycystic liver disease; ADTKD, autosomal dominant tubulointerstitial disease; AML, angiomyolipoma; ESKD, end-stage kidney disease; Hx, history; MCDK, multicystic dysplastic kidneys; MCN, multilocular cystic nephroma; MIC, Mayo imaging classification; NPV, negative predictive value; OFD, oral facial digital; Pheo, pheochromocytoma; PPV, positive predictive value; RCC, renal cell carcinoma; Rx, treatment; TKV, total kidney volume; TSC, tuberous sclerosis complex; UPJ, ureteropelvic junction; VHL, von Hippel-Lindau syndrome; VUR, vesicoureteral junction.

The application of genetic testing becomes essential when the diagnosis is inconclusive (e.g., lack of family history or atypical imaging findings) or when the goal is to rule out the disease at early stages and at a young age (e.g., preimplantation diagnosis or assessing potential living donors). Comprehensive pregenetic and postgenetic counseling should be provided to all individuals undergoing genetic testing. ^, With the advancements in next-generation sequencing (NGS), it is now possible to simultaneously test for multiple cystic diseases. Consequently, high-throughput sequencing methodologies have been established to investigate atypical presentations of ADPKD. Advanced genetic testing has explored possible manifestations, such as the contiguous TSC2/PKD1 deletion syndrome, “compound heterozygosity,” which involves having one PKD1 variant alongside a second variant in a non- PKD1 cystic gene (i.e., PKD2, COL4A1, or HNF1B ), or having a truncating PKD1 variant in trans, associated with a second nontruncating PKD1 variant. ^{, , ,} Genetic testing is also insightful in cases of significant intrafamilial disease variability, given the role of genetic mosaicism and biallelic disease, which can affect patients with ADPKD from the same family differently. Applications of genetic testing have been observed in patients with no apparent family history and atypical imaging findings that reflect new gene variants, such as GANAB, IFT140, DNAJB11, ALG9, ALG5, ALG8, COL4A3, COL4A4, and APOL1 variants in black patients with proteinuria. ^{, ,}

To standardize the process of diagnosis and medical documentation, the diagnosis of ADPKD could be also stratified on the basis of family history and kidney cysts findings ( Fig. 45.8 ). “Definite ADPKD” is established either clinically, with a family history of ADPKD and multiple renal cysts according to the Ravine/Pei criteria, or genetically through the detection of pathogenic PKD1 or PKD2 variants. ^, “Likely ADPKD” is assigned to individuals who exhibit typical ADPKD features, such as enlarged kidneys with more than 10 cysts per kidney, but who lack a family history; in these instances, genetic testing is recommended. A diagnosis of “possible ADPKD” is considered if the individual has normal-sized or mildly enlarged kidneys with cysts each measuring ≥5 mm (excluding parapelvic cysts) that exceed the 97.5th percentile of their demographic group, with no severe CKD or other cystic diseases. The specific cyst count thresholds used for this assessment are based on age and sex, derived from data on healthy potential kidney donors from contrast-enhanced abdominal CT scans ( Table 45.6 ).

ADPKD is characterized by a broad range of renal and extrarenal clinical manifestations. Typically, patients remain asymptomatic early in life, with the age of symptom onset varying widely. While the clinical manifestations may overlap in patients with ADPKD who have PKD1 or PKD2 pathogenic variants, those with PKD1 variants generally experience more severe symptoms, related to larger kidney size and earlier progression to ESKF. A summary of the major renal and extrarenal manifestations of ADPKD is provided in Fig. 45.9 .

Summary of the renal and extrarenal manifestations seen in autosomal dominant polycystic kidney disease.

ADPKD is a heterogeneous disease with a large phenotypic variability. As kidney cysts grow, kidney size and volume increase, leading to a gradual decline in GFR. The onset and rate of GFR decline varies among patients with some patients reaching ESKF in their fourth decade while others in their eighth decade. Given that GFR remains relatively stable during the first 2 to 3 decades of ADPKD, alternative prognostic biomarkers are essential to predict the risk of rapid progression and differentiate disease severity. Biomarkers such as TKV, height-adjusted TKV (htTKV), and PROPKD score based on clinical manifestations and PKD genotyping are typically used.

