Kidney stones and autosomal dominant polycystic kidney disease: a state-of-the-art review

Abstract

Kidney stones (nephrolithiasis/urolithiasis) are a clinically significant yet underrecognized complication of autosomal dominant polycystic kidney disease (ADPKD), with reported prevalence ranging from 3% to 59% due to differences in diagnostic criteria and study design. Patients with ADPKD are predisposed to uric acid and calcium oxalate stones, driven by metabolic abnormalities, such as low urine pH, hypocitraturia, hyperuricosuria, as well as structural factors including cyst-induced distortion of the collecting system and impaired urinary drainage. These anatomical changes complicate both diagnosis and intervention, posing challenges, such as reduced stone-free rates, longer operative times, increased need for repeat procedures, and higher complication risk. While non-contrast computed tomography (CT) remains the diagnostic gold standard, low-dose CT is preferred to minimize cumulative radiation exposure. Management generally aligns with that of the broader population and includes aggressive hydration, correction of metabolic derangements, dietary modification, and individualized urologic intervention. Tolvaptan, a vasopressin V2 receptor antagonist, may have additional benefit by increasing urine volume, reducing supersaturation, and potentially mitigating stone risk. This review integrates nephrology, urology, and imaging perspectives to summarize the current understanding of nephrolithiasis in ADPKD, including its pathophysiology, clinical manifestations, diagnostic challenges, and management. We propose an ADPKD-specific diagnostic and management algorithm to optimize prevention, evaluation, and treatment of stone disease in this complex population.

Introduction

Autosomal dominant polycystic kidney disease (ADPKD) is the most common inherited kidney disorder, affecting over 12 million people worldwide [1]. It is primarily caused by pathogenic variants in PKD1 or PKD2 [2], leading to the progressive development of fluid-filled renal cysts and kidney enlargement, and eventual kidney failure (KF) [3–6]. Tolvaptan, a vasopressin V2 receptor antagonist, remains the only U.S. Food and Drug Administration (FDA)-approved disease-modifying therapy for ADPKD and is indicated for adults at risk of rapidly progressive disease [7–12]. Beyond cyst growth and kidney function decline, ADPKD is associated with a range of renal and extrarenal complications. Among these, kidney stones (nephrolithiasis/urolithiasis) represent a significant kidney-related manifestation that contributes to morbidity [13,14]. Kidney stones in ADPKD can cause recurrent pain (Figure 1(A)), urinary obstruction, urinary tract infections, and decreased quality of life, and may also exacerbate progression to KF [15,16]. In this review, we examine the pathogenesis, diagnostic challenges, clinical impact, and management of nephrolithiasis in ADPKD, and propose a practical algorithm to optimize care for this unique patient population. We also highlight points of overlap and contrast with conditions such as cystinuria and medullary sponge kidney to broaden clinical relevance.

Figure 1.

Pain distribution, pathophysiology, and etiologic factors contributing to nephrolithiasis in autosomal dominant polycystic kidney disease (ADPKD). (A) Pain patterns in ADPKD-associated nephrolithiasis vary by stone location along the urinary tract. Renal pelvic stones typically cause deep, dull flank pain. Stones in the proximal ureter may present with sharp, colicky upper abdominal or flank pain, while those in the mid-ureter produce severe lateral abdominal pain. Distal ureteral stones commonly result in groin pain radiating to the genitals. Bladder stones are associated with suprapubic discomfort and pressure-like sensations. (B) The pathophysiology of kidney stones in ADPKD involves both metabolic and structural mechanisms. Metabolically, reduced urine volume leads to supersaturation of stone-forming solutes such as calcium, oxalate, and uric acid. Low urinary pH favors uric acid precipitation, while hypocitraturia and impaired ammoniagenesis further increase lithogenic risk. Structurally, renal cyst burden and distortion of the collecting system impair urinary drainage, promoting urinary stasis and reducing stone clearance. (C) Common lithogenic factors in ADPKD include dehydration, distorted renal anatomy, insulin resistance and obesity, and high animal protein intake. Protective factors include adequate hydration, a low-sodium and low-protein diet, and pharmacologic therapies such as tolvaptan – which increases urine volume and lowers urinary supersaturation – and potassium citrate, which alkalinizes urine and inhibits calcium and uric acid stone formation.

