The Experts below are selected from a list of 231 Experts worldwide ranked by ideXlab platform

Giovanni Gambaro - One of the best experts on this subject based on the ideXlab platform.

  • chronic pain in Medullary Sponge Kidney a rare and never described clinical presentation
    Journal of Nephrology, 2018
    Co-Authors: Giovanni Gambaro, David S Goldfarb, Rocco Baccaro, J Hirsch, N Topilow, Silvia Dalonzo, G Gambassi, Pietro Manuel Ferraro
    Abstract:

    Medullary Sponge Kidney (MSK) is a cause of nephrocalcinosis, associated with hematuria, renal colic, pyelonephritis. There are rare and atypical MSK cases characterized by chronic severe pain (CP), whose features are unknown, in particular the relationship with the stone disease activity. This study analyzes a cohort of MSK–CP patients belonging to three North-America self-support Facebook groups. Patients had to self-administer an on-line questionnaire (on intensity, progression and MSK-associated conditions, stone-related disease, pain features, drug use), the Brief Pain Inventory, the Fatigue Severity Score, and Wisconsin Quality of Life (WQL) in stone formers questionnaires. Ninety-two patients with a diagnosis of MSK joined our survey. Stone rate was very high (3.1 stones per patient-year, < 15% of patients had ≤ 1 stone per year). Most patients had repeated hospitalizations for stones symptoms (p < 0.001) or pain (p < 0.005). 71% of participants referred a daily pain that interfered strongly with everyday life and quality of life (WQL mean value 29.4). 69% used pain medications daily (70% opioids). In most cases, pain was associated with stone passage, while 15% referred a sine materia pain. We showed how MSK–CP symptoms affect very negatively on the quality of life of these patients. They also have a definite risk of progressing to end-stage Kidney disease. Generally, CP seems to be associated with an exceptionally high lithogenic activity, suggesting that a better and earlier metabolic treatment for stone prevention should be the first approach in these patients before mini-invasive treatments to prevent pain.

  • New non-renal congenital disorders associated with Medullary Sponge Kidney (MSK) support the pathogenic role of GDNF and point to the diagnosis of MSK in recurrent stone formers
    Urolithiasis, 2017
    Co-Authors: Paolo Ria, Antonia Fabris, Antonio Lupo, Alessandra Dalla Gassa, Gianluigi Zaza, Giovanni Gambaro
    Abstract:

    Medullary Sponge Kidney (MSK) is a congenital renal disorder. Its association with several developmental abnormalities in other organs hints at the likelihood of some shared step(s) in the embryogenesis of the Kidney and other organs. It has been suggested that the REarranged during Transfection (RET) proto-oncogene and the Glial cell line-Derived Neurotrophic Factor (GDNF) gene are defective in patients with MSK, and both RET and GDNF are known to have a role in the development of the central nervous system, heart, and craniofacial skeleton. Among a cohort of 143 MSK patients being followed up for nephrolithiasis and chronic Kidney disease at our institution, we found six with one or more associated non-renal anomalies: one patient probably has congenital hemihyperplasia and hypertrophic cardiomyopathy with adipose metaplasia and mitral valve prolapse; one has Marfan syndrome; and the other four have novel associations between MSK and nerve and skeleton abnormalities described here for the first time. The discovery of disorders involving the central nervous system, cardiovascular system and craniofacial skeleton in MSK patients supports the hypothesis of a genetic alteration on the RET–GDNF axis having a pivotal role in the pathogenesis of MSK, in a subset of patients at least. MSK seems more and more to be a systemic disease, and the identification of extrarenal developmental defects could be important in arousing the suspicion of MSK in recurrent stone formers.

  • Identification of GDNF Gene Sequence Variations in Patients with Medullary Sponge Kidney Disease
    2016
    Co-Authors: Dorella Del Prete, Antonio Lupo, Cataldo Abaterusso, Nicola Marchionna, Rosalba Cristofaro, Lina Artifoni, Giovanni Gambaro
    Abstract:

    Background and objectives: Medullary Sponge Kidney (MSK) is a rare nephropathy characterized by cystic anomalies of precalyceal ducts, nephrocalcinosis, renal stones, and tubule dysfunctions. Its association with various malformations and cases of familial aggregation supports the conviction that genetic factors are involved, but no genetic studies have been conducted to date. It is hypothesized that MSK is due to a disruption at the “ureteric bud/metanephric blastema ” interface caused by critical developmental genes functioning abnormally. Design, setting, participants, & measurements: Fifty-five apparently sporadic MSK patients were analyzed by direct DNA sequencing of all exons and exon-intron boundaries of glial cell-derived neurotrophic factor (GDNF) gene and rearranged during transfection (RET) gene, which have a leading role in renal development. Results: Two novel variants were found in heterozygosity in the MSK case population: GDNF{ENST00000344622}: c.45G>C and c.2718G>A in a putative binding domain for paired-box 2 transcription factor. As a whole, eight patients showed these variations: four patients carried the c.[45G>C; 2718G>A] complex allele, and the others had the c.2718G>A alone. A case-control study revealed that these two alleles were significantly associated with MSK. Five of the eight cases were found to be familial, and the allele variants cosegregated with the disease in a seemingly dominant patter