The CRISP (Consortium for Radiologic Imaging Studies of Polycystic Kidney Disease) studies demonstrated the utility of TKV as a prognostic marker for kidney function decline. A baseline TKV >1500 mL was strongly associated with a GFR decline of 4.33 mL/min/year, outperforming serum creatinine and albuminuria. TKV has been approved by the U.S. Food and Drug Administration as a prognostic biomarker in ADPKD. TKV measurements require precision imaging tools such as planimetry, but simplified techniques using MRI or CT can provide reliable estimates via the ellipsoid equation by measuring the sagittal, coronal, and axial kidney lengths. The Mayo Imaging Classification (MIC) is a practical, imaging-based model used to categorize ADPKD severity. Originally developed at the Mayo Clinic Translational PKD Center using data from a cohort of 590 ADPKD patients aged 15 to 80 years, the MIC has become a valuable tool for clinical trial selection and disease monitoring. Patients are classified as either typical (Mayo Class 1) or atypical (Mayo Class 2) ( Fig. 45.10 ). Typical ADPKD, representing 95% of cases, is characterized by bilateral kidney cysts that contribute nearly equally to TKV. Atypical ADPKD, accounting for 5% of cases, is further subdivided into Class 2A, where the disease is focal and asymmetric, and Class 2B, characterized by unilateral or bilateral atrophic kidneys. For MIC 1, patients are further subcategorized into five subclasses, MIC 1A through 1E, by adjusting TKV to height and age at time of imaging. The risk of progression to ESKF increases significantly from MIC 1A to 1E, making this classification an essential tool for identifying patients at higher risk who might benefit from disease-modifying treatments. Patients with MIC 1C, 1D, or 1E are considered at risk of rapid progression, defined as reaching ESKF before age 62. In contrast, those in lower-risk classes (1A and 2A) are less likely to benefit from clinical trials but still require regular monitoring every 3 to 5 years to reassess their progression risk.

Magnetic resonance imaging representation of typical (MIC-1A, 1B, 1C, 1D, and 1E) versus atypical (MIC-2A and 2B) autosomal dominant polycystic kidney disease.

PKD genotype is associated with prognostic insight. Patients with PKD2 variants reach ESKF 20 years after those with PKD1 variants. The Predicting Renal Outcomes in PKD (PROPKD) tool is a clinical scoring system designed to assess the risk of kidney function decline and progression to ESKF in ADPKD ( Table 45.7 ). It combines several clinical parameters (male, cyst infection, or bleeding before age 35, hypertension before age 35) and PKD genotype data ( PKD1 truncating, PKD1 nontruncating, or PKD2 ) into a single score, where a score of ≤3 predicts no risk of ESKF before age 60, with a negative predictive value (NPV) of 81.4%. A score >6 indicates a high likelihood of rapid progression to ESKF before age 60, with a positive predictive value (PPV) of 90.9%. Intermediate scores (4–6) indicate an uncertain prognosis, requiring closer monitoring and individualized assessment. Table 45.8 highlights the strengths and limitations of various methods for assessing the risk of rapid progression in ADPKD.

Other biomarkers have been explored in ADPKD including advanced imaging biomarkers, such as imaging texture analysis and cyst segmentation, which offer innovative methods to predict disease progression in ADPKD. Texture analysis, using features like entropy, gradient, and correlation from T2-weighted MRIs, enhances predictive models when combined with traditional factors like age and eGFR, effectively distinguishing patients at risk for advanced CKD. Cyst segmentation, demonstrated in the CRISP cohort, has shown strong correlations among markers like total cyst volume (TCV), renal parenchyma volume (RPV), and total cyst number (TCN) with kidney function decline over time. Among these, Cyst-Parenchyma Surface Area proved particularly predictive. Biomarkers for ADPKD progression fall into four categories: clinical (e.g., eGFR and demographics), imaging (e.g., TKV, MIC, and AI tools), genetic (e.g., PKD variants), and molecular, though the latter require further validation ( Fig. 45.11 ). While imaging biomarkers improve predictive accuracy, challenges remain in their routine clinical application, necessitating ongoing research and refinement. Fig. 45.12 represents the disease progression in ADPKD along with the associated symptoms.

The different biomarkers identified in autosomal dominant polycystic kidney disease (ADPKD) progression and prognosis.

