Autosomal Dominant Tubulointerstitial Kidney Disease: An Emerging Cause of Genetic CKD

Econimo, Laura; Schaeffer, Céline; Zeni, Luigi; Cortinovis, R; Alberici, Federico; Rampoldi, Luca; Scolari, Francesco; Izzi, Claudia

doi:10.1016/j.ekir.2022.08.012

Cited by 6 publications

(2 citation statements)

References 79 publications

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“…The low renin levels induced a decrease in eGFR associated with tubuloglomerular feedback (TGF). The clinical manifestations are childhood-onset anemia, hyperuricemia, gout, mild hypertension, hyperkalemia, and renal function insufficiency [ 32 ].…”

Section: Adtkds and Akimentioning

confidence: 99%

From Rare Disorders of Kidney Tubules to Acute Renal Injury: Progress and Prospective

Li,

Hou,

et al. 2024

Kidney Dis

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Background: Acute kidney injury (AKI) is a severe condition marked by rapid renal function deterioration and elevated mortality, with traditional biomarkers lacking sensitivity and specificity. Rare tubulointerstitial diseases encompass a spectrum of disorders, primarily including monogenic diseases, immune-related conditions, and drug-induced tubulointerstitial diseases. The clinical manifestations vary from the electrolyte and acid-base imbalance to kidney function insufficiency, which is associated with AKI in up to 20% of cases. Evidence indicated that rare tubulointerstitial diseases might provide new conceptual insights and perspectives for novel biomarkers and potential therapeutic strategies for AKI. Summary: Autosomal dominant tubulointerstitial kidney disease (ADTKD) and Fanconi syndrome (FS) are rare tubulointerstitial diseases. In ADTKD, UMOD and REN are closely related to AKI by affecting oxidative stress and tubuloglomerular feedback (TGF), which provide potential new biomarkers for AKI. Both rare tubulointerstitial diseases and AKI shared etiologies and treatment responses. From the mechanism standpoint, rare tubulointerstitial diseases and AKI involve tubular transporter injury, initially manifesting as tubular dysfunction in tubulointerstitial disorder and progressing to AKI because of the programmed cell death (PCD) with apoptosis, pyroptosis, or necroptosis of proximal tubule cells. Additionally, mitochondrial dysfunction has been identified as a common mechanism in both tubulointerstitial diseases and AKI induced by drugs, pSS, or monoclonal diseases. In the end, both AKI and FS patients and animal models responded well to the therapy of the primary diseases. Key messages: In this review, we describe an overview of ADTKD and FS to identify their associations with AKI. Mitochondrial dysfunction contributes to rare tubulointerstitial diseases and AKI, which might provide a potential therapeutic target.

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Section: Adtkds and Akimentioning

confidence: 99%

From Rare Disorders of Kidney Tubules to Acute Renal Injury: Progress and Prospective

Li,

Hou,

et al. 2024

Kidney Dis

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“…NPHP, as a stand-alone disease, has an estimated prevalence of 1:50,000, but it has also been implicated in several syndromic forms of PKD such as Joubert, Bardet-Biedl and Meckel-Gruber syndrome 6,7 . ADTKD is an umbrella of genetic conditions with clinicopathological features that overlap with those of NPHP 8 . In addition to kidney cysts, common pathologies in syndromic forms of PKD, are progressive decline in renal function, tubulointerstitial fibrosis, and tubular atrophy or degeneration without kidney enlargement.…”

Section: Introductionmentioning

confidence: 99%

Nephronophthisis-associated FBW7 mediates cyst-dependent decline of renal function in ADPKD

Patel,

Gerakopoulos,

Petsouki

et al. 2024

Preprint

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Nephronophthisis (NPHP) and autosomal dominant Polycystic Kidney Disease (ADPKD) are two genetically distinct forms of Polycystic Kidney Disease (PKD), yet both diseases present with kidney cysts and a gradual decline in renal function. Prevailing dogma in PKD is that changes in kidney architecture account for the decline in kidney function, but the molecular/cellular basis of such coupling is unknown. To address this question, we induced a form of proteome reprogramming by deleting Fbxw7 encoding FBW7, the recognition receptor of the SCFFBW7 E3 ubiquitin ligase in different segments of the kidney tubular system. Deletion of Fbxw7 in the medulla led to a juvenile-adult NPHP-like phenotype, where the decline in renal function was due to SOX9-mediated interstitial fibrosis rather than cystogenesis. In contrast, the decline of renal function in ADPKD is coupled to cystic expansion via the abnormal accumulation of FBW7 in the proximal tubules and other cell types in the renal cortex. We propose that FBW7 functions at the apex of a protein network that determines renal function in ADPKD by sensing architectural changes induced by cystic expansion.

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Hidden genetics behind glomerular scars: an opportunity to understand the heterogeneity of focal segmental glomerulosclerosis?

Mitrotti,

Giliberti,

Di Leo

et al. 2023

Pediatr Nephrol

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Focal segmental glomerulosclerosis (FSGS) is a complex disease which describes different kinds of kidney defects, not exclusively linked with podocyte defects. Since nephrin mutation was first described in association with early-onset nephrotic syndrome (NS), many advancements have been made in understanding genetic patterns associated with FSGS. New genetic causes of FSGS have been discovered, displaying unexpected genotypes, and recognizing possible site of damage. Many recent large-scale sequencing analyses on patients affected by idiopathic chronic kidney disease (CKD), kidney failure (KF) of unknown origin, or classified as FSGS, have revealed collagen alpha IV genes, as one of the most frequent sites of pathogenic mutations. Also, recent interest in complex and systemic lysosomal storage diseases, such as Fabry disease, has highlighted GLA mutations as possible causes of FSGS. Tubulointerstitial disease, recently classified by KDIGO based on genetic subtypes, when associated with UMOD variants, may phenotypically gain FSGS features, as well as ciliopathy genes or others, otherwise leading to completely different phenotypes, but found carrying pathogenic variants with associated FSGS phenotype. Thus, glomerulosclerosis may conceal different heterogeneous conditions. When a kidney biopsy is performed, the principal objective is to provide an accurate diagnosis. The broad spectrum of phenotypic expression and genetic complexity is demonstrating that a combined path of management needs to be applied. Genetic investigation should not be reserved only to selected cases, but rather part of medical management, integrating with clinical and renal pathology records. FSGS heterogeneity should be interpreted as an interesting opportunity to discover new pathways of CKD, requiring prompt genotype–phenotype correlation. In this review, we aim to highlight how FSGS represents a peculiar kidney condition, demanding multidisciplinary management, and in which genetic analysis may solve some otherwise unrevealed idiopathic cases. Unfortunately there is not a uniform correlation between specific mutations and FSGS morphological classes, as the same variants may be identified in familial cases or sporadic FSGS/NS or manifest a variable spectrum of the same disease. These non-specific features make diagnosis challenging. The complexity of FSGS genotypes requires new directions. Old morphological classification does not provide much information about the responsible cause of disease and misdiagnoses may expose patients to immunosuppressive therapy side effects, mistaken genetic counseling, and misguided kidney transplant programs.

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Autosomal Dominant Tubulointerstitial Kidney Disease: An Emerging Cause of Genetic CKD

Cited by 6 publications

References 79 publications

From Rare Disorders of Kidney Tubules to Acute Renal Injury: Progress and Prospective

From Rare Disorders of Kidney Tubules to Acute Renal Injury: Progress and Prospective

Nephronophthisis-associated FBW7 mediates cyst-dependent decline of renal function in ADPKD

Hidden genetics behind glomerular scars: an opportunity to understand the heterogeneity of focal segmental glomerulosclerosis?

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