Podocyturia: A Clue for the Rational Use of Amiloride in Alport Renal Disease

Trimarchi, Hernán; Canzonieri, Romina; Muryan, Alexis; Schiel, Amalia; Aráoz, Alicia; Paulero, Matías; Andrews, J. Matthew; Rengel, Tatiana; Forrester, Mariano; Lombi, Fernando; Pomeranz, Vanesa; Iriarte, Romina; Zotta, Elsa

doi:10.1155/2016/1492743

Cited by 13 publications

(17 citation statements)

References 27 publications

(35 reference statements)

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“…The same applies for proteinuria, nil or low at initial stages, and comparatively higher at later stages[ 26 ]. Podocyturia has been assessed in a wide variety of glomerulopathies, as well as in transplantation and in entities where the glomerulus is not primarily affected, as in polycystic kidney disease[ 26 , 27 , 29 , 30 , 37 , 38 ].…”

Section: Search For Podocyturia: Potentialitymentioning

confidence: 99%

Podocyturia: Potential applications and current limitations

Trimarchi

2017

WJN

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Chronic kidney disease is a prevalent condition that affects millions of people worldwide and is a major risk factor of cardiovascular morbidity and mortality. The main diseases that lead to chronic kidney disease are frequent entities as diabetes mellitus, hypertension and glomerulopathies. One of the clinical markers of kidney disease progression is proteinuria. Moreover, the histological hallmark of kidney disease is sclerosis, located both in the glomerular and in the interstitial compartments. Glomerulosclerosis underscores an irreversible lesion that is clinically accompanied by proteinuria. In this regard, proteinuria and glomerular sclerosis are linked by the cell that has been conserved phylogenetically not only to prevent the loss of proteins in the urine, but also to maintain the health of the glomerular filtration barrier: The podocyte. It can then be concluded that the link between proteinuria, kidney disease progression and chronic kidney disease is mainly related to the podocyte. What is this situation due to? The podocyte is unable to proliferate under normal conditions, and a complex molecular machinery exists to avoid its detachment and eventual loss. When the loss of podocytes in the urine, or podocyturia, is taking place and its glomerular absolute number decreased, glomerulosclerosis is the predominant histological feature in a kidney biopsy. Therefore, tissular podocyte shortage is the cause of proteinuria and chronic kidney disease. In this regard, podocyturia has been demonstrated to precede proteinuria, showing that the clinical management of proteinuria cannot be considered an early intervention. The identification of urinary podocytes could be an additional tool to be considered by nephrologists to assess the activity of glomerulopathies, for follow-up purposes and also to unravel the pathophysiology of podocyte detachment in order to tailor the therapy of glomerular diseases more appropriately.

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Section: Search For Podocyturia: Potentialitymentioning

confidence: 99%

Podocyturia: Potential applications and current limitations

Trimarchi

2017

WJN

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“…In patients with cancer, CD39-expressing Th17 cells predict poor clinical outcome. 81 Th17 cells generated in the absence of TGF-β that lack CD39 and CD73 fail to promote tumor growth and are endowed with antitumor functions. 82 Several studies suggest that Th17 and IL-17A promote antitumor immune responses.…”

Section: Cd39 and Th17 Responsesmentioning

confidence: 99%

On the mechanism of anti-CD39 immune checkpoint therapy

Allard

Stagg

2020

J Immunother Cancer

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With the coming of age of cancer immunotherapy, the search for new therapeutic targets has led to the identification of immunosuppressive adenosine as an important regulator of antitumor immunity. This resulted in the development of selective inhibitors targeting various components of the adenosinergic pathway, including small molecules antagonists targeting the high affinity A2A adenosine receptor and low affinity A2B receptor, therapeutic monoclonal antibodies (mAbs) and small molecules targeting CD73 and therapeutic mAbs targeting CD39. As each regulator of the adenosinergic pathway present non-overlapping biologic functions, a better understanding of the mechanisms of action of each targeted approach should accelerate clinical translation and improve rational design of combination treatments. In this review, we discuss the potential mechanisms-of-action of anti-CD39 cancer therapy and potential toxicities that may emerge from sustained CD39 inhibition. Caution should be taken, however, in extrapolating data from gene-targeted mice to patients treated with blocking anti-CD39 agents. As phase I clinical trials are now underway, further insights into the mechanism of action and potential adverse events associated with anti-CD39 therapy are anticipated in coming years.

