Etiology
The pathogenesis of medullary sponge kidney (MSK) is unknown. MSK may occur with other congenital defects such as hemihypertrophy (enlargement of one side of the body), Beckwith-Wiedemann syndrome (congenital disease), Caroli disease (fibropolycystic liver disease), congenital hepatic fibrosis, autosomal dominant polycystic kidney disease, and Ehlers-Danlos syndrome (connective tissue disorder).[3] In addition, Wilms tumor (chromosome 11p13) has been described in patients with both MSK and hemihypertrophy, and with both MSK and Beckwith-Wiedemann syndrome (chromosome 11p15).
The association with multiple other congenital disorders suggests that MSK is a developmental disorder of renal embryogenesis.[13] MSK may be caused by a disruption of the ureteric-bud/metanephric-blastema interface. One study demonstrated that 8 of 55 MSK patients, analyzed by direct DNA sequencing, had alleles containing variant sequences in the gene for glial cell-derived neurotrophic factor (GDNF).[14] Two mutations occurred in the 8 patients in a putative binding domain for a transcription factor. One case-control study showed that the alleles were associated with MSK. GDNF is the ligand for rearranged during transfection (RET), a proto-oncogene. Both RET and GDNF are critical in renal development, required for ureter and collecting-duct formation and for normal nephrogenesis, morphogenesis, and kidney growth. The RET-GDNF complex therefore appears to be a plausible cause of MSK.[3][15] RET and GDNF have a known non-renal role in the development of the central nervous system, heart, and craniofacial skeleton.[13] One cohort study of patients with known MSK showed an association between MSK and extra-renal developmental defects, further supporting the role of the RET-GDNF complex in the pathogenesis of MSK.[13] Investigators have also studied renal papillary cells of a patient with MSK who was heterozygous for a GDNF gene mutation.[16] Calcium phosphate deposits formed in only the MSK cultures and not in cells from healthy control patients. The MSK cells expressed osteocalcin and osteonectin, suggesting an osteoblast-like phenotype. Compared with control cells, GDNF was down-regulated in the MSK cells. Knocking down GDNF-expression in another kidney cell line also promoted calcium phosphate deposition when cells were incubated with calcifying medium.
In one study of MSK patients and family members, an autosomal-dominant pattern of inheritance was demonstrated in 27 of 50 MSK patients. In those 27, 73% (59 out of 81) of their first- and second-degree relatives (of both sexes) were diagnosed with MSK. The diagnosis in relatives was made by intravenous urography in 40, ultrasound in 14, and inferred in 5 deceased patients by a history of multiple calculi.[17] Affected relatives seem to have milder forms of MSK by biochemical profiles. In some, there may be mutations of the RET oncogene, which is important for normal kidney development. This gene may also play a role in parathyroid cell proliferation and development of the liver excretory system.[18][10]
Distal renal tubular acidosis has been found in several studies of MSK patients.[19][20][21] Two cases with renal tubular acidosis associated with mutations in H+ -adenosine triphosphatase genes have been reported.[22] However, some studies have not found overt distal renal tubular acidosis in any of their MSK patients.[23] Distal renal tubular acidosis and hypocitraturia may contribute to stone formation.[19][23] Distal renal tubular acidosis leads to low urine citrate (an inhibitor of calcium crystallization) and an alkaline urine pH, both of which favor calcium phosphate stone formation. In addition to tubular abnormalities, there may be mild defects in urinary concentration.[19][24] Hyperparathyroidism in some MSK patients was once thought to cause renal stones. However, nephrolithiasis has been shown to occur before hyperparathyroidism.[4]
Pathophysiology
Urinary stasis in ectatic tubules may contribute to the formation of renal stones, although conclusive evidence for this hypothesis has not been demonstrated. Renal stones in patients with MSK may be composed of calcium oxalate or calcium phosphate, or both. Reported incidence of MSK in recurrent stone formers varies from 3% to 20%.[3][10] Most studies measuring urinary citrate in stone formers with MSK have shown that these patients have hypocitraturia (defined as a urine citrate <300 mg/day).[6][20][23] Citrate inhibits calcium crystallization so that hypocitraturia is a risk factor for calcium stone formation.[6][20][23] It is not clear whether the distal tubule alone is affected. Proximal tubular defects have been suggested to be involved by an inability to reabsorb glucose.[24] Urinary tract infections (UTIs) may develop, probably due to urinary stasis and stone formation. Microscopic and gross hematuria may be seen in the absence or presence of stones. Hematuria is usually secondary to UTIs or stones.
Papillary biopsies of patients with MSK were stained for expression of the bone genes Runx2 and Osterix.[25] Although both genes were expressed in interstitial cells of papillae of MSK patients, no mineral deposition was seen at the sites of gene expression, arguing against a role of bone formation in this process.
Classification
Radiologic guide to classification[1]
There is no formal classification system for MSK, but it can be classified by radiologic findings.
Group I: patients with MSK on urogram but stone-free
Group II: patients with nephrocalcinosis (small calcium deposits in the kidneys), urinary infections, and hematuria
Group III: patients with nephrolithiasis (renal stones).
Grading system based on intravenous urography findings[2]
The following criteria for classification have been proposed, but they are not generally used:
Grade 1: unilateral involvement of 1 renal papilla (location where medullary collecting ducts converge)
Grade 2: bilateral involvement of only 1 papilla in each kidney
Grade 3: unilateral involvement of more than 1 papilla
Grade 4: bilateral involvement of at least 1 papilla.
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