Epidemiology of kidney stones in ADPKD

Patients with ADPKD appear to be at increased risk for kidney stone formation and its associated complications [6]. A recent meta-analysis [17] reported a wide prevalence range, from 3% to 59%, highlighting the substantial heterogeneity in study design, diagnostic criteria, and imaging modalities. Notably, there is paucity of data on true incidence, likely due to the relatively infrequent occurrence of symptomatic stone events and the underreporting of longitudinal outcomes in individual cohorts. Several limitations complicate accurate prevalence estimation. Many studies are of low quality, with inconsistent definitions of stone disease and varied use of imaging techniques [17]. Moreover, patients with ADPKD often undergo more frequent imaging surveillance compared to individuals with other forms of CKD, potentially leading to detection bias [18]. Some stones identified on imaging may actually represent cyst wall or parenchymal calcifications, further complicating prevalence estimates and contributing to current recommendations against routine stone screening in asymptomatic individuals. Despite these challenges, comparative studies suggest a higher prevalence of stones in ADPKD relative to unaffected family members, with a reported relative risk of 1.8 (95% CI: 1.3–2.6) and stone rates ranging from 3% to 12% in non-ADPKD relatives [17]. These data support an intrinsic predisposition to stone formation in ADPKD, beyond surveillance bias alone.

Characteristics of kidney stones in patients with ADPKD: Stone size is a key determinant of the likelihood of spontaneous passage, regardless of its location within the urinary tract. In general, stones less than 5 mm in diameter pass spontaneously in the majority of cases, while those measuring 5–7 mm have an approximately 50% chance of passing without intervention. Stones larger than 7 mm typically require procedural management to relieve obstruction or prevent complications [19]. In the general population, roughly 80% of urinary stones are calcium-based, comprising calcium oxalate and calcium phosphate, followed by struvite and uric acid stones, which account for 10% and 9%, respectively. Less than 1% of stones are composed of cystine, ammonium acid urate, or are drug-induced [19,20].

In contrast, patients with ADPKD exhibit a distinct lithogenic profile. Uric acid stones are notably more common in this population, comprising an estimated 40–60% of cases, followed by calcium oxalate stones, which occur in approximately 47% of patients, as summarized in Supplementary Table 1 [21–23]. Staghorn calculi, though relatively uncommon, may also be encountered in ADPKD and are likely related to recurrent UTIs and urinary stasis secondary to a distorted and poorly draining pelvicalyceal system [24,25].

Etiology of kidney stones in ADPKD patients

Metabolic risk factors for kidney stones in ADPKD

Supersaturation of urinary solutes is the fundamental driver of kidney stone formation [26]. Stone risk is determined by a balance between lithogenic promoters (e.g., calcium, oxalate, and uric acid) and inhibitors (e.g., citrate and magnesium) (Figure 1(B)) [26,27]. Low urine volume increases solute concentration, while urinary pH modulates solubility: calcium phosphate and struvite stones form in alkaline urine, whereas uric acid and cystine stones precipitate in acidic environments [26]. Stone nucleation is believed to originate in Randall’s plaques, which form at the basement membrane of the loop of Henle and are influenced by complex physicochemical and cellular mechanisms [26].

In ADPKD, multiple metabolic derangements have been implicated in stone formation, including low urine volume, acidic urine pH, hypocitraturia, hypomagnesiuria, hypercalciuria, hyperoxaluria, and hyperuricosuria [28–30]. However, the prevalence and pathophysiological relevance of these abnormalities remain inconsistently demonstrated across studies. Importantly, comparative analyses have not consistently revealed significant differences in metabolic profiles between ADPKD stone formers and non-stone formers.

Urine pH: A consistently low urinary pH (<5.5) is observed in most ADPKD patients, regardless of stone history [29]. Acidic urine enhances uric acid precipitation and reduces urinary citrate excretion, synergistically increasing lithogenic risk [31,32]. Notably, this low urinary pH occurs despite normal serum bicarbonate levels, suggesting the absence of overt metabolic acidosis (median HCO₃^- 25–26 mEq/L, p = 0.34) and instead indicating a selective defect in renal acid excretion [29].

Uric acid: Some patients with ADPKD and preserved kidney function exhibit hyperuricosuria, a potential contributor to uric acid stone formation [30]. However, hyperuricosuria is not uniformly present, and studies have found no consistent differences in serum uric acid levels or fractional uric acid excretion between ADPKD patients and non-ADPKD stone formers [21,22,33,34]. Instead, defective ammoniagenesis and persistently acidic urine have been proposed as central mechanisms [33]. For instance, ADPKD stone formers exhibit impaired ammonium excretion in response to NH₄Cl loading, similar to patients with uric acid stones, further promoting urinary acidification and uric acid crystallization [29].

