Glycine Amidinotransferase (GATM), Renal Fanconi Syndrome, and Kidney Failure

Background For many patients with kidney failure, the cause and underlying defect remain unknown. Here, we describe a novel mechanism of a genetic order characterized by renal Fanconi syndrome and kidney failure.Methods We clinically and genetically characterized members of five families with autosomal dominant renal Fanconi syndrome and kidney failure. We performed genome-wide linkage analysis, sequencing, and expression studies in kidney biopsy specimens and renal cells along with knockout mouse studies and evaluations of mitochondrial morphology and function. Structural studies examined the effects of recognized mutations.Results The renal disease in these patients resulted from monoallelic mutations in the gene encoding glycine amidinotransferase (GATM), a renal proximal tubular enzyme in the creatine biosynthetic pathway that is otherwise associated with a recessive disorder of creatine deficiency. In silico analysis showed that the particular GATM mutations, identified in 28 members of the five families, create an additional interaction interface within the GATM protein and likely cause the linear aggregation of GATM observed in patient biopsy specimens and cultured proximal tubule cells. GATM aggregates-containing mitochondria were elongated and associated with increased ROS production, activation of the NLRP3 inflammasome, enhanced expression of the profibrotic cytokine IL-18, and increased cell death.Conclusions In this novel genetic disorder, fully penetrant heterozygous missense mutations in GATM trigger intramitochondrial fibrillary deposition of GATM and lead to elongated and abnormal mitochondria. We speculate that this renal proximal tubular mitochondrial pathology initiates a response from the inflammasome, with subsequent development of kidney fibrosis.

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MO142A SINGLE-CENTER CASE SERIES OF 150 PATIENTS WITH RENAL FANCONI SYNDROME

Nephrology Dialysis Transplantation ◽

10.1093/ndt/gfab092.0020 ◽

2021 ◽

Vol 36 (Supplement_1) ◽

Author(s):

Xiaoxiao Shi ◽

Ying Wang ◽

Jiaying Li ◽

Zhixin Chen ◽

Tiantian Ma ◽

...

Keyword(s):

Fanconi Syndrome ◽

Case Series ◽

Pathological Features ◽

Interstitial Edema ◽

Renal Fanconi Syndrome ◽

Female Ratio ◽

Common Causes ◽

Male Female Ratio ◽

Proximal Tubular ◽

Renal Proximal Tubular

Abstract Background and Aims Renal Fanconi syndrome (RFS) is characterized by generalized dysfunctions of renal proximal tubular (PT) transport. The causes of FS can be inherited or acquired, the latter of which mostly includes drugs, heavy metals, monoclonal light chains (LC), and primary Sj gren’s syndrome (pSS). We intended to observe the clinico-pathological features of RFS with different etiologies. Method From January 2012 to September 2018, all the patients diagnosed as RFS in our hospital were enrolled. Their clinicopathological records were retrospectively reviewed. The diagnosis of RFS was defined as existence of ≥ 3 of the following five items alone or ≥ 2 items combined with an evidence of PT damages in kidney pathology: (I) normoglycemic glycosuria; (II) generalized aminoaciduria; (III) hypophosphatemia and hyperphosphaturia; (IV) hypouricemia and hyperuricosuria; (V) proximal RTA. Results: 1. Clinical characteristics We identified 150 RFS patients, with an average age of (45.9±14.2) years old and male: female ratio 1.3:1. They presented with different degrees of PT dysfunctions and the most common were hypophosphatemia (83.2%) and aminoaciduria (80.6%). Their mean eGFR levels were 76.3 (4.5-188.6) ml/min/1.73m2 with 73.5% had proteinuria. 2. Renal pathological features 47 RFS patients received kidney biopsy and the most common pathological diagnosis was interstitial nephritis. They all presented with different degrees of proximal tubule atrophy, defective brush border, interstitial edema and fibrosis. 3. Etiology-related clinicopathologic features The most common causes of our RFS were LC (14.0%), drugs (13.3%), and pSS (9.3%). Compared to pSS associated RFS, LC associated RFS patients showed a higher prevalence of bone involvement, more severe proteinuria and less severe hypokalemia (P < 0.05) despite similar eGFR levels. Specific renal pathological features were seen in different etiology groups, including crystalline formation and increased lysosomes in PT cells under electron microscope in LC associated RFS, and CD21 positive ectopic germinal center formation in renal interstitum in parts of the pSS associated RFS. Conclusion We identified 150 RFS with different etiologies and they showed etiology-specific patterns of PT dysfunctions and renal pathologic changes.