  • Medullary Sponge Kidney
    HAL CCSD, 2016
    Co-Authors: Giovanni Gambaro
    Abstract:

    International audienceMedullary Sponge Kidney (MSK) is a renal malformation that mostly shows recurrent renal stones; renal concentration and acidification defects, hypercalciuria and hypocitraturia are also common. Nephrocalcinosis and papillary duct ectasias are the morphological counterpart. Although MSK is frequently an apparently sporadic disorder, autosomal dominant inheritance has been observed in half of cases.The association of MSK with urinary tract developmental anomalies suggests that MSK belongs to the CAKUT disorders, and that its pathogenesis has to be investigated in one of the many steps of the Kidney and urinary tract morphogenesis. Actually some rare GDNF variants have been observed in subjects with familial MSK. Since the GDNF-RET interaction has a critical role in the Kidney-urinary tract development and nephronogenesis, it was proposed that those GDNF variants are disease causing mutations involved in at least some of the MSK cases. However, MSK is likely a heterogeneous genetic disorder and some of the sporadic cases are probably not genetic in origin. Data suggest that the distal acidification defect, that is frequently observed in MSK patients, plays a pivotal role in causing many of the clinical manifestations of MSK: defective bone mineralization, hypercalciuria, hypocitraturia and stone formation. This hypothesis is supported by the finding that treatment with potassium citrate strongly improves bone mineralization, reduces calciuria and prevents renal stones. However, urinary stasis in the prepapillary ectasias is also a relevant condition for renal stone formation since lithogenesis occurs also in patients without defective acidification

  • Nephrocalcinosis is a biomineralization phenomenon similar to bone mineralization
    HAL CCSD, 2016
    Co-Authors: Giovanni Gambaro
    Abstract:

    International audienceThe process of nephrocalcinosis can be observed in a wide range of pathological renal conditions. Some are congenital and genetically driven, others are acquired. Frequently it is hallmark of progressive chronic Kidney diseases leading to end stage renal disease. Nephrocalcinosis has been longly considered as a passive phenomenon of ectopic calcification due to pure physical-chemical reactions possibly on necrotic tissues.The Medullary Sponge Kidney (MSK) is typically associated with nephrocalcinosis. We had the unique chance to study a spontaneous calcification process in vitro on primary renal cells sprouting off collagenase digested papillary tissues obtained in a patient with MSK undergone nephrectomy and who was heterozygous for the c.-27 + 18G >A variant of the glial cell-derived neurotrophic factor (GDNF) gene. Cells from papillary tissues obtained in two subjects who had no MSK or nephrocalcinosis were also obtained and investigated. Beginning from cell culture passage 2, MSK and control cells formed nodules with a comportment similar to that of pericytes; however, in the MSK cultures the nodules spontaneously calcified while this did not occur in control cultures. Calcium phosphate (apatite) was the only mineral component of the spontaneous calcifications. The MSK cells disclosed morphology and immunophenotype similar to pericytes or stromal stem cells. The MSK cells expressed osteocalcin and osteonectin, i.e. an osteoblast-like phenotype, and at odds with the control cells, disclosed GDNF down-regulation. In GDNF knockdown HK2 cells, the culture in a calcifying medium promoted calcium phosphate deposition by moving the balance osteonectin/osteopontin in favour of osteonectin. We propose that the papilla (and the interstitial compartment of the renal medulla) is a perivascular niche in which pericyte/stromal-like cells may undergo differentiation along the osteogenic lineage under particular conditions and that GDNF down-regulation favours this phenomenon.Our data suggest that nephrocalcinosis is an active phenomenon of biomineralization mirroring bone mineralization

Nicola Marchionna - One of the best experts on this subject based on the ideXlab platform.

  • Identification of GDNF Gene Sequence Variations in Patients with Medullary Sponge Kidney Disease
    2016
    Co-Authors: Dorella Del Prete, Antonio Lupo, Cataldo Abaterusso, Nicola Marchionna, Rosalba Cristofaro, Lina Artifoni, Giovanni Gambaro
    Abstract:

    Background and objectives: Medullary Sponge Kidney (MSK) is a rare nephropathy characterized by cystic anomalies of precalyceal ducts, nephrocalcinosis, renal stones, and tubule dysfunctions. Its association with various malformations and cases of familial aggregation supports the conviction that genetic factors are involved, but no genetic studies have been conducted to date. It is hypothesized that MSK is due to a disruption at the “ureteric bud/metanephric blastema ” interface caused by critical developmental genes functioning abnormally. Design, setting, participants, & measurements: Fifty-five apparently sporadic MSK patients were analyzed by direct DNA sequencing of all exons and exon-intron boundaries of glial cell-derived neurotrophic factor (GDNF) gene and rearranged during transfection (RET) gene, which have a leading role in renal development. Results: Two novel variants were found in heterozygosity in the MSK case population: GDNF{ENST00000344622}: c.45G>C and c.2718G>A in a putative binding domain for paired-box 2 transcription factor. As a whole, eight patients showed these variations: four patients carried the c.[45G>C; 2718G>A] complex allele, and the others had the c.2718G>A alone. A case-control study revealed that these two alleles were significantly associated with MSK. Five of the eight cases were found to be familial, and the allele variants cosegregated with the disease in a seemingly dominant patter

  • long term treatment with potassium citrate and renal stones in Medullary Sponge Kidney
    Clinical Journal of The American Society of Nephrology, 2010
    Co-Authors: Antonia Fabris, Antonio Nouvenne, Antonio Lupo, Patrizia Bernich, Cataldo Abaterusso, Nicola Marchionna, Giovanni Gambaro
    Abstract:

    Background and objectives: Medullary Sponge Kidney (MSK) is a renal malformation typically associated with nephrocalcinosis and recurrent calcium stones. Incomplete distal renal tubular acidosis, hypocitraturia, and hypercalciuria are common. For stone prevention, patients with MSK generally receive the standard “stone clinic” recommendations and often receive potassium citrate (KC). However, the effect on stone recurrence of citrate treatment in these patients has never been studied. Design, setting, participants, & measurements: The issue was retrospectively analyzed on an outpatient basis in 97 patients with a radiologic diagnosis of MSK: 65 had at least one stone risk factor (SRF; hypercalciuria, hypocitraturia, hyperuricosuria, hyperoxaluria) and received KC [29 ± 8 (SD) mEq/d]; 10 patients with SRF and 22 without received only general stone clinic suggestions. Follow-up was 78 ± 13, 72 ± 15, and 83 ± 14 months, respectively. The 24-hour urinary excretion of calcium, oxalate, uric acid, citrate, and morning urine pH were investigated at baseline and at the end of follow-up. Results: Parallel to a significant rise in urinary citrate and decreased urinary calcium (all P Conclusions: Treatment with KC is effective in preventing renal stones in the typical patient with MSK. It seems that two clinical phenotypes among patients showing typical MSK features during radiologic study exist.

  • identification of gdnf gene sequence variations in patients with Medullary Sponge Kidney disease
    Clinical Journal of The American Society of Nephrology, 2010
    Co-Authors: Rossella Torregrossa, Antonia Fabris, Cataldo Abaterusso, Dorella Del Prete, Rosalba Cristofaro, Lina Artifoni, Franca Anglani, Alessia Gozzini, Annalisa Tanini, Nicola Marchionna
    Abstract:

    Background and objectives: Medullary Sponge Kidney (MSK) is a rare nephropathy characterized by cystic anomalies of precalyceal ducts, nephrocalcinosis, renal stones, and tubule dysfunctions. Its association with various malformations and cases of familial aggregation supports the conviction that genetic factors are involved, but no genetic studies have been conducted to date. It is hypothesized that MSK is due to a disruption at the “ureteric bud/metanephric blastema” interface caused by critical developmental genes functioning abnormally. Design, setting, participants, & measurements: Fifty-five apparently sporadic MSK patients were analyzed by direct DNA sequencing of all exons and exon-intron boundaries of glial cell-derived neurotrophic factor (GDNF) gene and rearranged during transfection (RET) gene, which have a leading role in renal development. Results: Two novel variants were found in heterozygosity in the MSK case population: GDNF{ENST00000344622}:c.−45G>C and c.−27+18G>A in a putative binding domain for paired-box 2 transcription factor. As a whole, eight patients showed these variations: four patients carried the c.[−45G>C; −27+18G>A] complex allele, and the others had the c.−27+18G>A alone. A case-control study revealed that these two alleles were significantly associated with MSK. Five of the eight cases were found to be familial, and the allele variants cosegregated with the disease in a seemingly dominant pattern of inheritance. Patients revealed no mutations in the RET gene. Conclusions: This is the first report identifying GDNF gene sequence variations in patients with MSK and suggesting a role for this gene in the pathogenesis of some cases of the disease.

