Medullary sponge kidney

INTRODUCTION — Medullary sponge kidney (MSK), originally called Lenarduzzi-Cacchi-Ricci disease, is a congenital disorder characterized by malformation of the terminal collecting ducts in the pericalyceal region of the renal pyramids [1,2]. This collecting duct dilatation, or ectasia, is associated with the formation of both small (microscopic) and large medullary so-called "cysts" that are often diffuse but do not involve the cortex. MSK is a well-known cause of nephrocalcinosis and calcium kidney stones, although the clinical phenotype may be more complex.

This topic will review the epidemiology, pathogenesis, clinical manifestations, diagnosis, and management of MSK. Issues related to the diagnosis and treatment of nephrocalcinosis and kidney stones are presented separately:

●(See "Nephrocalcinosis".)

●(See "Kidney stones in adults: Diagnosis and acute management of suspected nephrolithiasis".)

●(See "Kidney stones in adults: Prevention of recurrent kidney stones".)

●(See "Kidney stones in adults: Epidemiology and risk factors".)

EPIDEMIOLOGY — The prevalence of medullary sponge kidney (MSK) in the general population is unclear but is thought to be less than 0.5 to 1 percent [3]. The prevalence of MSK is much higher (12 to 20 percent) among patients who recurrently form calcium kidney stones [4-6]. MSK affects males and females equally and is generally diagnosed in adulthood but has also been reported in children [7].

PATHOGENESIS — The changes seen in medullary sponge kidney (MSK) are thought to reflect a developmental abnormality, though the underlying defect is not fully understood. The association of MSK with malformations affecting extrarenal sites such as hemihypertrophy and Beckwith-Wiedemann syndrome has led to speculation that the disorder results from a disruption of the interface between the ureteric bud and the metanephric blastema during embryonic development [8].

Evidence for genetic transmission of MSK is limited. Some patients with MSK have mutations in the gene for glial cell derived neurotropic factor (GDNF), which encodes a protein that is pivotal in kidney development [9]. One study suggested that mutations in GDNF may lead to osteogenic differentiation in renal papillary cells, resulting in MSK [10]. Other reports have suggested a role for other genes in the pathogenesis of MSK, such as PKHD1, the gene mutated in patients with autosomal recessive polycystic kidney disease (ARPKD) [11], and genes involved in autosomal recessive distal renal tubular acidosis [12]. However, a direct association between these genes and MSK has not been demonstrated.

Although occasional families with MSK appear to show autosomal dominant inheritance [4,13-16], a positive family history is often absent. Despite this, family clustering of MSK may be common. In a study of 50 patients with documented MSK, 27 had affected immediate family members identified with imaging (either contrast-enhanced computed tomography [CT] or ultrasound) or, among deceased family members, a suggestive clinical history [17,18]. Not all affected family members had a phenotype that was identical to that of the index cases. The responsible genotypes for this clustering are uncertain and were not due to mutations in GDNF. In another study, a mutation in HNF1 homeobox B (HNF1B) was identified in a family with nephrocalcinosis, imaging findings characteristic of MSK, and a pedigree consistent with autosomal dominant inheritance [19].

As described elsewhere, a common clinical manifestation of MSK is recurrent calcium phosphate and calcium oxalate stone formation (see 'Kidney stones and nephrocalcinosis' below). Several factors are thought to contribute to such formation:

●Affected patients often have well-established urinary risk factors for calcium stone formation, such as higher urinary excretion of calcium, oxalate, or uric acid and lower excretion of citrate [4-6,20]. The frequency of these abnormalities may be higher than in stone formers without MSK. Higher calcium excretion in patients with MSK may, in some patients, reflect impaired calcium reabsorption by the damaged collecting tubules [4]. (See "Kidney stones in adults: Epidemiology and risk factors".)

