1 Division of Nephrology, Department of Biomedical and Surgical Sciences, University Hospital of Verona, 2 Division of Nephrology and 3 Laboratory of Molecular Biology, Department of Medical and Surgical Sciences, University Hospital of Padova, Italy
Correspondence and offpriont requests to: Professor Giovanni Gambaro, MD, PhD, Divisione di Nefrologia, Dipartimento di Scienze Biomediche e Chirurgiche, Università di Verona, Ospedale Maggiore, Piazzale Stefani 1, 37126 Verona, Italy. Email: giovanni.gambaro{at}univr.it
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Abstract |
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Keywords: hyperparathyroidism; MEN-2A; renal hypoplasia; RET; sponge kidney
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Introduction |
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Though rare, the disorder is relatively common in patients who have recurrent calcium nephrolithiasis. It generally occurs sporadically, but familial cases have been reported [2,3], and it has been described in patients with various developmental disorders.
The pathogenesis of the disorder has yet to be elucidated; meanwhile, we are still facing old hypotheses (anomalous congenital development of renal tubules with secondary cystic dilations; collecting duct dilation secondary to obstruction by calcium salts; renal manifestation of a systemic connective tissue disorder; or renal manifestation of primary hyperparathyroidism).
The association of SK with various malformations supports the conviction that it is a developmental disorder. However, the recent scheme proposed for re-classifying developmental disorders of the kidney [4] does not consider SK at all.
The pathogenesis of SK ought to explain why anatomical structures of different embryological origin are involved (the collecting and precalyceal ducts, on the one hand, and the nephron, on the other) and why it is so often associated with hyperparathyroidism.
A few years ago, a patient was described who simultaneously had a medullary thyroid carcinoma and primary hyperparathyroidism (based on which a diagnosis of MEN-2a was advanced) together with SK and a RET gene mutation [5]. It was suggested that the association of SK and the RET mutation might be causal. It is worth noting that we can expect to find a RET gene mutation in a patient with a medullary thyroid carcinoma, since this occurs in 80% of these patients. Moreover, given the prevalence of the two conditions (as high as 10/100 000 for the thyroid cancer and up to 1/100 for SK), a chance association (the low probability of which is up to 1 per million) is nonetheless a possibility. However, the idea of the existence of pathogenic mechanisms common to the two diseases is attractive, because the RET gene plays an important part in renal development.
During renal embryogenesis, through the synthesis of chemotactic molecules, i.e. glial-derived neurotrophic factor (GDNF), the metanephric blastema prompts the ureteric bud to branch away from Wolff's mesonephric duct (ureteral induction) and approach and invade the blastema [6]. The tip of the bud expresses a GDNF receptor, RET. The binding of RET and GDNF is essential not only for the correct formation of ureters and collecting ducts (the latter also of Wolffian origin), but also for the induction of nephrogenesis and kidney growth [6]. In particular, the transition of the mesenchymal cells of the metanephros to nephronic cells, the correct polarization of renal tubular cells and the specialization of different tubular segments of the nephron all need differentiation messages originating from the ureteric budmetanephric blastema interface [6].
In light of these notions, we hypothesize that SK is the consequence of a disruption in the ureteric budmetanephric blastema interface. This would explain the concomitant occurrence of the alterations in precalyceal and collecting ducts (ectasias, hypercalciuria, type 1 RTA and urine concentration defects) and of the functional defects in the renal tubule (hypercalciuria, and abnormal Tmglucose and TmPHA).
To confirm such a hypothesis demands molecular studies but, if this hypothesis holds, we would expect to see other renal developmental anomalies of processes that may depend on RETGDNF binding in SK patients, such as unilateral renal agenesia, or unilateral or bilateral renal hypoplasia, or urinary tract duplication. It is worth noting that, in experiments involving the targeted inactivation of either the GDNF or RET genes, which leads to renal agenesia, some heterozygous animals develop unilateral renal agenesia or hypoplasia [7,8]. Anecdotal reports have also been published on the occurrence of horseshoe kidney [9] and unilateral renal aplasia [10] in SK patients. The first systematic analysis of SK patients to investigate this issue is reported herein.