This detailed classification organizes ADPKD biomarkers into four distinct groups. Genetic biomarkers include the type of genetic variant, highlighting the role of PKD1 pathogenic variants in severe presentations. Further delineation within PKD1 pathogenic variants reveals genotypic and intrafamilial variations. Clinical markers including age-indexed eGFR, PROPKD scores, and considerations of macrovascular diseases provide insights into risk factors, with males experiencing more severe ADPKD. Imaging biomarkers such as ht-TKV and TKV growth rate are approved as prognostic biomarkers in ADPKD while advanced imaging techniques offer nuanced insights. Molecular markers, divided into serum and urinary categories, include apelin, copeptin, bicarbonate, uric acid, FGF23, asymptomatic pyuria, urine/plasma urea ratio, and more, offering systemic and renal-specific perspectives.

Disease progression in autosomal dominant polycystic kidney disease (ADPKD).

This representation outlines the progressive stages of ADPKD in the context of chronic kidney disease (CKD). Starting with normal kidney function, the trajectory advances through hyperfiltration and impaired function, ultimately leading to end-stage kidney failure (ESKF), mandating interventions like dialysis or transplantation. Noteworthy early manifestations include cyst development, pain, hematuria, urinary tract infections (UTIs), and hypertension, with later stages featuring proteinuria, cyst infections, and stone formation. Different interventions are shown for different manifestations: tolvaptan for limiting cystic and disease progression, renin-angiotensin-aldosterone system (RAAS) blockers for hypertension, potassium citrate for stones, and antibiotics for UTIs. The comprehensive approach of conservative management proves crucial in addressing various ADPKD-associated symptoms including hematuria, stones, and pain, contributing to comprehensive patient care. MIC, Mayo imaging classification.

There have been significant advancements in improving kidney outcomes in ADPKD. The following section summarizes approaches to slow disease progression in ADPKD. Fig. 45.13 shows a detailed algorithm for the management of patients with ADPKD based on their risk to develop ESKF.

Treatment diagram of patients with autosomal dominant polycystic kidney disease (ADPKD).

ADPKD management starts with a confirmation of the diagnosis through imaging or genotype testing. Subsequently, patients are stratified based on abdominal imaging and clinical parameters. Slow progressors, classified as MIC 1A or 1B with a PROPKD score of 0 to 3, an annual GFR rate of decline <3 mL/min/SA per year, and an annual TKV rate of growth <5% per year, are identified. These individuals are expected to either not develop end-stage kidney disease (ESKD) or do so after the age of 62. Conversely, rapid progressors, categorized as MIC 1C, 1D, or 1E with a PROPKD score of 7 to 9, an EGFR rate of decline >3 mL/min/SA per year, and a TKV rate of growth >5% per year, require prompt intervention as ESKD is estimated before the age of 62. Management strategies differ accordingly: Slow progressors are reassured and their progression is reconfirmed in 2 to 3 years, while rapid progressors are referred to clinical trials and may be started on tolvaptan. Additionally, all patients are advised to adhere to lifestyle modifications including blood pressure control, regular physical activity, salt restriction, maintenance of serum bicarbonate levels >22, increased hydration, dietary adjustments, monitoring of cholesterol levels, and maintenance of a healthy body mass index (BMI).

Tolvaptan is recommended for adults aged 18 to 55 with evidence of rapid disease progression based on imaging (e.g., MIC 1C, 1D, and 1E) or eGFR decline >3 mL/min/1.73 m ² per year. Post hoc analyses suggest benefits for patients aged 56 to 65 with rapid progression (historical GFR rate of decline >3 mL/min per year) and CKD stages 3–4. Treatment is generally continued until KRT is required.

The most common side effects of Tolvaptan include polyuria, excessive thirst, and nocturia due to aquaretic effects. Tolvaptan-induced reversible hepatic injury (5.6%) necessitates regular monitoring of liver function tests, monthly in the first 18 months of therapy and every 3 months thereafter. The monitoring schedule involves biweekly testing for the first month, monthly testing for 18 months, and quarterly testing thereafter.

To mitigate nocturia and polyuria, dietary sodium restriction—particularly at the evening meal—can reduce osmolar load and aquaresis. Alternative strategies, such as adjunctive use of metformin or hydrochlorothiazide, have been explored to manage tolvaptan-induced polyuria, but long-term safety data remain insufficient to recommend these combinations. ^, Potential drug interactions with CYP3A inhibitors, such as certain antifungals, antibiotics, and antiretrovirals, must also be considered. Additionally, patients should avoid factors that may increase the risk of liver injury including excessive alcohol consumption and high-dose acetaminophen. To minimize hepatic risks, it is recommended that patients temporarily discontinue Tolvaptan during acute viral illnesses or events where significant alcohol intake is anticipated.