●Patients with MSK often form hydroxyapatite (calcium phosphate) concretions in the dilated tubules, which then act as the nidus for stone formation [4]. Two potential mechanisms may contribute to this nephrocalcinosis: stasis in the ectatic collecting ducts and an increased urine pH due to impaired local acidification in the terminal collecting duct. Although the urine pH may be appropriately acidic (less than 5.3) if the number of affected nephrons with impaired acidification is relatively low, some patients with MSK have incomplete distal renal tubular acidosis in which the urine pH remains above 5.3, even in the setting of an acid load [4,21]. Overt renal tubular acidosis has been described but is uncommon [12]. (See "Etiology and diagnosis of distal (type 1) and proximal (type 2) renal tubular acidosis".)

CLINICAL FEATURES

Clinical manifestations — The major clinical manifestations of patients with medullary sponge kidney (MSK) are kidney stones (which can cause flank pain and/or hematuria), hematuria, and urinary tract infections [2]. The age at diagnosis is typically 30 to 50 years; however, the range is wide with some teenagers presenting with renal colic.

Some patients with MSK are asymptomatic. In such patients, the disease either remains undiagnosed or is discovered incidentally with a radiographic study, such as a computed tomography (CT) urogram, performed for some other indication. Most patients are diagnosed after a typical episode of renal colic. (See 'Diagnosis' below.)

Kidney stones and nephrocalcinosis — The incidence of stones and nephrocalcinosis (the deposition of calcium phosphate or calcium oxalate in the kidney parenchyma) in patients with MSK is hard to determine since most patients with this disorder go undiagnosed [4]. However, the diagnosis is frequently made in patients being evaluated for recurrent nephrolithiasis. (See 'Epidemiology' above and 'When to suspect MSK' below.)

The stones in MSK are primarily composed of calcium phosphate and calcium oxalate. In the presence of urinary tract infection with urease-producing organisms, struvite may be a component as well. As previously described, several factors are thought to contribute to stone formation in this setting. (See 'Pathogenesis' above.)

Hematuria — Hematuria is another common symptom in MSK, and its presentation is highly variable [4]. It can occur in the presence or absence of stones, can be associated with nephrocalcinosis, can be microscopic or gross, and can be singular or recurrent. The bleeding is typically painless unless clots lead to ureteral obstruction or it is associated with nephrolithiasis.

Urinary tract infection — Urinary tract infection also occurs with increased frequency in MSK, especially in women. Approximately one-third of women with this disorder have two or more infections [5]. Stone formation and stasis in the cysts are probably contributing factors.

Decreased concentrating ability — Collecting tubule dysfunction can also lead to decreased maximum concentrating ability in these patients [4,21]. However, the defect is usually mild and does not lead to symptomatic polyuria except for occasional nocturia.

Diminished bone mineral density — Many patients with MSK appear to have decreased bone mineral density (BMD). One uncontrolled study demonstrated that patients with MSK and higher urine calcium excretion had diminished BMD; 59 percent of these patients had a T score between -1.0 and -2.5 (osteopenia), and 12 percent had a T score lower than -2.5 (osteoporosis) [22]. In a second study, 71 percent of patients had either osteopenia or osteoporosis, and BMD improved with potassium citrate therapy [22]. As with other calcium stone formers with higher urinary calcium excretion [23], there was an inverse correlation of lower BMD with higher urine calcium excretion.

In addition to higher urine calcium excretion, two further mechanisms may contribute to decreased BMD:

●Impaired acidification of the urine could result in reduced BMD, and treatment with potassium citrate is associated with improved BMD. However, impaired acidification has not been consistently demonstrated.

●An association between MSK and hyperparathyroidism has been observed [24], but this association is inconsistent and not clearly related to stone formation or diminished BMD [2].

Flank pain in the absence of stones — Pain is frequent in MSK patients because of stone passage and is generally related to stone activity. However, in rare patients, flank pain is reported in the absence of an obstructing kidney stone or urinary tract infection. The basis for pain in this setting is poorly understood.

