Mechanism of calcium oxalate renal stone formation and renal tubular cell injury

Abstract:   Formation of calcium oxalate stones tends to increase with age and begins from the attachment of a crystal formed in the cavity of renal tubules to the surface of renal tubular epithelial cells. Though most of the crystals formed in the cavity of renal tubules are discharged as is in the urine, in healthy people, crystals that attach to the surface of renal tubular epithelial cells are thought to be digested by macrophages and/or lysosomes inside of cells. However, in individuals with hyperoxaluria or crystal urine, renal tubular cells are injured and crystals easily become attached to them. Various factors are thought to be involved in renal tubular cell injury. Crystals attached to the surface of renal tubular cells are taken into the cells ( crystal–cell interaction ). And then the crystal and crystal aggregates grow, and finally a stone is formed.     

Kinetics and characterization of initially regenerating proximal tubules in S3 segment in response to various degrees of acute tubular injury.

BACKGROUND: We examined kinetics and characterization of regenerating proximal tubule (PT) cells after various degrees of tubular injury in S3 segments of PT and assessed label-retaining slow cycling cells in S3. METHODS: PT injury was induced by different doses of uranyl acetate (UA) injection into rats, and initially regenerating PTs were identified by in vivo bromodeoxyuridine (BrdU)-labelling before sacrifice or were examined on vimentin positivity. Next, the 3H-thymidine pulse/chase approach was applied to the early regenerating PTs identified by BrdU-labelling after UA injection. RESULTS: Low-dose UA induced focal PT depletion and initial BrdU positivity in the proximal three-quarters of the S3 segment of PT. Autoradiography showed the increased number of label-retaining and label-diluted cells in the proximal three-quarters of S3 in rats treated with low-dose UA compared to normal rats. High-dose UA induced almost complete PT depletion in the proximal three-quarters of S3 and less PT depletion in the distal quarter of S3 and initial BrdU+ cells were restrictedly found in the distal quarter of S3. Label-retaining and label-diluted cells were increasingly found in the entire S3 at day 7, but only label-retaining cells remained in similar numbers in the distal quarter of S3 until day 42. Initially regenerating PT cells with any doses of UA expressed vimentin, suggesting dedifferentiated PT cells. CONCLUSIONS: Initially regenerating cells after PT injury in S3 are dedifferentiated pre-existing PT cells, which may scatter throughout S3 and be responsible for focal repair of S3. Some initially regenerating PT cells in the distal S3 showed persistent label-retaining cells at day 42 after high-dose UA insult and contributed to renewal of the entire S3, thus they might be slow cycling cells with responsibility for S3 repair.     

Irreversible immunoexpression of matrix metalloproteinase-9 in proximal tubular epithelium of renal allografts with acute rejection

Kitajima K, Koike J, Nozawa S, Yoshiike M, Takagi M, Chikaraishi T. Irreversible immunoexpression of matrix metalloproteinase‐9 in proximal tubular epithelium of renal allografts with acute rejection.
Clin Transplant 2011: 25: E336–E344. © 2011 John Wiley & Sons A/S. Abstract: Background: Matrix metalloproteinase‐9 (MMP‐9) is the most important member of the MMP family responsible for the development and progression of various renal diseases. Our study aims to investigate the localization of MMP‐9 in human renal allografts and to assess whether MMP‐9 immunostaining is contributory to detect pathological change in renal biopsy. Methods: We examined 150 renal allograft biopsies (48 baseline and 102 follow‐up) from 49 transplants and analyzed the associations of clinical and histopathological data with the MMP‐9 staining intensity using a semi‐quantitative scoring. Results: MMP‐9 immunostaining in proximal tubule epithelium was negative before transplantation, but positive in biopsies with episodes, particularly with acute cellular rejection (ACR) and acute calcineurin inhibitor (CNI) toxicity. Tubulitis was the most significant association factor (p < 0.0001) with increased MMP‐9 staining intensity. The expression in proximal tubules remained augmented in allografts recovered from ACR episodes, while it was disappeared or diminished in those recovered from acute CNI toxicity or ischemia/reperfusion effects. Conclusion: These findings suggest the necessary participation of MMP‐9 in the pathogenesis of tubulitis and the subsequent stage of pathogenesis in ACR. Up‐regulation of MMP‐9 expression in the proximal tubule could be a new indicator of tubular injury and a predictive factor for the prognosis of renal allograft.     

