Impact of Donor Age on the Outcomes of Kidney Transplantation From Deceased Donors With Histologic Acute Kidney Injury.

PURPOSE: Kidney transplantation from elderly donors with acute kidney injury (AKI) has increased recently due to donor shortage, but the safety and prognosis are not well known. We examined the effect of donor age on the outcomes of kidney transplantation (KT) from donors with histologic AKI. MATERIALS AND METHODS: We retrospectively analyzed the medical records of 59 deceased-donor KTs with acute tubular necrosis (ATN) on preimplantation donor kidney biopsy between March 2012 and October 2017. Histologic evaluations of ATN, inflammation, glomerulosclerosis (GS), interstitial fibrosis, tubular atrophy, and arterial sclerosis were performed. RESULTS: Twenty and 39 recipients received kidneys from elderly (> 60, 68.9 ± 5.0 years) and young (≤ 60, 45.9 ± 9.6 years) donors with ATN, respectively. Among the elderly donors, significantly increased donor creatinine was observed in only 44% donors, and there were more diabetic patients and women and a higher proportion of GS than among the young donors. Six months after KT, estimated glomerular filtration rate was significantly lower in recipients who received kidneys from elderly donors compared to young donors. Donor creatinine level and AKI severity did not significantly affect the recipient outcomes in either group. However, the presence of ATN and GS were significant factors that exacerbated renal outcomes after KT from elderly donors only. On multivariate analysis, severe ATN was the strongest independent predictor of elderly recipient renal function. CONCLUSIONS: Histologic injury may predict renal outcomes in KT from elderly donors. A donor allocation protocol including preimplantation renal histology should be established for KT from elderly donors.

Human Alpha-1-Antitrypsin (hAAT) therapy reduces renal dysfunction and acute tubular necrosis in a murine model of bilateral kidney ischemia-reperfusion injury.

Several lines of evidence have demonstrated the anti-inflammatory and cytoprotective effects of alpha-1-antitrypsin (AAT), the major serum serine protease inhibitor. The aim of the present study was to investigate the effects of human AAT (hAAT) monotherapy during the early and recovery phase of ischemia-induced acute kidney injury. Mild renal ischemia-reperfusion (I/R) injury was induced in male C57Bl/6 mice by bilateral clamping of the renal artery and vein for 20 min. hAAT (80 mg/kg, Prolastin®) was administered daily intraperitoneally (i.p.) from day -1 until day 7 after surgery. Control animals received the same amount of human serum albumin (hAlb). Plasma, urine and kidneys were collected at 2h, 1, 2, 3, 8 and 15 days after reperfusion for histological and biochemical analysis. hAAT partially preserved renal function and tubular integrity after induction of bilateral kidney I/R injury, which was accompanied with reduced renal influx of macrophages and a significant decrease of neutrophil gelatinase-associated lipocalin (NGAL) protein levels in urine and plasma. During the recovery phase, hAAT significantly decreased kidney injury molecule-1 (KIM-1) protein levels in urine but showed no significant effect on renal fibrosis. Although the observed effect size of hAAT administration was limited and therefore the clinical relevance of our findings should be evaluated carefully, these data support the potential of this natural protein to ameliorate ischemic and inflammatory conditions.

Role of Oxidative Stress in Drug-Induced Kidney Injury.

The kidney plays a primary role in maintaining homeostasis and detoxification of numerous hydrophilic xenobiotics as well as endogenous compounds. Because the kidney is exposed to a larger proportion and higher concentration of drugs and toxins than other organs through the secretion of ionic drugs by tubular organic ion transporters across the luminal membranes of renal tubular epithelial cells, and through the reabsorption of filtered toxins into the lumen of the tubule, these cells are at greater risk for injury. In fact, drug-induced kidney injury is a serious problem in clinical practice and accounts for roughly 20% of cases of acute kidney injury (AKI) among hospitalized patients. Therefore, its early detection is becoming more important. Usually, drug-induced AKI consists of two patterns of renal injury: acute tubular necrosis (ATN) and acute interstitial nephritis (AIN). Whereas AIN develops from medications that incite an allergic reaction, ATN develops from direct toxicity on tubular epithelial cells. Among several cellular mechanisms underlying ATN, oxidative stress plays an important role in progression to ATN by activation of inflammatory response via proinflammatory cytokine release and inflammatory cell accumulation in tissues. This review provides an overview of drugs associated with AKI, the role of oxidative stress in drug-induced AKI, and a biomarker for drug-induced AKI focusing on oxidative stress.

Remote Ischemic Preconditioning and Contrast-Induced Nephropathy: A Systematic Review.