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Patients and methods |
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The following clinical and laboratory data were collected: serum calcium and phosphorus, parathyroid hormone, bicarbonate, creatinine clearance (established using the Cockroft and Gault formula; considered abnormal when <70 ml/min/1.73 m2 in females, <80 ml/min/1.73 m2 in males), calciuria, citraturia, fasting urine pH and hypertension (repeatedly observed values >140/90 mmHg in the sitting position after a 5 min rest, or therapy with antihypertensive drugs). In the few cases whose biochemical data were older than 2 years, blood analyses were repeated. Captopril renography and renal colour Doppler sonography were performed when appropriate.
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Results |
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When diagnosed with SK, six out of seven had hypercalciuria, three had renal acidification defects and one had isolated hypocitraturia, which were confirmed repeatedly during follow-up. During follow-up (range 112 years), three of the seven patients developed hyperparathyroidism (43 vs 4% in the group as a whole). None had had hypocalcaemia or hyperphosphataemia, or had used loop diuretics during the follow-up before the onset of hypercalcaemia, hypophosphataemia and hyperparathyroidism.
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Discussion |
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Abnormalities in the branching of the ureteral bud are thought to be responsible for urinary tract duplication, which includes the bifid renal pelvis (observed in patient no. 1). Although when discussing this case we cannot rule out a chance association with SK, our observation is not new [14] and fits quite well within the framework of our hypothesis.
Evaluating the small kidney always poses a problem, because of the difficulty in differentiating congenitally small, underdeveloped kidneys from secondarily small, atrophic kidneys. The criteria we chose to identify the six cases, however, seem adequate to rule out the latter condition. In fact, the patients histories exclude previous obstructive uropathies (a potential cause of renal hypotrophy, particularly in patients with urolithiasis), though this fact obviously relies to some degree on the patients recollections. Renal ischaemia was ruled out in the two hypertensive women by captopril renography; this is particularly important, because of the reported association of SK with renal artery fibromuscular dysplasia, a condition typical in hypertensive women. Furthermore, colour Doppler sonography in the six patients with small kidneys disclosed normal profiles, ruling out stenosis of the major renal arteries. The regular profiles of the small kidneys and the lack of calyceal deformities and scarring all support the assumption that these small kidneys are primarily underdeveloped, though according to our hypothesis SK could be associated with VUR. Indeed, the association of VUR and SK was reported previously [14]. The presence of VUR may actually point to defective branching processes during kidneyurinary tract development, but we found no sign of VUR by intravenous urography. Though this is not the gold standard diagnostic tool for such a condition, we cannot rule out the possibility that VUR had been present earlier and had resolved over time (as is generally the case).
Only patient no. 4 had congenital hemihypertrophy; the others had no somatic indicators of this condition. Congenital hemihypertrophy (OMIM 23500) is characterized by the asymmetric growth of the skull, face, trunk, limbs or digits, but it may also involve the viscera. In our opinion, this syndrome could not explain our findings, at least in five of our patients with one small kidney. This conviction is also supported by the observation that SK was bilateral in all subjects.
Renal failure is a possibility in patients with SK, though it is not particularly frequent. Renal failure in this disorder is believed to be related to renal infections, i.e. the formation of struvite stones, or to obstructive episodes or surgery [15]. In the whole group, the prevalence of reduced creatinine clearance was 7%, as in the literature [15], but all four patients with this finding were in the subgroup of patients with asymmetric kidneys and none of them had a history of infectious stones, obstruction or surgery, and they did not have abnormal main renal arteries. This would suggest that the renal anomaly detected in them is not just a trivial, modest reduction in the volume of one kidney, but that it may be a process affecting the entire parenchyma of both kidneys, reducing renal function globally. The derangement presumably is not limited to the typical precalyceal dilations of SK; it may be characterized by an insidious renal dysplasia responsible for the decline of renal function.