Critically ill,tubular injury,delayed early recovery: characteristics of acute kidney disease with renal oxalosis

ObjectsThis study aimed to analyze the clinicopathological features of acute kidney disease (AKD) with renal oxalosis.MethodsData for biopsy-proven AKD with oxalosis diagnosed from Jan 2011 to Oct 2018 was collected. The underlying diseases, dietary habits, clinical and pathological characteristics of newly emerging kidney disease were analyzed. The long-term renal prognosis was observed.ResultsA total of 23 patients were included, comprised of 18 men and 5 women with a mean age of 51.6 ± 15.9 years. The peak Scr was 669.9 ± 299.8 μmol/L, and 95.7% of patients had stage 3 acute kidney injury (AKI). Drug-induced tubulointerstitial nephritis (TIN) was the most common cause (65.2%) of AKD, followed by severe nephrotic syndrome (17.4%). All patients had pathological changes indicating TIN, and 11 patients were complicated with the newly emerging glomerular disease (GD). The risk of oxalosis caused by increased enterogenous oxalate absorption accounted for only 26.1%, and others came from new kidney diseases. The majority (75%) of abundant (medium to severe) oxalosis occurred in patients without GD. There were no significant differences in the score for tubular injury (T-IS) and interstitial inflammation with different severities of oxalosis. Rate of Scr decrease (ΔScr%) at 2 weeks was negatively correlated with the severity of oxalosis (R = −0.542, p = 0.037), score for T-IS (R = −0.553, p = 0.033), and age (R = −0.736, p = 0.002). The decrease in Scr at 4 weeks was correlated with T-IS (R = −0.433), but had no correlation with oxalosis.ConclusionsThe present findings revealed that 95.7% of AKD with secondary renal oxalosis occurred in critically ill patients. AKD from tubular injury was the prominent cause. Severe oxalosis contributed to delayed early recovery of AKD.     

Retinoic Acid Signaling Coordinates Macrophage-Dependent Injury and Repair after AKI

Retinoic acid (RA) has been used therapeutically to reduce injury and fibrosis in models of AKI, but little is known about the regulation of this pathway and what role it has in regulating injury and repair after AKI. In these studies, we show that RA signaling is activated in mouse and zebrafish models of AKI, and that these responses limit the extent of injury and promote normal repair. These effects were mediated through a novel mechanism by which RA signaling coordinated the dynamic equilibrium of inflammatory M1 spectrum versus alternatively activated M2 spectrum macrophages. Our data suggest that locally synthesized RA represses proinflammatory macrophages, thereby reducing macrophage-dependent injury post-AKI, and activates RA signaling in injured tubular epithelium, which in turn promotes alternatively activated M2 spectrum macrophages. Because RA signaling has an essential role in kidney development but is repressed in the adult, these findings provide evidence of an embryonic signaling pathway that is reactivated after AKI and involved in reducing injury and enhancing repair.     

Nitric oxide—mediated renal epithelial cell injury during hypoxia and reoxygenation

The potent endothelial-derived vasodilator nitric oxide (NO) has been identified as a protective agent in acute renal failure. However, some recent studies have suggested a detrimental effect of NO on rat proximal tubules exposed to hypoxia and reoxygenation. We determined whether NO metabolites cause intracellular oxidation during hypoxia and reoxygenation and whether this oxidative stress is linked to irreversible cell injury. Primary cultures of rat proximal tubular epithelial cells were studied in a subconfluent stage and subjected to 60 min hypoxia and 30 min reoxygenation. Intracellular oxidation was assessed by monitoring the conversion of nonfluorescent dihydrorhodamine 123 (DHR) to fluorescent rhodamine 123 as a probe for the long-lived oxidant peroxvnitrite. Hypoxia and reoxygenation produced a marked increase in cellular generation of oxidant species. Intracellular oxidation of DHR was reduced by approsimately 40% when cells were also exposed to the NO svnthase inhibitor L-NAME. Oxidation of DHR following hypoxia and reoxygenation was not affected by SOD or DATTU. A combination of SOD and L-NAME was no more effective than L-NAME alone. Hypoxia and reoxygenation produced substantial injury (as LDH release). There was a 40% reduction in LDH release when cells were pretreated with a NO synthase inhibitor. In summary, increased generation of NO capable of inducing intracellular oxidizing reactions and cell death occurred during renal hypoxia and reoxygenation.     