  • bone disease in Medullary Sponge Kidney and effect of potassium citrate treatment
    Clinical Journal of The American Society of Nephrology, 2009
    Co-Authors: Antonia Fabris, Antonio Nouvenne, Antonio Lupo, Patrizia Bernich, Cataldo Abaterusso, Nicola Marchionna, Chiara Canciani, Mauro Zamboni, Giovanni Gambaro
    Abstract:

    Background and objectives: In Medullary Sponge Kidney (MSK)—a common malformative renal condition in patients with calcium nephrolithiasis—hypercalciuria, incomplete distal renal tubular acidosis, and hypocitraturia are common. Clinical conditions with concomitant hypercalciuria and/or incomplete distal renal tubular acidosis are almost invariably associated with bone disease, making osteopathy highly likely in MSK, too. Patients with MSK have never been investigated for osteopathy; neither has the potential effect of potassium citrate administration (CA) on their urinary metabolic risk factors and on bone mineralization. Design, setting, participants, & measurements: These issues were retrospectively analyzed in 75 patients with MSK and primary stone risk factor (PSRF; hypercalciuria, hypocitraturia, hyperuricosuria, and/or hyperoxaluria) on an outpatient basis; 65 received CA (2.9 ± 0.8 g/d), whereas 10 received only general “stone clinic” suggestions. The 24-h urinary excretion of calcium, phosphate, oxalate, uric acid, and citrate; morning urine pH; serum biochemistry; and bone mineral density were investigated at baseline and at the end of follow-up (78 ± 13 and 72 ± 15 mo in groups A and B, respectively). Results: CA led to a significant rise in urinary pH and citrate and decreased urinary calcium and phosphate (all P < 0.001). Patients with MSK and PSRF had reduced bone density. Bone density improved significantly in the group that was treated with oral CA. Conclusions: Bone disease is very frequent in patients with MSK and concomitant PSRF. Long-term CA improves bone density. The concurrent effects of treatment on PSRF suggest that the subtle acidosis plays a pivotal role in bone disease and hypercalciuria in patients with MSK.

Antonia Fabris - One of the best experts on this subject based on the ideXlab platform.

  • New non-renal congenital disorders associated with Medullary Sponge Kidney (MSK) support the pathogenic role of GDNF and point to the diagnosis of MSK in recurrent stone formers
    Urolithiasis, 2017
    Co-Authors: Paolo Ria, Antonia Fabris, Antonio Lupo, Alessandra Dalla Gassa, Gianluigi Zaza, Giovanni Gambaro
    Abstract:

    Medullary Sponge Kidney (MSK) is a congenital renal disorder. Its association with several developmental abnormalities in other organs hints at the likelihood of some shared step(s) in the embryogenesis of the Kidney and other organs. It has been suggested that the REarranged during Transfection (RET) proto-oncogene and the Glial cell line-Derived Neurotrophic Factor (GDNF) gene are defective in patients with MSK, and both RET and GDNF are known to have a role in the development of the central nervous system, heart, and craniofacial skeleton. Among a cohort of 143 MSK patients being followed up for nephrolithiasis and chronic Kidney disease at our institution, we found six with one or more associated non-renal anomalies: one patient probably has congenital hemihyperplasia and hypertrophic cardiomyopathy with adipose metaplasia and mitral valve prolapse; one has Marfan syndrome; and the other four have novel associations between MSK and nerve and skeleton abnormalities described here for the first time. The discovery of disorders involving the central nervous system, cardiovascular system and craniofacial skeleton in MSK patients supports the hypothesis of a genetic alteration on the RET–GDNF axis having a pivotal role in the pathogenesis of MSK, in a subset of patients at least. MSK seems more and more to be a systemic disease, and the identification of extrarenal developmental defects could be important in arousing the suspicion of MSK in recurrent stone formers.

  • long term treatment with potassium citrate and renal stones in Medullary Sponge Kidney
    Clinical Journal of The American Society of Nephrology, 2010
    Co-Authors: Antonia Fabris, Antonio Nouvenne, Antonio Lupo, Patrizia Bernich, Cataldo Abaterusso, Nicola Marchionna, Giovanni Gambaro
    Abstract:

    Background and objectives: Medullary Sponge Kidney (MSK) is a renal malformation typically associated with nephrocalcinosis and recurrent calcium stones. Incomplete distal renal tubular acidosis, hypocitraturia, and hypercalciuria are common. For stone prevention, patients with MSK generally receive the standard “stone clinic” recommendations and often receive potassium citrate (KC). However, the effect on stone recurrence of citrate treatment in these patients has never been studied. Design, setting, participants, & measurements: The issue was retrospectively analyzed on an outpatient basis in 97 patients with a radiologic diagnosis of MSK: 65 had at least one stone risk factor (SRF; hypercalciuria, hypocitraturia, hyperuricosuria, hyperoxaluria) and received KC [29 ± 8 (SD) mEq/d]; 10 patients with SRF and 22 without received only general stone clinic suggestions. Follow-up was 78 ± 13, 72 ± 15, and 83 ± 14 months, respectively. The 24-hour urinary excretion of calcium, oxalate, uric acid, citrate, and morning urine pH were investigated at baseline and at the end of follow-up. Results: Parallel to a significant rise in urinary citrate and decreased urinary calcium (all P Conclusions: Treatment with KC is effective in preventing renal stones in the typical patient with MSK. It seems that two clinical phenotypes among patients showing typical MSK features during radiologic study exist.