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Approach to the patient with renal Fanconi syndrome, glycosuria, or aminoaciduria

10.1093/med/9780199592548.003.0041_update_001 ◽

2018 ◽

Author(s):

Detlef Bockenhauer ◽

Robert Kleta

Keyword(s):

Fanconi Syndrome ◽

Tubular Dysfunction ◽

Renal Fanconi Syndrome ◽

Renal Glycosuria ◽

Proximal Tubular Dysfunction ◽

Wide Range ◽

Proximal Tubular ◽

Proximal Tubular Function ◽

Low Molecular Weight Proteins ◽

Filtration Capacity

Up to 80% of filtered salt and water is returned back into the circulation in the proximal tubule. Several solutes, such as phosphate, glucose, low-molecular weight proteins, and amino acids are exclusively reabsorbed in this segment, so their appearance in urine is a sign of proximal tubular dysfunction. An entire orchestra of specialized apical and basolateral transporters, as well as paracellular molecules, mediate this reabsorption. Defects in proximal tubular function can be isolated (e.g. isolated renal glycosuria, aminoacidurias, or hypophosphataemic rickets) or generalized. In the latter case it is called the Fanconi–Debre–de Toni syndrome, based on the initial clinical descriptions. However, in clinical practice it is usually referred to as just the ‘renal Fanconi syndrome’. Severity of proximal tubular dysfunction can vary, and may coexist with some degree of loss of glomerular filtration capacity. Causes include a wide range of insults to proximal tubular cells, including a number of genetic conditions, drugs and poisons.

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P0274A NOVEL METHOD FOR THE ASSESSMENT OF RENAL BIOPSY WITH THE ACTIVATABLE FLUORESCENT PROBE

Nephrology Dialysis Transplantation ◽

10.1093/ndt/gfaa142.p0274 ◽

2020 ◽

Vol 35 (Supplement_3) ◽

Author(s):

Takuji Iyama ◽

Tomoaki Takata ◽

Yukari Mae ◽

Sosuke Taniguchi ◽

Ayami Ida ◽

...

Keyword(s):

Renal Biopsy ◽

Fluorescent Probe ◽

Renal Cortex ◽

Ex Vivo ◽

Biopsy Specimens ◽

Fluorescent Image ◽

Human Biopsy ◽

Proximal Tubular ◽

Renal Proximal Tubular Cells ◽

Renal Proximal Tubular

Abstract Background and Aims Renal biopsy is one of the most important procedures in nephrology. The histological analysis of biopsy tissues is important for the diagnosis and prognosis assessment of renal diseases, as well as determining the treatment strategy. It is necessary to obtain biopsy specimens containing renal cortex for such purpose. Although renal biopsy is the undisputed diagnostic procedure, there always is a need to weigh the benefits against the potential complications. A novel activatable fluorescent probe that reacts with a peptide, which is highly expressed in the renal cortex, has been developed. We evaluated the feasibility of this probe for assessing renal biopsy specimens. Method The fluorescent probe was firstly applied to renal proximal tubular cells in order to evaluate the fluorescent emission. Then the probe was applied to mouse kidneys ex vivo. Finally, it was applied to human biopsy specimens (n=12). Fluorescent images were acquired using commercially available digital camera equipped with optical interference filter. Fluorescent intensities were quantified and the intensities in cortex and medulla were compared. Results We observed fluorescent emission from the renal proximal tubular cells immediately after the administration of the fluorescent probe. The fluorescent intensity gradually increased with time. The fluorescence signal was detected in the mouse kidneys ex vivo without markedly affecting the tissue morphology. The probe on human biopsy specimens also emitted fluorescent and the fluorescent could be detected in all the patients examined. In addition, the cortico-medullary junction could be identified in the fluorescent image (Figure). The fluorescent intensities in renal cortex were remarkably stronger than in medulla. Conclusion Renal biopsy specimens can be assessed by fluorescent image using this activatable fluorescent probe. This novel fluorescent probe is useful in clinical nephrology.

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Evaluation of the proximal tubular function in hereditary renal Fanconi syndrome

Nephrology Dialysis Transplantation ◽

10.1093/ndt/gfn373 ◽

2008 ◽

Vol 23 (9) ◽

pp. 2719-2722 ◽

Cited By ~ 7

Author(s):

L. Monnens ◽

E. Levtchenko

Keyword(s):

Fanconi Syndrome ◽

Tubular Function ◽

Renal Fanconi Syndrome ◽

Proximal Tubular ◽

Proximal Tubular Function

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Clinical Heterogeneity and Phenotypic Expansion of NaPi-IIa–Associated Disease

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jc.2017-01592 ◽

2017 ◽

Vol 102 (12) ◽

pp. 4604-4614 ◽

Cited By ~ 11

Author(s):

Korcan Demir ◽

Melek Yıldız ◽

Hilla Bahat ◽

Michael Goldman ◽

Nisreen Hassan ◽

...