草酸钙结晶-肾小管细胞损伤机制研究进展

草酸钙是肾结石中最常见的化学成分。肾钙盐结晶是草酸钙结石形成的关键步骤之一,而近年来研究发现肾钙盐结晶形成与肾小管上皮细胞损伤密切相关。本文就草酸钙结石形成和肾小管上皮细胞损伤相互作用机制方面进行综述。     

Sulfenic Acid Modification of Endothelin B Receptor is Responsible for the Benefit of a Nonsteroidal Mineralocorticoid Receptor Antagonist in Renal Ischemia

AKI is associated with high mortality rates and the development of CKD. Ischemia/reperfusion (IR) is an important cause of AKI. Unfortunately, there is no available pharmacologic approach to prevent or limit renal IR injury in common clinical practice. Renal IR is characterized by diminished nitric oxide bioavailability and reduced renal blood flow; however, the mechanisms leading to these alterations are poorly understood. In a rat model of renal IR, we investigated whether the administration of the novel nonsteroidal mineralocorticoid receptor (MR) antagonist BR-4628 can prevent or treat the renal dysfunction and tubular injury induced by IR. Renal injury induced by ischemia was associated with increased oxidant damage, which led to a cysteine sulfenic acid modification in endothelin B receptor and consequently decreased endothelial nitric oxide synthase activation. These modifications were efficiently prevented by nonsteroidal MR antagonism. Furthermore, we demonstrated that the protective effect of BR-4628 against IR was lost when a selective endothelin B receptor antagonist was coadministered. These data describe a new mechanism for reduced endothelial nitric oxide synthase activation during renal IR that can be blocked by MR antagonism with BR-4628.     

Early detection of acute kidney injury: emerging new biomarkers

SUMMARY:   Acute kidney injury (AKI) has recently become the preferred term to describe the syndrome of acute renal failure (ARF) with 'failure' or 'ARF' restricted to patients who have AKI and need renal replacement therapy. ¹ This allows capture of the broader clinical spectrum of modest reductions in creatinine, which are themselves known to be associated with major increases in both short- and long-term mortality risk. ^2–5 It is hoped that this change in nomenclature will facilitate an expansion of our understanding of the underlying pathophysiology and also facilitate definitions of AKI, which allow comparisons among clinical trials of patients with similar duration and severity of illness. This review will cover the need for early detection of AKI and the role of urinary and plasma biomarkers, including enzymuria. The primary message is that use of existing criteria to diagnose AKI, namely elevation of the serum creatinine with or without oliguria, results in identification that is too late to allow successful intervention. New biomarkers are essential to change the dire prognosis of this common condition.     

Is patchy tubular injury a histopathological marker of acute rejection?

Abstract:  Renal allograft specimens often show patchy tubular injury (PTI), or patches of injured tubular sections. PTI reflects damage to the proximal tubules, and the histologic findings consist of tubular cell necrosis and tubular regeneration without tubulitis. Unlike acute tubular necrosis (ATN) in cadaveric donors, PTI can be observed in kidneys from living donors when there is no history of acute renal failure after transplantation. In this study, we examined the clinicopathological importance of PTI in acute rejection. Between April 2000 and May 2007, 2252 biopsies of living kidney grafts were performed at least one d after the transplant operation. Acute rejection was observed in 877 biopsies. Of these cases, 78 (8.9%) biopsies from 43 patients showed PTI. The severity of the PTI was graded semiquantitatively as follows: grade 1 cases had three or four damaged tubular sections, grade 2 cases had >5 sections, and grade 3 cases had >10 sections. The incidence of PTI was significantly higher in vascular rejection (VR) and antibody-mediated rejection (AMR) patients than in those experiencing tubulointerstitial rejection (TIR). The mean PTI score was significantly higher (2.00 ± 0.12) in VR than in TIR (1.39 ± 0.10) and AMR (1.68 ± 0.08) patients. The mean serum creatinine (sCr) at the time of biopsy was higher in VR patients than in AMR and TIR patients. Moreover, in VR patients, those with severer PTI developed higher sCr levels. These data suggest that PTI has a strong relationship with local ischemic damage delegated by VR, and the severity of PTI could be a practical histological marker in acute vascular rejection.     