Citrate: Citrate is a key inhibitor of calcium-based stones, preventing crystallization by chelating free calcium ions [35]. Hypocitraturia, defined as urinary citrate <1.67 mmol/d or <320 mg/d, is a common abnormality in ADPKD [36], affecting around 55% of patients independent of stone history [37]. Although studies consistently reported lower urinary citrate in ADPKD, statistical significance has varied [28,29,38]. In PKD rat models, citrate supplementation has been associated with delayed disease progression [39–41]. Moreover, urinary citrate declines with CKD progression and is associated with faster eGFR decline (3.7 vs. 2.3 mL/min/1.73 m² per year, p = 0.04) and earlier onset of KF (median 9 vs. 18 years, p = 0.002) [37]. In patients with mild kidney impairment (n = 26), hypocitraturia was associated with faster cyst growth (r = −0.575, p = 0.0023), although not with eGFR decline (r = 0.132, p = 0.5209) [32].

Despite its high prevalence, the role of hypocitraturia in stone formation in ADPKD remains debated. In one study, no significant difference was seen in the prevalence of hypocitraturia (<300 mg/d) between stone formers and non-stone formers (49% vs. 60%), though median citrate excretion was numerically lower among stone formers (247 mg/d vs. 337 mg/d) [28]. These levels are lower than previously reported averages (∼520 mg/d) in ADPKD patients [42]. When compared to non-ADPKD stone formers and healthy controls, hypocitraturia was significantly more common in ADPKD stone formers (69.4% vs. 38.3% vs. 12.5%; p < 0.05) [30]. Whether this reflects a distinct pathogenic mechanism or an association remains uncertain and warrants further investigation.

Calcium: Hypercalciuria appears to be less prominent in ADPKD than in other stone-forming populations. Torres et al. [38] reported a prevalence of only 11% among ADPKD stone formers, substantially lower than that observed in non-ADPKD patients where calcium oxalate stones predominates [43–45]. Similarly, multiple studies have shown no significant differences in 24-h urinary calcium, urate, or oxalate between ADPKD stone formers and non-stone formers [30]. Given the lower proportion of calcium-based stones in ADPKD patients, this finding supports the notion that hypercalciuria is not a principal lithogenic driver in this population [30].

Magnesium: Magnesium inhibits calcium oxalate crystal formation by competing with calcium for oxalate binding. One earlier study found significantly lower urinary magnesium in ADPKD stone formers compared to non-stone formers (64.6 mg/d vs. 92.6 mg/d, p < 0.005) [28]. However, this association was not replicated in a subsequent study: while hypomagnesiuria was more prevalent in stone formers (48% vs. 18.6%), median magnesium excretion was not significantly different [90.8 mg/d (IQR 67–105.5) vs. 92 mg/d (IQR 74–119), p = 0.731] [46].

Structural risk factors for kidney stones in ADPKD

Cystic expansion in ADPKD leads to distortion of the renal architecture and compression of the pelvicalyceal system, which promotes urinary stasis and impairs crystal clearance (Figure 1(B)) [47]. This not only predisposes to kidney stones but also to recurrent UTIs and tubular injury [1]. Stone formation has been correlated with increased cyst number and size (p < 0.05 and p < 0.005, respectively) [28]. A study from Brazil evaluating patients with preserved eGFR (CKD stage 1–2) reported a six-fold higher stone risk in those with TKV ≥ 500 mL [OR 6.30 (1.62–24.46); p = 0.008], although this association was not significant in later-stage CKD stage 3–5 [OR 3.30 (0.31–35.32); p = 0.32] [29]. However, other studies have not found differences in TKV between stone formers and non-stone formers in ADPKD [30], suggesting that structural burden alone may not fully account for stone risk and may require interaction with metabolic or genetic factors.

Genetic risk factors of kidney stones in ADPKD

Family history is a strong predictor of kidney stone disease, with up to 30–60% of patients reporting an affected relative [48]. More than 30 monogenic disorders, including primary hyperoxaluria, cystinuria, Dent disease, medullary sponge kidney, and ADPKD are associated with nephrolithiasis (Supplementary Figure 1, Supplementary Table 2) [26,49]. While PKD1 and PKD2 pathogenic variants account for the majority of ADPKD cases, variants in other genes may influence stone susceptibility. In an Italian cohort, patients with ADPKD-DNAJB11(n = 27) had a significantly higher prevalence of kidney stones compared to those with typical ADPKD due to PKD1 or PKD2 variants (62% vs. 29%, p = 0.01) [50]. Although the spectrum of monogenic stone disorders is well-characterized, the extent to which these variants contribute to stone risk in ADPKD remains unclear. It is plausible that additive effects involving known lithogenic quantitative trait loci (QTLs) underlie polygenic susceptibility in this population [51–54].