Patients should also be educated to temporarily withhold Tolvaptan in situations where they may be at risk for dehydration, such as during acute gastrointestinal illnesses (e.g., vomiting or diarrhea) or periods when fluid intake is restricted. Proper counseling ensures patients understand the importance of maintaining hydration and promptly resuming therapy once these conditions resolve.

Tolvaptan is contraindicated in pregnancy, lactation, uncorrected hyponatremia, history of liver injury, hypovolemia, and urinary obstruction. When initiated early in adulthood with preserved GFR, Tolvaptan is projected to delay the onset of ESKF by approximately 3.1 years for every 13.7 years of therapy. However, access to the medication may be influenced by regional health care policies and availability.

Management of ADPKD in children depends on the clinical manifestations: Asymptomatic patients may not require treatment before adulthood, while early symptomatic patients (such as those with hypertension) may require early treatment. The use of tolvaptan in children with ADPKD is still under investigation. A phase 3 clinical trial by Mekahli and colleagues showed the effect of tolvaptan in slowing kidney volume growth and the decline in eGFR over the period of 12 months, although these findings were not statistically significant, and there were no reports of drug-induced hepatic injury.

Ambulatory BP monitoring is the preferred method for diagnosing high BP and assessing treatment effectiveness in children aged 5 years and older. It provides a more accurate prediction of target organ damage compared with office measurements and can identify conditions like isolated nocturnal hypertension or nondipping patterns. If ambulatory BP monitoring is not available, routine office or home BP monitoring can be used as alternative methods. In children with ADPKD and hypertension, RAAS blockade is the preferred drug class to control high BP because it slows kidney function decline and cardiovascular disease progression. ^, Studies suggest that targeting BP at the 50th percentile using RAAS inhibitors can help maintain kidney function and reduce LVM index. While comparative studies in this specific population are limited, expert consensus supports the use of ACEI or ARBs due to their efficacy and generally favorable side effect profiles. ^,

While no randomized controlled trials specifically targeting lifestyle interventions in ADPKD children exist, general guidelines for pediatric populations and those with ESKF apply. Obesity and metabolic disturbances play a significant role in the pathogenesis of ADPKD in the pediatric population. These prevalent issues further exacerbate glomerular hyperfiltration, leading to a faster decline in kidney function and an increase in kidney volume. Additionally, they heighten the risk of hypertension in obese children. ^, Maintaining a healthy weight is essential, as obesity can accelerate kidney function decline in ADPKD. Salt intake in the pediatric population consuming a western diet exceeds the recommended amounts. Therefore reducing salt intake is crucial, given its association with kidney growth and disease progression. Although hydration is vital, the benefits of excessive water intake remain inconclusive. ^, Furthermore, a balanced diet that includes moderate protein is recommended to prevent malnutrition. ^,

A longitudinal study involving pediatric patients diagnosed with ADPKD younger than the age of 19 aimed to assess the utility of htTKV measured via a 3D US to discern rapidity of disease progression in children. Applying MIC to the pediatric population led to underestimation of the disease severity, especially in patients younger than 10. Subsequent adjustments to the MIC model parameters resulted in an improved distribution of patients across severity scores; however, it still failed to adequately include the full range of pediatric ages. Consequently, a predictive model was introduced, incorporating a formula based on htTKV (mL/m) = A × B ^{(age^1.6)} , with A, the starting htTKV at age 0 and B, the yearly htTKV % increase. This new model was able to better stratify the pediatric patients based on severity of the disease. Further validation using Mayo Clinic and CRISP data for the same age groups confirmed that the LIC model was better at sorting children into different risk levels compared with the MIC model.

Most children with ADPKD typically maintain adequate kidney function until their fourth decade of life. In some cases, glomerular hyperfiltration conceals the loss of GFR and is associated with a more significant increase in TKV, which leads to a faster GFR decline in the future. In fact, hypertensive children with ADPKD are more likely to experience a decline in kidney function when compared with normotensive children with ADPKD. A small number of symptomatic children are at risk for rapidly progressive disease that ultimately results in ESKF requiring KRT, ideally preemptive transplantation.