Flank pain may be acute, resembling renal colic, and may lead to emergency department visits; when imaging studies fail to demonstrate obstructing stones, hydrocalyx, or hydronephrosis, patients are frequently dismissed without receiving analgesics. Chronic pain can also occur and produce significant disability. In a minority of affected patients, this recurrent pain may become life changing and lead to chronic treatment with analgesics, including opiates [25].

Other associated conditions — Occasionally, patients manifest other clinical features that suggest a congenital disorder. As an example, hemihypertrophy, Marfan syndrome, hypertrophic cardiomyopathy, nerve and skeleton abnormalities, and urinary tract malformations have been described in patients with MSK [16,26,27].

Imaging findings — Patients with MSK frequently undergo imaging of the genitourinary tract that is performed for another indication. The appearance varies based upon the modality utilized:

●Intravenous pyelography (IVP) – The cystic dilatations in the kidneys of affected patients lead to the appearance on IVP of a "brush," or linear striations, radiating outward from some or all of the calyces (image 1 and image 2). Enlargement of the pyramids and intraductal concretions are also often seen. Calcium stones, if present, are typically small and, almost pathognomonically, occur in clusters limited to the affected calyces (image 3 and image 4). Most affected patients have bilateral involvement, but some have involvement of only one kidney or of only some calyces. These findings were most commonly noted in the past when an IVP was routinely performed for the evaluation of renal colic.

●Computed tomography (CT) – Noncontrast CT scan may reveal medullary nephrocalcinosis, suggestive of MSK, but this finding is seen in other disorders associated with higher urine calcium excretion or kidney stones, and tubular ectasia is not well seen with noncontrast CT as with IVP [28]. Multidetector CT urography permits the creation of high-resolution, three-dimensional displays that provide both cross-sectional and IVP-like images of the contrast-filled renal collecting systems, ureters, and urinary bladder (image 5). Multidetector CT urography can demonstrate the cystic dilations and "brush"-like striations in the renal papillae typically seen on IVP and is highly sensitive for the diagnosis of MSK [29].

●Other modalities – Ultrasonography typically reveals a uniformly echogenic corticomedullary junction due to calcium deposits in the affected regions. Plain radiographs may be normal or demonstrate the presence of linear and rounded medullary calcifications. These findings, while characteristic of MSK, are nonspecific and can be seen in other conditions that can cause nephrocalcinosis.

DIAGNOSIS

When to suspect MSK — The diagnosis of medullary sponge kidney (MSK) should be suspected in any patient who presents with any of the following:

●Recurrent calcium kidney stones

●Nephrocalcinosis

●Flank pain of unknown etiology

Establishing the diagnosis — Although MSK may be suspected on clinical grounds, the diagnosis is established radiographically. A definitive radiologic diagnosis is provided by the finding of cystic dilations in the kidney, with pooling of radiocontrast leading to a calyceal "brush"-like appearance, in combination with either nephrocalcinosis or nephrolithiasis. These characteristic findings can only be properly identified by intravenous pyelography (IVP), which is rarely performed, or multidetector computed tomography (CT) urography. (See 'Imaging findings' above.)

In most patients with recurrent calcium kidney stones, it is generally not necessary to establish the diagnosis of MSK by one of these imaging techniques, because MSK is usually a benign disease with no specific treatment (other than therapy directed at stone prevention) and failure to make the diagnosis has no adverse consequences. In addition, both IVP and multidetector CT urography are associated with a significant dose of radiation. However, in some patients, such as those with nephrocalcinosis of unknown etiology or those with unexplained flank pain, further evaluation with multidetector CT urography may be reasonable.

Although MSK will continue to be detected at centers where IVP is routinely employed to evaluate patients with suspected kidney stones (or if multidetector CT urography is used for a separate indication such as hematuria), the widespread availability of noncontrast CT to diagnosis kidney stones has decreased the frequency by which MSK is discovered.

Occasionally, MSK may be diagnosed by ureteroscopy when this procedure is performed in patients with symptomatic nephrolithiasis. In one study, the kidney papillae in such patients had a distinctive "billowy" appearance with yellow and white plaque, with small ductal stones and mineralized plugs in the inner medullary collecting ducts and ducts of Bellini [30].