Diagnosis of kidney stones in ADPKD

Detecting kidney stones in ADPKD presents unique challenges due to cystic distortions, nephrocalcinosis, and cyst wall calcifications, all of which can obscure imaging findings and confound interpretation [38]. Non-contrast CT (NCCT) remains the gold standard, with an estimated sensitivity of 95%, outperforming ultrasound (US) and intravenous urography (IVU) in detecting stones and delineating their size, density, and location (Table 1) [59–63]. However, NCCT may miss small stones (<3 mm), particularly when slice thickness exceeds 5 mm [64]. Nevertheless, CT remains superior to US for detecting small and ureteral stones [65].

Table 1.

Imaging techniques in diagnosing kidney stones in autosomal dominant polycystic kidney disease.

Imaging modality	Sensitivity	Specificity	Additional notes for ADPKD
Ultrasonography	61% (Median) [55]	97% (Median) [55]	May miss stones secondary to parenchymal calcifications [38], inferior results for obese patients [56].
Non-contrast computed tomography (CT)	98% (Median) [55]	97% (Median) [55]	No relevant contraindications.
Low-dose CT (<3 mSv)	99% (Mean) [57]	94% (Mean) [57]	No special considerations were found for those with cyst burden in our database search.
Dual-energy computed tomography (CT)	94% (Mean) [58]	91% (Mean) [58]	No special considerations were found for those with cyst burden in our database search.
Kidney-Ureter-Bladder (KUB) Scan	57% (Median) [55,59]	76% (Median) [55,59]	Least efficacious in detecting uric acid stones [59].
Magnetic resonance imaging (MRI)	82% (Median) [55]	98.3% (Median) [55]	Scarce studies; generally excluded for detecting kidney stones in all patient types [59].
Intravenous pyelography	70% (Median) [55]	95% (Median) [55]	Least efficacious in detecting uric acid stones [59].

Note: Data from individual studies was variable. The above values were derived from meta-analysis reviews.

US, while attractive due to safety, cost-effectiveness, and lack of radiation exposure [62], has reduced sensitivity (∼81%) due to cyst burden and anatomical distortion [30,66]. In a study of 125 ADPKD patients, US failed to identify stones in 20 patients subsequently confirmed to have stones on NCCT [29]. US is less reliable in patients with obesity and in detecting residual fragments <5 mm, leading to underestimation of stone burden [67].

Routine screening for kidney stones in ADPKD lacks consensus. Most centers do not perform routine imaging unless the patient is symptomatic. For stone-naïve individuals, imaging approaches vary: some centers incorporate US during initial ADPKD evaluation, while others favor low-dose NCCT for greater sensitivity and stone characterization [6]. US cannot distinguish between uric acid and calcium-based stones but NCCT can provide indirect differentiation via Hounsfield unit (HU) density: calcium-based stones typically have higher HU values (mean 890 ± 20), while uric acid stones have significantly lower HU values (mean 484 ± 44). A threshold of HU ≤ 500 combined with urine pH ≤ 5.5 predicts uric acid stones with a sensitivity of 86% and specificity of 98%, performance that improves further for stones >4 mm [68]. Dual-energy CT (DECT), though less widely available, provides 100% sensitivity and specificity for stone composition analysis [69].

Conventional modalities, such as kidney, ureter, and bladder (KUB) radiography and intravenous pyelogram (IVP) have largely been replaced by CT urography (CTU) and MR urography (MRU) [59]. CT scout films only offer 17% sensitivity for tracking ureteral stones, compared to 48% with KUB [70].

Given the increased imaging burden in ADPKD patients, cumulative radiation exposure must be considered [18,32,37]. Low-dose CT (<3 mSv) offers a viable alternative with 99% sensitivity and 94% specificity, significantly reducing radiation risks without sacrificing diagnostic accuracy [57].

Magnetic resonance imaging (MRI) has limited utility in direct kidney stone detection, with sensitivity estimated at 82% and specificity at 98%. However, these figures largely reflect indirect findings such as hydronephrosis, not visualization of calculi themselves [59]. MRI is most commonly reserved for pregnant patients when US is inconclusive, and CT is contraindicated. Its high cost, long acquisition time, and lower diagnostic accuracy limit routine use [59]. Novel techniques, such as ultrashort echo time (UTE) MRI and quantitative susceptibility mapping (QSM) may enhance diagnostic performance [55,71,72]. QSM, in particular, shows promise as radiation-free modality for detecting urinary tract calcifications in ADPKD, although its resolution remains limited for stones ≤1 mm [73].