BACKGROUND: The use of imaging is increasing in clinical practice either for diagnosis or intervention. In these aims, contrast medium (CM) is widely used. However, CM administration can induce contrast-induced nephropathy (CIN). The incidence of CIN varies from 2% to 50% depending on patient risk factors, and CIN is the third cause of renal insufficiency. To date, methods such as hyperhydration to prevent CIN have a low level of evidence. Remote ischemic preconditioning (RIPC), which has already proved its efficiency in the cardiology field, seems to be a promising technique for CIN prevention. The aim of this work was to carry out a systematic review of the literature of the randomized clinical studies on RIPC in the prevention of CIN in man. METHODS: We conducted a systematic review of randomized clinical studies on the RIPC in the prevention of CIN in man. Documentary sources were PubMed articles published until June 2015. Randomized clinical trials of RIPC in preventing CIN in human were reviewed. RESULTS: Five articles were selected for the analysis. One article studied the impact of RIPC in a population at high risk of CIN, whereas the other 4 analyzed populations at low, moderate or unknown risk of CIN. In 4 studies, except the later one, the risk of CIN was based on the Mehran score that was previously published. In the high-risk population, a decrease in the incidence of CIN was found in the RIPC group compared with the control group (12% against 40%; P = 0.002). Among the 3 other studies using the Mehran's score, one also demonstrated the interest of such a procedure in a subgroup of high-risk patients. A second one found a low incidence of CIN in the RIPC group ([5 of 47; 10%] as compared with a control group [17 of 47; 36%] P = 0.003) in patients at the low risk of CIN. In another low-risk population, a significant lower level of a biological marker (liver-type fatty acid-binding protein) that assesses a renal impairment was found in the RIPC compared with the control group. CONCLUSIONS: Only 5 studies were found in this search, which may constitute a limitation. However, RIPC appears as a promising method to prevent CIN since it is a noninvasive, low cost, easy, and safe method. More randomized controlled trials are needed to confirm these preliminary results.

Presence of arteriolar hyalinosis in post-reperfusion biopsies represents an additional risk to ischaemic injury in renal transplant.

AIM: The role of post-reperfusion biopsy findings as a predictor of early and long-term graft function and survival is still a target of research. METHODS: We analyzed data from 136 post-reperfusion biopsies performed in deceased donor renal transplanted patients from November 2008 to May 2012. We analyzed the presence of acute tubular necrosis (ATN), arteriolar hyalinosis (AH), intimal thickness (IT), interstitial fibrosis (IF) and glomerulosclerosis (GS). We also analyzed the impact of donor features on the following outcomes: delayed graft function (DGF) and chronic allograft dysfunction defined as eGFR < 60 mL/min at 1 year. RESULTS: The mean donor age was 41 years, 26% of whom were extended criteria donors (ECD), 33% had hypertension and 50% had cerebral vascular accident (CVA) as the cause of death. ATN was present in 87% of these biopsies, AH in 31%, IF in 21%, IT in 27% and GS in 32%. DGF occurred in 80% and chronic allograft dysfunction was present in 53%. AH was the only histological finding associated with DGF and chronic allograft dysfunction at 1 year. Patients with AH had a lower eGFR at 1 year than patients without it (49.8 mL/min × 64.5 mL/min, P = 0.02). In the multivariate analysis, risk variables for development of chronic graft dysfunction were male sex (odds ratio [OR] = 3.159 [CI: 1.22-8.16]; P = 0.018), acute rejection (OR = 8.91 [CI: 2.21-35.92]; P = 0.002), donor hypertension (OR = 2.94 [CI: 1.10-7.84]; P = 0.031), AH (OR = 3.96 [CI: 1.46-10.70]; P = 0.007) and eGFR at discharge (OR = 0.96 [CI: 0.93-0.98]; P = 0.005). In multivariate analysis, risk factors for AH were donor age ≥ 50 years (OR = 2.46 [CI: 1.10-5.44]; P = 0.027) and CVA as the cause of donor death (OR = 2.33 [CI: 1.05-5.15]; P = 0.007). CONCLUSION: The presence of AH in post-reperfusion biopsies is a marker of ageing and vascular disease and was associated with DGF and a one year poorer renal function. AH in donor biopsies superimposed to long ischaemic time is a predictor of renal function. The management of immunosuppression based on the presence of AH in post-reperfusion biopsy could be useful to improve long term graft function.

Renal Klotho expression in patients with acute kidney injury is associated with the severity of the injury.