Proteomic studies have identified laminin subunit alpha 2 (LAMA-2) as a potential urinary biomarker for the diagnosis of MSK [31]. In a study that analyzed the urine proteome of 22 patients with MSK and 22 control patients with idiopathic calcium nephrolithiasis, the protein LAMA-2 correlated best with the diagnosis of MSK. Additional studies are required to validate these findings.

DIFFERENTIAL DIAGNOSIS — In a patient with characteristic findings on computed tomography (CT) urography or intravenous pyelography (IVP), the diagnosis of medullary sponge kidney (MSK) can be made with reasonable confidence.

However, patients with MSK will more commonly present with nephrocalcinosis detected as an incidental finding by an alternate imaging study, such as ultrasound. It is not unusual for radiologists to consider nephrocalcinosis "consistent with MSK," but this conclusion is generally not appropriate. Because reduced glomerular filtration rate (GFR) is unusual in MSK, alternative diagnoses should be considered in the patient with suspected MSK and decreased GFR. As an example, patients with autosomal dominant tubulointerstitial kidney disease (ADTKD) may have similar imaging findings [32] but have a reduced GFR and can progress to end-stage kidney disease (ESKD). (See "Autosomal dominant tubulointerstitial kidney disease".)

The differential diagnosis of nephrocalcinosis is broad and is discussed elsewhere. (See "Nephrocalcinosis", section on 'Risk factors and causes'.)

Patients with MSK may also present with calcium nephrolithiasis or hematuria. The evaluation of patients presenting with these findings is presented separately:

●(See "Kidney stones in adults: Epidemiology and risk factors".)

●(See "Kidney stones in adults: Prevention of recurrent kidney stones".)

●(See "Etiology and evaluation of hematuria in adults".)

MANAGEMENT — There is no specific therapy for medullary sponge kidney (MSK). Treatment is indicated only for recurrent stone formation and for urinary tract infection (using appropriate antimicrobial therapy).

Treatment of kidney stones — Treatment of calcium stones in patients with MSK, as it does in patients with idiopathic calcium stones, varies according to the specific underlying metabolic abnormality demonstrated by 24-hour urine collections. (See "Kidney stones in adults: Prevention of recurrent kidney stones".)

In an uncontrolled, retrospective study of 97 patients with MSK, the predominant risk factors for nephrolithiasis were higher urine calcium and lower urine citrate excretion [33]. Potassium citrate therapy (mean dose of 30 mEq/day) for an average of 6.5 years was associated with a reduction in stone formation rate from 0.58 to 0.10 stones per patient per year. Similar benefits to potassium citrate therapy have been reported in other observational studies [34].

Treatment of flank pain — As noted above, rare patients with MSK have flank pain in the absence of obstructing kidney stones (see 'Flank pain in the absence of stones' above). In such patients, low-quality data suggest that ureteroscopic holmium laser papillotomy, in which the papillary urothelium overlying cystic dilations and ductal calcifications is vaporized, may produce durable pain relief in a substantial proportion of patients [35-37]. Some patients may experience pain relief only with long-term use of opiates. Other ablative therapies for chronic flank pain, such as renal denervation, have not been specifically studied in patients with MSK.

Routine monitoring — In patients with MSK who have kidney stones, we monitor kidney function (serum creatinine and/or estimated glomerular filtration rate [eGFR]) annually. Although most of these patients will have normal and stable kidney function over time, some with multiple stone-induced episodes of obstruction may develop chronic kidney disease (CKD). We also monitor kidney function annually in asymptomatic patients with MSK since some of these patients may have been misdiagnosed with MSK and have other causes of nephrocalcinosis that can lead to CKD.

In addition, in patients with kidney stones, some experts monitor 24-hour urine calcium and citrate excretion annually to monitor for the development of incomplete distal renal tubular acidosis. (See 'Pathogenesis' above and "Etiology and diagnosis of distal (type 1) and proximal (type 2) renal tubular acidosis", section on 'Incomplete distal RTA'.)