Manifestations of kidney stone disease in patients with ADPKD

Nearly 50% of ADPKD patients with nephrolithiasis are asymptomatic, with stones often discovered incidentally on imaging [74]. When symptoms occur, they typically include fluctuating flank pain and hematuria, both of which may mimic other ADPKD complications, such as cyst hemorrhage or infection, complicating the differential diagnosis [17,26,75]. Pain severity often correlates with the degree of urinary tract obstruction. Stones lodged in the renal calyces tend to remain asymptomatic, while acute, severe pain arises when stones migrate and cause obstruction (Figure 1(A)) [75,76].

Other symptoms may include nausea, vomiting, dysuria, and urinary urgency [26]. Beyond symptomatology, kidney stones in ADPKD can contribute to decline in kidney function by precipitating obstructive nephropathy, recurrent UTIs, and hematuria-related complications [77].

ADPKD patients with kidney stones exhibit different clinical and metabolic profiles. Compared to those without stones, they have significantly higher systolic (155 ± 12 mmHg vs. 145 ± 8 mmHg) and diastolic blood pressure (105 ± 0.9 mmHg vs. 92 ± 1.28 mmHg), increased body mass index (28 ± 2.4 vs. 25.7 ± 0.6), and elevated serum total cholesterol and triglyceride levels [78]. Moreover, ADPKD patients are more likely to require hospital evaluation for kidney stones than non-ADPKD individuals (HR 1.6, 95% CI 1.3–2.1), although their likelihood of undergoing a surgical stone intervention is not significantly higher (HR 1.2, 95% CI 0.9–1.3) [79].

Management of kidney stones in ADPKD

Initial evaluation

The initial approach to kidney stones in ADPKD largely parallels that of the general population [6,80]. The 2025 Kidney Disease: Improving Global Outcomes (KDIGO) guidelines recommend obtaining two 24-h urine collections and a spot urine sample to assess modifiable lithogenic risk factors, with subsequent testing guided by stone severity and recurrence [6]. Repeat stone analysis and follow-up imaging are recommended for patients who do not respond to initial interventions [81]. The diagnostic and therapeutic approach to kidney stones can follow either an acute-care pathway (Figure 2(A)) or a chronic/preventive pathway (Figure 2(B)).

Figure 2.

Diagnostic and therapeutic approach to nephrolithiasis in autosomal dominant polycystic kidney disease (ADPKD). This figure illustrates a practical, stepwise framework for managing kidney stones in ADPKD, addressing both acute presentations (Panel A) and chronic stone disease (Panel B). Panel A focuses on triaging patients presenting with flank pain, hematuria, dysuria, nausea, or vomiting. Initial work-up includes vital signs, laboratory tests (CBC, CMP, UA, urine culture), and pregnancy testing when applicable, followed by imaging, preferably non-contrast CT or ultrasound. Patients at high risk for complications (e.g., obstructive uropathy, urosepsis, and bilateral stones with AKI risk) should be admitted, while clinically stable individuals may be managed on an outpatient basis. Assessment distinguishes first-time from recurrent stone formers and excludes other causes such as cyst hemorrhage or UTI. Pain is managed with acetaminophen, NSAIDs (used cautiously in ADPKD), or opioids, along with hydration, antiemetics, and alpha-blockers. Stone management is stratified by size and infection status: stones <5 mm typically passes spontaneously; 5–10 mm stones may benefit from medical expulsion therapy; stones >10 mm or those associated with infection warrant urgent urologic evaluation. First-line surgical interventions include ureteroscopy (URS) and shock wave lithotripsy (SWL) for upper tract stones ≤20 mm, and percutaneous nephrolithotomy (PCNL) for larger or lower pole stones. Laparoscopic or open surgery is reserved for refractory cases. Panel B outlines a long-term management approach for recurrent or chronic stone formers. Metabolic evaluation includes 24-h urine collections and periodic stone analysis. Preventive strategies focus on lifestyle and dietary modifications: increasing fluid intake (≥3 L/d), limiting sodium and animal protein intake, ensuring adequate dietary calcium, and managing metabolic abnormalities (e.g., hypocitraturia and hypercalciuria). Potassium citrate may be used for urine alkalization in patients with uric acid or hypocitraturic calcium stones, while thiazide diuretics are recommended in hypercalciuric patients. Tolvaptan may offer additional benefit by reducing urine supersaturation and slowing disease progression in rapidly progressive ADPKD. This algorithm integrates current evidence and clinical guidelines with ADPKD-specific considerations to assist clinicians in individualizing care across the continuum of stone disease. ADPKD: autosomal dominant polycystic kidney disease; AKI: acute kidney injury; CBC: complete blood count; CMP: comprehensive metabolic panel; CT: computed tomography; DECT: dual-energy computed tomography; IV: intravenous; NSAIDs: Nonsteroidal anti-inflammatory drugs; PCNL: percutaneous nephrolithotomy; SFR: stone-free rate; SWL: shock wave lithotripsy; UA: urinalysis; UCx: urine culture; URS: ureteroscopy; UTI: urinary tract infection.