  • identification of gdnf gene sequence variations in patients with Medullary Sponge Kidney disease
    Clinical Journal of The American Society of Nephrology, 2010
    Co-Authors: Rossella Torregrossa, Antonia Fabris, Cataldo Abaterusso, Dorella Del Prete, Rosalba Cristofaro, Lina Artifoni, Franca Anglani, Alessia Gozzini, Annalisa Tanini, Nicola Marchionna
    Abstract:

    Background and objectives: Medullary Sponge Kidney (MSK) is a rare nephropathy characterized by cystic anomalies of precalyceal ducts, nephrocalcinosis, renal stones, and tubule dysfunctions. Its association with various malformations and cases of familial aggregation supports the conviction that genetic factors are involved, but no genetic studies have been conducted to date. It is hypothesized that MSK is due to a disruption at the “ureteric bud/metanephric blastema” interface caused by critical developmental genes functioning abnormally. Design, setting, participants, & measurements: Fifty-five apparently sporadic MSK patients were analyzed by direct DNA sequencing of all exons and exon-intron boundaries of glial cell-derived neurotrophic factor (GDNF) gene and rearranged during transfection (RET) gene, which have a leading role in renal development. Results: Two novel variants were found in heterozygosity in the MSK case population: GDNF{ENST00000344622}:c.−45G>C and c.−27+18G>A in a putative binding domain for paired-box 2 transcription factor. As a whole, eight patients showed these variations: four patients carried the c.[−45G>C; −27+18G>A] complex allele, and the others had the c.−27+18G>A alone. A case-control study revealed that these two alleles were significantly associated with MSK. Five of the eight cases were found to be familial, and the allele variants cosegregated with the disease in a seemingly dominant pattern of inheritance. Patients revealed no mutations in the RET gene. Conclusions: This is the first report identifying GDNF gene sequence variations in patients with MSK and suggesting a role for this gene in the pathogenesis of some cases of the disease.

  • bone disease in Medullary Sponge Kidney and effect of potassium citrate treatment
    Clinical Journal of The American Society of Nephrology, 2009
    Co-Authors: Antonia Fabris, Antonio Nouvenne, Antonio Lupo, Patrizia Bernich, Cataldo Abaterusso, Nicola Marchionna, Chiara Canciani, Mauro Zamboni, Giovanni Gambaro
    Abstract:

    Background and objectives: In Medullary Sponge Kidney (MSK)—a common malformative renal condition in patients with calcium nephrolithiasis—hypercalciuria, incomplete distal renal tubular acidosis, and hypocitraturia are common. Clinical conditions with concomitant hypercalciuria and/or incomplete distal renal tubular acidosis are almost invariably associated with bone disease, making osteopathy highly likely in MSK, too. Patients with MSK have never been investigated for osteopathy; neither has the potential effect of potassium citrate administration (CA) on their urinary metabolic risk factors and on bone mineralization. Design, setting, participants, & measurements: These issues were retrospectively analyzed in 75 patients with MSK and primary stone risk factor (PSRF; hypercalciuria, hypocitraturia, hyperuricosuria, and/or hyperoxaluria) on an outpatient basis; 65 received CA (2.9 ± 0.8 g/d), whereas 10 received only general “stone clinic” suggestions. The 24-h urinary excretion of calcium, phosphate, oxalate, uric acid, and citrate; morning urine pH; serum biochemistry; and bone mineral density were investigated at baseline and at the end of follow-up (78 ± 13 and 72 ± 15 mo in groups A and B, respectively). Results: CA led to a significant rise in urinary pH and citrate and decreased urinary calcium and phosphate (all P < 0.001). Patients with MSK and PSRF had reduced bone density. Bone density improved significantly in the group that was treated with oral CA. Conclusions: Bone disease is very frequent in patients with MSK and concomitant PSRF. Long-term CA improves bone density. The concurrent effects of treatment on PSRF suggest that the subtle acidosis plays a pivotal role in bone disease and hypercalciuria in patients with MSK.

Gambaro Giovanni - One of the best experts on this subject based on the ideXlab platform.

  • Sphingomyelin and Medullary Sponge Kidney disease: a biological link identified by omics approach
    'Frontiers Media SA', 2021
    Co-Authors: Granata Simona, Bruschi Maurizio, Deiana Michela, Petretto Andrea, Lombardi Gianmarco, Verlato Alberto, Elia Rossella, Candiano Giovanni, Malerba Giovanni, Gambaro Giovanni
    Abstract:

