Guerrino Lenarduzzi in 1946
Picture taken during a Meeting of the Venetian Radiologists held in Venice on May 19, 1946. Lenarduzzi is in the front row, holding a hat and briefcase.
The first description of this “uncommon pyelographic finding (dilation of the intrarenal urinary tract)” was published by Lenarduzzi in 1939 in abstract form, in the Proceedings of the Venetian Regional Association of Radiologists). The patient was very probably the one described a decade later as the “Premier case – C…Rino, âgé de quarante ans…” in the first detailed account of the condition by Cacchi and Ricci. Indeed, Cacchi and Ricci themselves wrote that this case had been diagnosed 11 years earlier.
Lenarduzzi correctly interpreted the radiological finding of MSK. He clearly realized that the radio-opaque spots were ectatic collecting ducts, not papillary cysts. Indeed, cysts are closed cavities, so they should not communicate with the urinary system, whereas in MSK the pyramids are like a sponge after the water has been squeezed out of it – hence the name of the condition.
Opacified urine in dilated collecting tubules shows a typical striated pattern inside the papillae of the affected kidney, sometimes with the appearance of flames or bouquets of flowers. Since these “ectatic” tubular structures are very thin, it takes high-definition imaging methods to disclose them. Given its high spatial resolution (capable of revealing ectatic ducts), iv. urography was the gold standard for diagnosing MSK until recently.
MSK can only be suspected on clinical and laboratory grounds. Neither the demonstration of nephrocalcinosis and multiple small calcium concretions spotted in the papillary medulla on KUB X-ray or CT without contrast, nor hyperechoic papillae on US are diagnostic.
The essential feature of the diagnostic image must demonstrate ectatic precalyceal papillary collecting ducts, the anatomical landmark of MSK.
Bilateral MSK and left kidney megacalycosis. Typical blushes are visible in all papillae in the right and left kidneys; the left kidney is remarkable, however, for the associated dilated calyces (megacalycosis) with a normal renal pelvis, which rules out any obstructive cause and suggests a malformative origin.
Having abandoned urography as part of the diagnostic work-up for renal stones in favor of the multidetector CT (with and without a contrast medium) because the latter has a better diagnostic performance in cases of renal colic and urological diseases in general, is negatively influencing our chance of diagnosing MSK. Although CT can disclose the biggest “cystic” dilations of the pre-papillary collecting ducts, unfortunately neither basal CT nor uro-CT (unlike urography) have the high spatial resolution needed to reveal the most common forms of MSK, characterized by dilated ducts and small “cysts”.
Although MSK may be silent, its anatomical characteristics and association with tubular dysfunctions explain its most common manifestations, i.e. nephrolithiasis and pyelonephritis. Macro- and microhematuria, renal failure and hyperparathyroidism can also occur, though less frequently.
Hypercalciuria and hypocitraturia are also very common. In our experience, 100% of typical MSK patients had hypercalciuria and 83% had hypocitraturia, although others have reported lower rates of their occurrence (58% and 19%, respectively). Hypercalciuria, a relatively high urine pH, hypocitraturia, and urinary stasis in the dilated papillary duct trigger the formation of calcium phosphate and/or calcium oxalate stones. Chemical analyses on our MSK patients’ stones showed that 67% of them were mainly calcium phosphate and 33% were calcium oxalate.
MSK is rarely manifest in children, but when this happens the disease is rather severe and the bone-related consequences of dRTA prevail, with failure to thrive, short stature, and rickets-like symptoms
MSK can occur in association with renal developmental anomalies and tumors such as Wilms tumor, horse-shoe kidney, contralateral congenital small kidney, and occasionally with pyelo-ureteral abnormalities, or hypertrophic disorders like Beckwith-Wiedemann syndrome and congenital hemihypertrophy. It may also be associated with liver disorders, such as congenital dilation of the intrahepatic bile ducts (Caroli’s disease) and hepatic fibrosis.
Any hypothesis on the pathogenesis of MSK should explain the concomitant occurrence of alterations in the ureteric bud-derived precalyceal and collecting ducts (i.e. the “lower nephron”), such as “cysts”, nephrocalcinosis and acidification, and concentration defects, as well as in the metanephric blastema-derived nephron (“upper nephron”), such as proximal tubular defects.
A case was described of a medullary thyroid carcinoma presenting with concomitant primary hyperparathyroidism (prompting the diagnosis of MEN-2a) together with MSK, and a RET proto-oncogene gene mutation, and it was claimed that the MSK/RET-mutation association may be causal. However, we expect to find a RET mutation in a patient with a medullary thyroid carcinoma, since this occurs in 80% of cases. Moreover, given the prevalence of the two conditions (as high as 10/100,000 for the former, up to 1/100 for MSK), the probability of a chance association (up to 1 per million people), though very low, is nonetheless a possibility. The idea of common pathogenic mechanisms in the two diseases is attractive, however, since RET plays a huge part in renal development.
RET and GDNF knockout mice has a defective renal morphogenesis. Thus it is evident that RET and GDNF has a relevant role in kidney embryogenesis.
During nephrogenesis, GDNF synthesized by the metanephric blastema, induces ureteric bud outgrowth and branching from Wolff’s duct. GDNF requires a receptor tyrosine kinase (RET) and a co-receptor (GFRa1) for the downstream signaling pathway.
The ureteral bud approaches and invades the blastema. The top of the bud expresses a GDNF receptor, RET. Binding between RET and GDNF is essential not only for correct ureter and collecting duct formation (they also are Wolffian in origin), but also for the induction of nephrogenesis, morphogenesis and kidney growth. In particular, the transition of mesenchymal cells of the metanephros to nephronic cells, the correct polarization of renal tubular cells, and the specialization of the different tubular segments of the nephron, all need differentiation “messages” originating from the ureteral-bud/metanephric-blastema interfacace.
Given the key role of the GDNF-RET interaction in kidney-urinary tract development and nephronogenesis, anomalies in these molecules could be reasonable candidates for explaining a disorder such as MSK, which discloses abnormalities in both the lower and the upper nephron, and is often associated with urinary tract developmental anomalies.
Although it is considered a sporadic disease, a recent study has shown that 50% of MSK stone-forming patients have relatives with milder forms of MSK, and that MSK is inherited apparently as an autosomal dominant disease with a reduced penetrance and variable expressivity.
Assuming that MSK is a developmental disorder, the genes governing renal development are very likely to be involved.
We hypothesized that MSK might result from a disruption at the “ureteric bud-metanephric mesenchyme” interface, probably due to disease-causing mutations or specific polymorphisms of GDNF and RET genes, or particular GDNF/RET genotype interactions. Studying 55 apparently sporadic MSK cases and 85 healthy controls, we detected 8 MSK patients heterozygous for two, hitherto unknown, rare variants of the GDNF gene located in a putative binding domain for PAX2, i.e. the c.-45G>C and c.-27+18G>A variants, which were both found significantly associated with MSK.
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