Nephrolithiasis in Autosomal Dominant Polycystic Kidney Disease

Abstract

Background and Purpose:

Autosomal dominant polycystic kidney disease (ADPKD) manifests with renal and extrarenal abnormalities and is inherited in an autosomal dominant fashion. In addition to multiple renal cysts, abnormalities such as liver cysts (80%), pancreatic cysts, splenic cysts, pulmonary cysts, berry aneurysms in the distribution of arterial circle of Willis (8%), colonic diverticula, mitral valve prolapse, etc., can be present. The condition will develop in half of the offspring of affected persons because of its 100% penetrance. Nephrolithiasis in patients with ADPKD is not infrequent and, given the importance of preservation of renal function in this subset of patients, a clear understanding of the management options available and their advantages and disadvantages is absolutely essential and critical in better patient outcomes. This article is an endeavor in this direction and provides a review of the current available literature.

Materials and Methods:

An electronic database search of Medline, Embase, and Cochrane library was performed to search for the available literature in January 2010 with no restrictions in terms of date or language. The search terms used were ADPKD, nephrolithiasis, percutaneous nephrolithotomy, shockwave lithotripsy, flexible ureterorenoscopy, congenital kidney disorders, etc., separately and in various combinations. The articles so extracted were scrutinized for relevance and selected for the review.

Introduction

A utosomal Dominant Polycystic Kidney Disease (ADPKD) is an inherited systemic disorder, the most common type of which is caused by an abnormality in the polycystin-1 gene (PKD-1) located on the short arm of chromosome 16.¹ The other less common type, which accounts for 5% to 10% of cases of ADPKD, is caused by an abnormality in the polycystin-2 gene (PKD-2) that is located on the long arm of chromosome 4.^2,3 The less common type usually presents after the third decade of life and has an incidence of about 1:500 to 1:1000 live births with no sexual or racial predisposition.⁴

PKD-1 manifests early, worsening rapidly over the years and leading to end-stage renal disease (ESRD) in the fifth to sixth decade of life. PKD-2, on the other hand, has a slower rate of progression and consequently delayed development of ESRD. ADPKD is more severe when inherited from the mother⁵ and, in such cases, tends to manifest early in a severe form in subsequent generations.

PKD-1 and PKD-2 arise as a result of a mutation in the polycystin-1 and polycystin-2 genes, respectively. These code for polycystin-1 and polycystin-2 glycoproteins, respectively. Polycystin-1 and polycystin-2 are transmembrane glycoproteins that are found in the tubular epithelial cells, and they inhibit epithelial proliferation via several pathways/mechanisms, including the extracellular signal regulated kinase pathway⁶ and the mammalian target of rapamycin pathway.⁷ Hence, a defect in these proteins leads to unopposed proliferation of tubular epithelium, which leads to cyst formation.

Diagnosis of ADPKD

The diagnosis of ADPKD is based on the radiologic evidence of more than one unilateral or bilateral fluid-filled renal cyst in adults with a positive family history. Ultrasonography is the basic imaging modality used in the detection of ADPKD. The classical ultrasonographic description is a simple round cyst with sharp, smooth margins, free of septae and calcifications and an echo-free interior.

Ultrasonographic diagnosis is currently based on Ravine criteria.⁸ The number of cysts needed for diagnosis (Table 1) is age dependent; ie, ≥2 unilateral or bilateral cysts in patients who are younger than 30 years of age, ≥2 bilateral cysts in patients between 30 and 59 years, and ≥4 bilateral cysts in patients older than 60 years.

Table 1.

Ravine Ultrasonographic Criteria for Diagnosing Autosomal Dominant Polycystic Kidney Disease

	Number of cysts in both kidneys (total)
Age in years	Positive family history	Negative family history
<30	2	5
30–60	4	5
>60	8	8

Table adapted from Ravine D, Gibson RN, Walker RG, et al.⁸

MRI and CT are the other imaging methods that can be used for diagnosis of ADPKD. There are separate criteria for MRI diagnosis of ADPKD⁹ and are again based on age and number of cysts found (Table 2). Genetic diagnosis that involves direct or indirect detection of mutations is cumbersome and expensive and, hence, not used routinely in practice.⁵ Patients with ADPKD may present with nephrolithiasis in addition to hypertension, flank pain, hematuria, urinary tract infections, and renal failure.

Table 2.

