Vancomycin-Associated Cast Nephropathy Luque, Yosu; Louis, Kevin; Jouanneau, Chantal ...
Journal of the American Society of Nephrology,
06/2017, Letnik:
28, Številka:
6
Journal Article
Recenzirano
Odprti dostop
Vancomycin is a widely prescribed antibiotic, but the exact nature of vancomycin-associated nephrotoxicity is unclear, in particular when considering the frequent coadministration of aminoglycosides. ...We describe here the initial case of a 56-year-old woman with normal renal function developing unexplained ARF without hypovolemia after administration of vancomycin without coadministration of aminoglycosides. Studying the patient's renal biopsy specimen, we ascertained that obstructive tubular casts composed of noncrystal nanospheric vancomycin aggregates entangled with uromodulin explained the vancomycin-associated ARF. We developed in parallel a new immunohistologic staining technique to detect vancomycin in renal tissue and confirmed retrospectively that deleterious vancomycin-associated casts existed in eight additional patients with acute tubular necrosis in the absence of hypovolemia. Concomitant high vancomycin trough plasma levels had been observed in each patient. We also reproduced experimentally the toxic and obstructive nature of vancomycin-associated cast nephropathy in mice, which we detected using different
imaging techniques. In conclusion, the interaction of uromodulin with nanospheric vancomycin aggregates represents a new mode of tubular cast formation, revealing the hitherto unsuspected mechanism of vancomycin-associated renal injury.
Few studies have examined the relative risk of recurrence of different stone types. The object of the present study was to evaluate the tendency for stone recurrence as a function of major mineral ...composition of the stones and morphological characteristics of the stones. This study was carried out using 38,274 stones for which we had data available to specify if the stone was from the first or a subsequent urinary stone episode. Stones were analyzed for morphology by stereomicroscope and for composition by infrared spectroscopy. Overall, 42.7% of stones were from patients who had had a previous stone event, with these being more frequent in men (44.4%) than in women (38.9%,
p
< 0.0001). Age of first stone occurrence was lowest for dihydroxyadenine (15.7 ± 16.6 years) and highest for anhydrous uric acid (62.5 ± 14.9 years), with the average age of first stones of calcium oxalate falling in the middle (40.7 ± 14.6 years for calcium oxalate dihydrate, and 48.4 ± 15.1 years for calcium oxalate monohydrate, COM). By composition alone, COM was among the least recurrent of stones, with only 38.0% of COM stones coming from patients who had had a previous episode; however, when the different morphological types of COM were considered, type Ic—which displays a light color, budding surface and unorganized section—had a significantly greater rate of recurrence, at 82.4% (
p
< 0.0001), than did other morphologies of COM. Similarly, for stones composed of apatite, morphological type IVa2—a unique form with cracks visible beneath a glossy surface—had a higher rate of recurrence than other apatite morphologies (78.8 vs. 39–42%,
p
< 0.0001). Stone mineral type alone is insufficient for identifying the potential of recurrence of the stones. Instead, the addition of stone morphology may allow the diagnosis of highly recurrent stones, even among common mineral types (e.g., COM) that in general are less recurrent.
Idiopathic kidney stones originate mainly from calcium phosphate deposits at the tip of renal papillae, known as Randall’s plaques (RPs), also detected in most human kidneys without stones. However, ...little is known about the mechanisms involved in RP formation. The localization and characterization of such nanosized objects in the kidney remain a real challenge, making their study arduous. This study provides a nanoscale analysis of the chemical composition and morphology of incipient RPs, characterizing in particular the interface between the mineral and the surrounding organic compounds. Relying on data gathered from a calculi collection, the morphology and chemical composition of incipient calcifications in renal tissue were determined using spatially resolved electron energy-loss spectroscopy. We detected microcalcifications and individual nanocalcifications found at some distance from the larger ones. Strikingly, concerning the smaller ones, we show that two types of nanocalcifications coexist: calcified organic vesicles and nanometric mineral granules mainly composed of calcium phosphate with carbonate in their core. Interestingly, some of these nanocalcifications present similarities with those reported in physiological bone or pathological cardiovascular biominerals, suggesting possible common formation mechanisms. However, the high diversity of these nanocalcifications suggests that several mechanisms may be involved (nucleation on a carbonate core or on organic compounds). In addition, incipient RPs also appear to present specific features at larger scales, revealing secondary calcified structures embedded in a fibrillar organic material. Our study proves that analogies exist between physiological and pathological biominerals and provides information to understand the physicochemical processes involved in pathological calcification formation.