    Background: Molecular biology has recently added new insights into the comprehension of the physiopathology of the Medullary Sponge Kidney disease (MSK), a rare Kidney malformation featuring nephrocalcinosis and recurrent renal stones. Pathogenesis and metabolic alterations associated to this disorder have been only partially elucidated.Methods: Plasma and urine samples were collected from 15 MSK patients and 15 controls affected by idiopathic calcium nephrolithiasis (ICN). Plasma metabolomic profile of 7 MSK and 8 ICN patients was performed by liquid chromatography combined with electrospray ionization tandem mass spectrometry (UHPLC-ESI-MS/MS). Subsequently, we reinterrogated proteomic raw data previously obtained from urinary microvesicles of MSK and ICN focusing on proteins associated with sphingomyelin metabolism. Omics results were validated by ELISA in the entire patients' cohort.Results: Thirteen metabolites were able to discriminate MSK from ICN (7 increased and 6 decreased in MSK vs. ICN). Sphingomyelin reached the top level of discrimination between the two study groups (FC: -1.8, p < 0.001). Ectonucleotide pyrophophatase phosphodiesterase 6 (ENPP6) and osteopontin (SPP1) resulted the most significant deregulated urinary proteins in MSK vs. ICN (p < 0.001). ENPP6 resulted up-regulated also in plasma of MSK by ELISA.Conclusion: Our data revealed a specific high-throughput metabolomics signature of MSK and indicated a pivotal biological role of sphingomyelin in this disease

  • Proteomic Analysis of Urinary Extracellular Vesicles Reveals a Role for the Complement System in Medullary Sponge Kidney Disease
    'MDPI AG', 2019
    Co-Authors: Bruschi Maurizio, Granata Simona, Petretto Andrea, Candiano Giovanni, Gambaro Giovanni, Fabris Antonia, Ghiggeri, Gian Marco, Zaza Gianluigi
    Abstract:

    Medullary Sponge Kidney (MSK) disease is a rare and neglected Kidney condition often associated with nephrocalcinosis/nephrolithiasis and cystic anomalies in the precalyceal ducts. Little is known about the pathogenesis of this disease, so we addressed the knowledge gap using a proteomics approach. The protein content of microvesicles/exosomes isolated from urine of 15 MSK and 15 idiopathic calcium nephrolithiasis (ICN) patients was investigated by mass spectrometry, followed by weighted gene co-expression network analysis, support vector machine (SVM) learning, and partial least squares discriminant analysis (PLS-DA) to select the most discriminative proteins. Proteomic data were verified by ELISA. We identified 2998 proteins in total, 1764 (58.9%) of which were present in both vesicle types in both diseases. Among the MSK samples, only 65 (2.2%) and 137 (4.6%) proteins were exclusively found in the microvesicles and exosomes, respectively. Similarly, among the ICN samples, only 75 (2.5%) and 94 (3.1%) proteins were exclusively found in the microvesicles and exosomes, respectively. SVM learning and PLS-DA revealed a core panel of 20 proteins that distinguished extracellular vesicles representing each clinical condition with an accuracy of 100%. Among them, three exosome proteins involved in the lectin complement pathway maximized the discrimination between MSK and ICN: Ficolin 1, Mannan-binding lectin serine protease 2, and Complement component 4-binding protein beta. ELISA confirmed the proteomic results. Our data show that the complement pathway is involved in the MSK, revealing a new range of potential therapeutic targets and early diagnostic biomarkers

  • Proteomic-based research strategy identified laminin subunit alpha 2 as a potential urinary-specific biomarker for the Medullary Sponge Kidney disease.
    'Elsevier BV', 2017
    Co-Authors: Fabris Antonia, Granata Simona, Bruschi M, Santucci L, Candiano G, Petretto A, Dalla Gassa Alessandra, Antonucci Nadia, Gm Ghiggeri, Gambaro Giovanni
    Abstract:

    Medullary Sponge Kidney (MSK) disease, a rare Kidney malformation featuring recurrent renal stones and nephrocalcinosis, continues to be diagnosed using expensive and time-consuming clinical/instrumental tests (mainly urography). Currently, no molecular diagnostic biomarkers are available. To identify such we employed a proteomic-based research strategy utilizing urine from 22 patients with MSK and 22 patients affected by idiopathic calcium nephrolithiasis (ICN) as controls. Notably, two patients with ICN presented cysts. In the discovery phase, the urine of 11 MSK and 10 controls, were randomly selected, processed, and analyzed by mass spectrometry. Subsequently, several statistical algorithms were undertaken to select the most discriminative proteins between the two study groups. ELISA, performed on the entire patients' cohort, was used to validate the proteomic results. After an initial statistical analysis, 249 and 396 proteins were identified exclusive for ICN and MSK, respectively. A Volcano plot and ROC analysis, performed to restrict the number of MSK-associated proteins, indicated that 328 and 44 proteins, respectively, were specific for MSK. Interestingly, 119 proteins were found to differentiate patients with cysts (all patients with MSK and the two ICN with renal cysts) from ICN without cysts. Eventually, 16 proteins were found to be common to three statistical methods with laminin subunit alpha 2 (LAMA-2) reaching the higher rank by a Support Vector Machine, a binary classification/prediction scheme. ELISA for LAMA-2 validated proteomic results. Thus, using high-throughput technology, our study identified a candidate MSK biomarker possibly employable in future for the early diagnosis of this disease