A prospective cohort study of acute kidney injury and kidney outcomes,cardiovascular events,and death

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Severity of illness scores and the outcome of acute tubular necrosis

The outcome of patients with acute renal failure (ARF)due to acute tubular necrosis (ATN) was evaluated inthis study. Two hundred and twenty-two patients witha mean age of 55.l ± 17.7 years (range 19–97years; male 153, female 69) who developed ATN in theperiod from July 1991 through January 1997 werestudied. Patients were divided into four groupsaccording to their APACHE II scores at the time of thediagnosis of ATN. Group I included patients with anAPACHE II score of 14 or less (n = 70), Group II with ascore of 15–18 (n = 52), Group III with a score of 19–23(n = 58), and group IV with a score of 24 or above(n = 42). The mean APACHE II score for each of the fourstudy groups was 11 ± 0.4, 16 ± 0.2, 20 ±0.2, and 29 ± 0.7, respectively. Patient survivalwas evaluated by the Kaplan-Meier analysis withcensorship at 12 months. Survival rates at 180 dayswere 67%, 47%, 39%, and zero%, for group I through IV respectively, χ² = 27.99, p < 0.0001,with a median survival of >365, 120, 31, and 11days, for groups I through IV, respectively. For patients with oliguria (n = 88) survival at 180days was 23% vs. 58% for patients without oliguria(n = 134), p < 0.0001, median survival 13 vs. 364 d.Six months survival of those who required dialysis(n = 79) was 25% vs. 58% for those whom dialysis wasnot needed (n = 143), p = 0.001, median survival 15 vs.364 d, respectively. In patients with sepsis (n = 58),6 months survival was 35% vs. 50% for those withoutsepsis (n = 164), p = 0.013, median survival 14 vs. 169 d. In patients who required mechanical ventilation(n = 72), 6 months survival was 17% vs. 62% for those whodid not need respiratory support (n = 150), p = 0.0001,median survival 13 vs. > 365 d, respectively. Finally, 6 months survival in patients with one(kidney only), two, three, and four organ failure was76, 30, 11, and zero percent, respectively, p = 0.0001,median survival > 365, 16, 11, and 12 days,respectively. We conclude that the use of the APACHE II score forthe stratification of the severity of illness could beof clinical utility in predicting mortality inpatients with ATN. Other predictors of poor prognosisinclude the need for dialysis, the presence ofoliguria, the need for mechanical ventilation, thepresence of sepsis, and the number of failed organs. This revised version was published online in August 2006 with corrections to the Cover Date.     

Postpartum acute kidney injury: a review of 99 cases

Postpartum acute kidney injury (PPAKI) constitutes an important cause of obstetric AKI. It is associated with high maternal and fetal mortality in developing nations. The aim of this study is to survey the etiology and outcomes of PPAKI in a tertiary care Indian hospital. Ninety-nine patients, without prior comorbidities, treated for PPAKI, between 2005–2014 at M.S. Ramaiah Medical College, were included for analysis in this retrospective, observational study. AKI was analyzed in terms of maximal stage of renal injury attained as per RIFLE criteria. Outcomes included requirement for renal replacement therapy (RRT), maternal and fetal outcomes. PPAKI constituted 60% of all obstetric AKI cases. Median maternal age was 23 years and 52% of patients were primigravidas. Mean serum creatinine was 4.1?mg/dL. Failure (33%) and injury (31%) were the major categories as per RIFLE criteria. Thirty-nine percent of cases required RRT. Sepsis, particularly puerperal sepsis, was the leading causes of PPAKI (75% of cases) and maternal mortality (94% of deaths). Maternal and fetal mortality were 19% and 22% respectively. The incidence of cortical necrosis was 10.3%. Three patients required long-term RRT. In conclusion, consistent with other Indian literature, we report a high incidence of PPAKI. We found incremental mortality on moving from “Risk” to “Failure” category of RIFLE. PPAKI was associated with high maternal and fetal mortality with sepsis being the leading cause. Our study highlights the need for provision of better quality of maternal care and fetal monitoring to decrease mortality associated with PPAKI in developing countries.     