Research on pathological calcifications constitutes an exciting topic at the interface between physics, chemistry
and medicine. The relationship between their physicochemical characteristics and the ...pathology responsible for their
formation offers a unique opportunity to perform a significant medical diagnosis, to assess the interaction between drugs
and these biological entities as well as to develop new drugs. Regarding synchrotron radiation, the emergence of
microbeam allows the clinician to perform an early diagnosis. Indeed, we will start this review with a clinical case where
Fourier transform infrared spectroscopy using synchrotron radiation as a probe allowed the clinician to save the kidney
function of a patient. Following this example, we will see that investigations on pathological calcifications constitute an
elegant way to gather major information on different public health problems such type 2 diabetes as well as on rare
diseases. To attain this goal, this mini-review dedicated to structural and chemical investigations and based on selected
and recent data collected through techniques using third generation synchrotron radiation as a probe is proposed to the
reader.
Cardiovascular disease including vascular calcification (VC) remains the leading cause of death in patients suffering from chronic kidney disease (CKD). The process of VC seems likely to be a tightly ...regulated process where vascular smooth muscle cells are playing a key role rather than just a mere passive precipitation of calcium phosphate. Characterisation of the chemical and crystalline structure of VC was mainly led in patients or animal models with CKD. Likewise, Mg2+ was found to be protective in living cells although a potential role for Mg2+ could not be excluded on crystal formation and precipitation. In this study, the crystal formation and the role of Mg2+ were investigated in an in vitro model of primary human aortic vascular smooth muscle cells (HAVSMC) with physical techniques.
In HAVSMC incubated with increased Ca x Pi medium, only calcium phosphate apatite crystals (CPA) were detected by Micro-Fourier Transform InfraRed spectroscopy (µFTIR) and Field Effect Scanning Electron Microscope (FE-SEM) and Energy Dispersive X-ray spectrometry (EDX) at the cell layer level. Supplementation with Mg2+ did not alter the crystal composition or structure. The crystal deposition was preferentially positioned near or directly on cells as pictured by FE-SEM observations and EDX measurements. Large µFTIR maps revealed spots of CPA crystals that were associated to the cellular layout. This qualitative analysis suggests a potential beneficial effect of Mg2+ at 5 mM in noticeably reducing the number and intensities of CPA µFTIR spots.
For the first time in a model of HAVSMC, induced calcification led to the formation of the sole CPA crystals. Our data seems to exclude a physicochemical role of Mg2+ in altering the CPA crystal growth, composition or structure. Furthermore, Mg2+ beneficial role in attenuating VC should be linked to an active cellular role.
Non-invasive multi-scale and multimodal 3D characterization of heterogeneous or hierarchically structured intact mesoscale samples is of paramount importance in tackling challenging scientific ...problems. Scanning hard X-ray tomography techniques providing simultaneous complementary 3D information are ideally suited to such studies. However, the implementation of a robust on-site workflow remains the bottleneck for the widespread application of these powerful multimodal tomography methods. In this paper, we describe the development and implementation of such a robust, holistic workflow, including semi-automatic data reconstruction. Due to its flexibility, our approach is especially well suited for on-the-fly tuning of the experiments to study features of interest progressively at different length scales. To demonstrate the performance of the method, we studied, across multiple length scales, the elemental abundances and morphology of two complex biological systems, Arabidopsis plant seeds and mouse renal papilla samples. The proposed approach opens the way towards routine multimodal 3D characterization of intact samples by providing relevant information from pertinent sample regions in a wide range of scientific fields such as biology, geology, and material sciences.