Magnetic Resonance Imaging Criteria for the Diagnosis of Autosomal Dominant Polycystic Kidney Disease

Age in years	Number of cysts in both kidneys (Total)
<30	≥5
30 – 44	≥6
45 – 59 (males)	>6
45 – 59 (females)	>9

Table adapted from Nascimento AB, Mitchell DG, Zhang XM, et al.⁹

ADPKD and Nephrolithiasis

The incidence of nephrolithiasis is about 5 to 10 times higher in patients with ADPKD than in the general population.¹⁰ Approximately 25% of these patients are symptomatic,^11,12 with symptoms mostly in the form of recurrent severe flank pain and hematuria¹⁰ necessitating urologic intervention. One-third have nephrolithiasis confirmed on a CT scan.¹³ A noncontrast CT of the kidneys, ureters, and bladder is considered an investigation of choice in patients with ADPKD who are suspected of having nephrolithiasis.^13,14

The higher incidence has been ascribed to the combination of anatomic and metabolic risk factors in patients with ADPKD. Anatomic distortions because of the cysts in ADPKD cause compression of the pelvicaliceal system that leads to urinary stasis, delayed washout of crystals, higher risk of urinary tract infections, and, hence, increased incidence of stone formation.¹⁵ Patients with a greater number of cysts and a larger predominant cyst size are considered to be at a higher risk of stone formation.¹⁶

The most common metabolic abnormalities in patients with ADPKD that contribute to nephrolithiasis include hypocitruria, aciduria or low urinary pH, abnormal transport of ammonia, and distal acidification defects.¹⁷ In addition to lower citrate levels, patients with ADPKD have been shown to have low levels of urinary magnesium, phosphate, and potassium.¹⁶ Both magnesium and citrate are powerful inhibitors of crystal formation and aggregation,^18,19 and studies have also shown that decreased levels of urinary magnesium and citrate are significant risk factors for renal stone disease.^20,21

The most common stone types in patients with ADPKD are uric acid (57%) and/or calcium oxalate (47%).^17,22 Hypercalciuria and hyperoxaluria thus have a less relevant role in ADPKD patients with nephrolithiasis. Although uric acid stones are more common in patients with ADPKD, no difference has been found in the prevalence of hyperuricemia and fractional excretion of uric acid compared with non-ADPKD stone formers.^17,23 A defective ammonium excretion leading to low urinary pH has been suggested as the possible explanation in ADPKD patients with uric acid stones.²³

Management of Nephrolithiasis in ADPKD

Although the principles of management of nephrolithiasis in patients with ADPKD are the same as in patients with normal kidneys, closer monitoring and earlier intervention might be necessary especially in the subgroup with deranged kidney function or those with limited kidney function reserve. The indications that warrant early intervention are recurrent pain, hematuria, urinary tract infections, obstructive uropathy, and deteriorating renal function. The size and location of the kidney stones in a polycystic kidney also influence the choice of treatment.

Open surgery was almost universally used in managing stones in patients with polycystic kidneys about 15 to 20 years ago,^12,15 but now such patients can safely be treated with noninvasive or minimally invasive methods, such as shockwave lithotripsy (SWL), percutaneous nephrolithotomy (PCNL), flexible ureterorenoscopy (FURS), and laser fragmentation.

SWL has proven to be the management option of choice for the majority of renal stones.²⁴ Use of SWL to treat patients with nephrolithiasis and ADPKD, however, is supported by only a few small studies. SWL is noninvasive and less cumbersome for patients, but there may be concerns such as potential risk of traumatic hemorrhage into the cysts, traumatic loss of nephrons because of shockwaves, and decreased clearance of the stone load.

In a study performed between 1990 and 1994 by Delakas and associates,²⁵ 13 patients with ADPKD and nephrolithiasis, comprising 16 renal units, were treated with SWL. Of the 16 stones, 12 were less than 2 cm. Ten renal units had complete fragmentation with one session, three units had successful complete fragmentation after a second SWL session, and three units had no fragmentation and needed other procedures. Overall, the success rate was 84.6% (11 of 13 patients). There were no complications necessitting hospitalization, and ultrasonography performed 5 days later in eight patients who had transient hematuria failed to reveal any hemorrhage into the cyst.

In related studies by Al Tawheed and colleagues²⁶ and Chen and coworkers²⁷ in patients with nephrolithiasis in kidneys with anatomic abnormalities, including ADPKD, it was concluded that SWL is the primary management option. In another study performed by Frick and colleagues²⁸ on 34 children who were treated by SWL for nephrolithiasis in polycystic kidneys, 16 of 17 children who appeared for 12-month follow-up were stone free. Martinez Sarmiento and associates²⁹ also reported that SWL was safe and effective in treating six of their patients (eight renal units) with ADPKD and nephrolithiasis. None of the patients had any complications in this group.

Cass³⁰ and Deliveliotis and coworkers³¹ in their small studies, however, concluded that renal cysts interfere with the passage of stone fragments because of impediment of drainage and urinary stasis from the stretching and distortion of the caliceal system and that the rates of clearance of stone load were lesser compared with the non-ADPKD kidneys. Both do conclude, however, that hemorrhage into the cysts is not an issue at all.

There have been no studies to assess the traumatic loss of nephrons after SWL in patients with ADPKD per se, but studies in non-ADPKD patients have shown no long-term deterioration in glomerular filtration rate (GFR) or renal function. Jaeger and associates³² in their study performed in dogs found extensive histologic changes limited to areas that were exposed to SWL. The changes included hemorrhage and sometimes direct tubular damage with scar formation after 3 months, but this was not reflected in the renal function parameters, leading them to believe that the changes were transient.³³

Physiologic studies on non-ADPKD kidneys in animals do show various transient physiologic changes in GFR and renal blood flow,^34,35 but various studies using biochemical and isotope studies have failed to show any definite evidence of loss of renal function,^35,36 provided that it was normal initially.