Prevention strategies for kidney stones in ADPKD

Hydration and diet: Maintaining a urine output of ≥ 2.5 L/d is critical, with evidence suggesting a 60–80% reduction in stone risk in the general population (Figure 1(C)) [82,83]. Comorbid conditions such as obesity, diabetes mellitus, and metabolic syndrome should be addressed, as they are associated with increased stone risk [80]. Dietary modification, including increased intake of fruits, vegetables, and dietary calcium, along with reduced sodium and animal protein, align with general cardiovascular and metabolic health goals [6,80]. Personalized dietary counseling is essential. Notably, ketogenic diets have been associated with an 8% increased risk of uric acid or mixed stones, highlighting the need for caution in patients adopting such regimens [84].

Medical management of kidney stones in ADPKD

Correction of electrolyte imbalances, management of UTIs, and timely relief of urinary obstruction remain foundational. Selection of pharmacological or surgical interventions should account for anatomical distortion due to cyst burden [85].

Thiazide diuretics: Recommended by AUA (Grade B), thiazide reduce urinary calcium excretion and recurrence in hypercalciuric stone formers [81]. However, thiazide should be used with caution due to the possibility of increasing vasopressin and worsening disease progression, although a more recent study has not demonstrated a detrimental effect on the rate of disease progression in ADPKD [86].

Tolvaptan: As a vasopressin V2 receptor antagonist, tolvaptan increases urine volume and slows cyst growth and eGFR decline in ADPKD [87,88]. A secondary analysis of the TEMPO 3:4 trial reported a 37% reduction in kidney stones events and decreased kidney pain in patients receiving tolvaptan [89]. In a separate cohort, tolvaptan use was associated with reduced urinary supersaturation of brushite, calcium oxalate, and uric acid, along with higher urinary calcium and citrate excretion [90]. The effects may reflect direct V2R antagonism and indirect compensatory responses (e.g., V1a/B1b activation) [88,91]. Given data linking calcium oxalate crystal deposition to accelerated cystogenesis, tolvaptan’s benefits may extend beyond cAMP-mediated proliferation suppression to include stone prevention [32].

Urinary alkalinization and stone dissolution: Alkalinizing agents such as potassium citrate, magnesium bicarbonate, or sodium bicarbonate are first-line therapies for uric acid and cystine stones [92,93]. In a retrospective study of 272 patients, dissolution therapy achieved a 61% success rate over three months, particularly in patients with smaller, low-density stones [92]. While similar outcomes are anticipated in ADPKD, supporting data are limited [30]. Potassium citrate may benefit hypocitraturic calcium oxalate stone formers and those with distal acidification defects [1], though over-alkalinization may increase calcium phosphate stone risk [19,62]. Monitoring urinary pH is critical. Allopurinol or febuxostat may be used in hypouricemic patients, but routine use remains controversial [80].

Analgesia: NSAIDs and opioids are commonly used for acute renal colic (Figure 2(A)) [75]. Short-term NSAID use is favored due to superior pain control and reduced need for rescue analgesia, but nephrotoxicity must be considered in ADPKD [62,75]. Acetaminophen may be preferable to opioids in certain cases and has shown comparable efficacy to NSAIDs [94].

Medical expulsion therapy: Alpha-blockers, particularly for distal ureteral stones, are supported by EAU and AUA guidelines [81,93]. In a randomized trial, alfuzosin significantly shortened stone passage time (5.2 ± 4.8 vs. 8.5 ± 7.0 d, p = 0.003) and improved pain control (p = 0.0005) [95]. Evidence for corticosteroids, calcium channel blockers, and PDE5 inhibitors remains inconclusive [62].

Surgical interventions in patients with ADPKD: Approximately, 20% of symptomatic ADPKD patients require surgical intervention (Table 2) [21].