According to our hypothesis, i.e. that SK is due to a disruption of the ureteric budmetanephric blastema interface, the transition of the mesenchymal cells of the metanephros to nephronic cells, or in other words the development of a normal renal parenchyma, ought to be impaired [6]. If this is the case, then it is hardly surprising that: (i) several carrier functions are altered, both in the nephron (of metanephric origin) and in the papillary and collecting ducts (of Wolffian origin); and (ii) most of our subjects have a reduced renal function.
SK is reportedly associated with a number of renalureteral malformations, e.g. with horseshoe kidney [9], with congenital mega-ureter and unilateral renal aplasia [10], and with familial co-segregation with different ureteral abnormalities (ureteropelvic junction obstruction, bifid pelvis, duplicated ureter and VUR) [14]. An association with Wilms tumour has also been described [16]. It is now believed that all these conditions stem from the derangement of the molecular processes involved in ureteral bud branching and cross-talk with the metanephric mesenchyme, or from the mutations of genes responsible for critical molecules involved in these mechanisms (i.e. the WT-1 in Wilms tumour, RET, GDNF, etc.). Therefore, the reports mentioned also support our hypothesis.
The prevalence of developmental abnormalities in our SK group was 1:10. To the best of our knowledge, however, there is no published study that indicates the prevalence of primary renal volume asymmetry. That the left kidney is longer than the right one is well known, but the difference is in the range of a few millimetres. As to true renal hypoplasia, most authoritative textbooks report this to be a rare finding in the general population. However, the 1:10 prevalence observed by us is distinctly higher than the prevalence of similar developmental abnormalities of the kidney and ureteral tract in the general population [12]. This finding again suggests that SK and these developmental abnormalities share similar pathogenic mechanisms.
The abnormal interfacing of the ureteral bud with the blastema might result from environmental factors (drugs, viruses, etc.) during pregnancy. However, it might also be genetically driven, despite the rarity of cases of familial SK [2,3] and the most frequent sporadic pattern, which may be explained by a number of mechanisms: (i) incomplete penetrance of germline mutations; (ii) the need for a two-hit phenomenon for the appearance of SK; (iii) the need for unfavourable genotype combinations, e.g. between specific RET and GDNF alleles, for the appearance of SK; (iv) the need for a concomitant mutation of the GDNF ligand gene; or (v) SK is not a simple Mendelian trait, but follows a polygenic pattern of inheritance affected by modifier genesas in another disorder due to RET gene mutations, Hirschprung's disease, which like SK notably also occurs quite often in sporadic forms [17].
In the framework of our hypothesis, we consider the interaction of RET with GDNF to be the prime candidate for the pivotal pathogenic mechanism. That three out of seven of our patients developed hyperparathyroidism during follow-up may support the role of the RET gene, because its mutations cause MEN-2a, which includes, among other endocrine disorders, primary hyperparathyroidism.
If some RET gene mutation or polymorphism responsible for SK also weakens the control of parathyroid cell proliferation, a negative calcium balance (due to the renal leak hypercalciuria of SK patients, or vitamin D deficiency, etc.) or decreased renal function putatively might trigger parathyroid cell proliferation, leading to hyperparathyroidism.
Other candidate gene products may be considered, such as the glial-derived factor neurturin or the WT1 genes, and many others, including Eya-1, integrins, PAX2, laminin 5, AgtR2, FGFs, MT1-MMP, MMP9, TIMP1 and TIMP2, all involved in the process of nephrogenesis [6]. However, since most of them continue to be active after embryogenesis, they are less likely to be involved, because patients with SK do not manifest disorders due to mutations of these genes and generally look otherwise normal.
We now know that neurological and cardiac anatomical and functional malformational disorders (e.g. Fallot's tetralogy, rhythm disorders and sudden death syndromes) are due to non-lethal defects in genes expressed only during embryogenesis. If our findings are confirmed by molecular studies, SK might be the first renal disorder to join this category.
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Acknowledgments |
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Conflict of interest statement. None declared.
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References |
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