Dihydroxyadenine crystal-induced nephropathy presenting with rapidly progressive renal failure

Verma, Ritu; Manickam, Niraimathi; Prasad, Pallavi; Agrawal, Vinita

doi:10.23876/j.krcp.2018.37.3.287

Cited by 8 publications

(7 citation statements)

References 8 publications

(8 reference statements)

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“…These mineral nanoparticles can cause tubular damage and initiate local inflammation, leading to interstitial fibrosis [60]. Similar findings have been reported with myeloma-light chain-associated proximal tubulopathy with crystal formation [61,62]; the appearance of which is similar to that seen with CKDmfo. Figure 1 illustrates the conceptual drawing of a parts of a nephron, demonstrating the process of nanomineral formation in renal tubules.…”

Section: Toxic Tubular Nephropathysupporting

confidence: 66%

Factors Affecting the Environmentally Induced, Chronic Kidney Disease of Unknown Aetiology in Dry Zonal Regions in Tropical Countries—Novel Findings

Wimalawansa¹,

Dissanayake

2019

Environments

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A new form of chronic tubulointerstitial kidney disease (CKD) not related to diabetes or hypertension appeared during the past four decades in several peri-equatorial and predominantly agricultural countries. Commonalities include underground stagnation of drinking water with prolonged contact with rocks, harsh climatic conditions with protracted dry seasons, and rampant poverty and malnutrition. In general, the cause is unknown, and the disease is therefore named CKD of unknown aetiology (CKDu). Since it is likely caused by a combination of factors, a better term would be CKD of multifactorial origin (CKDmfo). Middle-aged malnourished men with more than 10 years of exposure to environmental hazards are the most vulnerable. Over 30 factors have been proposed as causative, including agrochemicals and heavy metals, but none has been properly tested nor proven as causative, and unlikely to be the cause of CKDmfo/CKDu. Conditions such as, having favourable climatic patterns, adequate hydration, and less poverty and malnutrition seem to prevent the disease. With the right in vivo conditions, chemical species such as calcium, phosphate, oxalate, and fluoride form intra-renal nanomineral particles initiating the CKDmfo. This article examines the key potential chemical components causing CKDmfo together with the risk factors and vulnerabilities predisposing individuals to this disease. Research findings suggest that in addition to drinking water from stagnant sources that contain high ionic components, more than 10 years of exposure to environmental nephrotoxins and micronutrient malnutrition are needed to contract this fatal disease.

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Section: Toxic Tubular Nephropathysupporting

confidence: 66%

Factors Affecting the Environmentally Induced, Chronic Kidney Disease of Unknown Aetiology in Dry Zonal Regions in Tropical Countries—Novel Findings

Wimalawansa¹,

Dissanayake

2019

Environments

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“…In the present study, we describe the results of Raman spectroscopy of kidney tissue in the CKD model. We induced CKD by oral administration of 6% adenine as an earlier published method, [ 6 ] whereas in other research, adenine was given mixed with feed at a concentration of 0.75% (w/w) for 4 weeks [ 23 ] or modified to another concentration. [ 24 ] We showed that adenine administration led to weight loss and morphological changes of kidney tissue, which can be easily observed.…”

Section: Discussionmentioning

confidence: 99%

“…Adenine phosphoribosyltransferase (APRT) is required for the metabolism of adenine to adenosine monophosphate (AMP). [ 6 ] The deficiency of the APRT leads to over‐production and renal excretion of 2,8‐dihydroxyadenine (DHA), which could be a result of the formation of kidney stone causing CKD. [ 7 ]…”

Section: Introductionmentioning

confidence: 99%

“…Adenine phosphoribosyltransferase (APRT) is required for the metabolism of adenine to adenosine monophosphate (AMP). [6] The deficiency of the APRT leads to over-production and renal excretion of 2,8-dihydroxyadenine (DHA), which could be a result of the formation of kidney stone causing CKD. [7] Tryptophan (Trp) is an essential amino acid that has two primary metabolic pathways: serotonin pathways and kynurenine (Kyn) pathways.…”

Section: Introductionmentioning

confidence: 99%

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Identification of biomarkers on kidney failure by Raman spectroscopy