Canonical BMP signaling in tubular cells mediates recovery after acute kidney injury

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Acute kidney injury in children

Acute kidney injury (AKI) (previously called acute renal failure) is characterized by a reversible increase in the blood concentration of creatinine and nitrogenous waste products and by the inability of the kidney to regulate fluid and electrolyte homeostasis appropriately. The incidence of AKI in children appears to be increasing, and the etiology of AKI over the past decades has shifted from primary renal disease to multifactorial causes, particularly in hospitalized children. Genetic factors may predispose some children to AKI. Renal injury can be divided into pre-renal failure, intrinsic renal disease including vascular insults, and obstructive uropathies. The pathophysiology of hypoxia/ischemia-induced AKI is not well understood, but significant progress in elucidating the cellular, biochemical and molecular events has been made over the past several years. The history, physical examination, and laboratory studies, including urinalysis and radiographic studies, can establish the likely cause(s) of AKI. Many interventions such as ‘renal-dose dopamine’ and diuretic therapy have been shown not to alter the course of AKI. The prognosis of AKI is highly dependent on the underlying etiology of the AKI. Children who have suffered AKI from any cause are at risk for late development of kidney disease several years after the initial insult. Therapeutic interventions in AKI have been largely disappointing, likely due to the complex nature of the pathophysiology of AKI, the fact that the serum creatinine concentration is an insensitive measure of kidney function, and because of co-morbid factors in treated patients. Improved understanding of the pathophysiology of AKI, early biomarkers of AKI, and better classification of AKI are needed for the development of successful therapeutic strategies for the treatment of AKI.     

Role of serotonin in the regulation of renal proximal tubular epithelial cells

In various renal injuries, tissue damage occurs and platelet activation is observed. Recent studies suggest that some factors, such as serotonin, are released into microenvironment upon platelet activation following renal injury. In the present study, we aimed to investigate whether platelets and platelet-released serotonin are involved in the functional regulation of renal proximal tubular epithelial cells (PTECs). PTECs were obtained by primary cell culture and treated with platelet lysate (PL) (2?×?10⁶/mL, 4?×?10⁶/mL, 8?×?10⁶/mL) or serotonin (1?μM or 5?μM) for 12 or 24?h. Phenotypic transdifferentiation of epithelial cells into myofibroblasts were demonstrated under light microscope and confirmed by the determination of α-smooth muscle actin gene expression. Serotonin and PL were shown to induce epithelial–mesenchymal transdifferentiation of PTECs. After stimulation of PTECs with serotonin or PL, matrix metalloproteinase-2, tissue inhibitor of metalloproteinase-1, and collagen-α1 gene expressions, which were reported to be elevated in renal injury, were determined by real-time PCR and found to be upregulated. Expressions of some inflammatory cytokines such as tumor necrosis factor-α, interleukin-6, and transforming growth factor-β1 were found to be increased in both protein and gene levels. Recently there is no published report on the effect of serotonin on renal PTECs. Results obtained in this study have lightened the role of serotonin and platelet-mediated effects of serotonin on fibrotic and inflammatory processes in PTECs.     

Inhibition of growth by calcitriol in a proximal tubular cell line (OK)

Calcitriol has been shown to inhibit (i) cell proliferationof renal carcinoma cell lines and of cultured adult human mesangialcells in vitro, and (ii) renal compensatory growth in vivo.In the present study we examined the effects of calcitriol onDNA synthesis and cell replication in an immortalized cell lineshowing the phenotypic characteristics of proximal tubular cells(opossum kidney, OK cells). The viability of OK cells was notaffected by calcitriol (Trypan-blue exclusion, LDH and K⁺ release),but the cells did not convert ³H-25(OH)₂ to 3H-1,25(OH)₂D3.In the log growth phase, calcitriol (but not alternative vitaminD metabolites) caused dose-dependent (1012 to 10^–6 M)inhibition of radiothymidine incorporation. Inhibition was calciumdependent, i.e. it was more pronounced at the lower nominalcalcium concentration in tissue culture media (0.9 versus 1.8mmol/l) and amplified by coincubation with nifedipine (I µM).Inhibition of DNA synthesis was paralleled by inhibition ofcell replication (growth curve) under basal conditions and afterstimulation with EGF (10 ng/ml). In conclusion, calcitriol inhibitsproliferation of proximal tubular cells which normally express1-alpha- hydroxylase activity.