Table 2.

Urological surgery for kidney stone management in ADPKD.

Treatment	Clinical indications	Advantages	Disadvantages
Shock wave lithotripsy (SWL)	Non-lower pole kidney stones ≤20 mm; lower pole kidney stones ≤10 mm [93,96]	Least morbidity and lowest complication rate [93,97,98], post-operative cyst bleeding is not prevalent in ADPKD [99,100], least invasive intervention [93], and lower stone free rate (SFR)	Not advised for obesity, pregnancy, persistent UTIs, distal urinary obstruction, bleeding disorders, or arterial aneurysm in proximity [93]. Uric acid stones are more difficult to treat.
Ureteroscopy (URS) with laser lithotripsy -flexible, or semi-rigid,	Non-lower pole renal stones ≤20 mm; lower pole renal stones ≤10 mm [93,96]; Ureteral stones; alternative to PCNL in high-risk patient [93,96]	Superior stone free rate relative to SWL [93,101]; least affected by kidney cysts [102]	Infection, thrombosis, emboli, and strictures [93,103]
Percutaneous nephrolithotomy (PCNL)	Non-lower pole renal stones >20 mm; lower pole renal stones >10 mm [93,96]; Lack of retrograde access [67]	Most optimal in treating large calculi in comparison to other treatments due to high stone free rate SFR [93]	Most invasive and highest potential procedural complications in ADPKD: cyst infection with fever, paralytic ileus, and hemorrhage requiring blood transfusion [67,104,105]
Open or laparoscopic surgery	Large, impacted, inaccessible ureteral or renal stones [106,107] Calyceal diverticulum; Nonfunctional renal unit	Less morbidity and faster recovery with laparoscopic surgery as opposed to open [108]; higher initial SFR and reduced transfusion rate compared to PCNL [109]	Most invasive treatment modality. Last resort amid failure of other noninvasive procedures [110]. Large ADPKD kidneys are a significant challenge [102]

Shock wave lithotripsy (SWL): SWL is the least invasive option and is most effective for stones ≤10 mm [96]. Early studies reported low stone-free rates (SFRs) in ADPKD (43%) [74], but more recent data suggest SFRs of up to 85% at 3 months, though repeat interventions were often needed [99]. SWL is safe in children with polycystic kidneys (n = 17), achieving a 94% SFR at 12 months [111], but anatomic distortion in adults, particularly calyceal or infundibular changes, can hinder fragment clearance [112]. Although initial concerns included risks of cyst hemorrhage and nephron loss [113], recent studies have not confirmed these complications [112,114]. In a study of 13 ADPKD patients, SWL achieved an 84.6% success rate, with no major complications including cyst hemorrhage [99]. Transient tubular dysfunction may occur post-SWL but typically resolves within two weeks [115].

Ureteroscopy (URS): URS offers direct visualization and is adaptable to complex anatomy. However, significant cyst burden may limit calyceal access [105]. URS shows superior SFRs compared to SWL and is effective for stones < 20 mm, including staged flexible ureteroscopy (fURS) with laser lithotripsy [93,101,116]. A study of 45 patients undergoing fURS with holmium laser lithotripsy (mean stone size: 5.6 mm, range 3–17 mm) reported SFRs of 84.5% after one session and 92.3% after two sessions, with only minor complications (flank pain, low-grade fever, and stent discomfort) [117]. URS does not increase perioperative complications compared to non-ADPKD patients, although hospital readmissions may be more common [56].

Percutaneous nephrolithotomy (PCNL): PCNL is preferred for large and complex stones but is technically challenging in ADPKD due to distorted parenchyma and narrow calyces [105,118,119]. Risks include cyst infection, rupture, hemorrhage, and loss of renal function [120]. US-guided PCNL improves safety by avoiding cysts [121]. In a study of 22 ADPKD patients (16 with serum creatinine >1.5 mg%), PCNL achieved an 88% SFR, but 13% required blood transfusions and 18% developed fever [104]. Residual fragments are common and may necessitate second-look PCNL, URS, or adjunctive citrate therapy [118].

Procedure selection: SWL and URS are generally preferred for upper tract stones <20 mm, with choice guided by stone characteristics, anatomy, and local expertise. SWL is the least invasive but has the lowest SFR. URS offers higher efficacy with modest risk. PCNL provides the highest SFR for large stones but is associated with greater morbidity [93,97,98]. A 2020 systematic review reported significant variability in outcomes across surgical modalities, driven by patient selection, and imaging techniques [67].