Gulyamov

Shamshiddinova

Bae

et al. 2021

J Raman Spectroscopy

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Chronic kidney disease (CKD) is a global health problem. Our study employed Raman spectroscopy for the first time to analyze potential biomarker such as tryptophan (Trp) on kidney failure and show the difference between normal and CKD groups. Adenine model of CKD characterized most of the physiological changes observed in human CKD. For that, 6‐week‐old Wistar male rats were assigned to the two groups: the control group, 0.5% carboxymethyl cellulose (CMC) was administered; the CKD group, adenine was administered to rats at a dose 600 mg/kg for 10 days. The Raman spectra were obtained in the spectral range of 100–2500 cm−1. The excitation source was 532 nm, the laser power was ~40 mW, and the analyzed tissue area was 10.02 × 82.12 μm2. The results showed a significant reduction in the case of Raman peak intensities at 748, 1359, 1554, and 1636 cm−1, which can be assigned as Trp. Moreover, it was shown that tyrosine at 1169 cm−1 and phenylalanine at 1001 cm−1 decreased in the CKD group. Trp and kynurenine (Kyn) levels in kidney tissue and plasma were analyzed by using the high‐performance liquid chromatography (HPLC). The Trp concentrations in plasma and kidney tissue significantly decreased in CKD 7.4 μg/ml and 0.1 μg/mg, respectively. However, Kyn level was not a statistically significant change in kidney tissue. In this work, we showed that Raman spectroscopy usage in CKD model and Raman spectroscopy can be considered a promising technique for semi‐quantitative analysis of potential biomarkers such as phenylalanine, tyrosine, and Trp of renal function because of the little or no need for sample preparation, and it is easily observing several biomarkers at the same time. The utilization of multivariate analysis method, such as partial least square analysis can be considered as a promising tool for the discrimination of control and CKD groups.

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“…18 The estimated prevalence of this disorder is 1:50,000-1:100,000, but some reports suggest that these numbers might be an underestimation. [19][20][21] 2,8-DHA nephropathy can also recur in transplanted kidneys and frequently results in allograft failure in undertreated individuals. [22][23][24] The standard therapy consists of a xanthine oxidoreductase inhibitor, allopurinol or febuxostat, 21,25 which can prevent or ameliorate the progressive course of the disease if initiated early.…”

mentioning

confidence: 99%

Cellular and Molecular Mechanisms of Kidney Injury in 2,8-Dihydroxyadenine Nephropathy

Klinkhammer

Djudjaj

Kunter³

et al. 2020

JASN

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BackgroundHereditary deficiency of adenine phosphoribosyltransferase causes 2,8-dihydroxyadenine (2,8-DHA) nephropathy, a rare condition characterized by formation of 2,8-DHA crystals within renal tubules. Clinical relevance of rodent models of 2,8-DHA crystal nephropathy induced by excessive adenine intake is unknown.MethodsUsing animal models and patient kidney biopsies, we assessed the pathogenic sequelae of 2,8-DHA crystal-induced kidney damage. We also used knockout mice to investigate the role of TNF receptors 1 and 2 (TNFR1 and TNFR2), CD44, or alpha2-HS glycoprotein (AHSG), all of which are involved in the pathogenesis of other types of crystal-induced nephropathies.ResultsAdenine-enriched diet in mice induced 2,8-DHA nephropathy, leading to progressive kidney disease, characterized by crystal deposits, tubular injury, inflammation, and fibrosis. Kidney injury depended on crystal size. The smallest crystals were endocytosed by tubular epithelial cells. Crystals of variable size were excreted in urine. Large crystals obstructed whole tubules. Medium-sized crystals induced a particular reparative process that we term extratubulation. In this process, tubular cells, in coordination with macrophages, overgrew and translocated crystals into the interstitium, restoring the tubular luminal patency; this was followed by degradation of interstitial crystals by granulomatous inflammation. Patients with adenine phosphoribosyltransferase deficiency showed similar histopathological findings regarding crystal morphology, crystal clearance, and renal injury. In mice, deletion of Tnfr1 significantly reduced tubular CD44 and annexin two expression, as well as inflammation, thereby ameliorating the disease course. In contrast, genetic deletion of Tnfr2, Cd44, or Ahsg had no effect on the manifestations of 2,8-DHA nephropathy.ConclusionsRodent models of the cellular and molecular mechanisms of 2,8-DHA nephropathy and crystal clearance have clinical relevance and offer insight into potential future targets for therapeutic interventions.

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Dihydroxyadenine crystal-induced nephropathy presenting with rapidly progressive renal failure

Cited by 8 publications

References 8 publications

Factors Affecting the Environmentally Induced, Chronic Kidney Disease of Unknown Aetiology in Dry Zonal Regions in Tropical Countries—Novel Findings

Factors Affecting the Environmentally Induced, Chronic Kidney Disease of Unknown Aetiology in Dry Zonal Regions in Tropical Countries—Novel Findings

Identification of biomarkers on kidney failure by Raman spectroscopy

Cellular and Molecular Mechanisms of Kidney Injury in 2,8-Dihydroxyadenine Nephropathy

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