In patients with MSK who have higher urine calcium excretion, some experts monitor bone mineral density (BMD) annually by dual-energy x-ray absorptiometry (DXA) since these patients commonly have low BMD and may be at risk for developing osteopenia or osteoporosis. (See 'Diminished bone mineral density' above.)

PROGNOSIS — Medullary sponge kidney (MSK) has an excellent long-term prognosis [4]. The plasma creatinine concentration remains normal in most cases. However, stone-induced episodes of obstruction can lead to transient reductions in the glomerular filtration rate (GFR), and numerous episodes of obstruction and/or recurrent infection can occasionally lead to end-stage kidney disease (ESKD) [38].

To aid in identifying patients at greatest risk for complications, a grading system for MSK has been proposed based upon a single cohort of 29 patients from one institution [39]:

●Grade 1 − One calyx in one kidney affected

●Grade 2 − One calyx affected bilaterally

●Grade 3 − More than one calyx affected in one kidney

●Grade 4 − More than one calyx affected bilaterally

In this cohort, higher grades were associated with more symptomatic stone episodes, more hospitalizations, and more urological interventions. This grading system has not been validated or reproduced outside of the original institution or in a larger group of patients.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Chronic kidney disease in adults".)

SUMMARY AND RECOMMENDATIONS

●Epidemiology – Medullary sponge kidney (MSK) is a relatively common congenital disorder that is characterized by malformation of the terminal collecting ducts in the pericalyceal region of the renal pyramids. The prevalence of MSK in the general population is unclear but is thought to be less than 1 percent. The prevalence of MSK is much higher among patients who recurrently form calcium kidney stones. (See 'Epidemiology' above.)

●Pathogenesis – The changes seen in MSK are thought to reflect a developmental abnormality, though the underlying defect is not known. Although occasionally familial, there is little evidence for genetic transmission of MSK, and there are no known responsible genes, other than the glial cell derived neurotrophic factor (GDNF) gene in a small number of cases. (See 'Pathogenesis' above.)

●Clinical manifestations – The major clinical manifestations of patients with MSK are kidney stones (which can cause flank pain and/or hematuria), hematuria, and urinary tract infections. The age at diagnosis is typically 30 to 50 years; however, the range is wide with some teenagers presenting with renal colic. Some patients with MSK are asymptomatic. In such patients, the disease either remains undiagnosed or is discovered incidentally with a radiographic study performed for some other indication. Most patients are diagnosed after a typical episode of renal colic. (See 'Clinical manifestations' above.)

●Diagnosis – The diagnosis of MSK should be suspected in any patient who presents with recurrent calcium kidney stones, nephrocalcinosis, or flank pain of unknown etiology. The diagnosis is established radiographically by the finding of cystic dilations in the kidney, with pooling of radiocontrast leading to a calyceal "brush"-like appearance (image 1 and image 2 and image 5), in combination with either nephrocalcinosis or nephrolithiasis. These characteristic findings can only be properly identified by intravenous pyelography (IVP), which is rarely performed, or multidetector computed tomography (CT) urography. (See 'Diagnosis' above.)

●Management – There is no specific therapy for MSK. Treatment is indicated only for recurrent stone formation and for urinary tract infection (using appropriate antimicrobial therapy). In patients with MSK who develop severe, disabling flank pain not related to kidney stones, we suggest ureteroscopic holmium laser papillotomy (Grade 2C). Some patients who undergo this procedure may have pain relief and not require chronic analgesic therapy, such as with opiates. (See 'Management' above.)

●Prognosis – MSK has an excellent long-term prognosis. The plasma creatinine concentration remains normal in most cases. However, stone-induced episodes of obstruction can lead to acute kidney injury (AKI), and numerous episodes of obstruction and/or recurrent infection can occasionally lead to chronic kidney disease (CKD). (See 'Prognosis' above.)