ADPKD phenotypic spectrum entails a wide range of diseases with variable phenotypic and genotypic characteristics associated with monoallelic causes of cystic kidney disease (e.g., PKD1, PKD2, GANAB, DNAJB11, IFT140, ALG5, ALG6, ALG8, ALG9, NEK8, and monoallelic PKHD1 ). ^, The various genotypes are summarized in Table 45.4 .

NEK8.

Certain pathogenic variants in NEK8 have been associated with early onset forms of PKD ( Fig. 45.14 ). Monoallelic variants primarily cause kidney phenotypes, resembling ADPKD, while biallelic variants result in severe syndromic ciliopathies with extrarenal features. ^, Specific NEK8 variants, like p.Arg45Trp and p.Lys157Gln, are linked to childhood ESKF, often requiring bilateral nephrectomies. These presentations overlap with ARPKD and ADPKDveo but align more closely with ADPKD inheritance and cyst localization.

Computed tomography scans (A, cross-sectional cut vs. B, coronal cut) of a 5-year-old female patient with NEK8 variant and eGFR of 25 mL/min/1.73 m ² , manifesting with early onset autosomal dominant polycystic kidney disease.

Tuberous sclerosis complex (TSC) is a genetic syndrome characterized by pathogenic variants in TSC1 (chromosome 9q34) or TSC2 (chromosome 16p13), affecting 1 in 6000 individuals. TSC1 encodes hamartin, while TSC2 encodes tuberin. Together, they form a complex that regulates cell size and organ growth via inhibition of the mTOR pathway. Variants in either gene lead to constitutive mTOR activation, driving abnormal cellular proliferation and tumor development. ^,

TSC diagnosis requires specific major features (renal angiomyolipomas [AML], facial angiofibromas, nontraumatic ungual or periungual fibromas, hypomelanotic macules, shagreen patches, retinal nodular hamartomas, cerebral cortical tubers, subependymal nodules, subependymal giant cell astrocytomas, benign cardiac rhabdomyomas, and pulmonary lymphangioleiomyomatosis) or minor features (renal cysts, nonrenal hamartomas, hamartomatous rectal polyps, retinal achromic patches, cerebral white matter radial migration tracts, bone cysts, gingival fibromas, and “confetti” skin lesions) ( Fig. 45.15 ). Abdominal MRI is preferred for evaluating AMLs and detecting lipid-poor lesions. ^, Additional imaging may reveal extrarenal findings like aortic aneurysms and neuroendocrine tumors.

Imaging representation of a 33-year-old woman diagnosed with tuberous sclerosis complex complex (eGFR at imaging of 60 mL/min/1.73 m ² ) on computed tomography scan (A) and magnetic resonance imaging (B) ( arrow showing angiomyolipomas).

Kidney involvement includes AMLs, simple cysts, oncocytomas, clear cell RCCs, lymphangiomatous cysts, and, rarely, focal segmental glomerulosclerosis. AMLs consist of abnormal vessels, smooth muscle, and fat. Epithelioid AMLs, although rare, may undergo malignant transformation. Renal cysts occur in up to 32% of patients, often asymptomatic and without the need for routine surveillance unless associated with AMLs. ^,

TSC2/PKD1 contiguous gene syndrome (CGS), resulting from deletions of TSC2 and PKD1 on chromosome 16p13, causes early onset ADPKD with more severe renal manifestations ( Fig. 45.16 ) including hypertension and ESKF by the second or third decade. ^, In contrast, non-CGS TSC patients typically have milder renal cystic disease.

Imaging representation of a 2-year-old male patient with TSC2 / PD1 continuous gene syndrome (eGFR at imaging of 108 mL/min/1.73 m ² ).

TSC is associated with two main manifestations: 1. Cystic kidney disease: Small, asymptomatic renal cysts are common, and often discovered incidentally. Surveillance focuses on AMLs due to their growth potential and RCC risk. TSC2/PKD1 CGS requires high suspicion in young patients with hypertension and early onset cystic disease ^, ; 2. Glomerulocystic kidney disease: Rare and typically diagnosed in neonates, it presents with segmental lesions and enlarged kidneys with cysts. ^,

Disruptions in mTOR signaling and primary cilia deflection contribute to renal cystic diseases in TSC, which are second only to AMLs as common renal findings. ^{, , , ,}