  • Spontaneous calcification process in primary renal cells from a Medullary Sponge Kidney patient harbouring a GDNF mutation
    'Wiley', 2015
    Co-Authors: Mezzabotta F, Gambaro Giovanni, Fabris A., D'angelo A., Cristofaro R, Ceol M, Del Prete D, Priante G, Familiari A, Anglani F
    Abstract:

    Medullary nephrocalcinosis is a hallmark of Medullary Sponge Kidney (MSK). We had the opportunity to study a spontaneous calcification process in vitro by utilizing the renal cells of a patient with MSK who was heterozygous for the c.-27 + 18G>A variant in the GDNF gene encoding glial cell-derived neurotrophic factor. The cells were obtained by collagenase digestion of papillary tissues from the MSK patient and from two patients who had no MSK or nephrocalcinosis. These cells were typed by immunocytochemistry, and the presence of mineral deposits was studied using von Kossa staining, scanning electron microscopy analysis and an ALP assay. Osteoblastic lineage markers were studied using immunocytochemistry and RT-PCR. Staminality markers were also analysed using flow cytometry, magnetic cell separation technology, immunocytochemistry and RT-PCR. Starting from p2, MSK and control cells formed nodules with a behaviour similar to that of calcifying pericytes; however, Ca2 PO4 was only found in the MSK cultures. The MSK cells had morphologies and immunophenotypes resembling those of pericytes or stromal stem cells and were positive for vimentin, ZO1, \u3b1SMA and CD146. In addition, the MSK cells expressed osteocalcin and osteonectin, indicating an osteoblast-like phenotype. In contrast to the control cells, GDNF was down-regulated in the MSK cells. Stable GDNF knockdown was established in the HK2 cell line and was found to promote Ca2 PO4 deposition when the cells were incubated with calcifying medium by regulating the osteonectin/osteopontin ratio in favour of osteonectin. Our data indicate that the human papilla may be a perivascular niche in which pericyte/stromal-like cells can undergo osteogenic differentiation under particular conditions and suggest that GDNF down-regulation may have influenced the observed phenomenon

  • Medullary Sponge Kidney
    'Ovid Technologies (Wolters Kluwer Health)', 2013
    Co-Authors: Gambaro Giovanni, Danza Francesco, Fabris A.
    Abstract:

    After it was first described in 1939, Medullary Sponge Kidney (MSK) received relatively little attention. This was because it was believed to have a low prevalence and because it was considered a benign condition. Studies in recent years have been changing these convictions however, hence the present review

Cataldo Abaterusso - One of the best experts on this subject based on the ideXlab platform.

  • Identification of GDNF Gene Sequence Variations in Patients with Medullary Sponge Kidney Disease
    2016
    Co-Authors: Dorella Del Prete, Antonio Lupo, Cataldo Abaterusso, Nicola Marchionna, Rosalba Cristofaro, Lina Artifoni, Giovanni Gambaro
    Abstract:

    Background and objectives: Medullary Sponge Kidney (MSK) is a rare nephropathy characterized by cystic anomalies of precalyceal ducts, nephrocalcinosis, renal stones, and tubule dysfunctions. Its association with various malformations and cases of familial aggregation supports the conviction that genetic factors are involved, but no genetic studies have been conducted to date. It is hypothesized that MSK is due to a disruption at the “ureteric bud/metanephric blastema ” interface caused by critical developmental genes functioning abnormally. Design, setting, participants, & measurements: Fifty-five apparently sporadic MSK patients were analyzed by direct DNA sequencing of all exons and exon-intron boundaries of glial cell-derived neurotrophic factor (GDNF) gene and rearranged during transfection (RET) gene, which have a leading role in renal development. Results: Two novel variants were found in heterozygosity in the MSK case population: GDNF{ENST00000344622}: c.45G>C and c.2718G>A in a putative binding domain for paired-box 2 transcription factor. As a whole, eight patients showed these variations: four patients carried the c.[45G>C; 2718G>A] complex allele, and the others had the c.2718G>A alone. A case-control study revealed that these two alleles were significantly associated with MSK. Five of the eight cases were found to be familial, and the allele variants cosegregated with the disease in a seemingly dominant patter

  • long term treatment with potassium citrate and renal stones in Medullary Sponge Kidney
    Clinical Journal of The American Society of Nephrology, 2010
    Co-Authors: Antonia Fabris, Antonio Nouvenne, Antonio Lupo, Patrizia Bernich, Cataldo Abaterusso, Nicola Marchionna, Giovanni Gambaro
    Abstract:

    Background and objectives: Medullary Sponge Kidney (MSK) is a renal malformation typically associated with nephrocalcinosis and recurrent calcium stones. Incomplete distal renal tubular acidosis, hypocitraturia, and hypercalciuria are common. For stone prevention, patients with MSK generally receive the standard “stone clinic” recommendations and often receive potassium citrate (KC). However, the effect on stone recurrence of citrate treatment in these patients has never been studied. Design, setting, participants, & measurements: The issue was retrospectively analyzed on an outpatient basis in 97 patients with a radiologic diagnosis of MSK: 65 had at least one stone risk factor (SRF; hypercalciuria, hypocitraturia, hyperuricosuria, hyperoxaluria) and received KC [29 ± 8 (SD) mEq/d]; 10 patients with SRF and 22 without received only general stone clinic suggestions. Follow-up was 78 ± 13, 72 ± 15, and 83 ± 14 months, respectively. The 24-hour urinary excretion of calcium, oxalate, uric acid, citrate, and morning urine pH were investigated at baseline and at the end of follow-up. Results: Parallel to a significant rise in urinary citrate and decreased urinary calcium (all P Conclusions: Treatment with KC is effective in preventing renal stones in the typical patient with MSK. It seems that two clinical phenotypes among patients showing typical MSK features during radiologic study exist.

  • identification of gdnf gene sequence variations in patients with Medullary Sponge Kidney disease
    Clinical Journal of The American Society of Nephrology, 2010
    Co-Authors: Rossella Torregrossa, Antonia Fabris, Cataldo Abaterusso, Dorella Del Prete, Rosalba Cristofaro, Lina Artifoni, Franca Anglani, Alessia Gozzini, Annalisa Tanini, Nicola Marchionna
    Abstract:

    Background and objectives: Medullary Sponge Kidney (MSK) is a rare nephropathy characterized by cystic anomalies of precalyceal ducts, nephrocalcinosis, renal stones, and tubule dysfunctions. Its association with various malformations and cases of familial aggregation supports the conviction that genetic factors are involved, but no genetic studies have been conducted to date. It is hypothesized that MSK is due to a disruption at the “ureteric bud/metanephric blastema” interface caused by critical developmental genes functioning abnormally. Design, setting, participants, & measurements: Fifty-five apparently sporadic MSK patients were analyzed by direct DNA sequencing of all exons and exon-intron boundaries of glial cell-derived neurotrophic factor (GDNF) gene and rearranged during transfection (RET) gene, which have a leading role in renal development. Results: Two novel variants were found in heterozygosity in the MSK case population: GDNF{ENST00000344622}:c.−45G>C and c.−27+18G>A in a putative binding domain for paired-box 2 transcription factor. As a whole, eight patients showed these variations: four patients carried the c.[−45G>C; −27+18G>A] complex allele, and the others had the c.−27+18G>A alone. A case-control study revealed that these two alleles were significantly associated with MSK. Five of the eight cases were found to be familial, and the allele variants cosegregated with the disease in a seemingly dominant pattern of inheritance. Patients revealed no mutations in the RET gene. Conclusions: This is the first report identifying GDNF gene sequence variations in patients with MSK and suggesting a role for this gene in the pathogenesis of some cases of the disease.

  • bone disease in Medullary Sponge Kidney and effect of potassium citrate treatment
    Clinical Journal of The American Society of Nephrology, 2009
    Co-Authors: Antonia Fabris, Antonio Nouvenne, Antonio Lupo, Patrizia Bernich, Cataldo Abaterusso, Nicola Marchionna, Chiara Canciani, Mauro Zamboni, Giovanni Gambaro
    Abstract:

    Background and objectives: In Medullary Sponge Kidney (MSK)—a common malformative renal condition in patients with calcium nephrolithiasis—hypercalciuria, incomplete distal renal tubular acidosis, and hypocitraturia are common. Clinical conditions with concomitant hypercalciuria and/or incomplete distal renal tubular acidosis are almost invariably associated with bone disease, making osteopathy highly likely in MSK, too. Patients with MSK have never been investigated for osteopathy; neither has the potential effect of potassium citrate administration (CA) on their urinary metabolic risk factors and on bone mineralization. Design, setting, participants, & measurements: These issues were retrospectively analyzed in 75 patients with MSK and primary stone risk factor (PSRF; hypercalciuria, hypocitraturia, hyperuricosuria, and/or hyperoxaluria) on an outpatient basis; 65 received CA (2.9 ± 0.8 g/d), whereas 10 received only general “stone clinic” suggestions. The 24-h urinary excretion of calcium, phosphate, oxalate, uric acid, and citrate; morning urine pH; serum biochemistry; and bone mineral density were investigated at baseline and at the end of follow-up (78 ± 13 and 72 ± 15 mo in groups A and B, respectively). Results: CA led to a significant rise in urinary pH and citrate and decreased urinary calcium and phosphate (all P < 0.001). Patients with MSK and PSRF had reduced bone density. Bone density improved significantly in the group that was treated with oral CA. Conclusions: Bone disease is very frequent in patients with MSK and concomitant PSRF. Long-term CA improves bone density. The concurrent effects of treatment on PSRF suggest that the subtle acidosis plays a pivotal role in bone disease and hypercalciuria in patients with MSK.