Keyword(s):

Fanconi Syndrome ◽

Loss Of Function ◽

Renal Fanconi Syndrome ◽

Whole Exome ◽

Proximal Tubular ◽

History Of ◽

Proximal Tubulopathy ◽

Idiopathic Infantile Hypercalcemia ◽

Close Relatives

Abstract Context NaPi-IIa, encoded by SLC34A1, is a key phosphate transporter in the mammalian proximal tubule and plays a cardinal role in renal phosphate handling. NaPi-IIa impairment has been linked to various overlapping clinical syndromes, including hypophosphatemic nephrolithiasis with osteoporosis, renal Fanconi syndrome with chronic kidney disease, and, most recently, idiopathic infantile hypercalcemia and nephrocalcinosis. Objectives We studied the molecular basis of idiopathic infantile hypercalcemia with partial proximal tubulopathy in two apparently unrelated patients of Israeli and Turkish descent. Design Genetic analysis in two affected children and their close relatives was performed using whole-exome sequencing, followed by in vitro localization and trafficking analysis of mutant NaPi-IIa. Results Mutation and haplotype analyses in both patients revealed a previously described homozygous loss-of-function inserted duplication (p.I154_V160dup) in NaPi-IIa, which is inherited identical-by-descent from a common ancestor. The shared mutation was originally reported by our team in two adult siblings with renal Fanconi syndrome, hypophosphatemic bone disease, and progressive renal failure who are family members of one of the infants reported herein. In vitro localization assays and biochemical analysis of p.I154_V160dup and of additional NaPi-IIa mutants harboring a trafficking defect indicate aberrant retention at the endoplasmic reticulum in an immature and underglycosylated state, leading to premature proteasomal degradation. Conclusions Our findings expand the phenotypic spectrum of NaPi-IIa disruption, reinforce its link with proximal tubular impairment, enable longitudinal study of the natural history of the disease, and shed light on cellular pathways associated with loss of function and impaired trafficking of NaPi-IIa mutants.

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Hypokalemia: A potentially life-threatening complication of tenofovir therapy

SAGE Open Medical Case Reports ◽

10.1177/2050313x17741010 ◽

2017 ◽

Vol 5 ◽

pp. 2050313X1774101 ◽

Cited By ~ 1

Author(s):

Abhilash Koratala ◽

Rupam Ruchi

Keyword(s):

Cardiac Arrest ◽

Fanconi Syndrome ◽

Transcriptase Inhibitor ◽

Tubular Dysfunction ◽

Nucleotide Analog ◽

Life Threatening ◽

Proximal Tubular ◽

Life Threatening Complication ◽

Renal Proximal Tubular ◽

Reverse Transcriptase Inhibitor

Tenofovir is a nucleotide analog reverse transcriptase inhibitor approved for the treatment of HIV and hepatitis B infections. It is widely prescribed and an integral part of the recommended regimens for the treatment of HIV infection in antiretroviral-naive patients. Tenofovir is implicated in renal proximal tubular dysfunction, which can be associated with Fanconi syndrome and hypokalemia. When the hypokalemia is severe, it can lead to life-threatening complications. We describe the case of a 59-year-old woman who suffered a cardiac arrest secondary to severe hypokalemia from tenofovir use.

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Cell-Based Phenotypic Drug Screening Identifies Luteolin as Candidate Therapeutic for Nephropathic Cystinosis

Journal of the American Society of Nephrology ◽

10.1681/asn.2019090956 ◽

2020 ◽

Vol 31 (7) ◽

pp. 1522-1537

Author(s):

Ester De Leo ◽

Mohamed A. Elmonem ◽

Sante Princiero Berlingerio ◽

Marine Berquez ◽

Beatrice Paola Festa ◽

...

Keyword(s):

Safety Profile ◽

High Throughput Screening ◽

Fanconi Syndrome ◽

Lysosomal Storage Diseases ◽

Nephropathic Cystinosis ◽

Lysosomal Storage ◽

Renal Fanconi Syndrome ◽

Cystine Transporter ◽

Proximal Tubular Epithelial Cells ◽

Proximal Tubular

BackgroundMutations in the gene that encodes the lysosomal cystine transporter cystinosin cause the lysosomal storage disease cystinosis. Defective cystine transport leads to intralysosomal accumulation and crystallization of cystine. The most severe phenotype, nephropathic cystinosis, manifests during the first months of life, as renal Fanconi syndrome. The cystine-depleting agent cysteamine significantly delays symptoms, but it cannot prevent progression to ESKD and does not treat Fanconi syndrome. This suggests the involvement of pathways in nephropathic cystinosis that are unrelated to lysosomal cystine accumulation. Recent data indicate that one such potential pathway, lysosome-mediated degradation of autophagy cargoes, is compromised in cystinosis.MethodsTo identify drugs that reduce levels of the autophagy-related protein p62/SQSTM1 in cystinotic proximal tubular epithelial cells, we performed a high-throughput screening on the basis of an in-cell ELISA assay. We then tested a promising candidate in cells derived from patients with, and mouse models of, cystinosis, and in preclinical studies in cystinotic zebrafish.ResultsOf 46 compounds identified as reducing p62/SQSTM1 levels in cystinotic cells, we selected luteolin on the basis of its efficacy, safety profile, and similarity to genistein, which we previously showed to ameliorate other lysosomal abnormalities of cystinotic cells. Our data show that luteolin improves the autophagy–lysosome degradative pathway, is a powerful antioxidant, and has antiapoptotic properties. Moreover, luteolin stimulates endocytosis and improves the expression of the endocytic receptor megalin.ConclusionsOur data show that luteolin improves defective pathways of cystinosis and has a good safety profile, and thus has potential as a treatment for nephropathic cystinosis and other renal lysosomal storage diseases.

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