AMLs often do not require immediate treatment. They warrant regular monitoring (every 1–3 years) with abdominal MRI. Interventions, such as selective arterial embolization, radiofrequency ablation, or cryoablation, are reserved for symptomatic AMLs, particularly those >4 cm due to bleeding risks. ^, Renal-sparing surgery is preferred to preserve kidney function. mTOR inhibitors like everolimus significantly reduce AML volume and are recommended for large or symptomatic AMLs. The EXIST-2 trial demonstrated the efficacy of everolimus in reducing AML size, though long-term risks and benefits require further study. For cystic disease, managing hypertension and monitoring for ESKF are priorities. In cases requiring kidney transplantation, bilateral nephrectomy may precede the procedure to mitigate hemorrhage and RCC risks. While mTOR inhibitors show promise for AMLs, their efficacy in ADPKD-related cystic disease remains inconsistent. Adaptive mechanisms may explain paradoxical increases in cystic and AML volumes during prolonged treatment, as observed in some cases. ^{, ,}

Von Hippel-Lindau (VHL) syndrome is a rare genetic disorder caused by variants in the VHL tumor suppressor gene on chromosome 3p25-p26. It is characterized by benign and malignant growths in the eyes, brain, spinal cord, adrenal glands, and kidneys. Renal manifestations include benign cysts and clear cell carcinoma (RCC), with cysts present in 50% to 66% of patients, typically emerging in the third or fourth decade of life. These cysts are often asymptomatic and rarely lead to ESKF. ^,

The VHL gene encodes pVHL proteins (about 30 kDa and 19 kDa) that suppress RCC growth by degrading HIF-α subunits. Under normoxic conditions, pVHL targets HIF-Iα and HIF-2α for degradation. In hypoxia, stabilized HIF-α translocates to the nucleus, promoting angiogenesis, erythropoiesis, and mitogenesis. Although HIF activation is necessary for VHL-associated tumors, it is not sufficient, as evidenced by Chuvash polycythemia (caused by homozygous VHL missense variant), which features elevated HIF but lacks typical VHL tumors.

Additional cellular functions of pVHL include apoptosis regulation, cilia maintenance, and extracellular matrix deposition. Loss of heterozygosity at the VHL locus in renal cysts from VHL patients suggests cyst formation is an early step in RCC pathogenesis. Renal cysts and RCC cells in VHL often exhibit reduced or rudimentary cilia. ^,

VHL is diagnosed through clinical criteria (e.g., central nervous system [CNS] or retinal hemangioblastomas, RCC, or family history) and confirmed via genetic testing, which has near-100% sensitivity. ^, Screening begins with abdominal ultrasound by age 8, advancing to MRI at age 16 if abnormalities are detected. Regular imaging (MRI or CT, every other year) is essential for monitoring visceral lesions in the kidneys, pancreas, adrenals, brain, and spine ( Fig. 45.17 ). Renal cysts often precede RCC, which has a mean onset at age 35 and affects up to 70% of VHL patients by age 60. RCCs in VHL are typically clear cells, low-grade, and more likely to be multicentric and bilateral. ^, Metastatic RCC is the leading cause of death in VHL. ^, Early detection of asymptomatic RCCs can improve outcomes.

Imaging representation of a 38-year-old male with Von Hippel-Lindau disease on computed tomography scan (A) and magnetic resonance imaging (B) (estimated glomerular filtration rate at imaging of 85 mL/min/1.73 m ² ).

Effective management of VHL syndrome requires early detection and close monitoring of complications including RCC and CNS lesions. Recommended surveillance includes annual physical and ophthalmologic examinations, blood or urinary catecholamine/metanephrine levels, and periodic imaging (ultrasound, MRI, or CT). Renal lesion management aims to preserve renal function while minimizing invasive procedures. For tumors ≥3 cm, partial nephrectomy is the preferred approach based on the National Cancer Institute’s “3-cm rule,” as smaller tumors rarely metastasize. ^, Minimally invasive therapies, such as radiofrequency ablation and cryotherapy, are effective for smaller lesions and require regular follow-up. Targeted therapies including mTOR inhibitors (e.g., temsirolimus and everolimus) and tyrosine kinase inhibitors (e.g., sunitinib) have shown potential in treating VHL-associated tumors by inhibiting angiogenesis and tumor growth through VEGF, PDGF, and TGF-β signaling pathways. ^,