Rutz-Danielczak and associates³⁷ in their study of 30 non-ADPKD patients found a similar outcome, and they concluded that SWL treatment leads to transient dysfunction of the proximal tubule and that function recovers in 2 weeks.³⁷ The restoration of function, however, may partly be from the additional contribution of the other kidney. Studies in patients with a solitary kidney who were undergoing SWL eliminate the compensatory effects of the untreated contralateral kidney and have shown an average long-term deterioration of renal function in about 22% of patients.³⁸ This could reflect in biochemical deterioration in a patient with ADPKD, especially if the renal function is abnormal to start with. It was comparable to deterioration in long-term renal function in 29% of patients with solitary kidney who were undergoing PCNL.³⁹

PCNL in ADPKD can be challenging because of the distortion of the anatomy by the cystic nature of the kidneys. Because of the compressive effects of the cysts, the caliceal spaces are often narrow and elongated, leading to difficulty in puncture and subsequent tract dilatation. The cysts can come in the way of the puncture and, in some cases, might need to be aspirated before a puncture is achieved. It is relatively a more invasive procedure, and there are concerns regarding loss of nephrons at the puncture site. There have been only a few reports^16,40regarding the use of PCNL in patients with ADPKD, and of a total of about six renal units, five were managed successfully by PCNL.

In a recent report by Umbreit and colleagues,⁴¹11 renal units in nine patients with ADPKD and nephrolithiasis were managed with PCNL. Only two renal units needed additional endoscopic procedures. There were no intraoperative or postoperative complications. In a mean follow-up of 2.7 years, none of the patients had deterioration in renal function, and a CT at a median follow-up of 32 months showed no recurrence of nephrolithiasis. Multiple puncture tracts were needed in 5 of the 11 renal units. Cyst aspiration was needed in three renal units. The authors recommended PCNL as a safe and efficacious second-line management option for large and multiple upper tract calculi.

Al-Kandari and coworkers⁴²in a recent study that involved 19 patients with ADPKD and nephrolithiasis have shown a success rate approaching that in non-ADPKD kidneys when managed with PCNL. There was no significant morbidity, and the renal function remained stable. Various studies in pigs⁴³ and humans⁴⁴ with non-ADPKD kidneys have also failed to demonstrate any long-term deterioration in renal function. The same, however, cannot be said if multiple tracts are used, especially in patients who have abnormal function to begin with.⁴⁵

The thin laser fibers and nitinol retrieving devices allow greater flexibility and maneuverability because of minimal interference in the deflection of the tip of the flexible ureterorenoscope,⁴⁶ thus providing easier access to stones in hard to reach areas of the kidney as well. FURS also has the advantage of having no potential to cause traumatic nephron loss and being independent of anatomic variations from the cystic disease. It may be a beneficial option in ADPKD patients with bleeding diathesis, morbid obesity, and solitary kidney.

There are not many reports or case series of ADPKD patients with nephrolithiasis who were treated with FURS and/or laser. Ng and coworkers⁴⁰ in their study in 13 cases of ADPKD with nephrolithiasis showed that all minimally invasive interventions can be effectively and safely used based on the position of stones as in normal kidneys. This included SWL, PCNL, ureteroscopic manipulation, ureteroscopic laser, and, in one case, extended pyelolithotomy. In their study, however, none of the renal stones were dealt with ureteroscopically. Kuo and associates⁴⁷ in their randomized trial in non-ADPKD patients showed that FURS was as effective if not better than SWL or PCNL for lower pole stones, especially those less than 1 cm.

Because metabolic factors contribute to stone formation, a proper metabolic evaluation should be conducted to diagnose specific, treatable metabolic disorders, thereby reducing the frequency of recurrent stone disease in such cases.⁴⁸

Conclusion

The management of nephrolithiasis in patients with ADPKD should be similar to those in non-ADPKD patients, although earlier intervention and closer monitoring may be mandatory. Preserving the renal function should be kept in mind when deciding the primary management plan. The principles of formulating a management plan otherwise should be no different from one for a non-ADPKD patient.

All management options have pros and cons. and the decision to adopt a particular modality should be based on well defined-factors. The factors include stone factors (number, size, and composition), spatial factors (stone location, spatial anatomy of the collecting system, hydronephrosis, and caliceal diverticula), and patient factors such as morbid obesity, coagulation disorders, solitary kidney, and renal insufficiency.

In terms of preservation of function, FURS and laser might be the best options, but such assumptions need to be validated by further studies. Because of the relative rarity of patients with ADPKD, a multicenter trial would help generate a cohort large enough to provide a statistically valid result.

Footnotes

Disclosure Statement

No competing financial interests exist.

Abbreviations Used

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