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“…In our cell lines, the co‐expression of a marker of immature podocytes such as PAX2 along with COL4 α3, α4, and α5 collagen chains could suggest a progenitor stage; however, as proven for other ATS‐related disorders such as focal glomerular sclerosis (Bariety et al., ; Barisoni et al., ), it is likely that the impaired podocytes encounter a process of dysregulation and dedifferentiated and then re‐express markers of immature cells such as PAX2 as in fetal glomeruli. Podocyturia has been previously reported to be an indicator of early glomerular damage (Trimarchi et al., ; Vogelmann et al., ). In line with this hypothesis, we were not able to isolate urine‐derived cell lines from healthy individuals (Table ) confirming that a GBM damage is necessary for podocytes‐lineage cells to be filtered through the glomerulus and thus that podocyturia can be used as biomarker of disease progression and response to treatment.…”

Section: Discussionmentioning

confidence: 98%

“…Commonly drug‐based approaches in ATS include angiotensin‐converting enzyme inhibitor (ACE‐I) and angiotensin receptor blockers, which are employed to reduce proteinuria and thus retard kidney disease progression and cardiovascular morbidity and mortality. Conventional treatment is commonly started for urinary proteins/urinary creatinine levels above 0.2 mg. A recent case report indicated that low‐dosage Amiloride treatment, acting in the very early stage of disease, is able to decrease podocyturia in an ATS patient (Trimarchi et al., ), Therefore, our cell line provides a clean system to test for the effect of repurposing of Amiloride or other drugs on disease‐relevant cell lines and to evaluate the possibility of a patophysiologically based therapeutic approach. The possibility of directly reverting collagen IV causative mutations in ATS injured podocytes has not yet been explored.…”

Section: Discussionmentioning

confidence: 99%

“…Several works, have recently proven that podocytes excretion (podocyturia) is a silent phenomenon that precedes proteinuria (Trimarchi et al., ; Vogelmann et al., ) and may be a more sensitive indicator of glomerular disease activity and damage than proteinuria (Hara et al., ; Nakamura et al., ; Vogelmann et al., ; Yu et al., ) suggesting the possibility of isolating podocytes or podocytes precursors in GBM damage‐related disorders. Although urine‐derived podocytes cell cultures have recently been established in other GBM‐damage related diseases (Lazzeri et al., ), no studies so far have demonstrated the possibility of directly isolating podocytes from ATS patients’ urine samples, providing an easily available patient‐derived cell system closer to podocytes’ physiological conditions.…”

Section: Introductionmentioning

confidence: 99%

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Urine-derived podocytes-lineage cells: A promising tool for precision medicine in Alport Syndrome

et al. 2017

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Alport Syndrome (ATS) is a rare genetic disorder caused by collagen IV genes mutations, leading to glomerular basement membrane damage up to end-stage renal disease. Podocytes, the main component of the glomerular structure, are the only cells able to produce all the three collagens IV alpha chains associated with ATS and thus, they are key players in ATS pathogenesis. However, podocytes-targeted therapeutic strategies have been hampered by the difficulty of non-invasively isolating them and transcripts-based diagnostic approaches are complicated by the inaccessibility of other COL4 chains-expressing cells. We firstly isolated podocyte-lineage cells from ATS patients' urine samples, in a non-invasive way. RT-PCR analysis revealed COL4A3, COL4A4, and COL4A5 expression. Transcripts analysis on RNA extracted from patient's urine derived podocyte-lineage cells allowed defining the pathogenic role of intronic variants, namely one mutation in COL4A3 (c.3882+5G>A), three mutations in COL4A4 (c.1623+2T>A, c.3699_3706+1del, c.2545+143T>A), and one mutation in COL4A5 (c.3454+2T>C). Therefore, our cellular model represents a novel tool, essential to unequivocally prove the effect of spliceogenic intronic variants on transcripts expressed exclusively at a glomerular level. This process is a key step for providing the patient with a definite molecular diagnosis and with a proper recurrence risk. The established system also opens up the possibility of testing personalized therapeutic approaches on disease-relevant cells.

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Podocyturia: A Clue for the Rational Use of Amiloride in Alport Renal Disease

Cited by 13 publications

References 27 publications

Podocyturia: Potential applications and current limitations

Podocyturia: Potential applications and current limitations

On the mechanism of anti-CD39 immune checkpoint therapy

Urine-derived podocytes-lineage cells: A promising tool for precision medicine in Alport Syndrome

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