Prostatic stones are a common condition in older men in industrialized countries. However, aging appears not to be the unique pathogenesis of these calcifications. Our morpho-constitutional ...investigation of 23 stone samples suggested that infection has a significant role in the lithogenic process of prostate calcifications, even without detection of infection by clinical investigation. Most stones (83%) showed bacterial imprints and/or chemical composition, suggestive of a long-term infection process. Chronic infection may induce persistent inflammation of the tissue and secondarily, a cancerization process within a few years. Thus, the discovery of prostate calcifications by computerized tomodensitometry, for example, might warrant further investigation and management to search for chronic infection of the prostate gland.
Rhabdomyolysis is a risk factor for acute kidney injury, transition towards chronic kidney disease, and death. The role of calcium phosphate deposits in the mechanisms of rhabdomyolysis-induced acute ...kidney injury (RAKI) is still unclear. Better insight of the role calcium in RAKI could lead to new therapeutic avenues. Here, we show in a mice model of RAKI that calcium phosphate deposits were frequent in the kidney (hydroxyapatite) and partly correlated with the severity of the kidney injury. However, the intensity of deposits was highly heterogeneous between mice. Treatment with sodium chloride, sodium bicarbonate or inorganic pyrophosphate (PPi; an inhibitor of the calcium phosphate crystallization), or combinations thereof, did not improve kidney outcomes and hydroxyapatite deposition during RAKI. Unexpectedly, Abcc6 knockout mice (ko), characterized by PPi deficiency, developed less severe RAKI despite similar rhabdomyolysis severity, and had similar hydroxyapatite deposition suggesting alternative mechanisms. This improved kidney outcome at day 2 translated to a trend in improved glomerular filtration rate at month 2 in Abcc6
mice and to significantly less interstitial fibrosis. In addition, whereas the pattern of infiltrating cells at day 2 was similar between wt and ko mice, kidneys of Abcc6
mice were characterized by more CD19
B-cells, less CD3
T-cells and a lower R1/R2 macrophage ratio at month 2. In summary, kidney calcium phosphate deposits are frequent in RAKI but hydration with sodium bicarbonate or sodium chloride does not modify the kidney outcome. Blocking ABCC6 emerges as a new option to prevent RAKI and subsequent transition toward kidney fibrosis.
Pseudoxanthoma elasticum (PXE) is a genetic disease caused by mutations in the
gene that result in low pyrophosphate levels and subsequent progressive soft tissue calcifications. PXE mainly affects ...the skin, retina, and arteries. However, many patients with PXE experience kidney stones. We determined the prevalence of this pathology in patients with PXE and examined the possible underlying mechanisms in murine models.
We conducted a retrospective study in a large cohort of patients with PXE and analyzed urine samples and kidneys from
mice at various ages. We used Yasue staining, scanning electron microscopy, electron microscopy coupled to electron energy loss spectroscopy, and Fourier transform infrared microspectroscopy to characterize kidney calcifications.
Among 113 patients with PXE, 45 (40%) had a past medical history of kidney stones. Five of six computed tomography scans performed showed evidence of massive papillary calcifications (Randall plaques).
mice spontaneously developed kidney interstitial apatite calcifications with aging. These calcifications appeared specifically at the tip of the papilla and formed Randall plaques similar to those observed in human kidneys. Compared with controls,
mice had low urinary excretion of pyrophosphate.
The frequency of kidney stones and probably, Randall plaque is extremely high in patients with PXE, and
mice provide a new and useful model in which to study Randall plaque formation. Our findings also suggest that pyrophosphate administration should be evaluated for the prevention of Randall plaque and kidney stones.
Stone analysis by physical methods is critical to determine their chemical nature and to diagnose the underlying conditions affecting kidney stone formers. This analysis should be completed by a ...morphologic examination of stone surface and section, leading to the diagnosis of anatomical or metabolic disorders and of specific diseases. Crystalluria study, the analysis of urine crystals, provides complementary information and is extremely useful for both diagnosis and patient follow-up. This review describes briefly how these techniques may be used and in which conditions stone morphology and urine crystal description are particularly relevant for patients medical care.
PDF