Laparoscopic and open surgery: Laparoscopic ureterolithotomy (LU) may be considered for large (>15 mm), impacted ureteral stones when less invasive options fail [55,93,106,107]. While LU offers higher SFR and low complication rates, its safety in ADPKD remains unproven due to concerns over cyst rupture and anatomical displacement.

Conclusion

Kidney stone disease is a prevalent and clinically significant complication in ADPKD, contributing to pain, infections, hospitalizations, and possibly accelerated disease progression. While both metabolic and structural abnormalities contribute to stone formation, frequent imaging in ADPKD may inflate prevalence estimates. Diagnosis relies on NCCT, with US serving as a safer but less sensitive alternative in cystic kidneys. Management should prioritize hydration, correction of metabolic derangements, and tailored procedural approaches that account for anatomical complexity. Future research should explore targeted therapies, such as microbiome modulation, metabolic interventions, and refined surgical techniques, to reduce stone burden and mitigate its impact on ADPKD progression.

Funding Statement

Dr. Chebib is supported by the Mayo Clinic Florida RACER Award, CURE2030 Award, CATALYST Award, Department of Medicine Team Science Award, the Mayo Clinic Pirnie Polycystic Kidney Disease (PKD) Center, the Zell Family Foundation, and the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) U54 DK144863 and R01 DK142878.

Disclosure statement

FTC received research funding from Otsuka Pharmaceuticals, Regulus, and Natera Inc, has a patent on ‘Probenecid as a treatment in ADPKD’ and he is a member of Board of Directors in the PKD Foundation.

ND discloses consultancy for Natera, Otsuka, and Vertex; advisory committee for PKD Foundation; and clinical trial funding from Regulus, Reata, and Vertex.

The authors have no conflicts of interest to declare.

Authors’ contributions-CRediT statement

-Abdul Hamid Borghol, Dr. (First-author): Study conceptualization, methodology, project administration, supervision, writing-original draft, writing-review & editing, visualization, Final approval & Accountability.

-Masara Azooz, Ms (Co-author): Visualization, writing-original draft, writing-Review and editing (co-writing the original draft with AHB, drafting all tables, Final approval & Accountability).

-Marie Therese Bou Antoun, Dr. (Co-author): Visualization, writing-Review and Editing (drafting Figure 2(A,B) as well as reviewing the manuscript, Final approval & Accountability).

-Levon Souvalian, Dr. (Co-author): writing-original draft, writing-review & editing (writing the treatment section and then reviewing the original draft, Final approval & Accountability).

-Besher Shami, Dr. (Co-author): Visualization, writing-review & editing (drafted Figure 1 and reviewed/edited the manuscript, Final approval & Accountability).

-Jonathan Mina, Dr. (Co-author): writing-original draft, writing-review & editing (providing the original draft, drafting the tables and reviewing the manuscript, Final approval & Accountability).

-Fadi George Munairdjy Debeh, Dr. (Co-author): Visualization, writing-review & editing (Radiologist expert-reviewed the imaging part of the manuscript as well as providing the images for Supplementary Figure 1, Final approval & Accountability).

-Ahmad Ghanem, Dr. (Co-author): Visualization, writing-review & editing (Figures 2(A,B), as well as reviewing/editing the manuscript, Final approval & Accountability).

-Hashem Sandouk, Dr. (Co-author): Visualization, writing-review & editing (helped with Figure 1, and reviewing the manuscript, Final approval & Accountability).

-Vineetha Rangarajan, Dr. (Co-author): writing-original draft, visualization (nephrologist, helped with the original draft, treatment algorithms and reviewing the manuscript, Final approval & Accountability).

-Dana Hanna, Dr. (Co-author): Visualization (radiologist in training, helped with the imaging part and procuring the images for Supplementary Figure 1, Final approval & Accountability).

-Christopher Dilan Naranjo, Dr. (Co-author): Writing-Review & editing (Nephrologist, helped with reviewing/editing the manuscript, Final approval & Accountability).

-Yelena R Drexler, Dr. (Co-author): Writing-Review & editing (PKD expert, helped with reviewing/editing the manuscript, Final approval & Accountability).

-Sayna Norouzi, Dr. (Co-author): Writing-Review & editing (PKD expert, helped with reviewing/editing the final draft, Final approval & Accountability).

-Anahita Noruzi, Dr. (Co-author): Writing-Review & editing (PKD/molecular scientist working on stone diseases, helped with reviewing/editing the final draft, Final approval & Accountability), Methodology, Supervision, Writing-Review & editing.