BACKGROUND/AIMS: The potential physiologic roles of Klotho in acute kidney injury (AKI) have recently been demonstrated in animal models. However, to date, there have been no human studies investigating the expression of renal Klotho in AKI. METHODS: We retrospectively collected biopsy specimens and clinical data of AKI patients between January 2001 and December 2012. Klotho expression was determined by immunohistochemical staining, and the clinical-pathological correlation was examined. RESULTS: Among the 34 patients diagnosed with acute tubular necrosis or acute tubulointerstitial nephritis, 21 patients without chronic histological lesions were included. The mean age was 37.3 ± 18.5 years and the mean peak creatinine level was 8.2 ± 5.5 mg/dL. In total, 10 patients (47.6%) received temporary renal replacement therapy (RRT); however, 17 patients (81%) showed functional recovery with creatinine levels of < 1.3 mg/dL after 1 month. The intensity of Klotho expression was scored as a percentage of Klotho-positive area. The renal Klotho score showed a significant negative correlation with the initial or peak creatinine level. When the patients were divided into three groups according to the Klotho score (low, middle, high), the low group had a significantly higher peak creatinine level and a more frequent requirement for RRT. However, the Klotho score was not a significant predictor of renal recovery. CONCLUSIONS: The results demonstrated that renal Klotho expression in humans decreased significantly according to the severity of AKI, regardless of the etiology, and that low expression was associated with a poor short-term outcome.

Resistance index measured by Doppler ultrasound as a predictor of graft function after kidney transplantation.

INTRODUCTION: Doppler ultrasound (US) has become the primary imaging technique for the evaluation of renal transplants. It provides information about the intrarenal resistance index (RI). A high RI is seen in every form of graft dysfunction. In this article, we review the utility of sonography, particularly the intrarenal RI measured early after renal transplant, as a predictor of acute and chronic clinical outcome in patients. RESULTS: RI is a valuable marker to determine graft function and related vascular complications. It reveals a strong correlation with serum creatinine levels measured days after transplant. Its elevation is typical for acute tubular necrosis and can be used to predict its duration. An RI >1 (absent end-diastolic flow) seen in the first weeks after transplant is associated with impaired renal graft recovery. In addition, it is an early predictor of chronic allograft nephropathy (even correlated with biopsy results), which will allow a change in therapy. CONCLUSIONS: RI measured serially in the early period after kidney transplantation is a valuable marker for determining renal graft function. It is also useful for demonstrating various types of graft dysfunction; however, it cannot differentiate between them. In recent studies, extrarenal factors in kidney transplantation (eg, recipient's age) may significantly influence RI in the recipient, demonstrating that RI depends on the vascular characteristics of the recipient and not on the graft itself.

Power doppler sonography in early renal transplantation: does it differentiate acute graft rejection from acute tubular necrosis?

To evaluate the role of power Doppler in the identification and differentiation between acute renal transplant rejection and acute tubular necrosis (ATN), we studied 67 live donor renal transplant recipients. All patients were examined by spectral and power Doppler sonography. Assessment of cortical perfusion (CP) by power Doppler was subjective, using our grading score system: P0 (normal CP); homogenous cortical blush extending to the capsule, P1 (reduced CP); cortical vascular cut-off at interlobular level, P2 (markedly reduced CP); scattered cortical color flow at the interlobar level. Renal biopsies were performed during acute graft dysfunction. Pathological diagnoses were based on Banff classification 1997. The Mann- Whitney test was used to test the difference between CP grades with respect to serum creatinine (SCr), and resistive index (RI). For 38 episodes of acute graft rejection grade I, power Doppler showed that CP was P1 and RI ranging from 0.78 to 0.89. For 21 episodes of acute graft rejection grade II, power Doppler showed that CP was P1, with RI ranging from 0.88 to >1. Only one case of grade III rejection had a CP of P2. Twelve biopsies of ATN had CP of P0 and RI ranging from 0.80 to 0.89 There was a statistically significant correlation between CP grading and SCr (P <0.01) as well as between CP grading and RI (P <0.05). CP grading had a higher sensitivity in the detection of early acute rejection compared with RI and cross-sectional area measurements. We conclude that power Doppler is a non-invasive sensitive technique that may help in the detection and differentiation between acute renal transplant rejection and ATN, particularly in the early post-transplantation period.

Effects of Schizolobium parahyba extract on experimental Bothrops venom-induced acute kidney injury.

BACKGROUND: Venom-induced acute kidney injury (AKI) is a frequent complication of Bothrops snakebite with relevant morbidity and mortality. The aim of this study was to assess the effects of Schizolobium parahyba (SP) extract, a natural medicine with presumed anti-Bothrops venom effects, in an experimental model of Bothrops jararaca venom (BV)-induced AKI. METHODOLOGY: Groups of 8 to 10 rats received infusions of 0.9% saline (control, C), SP 2 mg/kg, BV 0.25 mg/kg and BV immediately followed by SP (treatment, T) in the doses already described. After the respective infusions, animals were assessed for their glomerular filtration rate (GFR, inulin clearance), renal blood flow (RBF, Doppler), blood pressure (BP, intra-arterial transducer), renal vascular resistance (RVR), urinary osmolality (UO, freezing point), urinary neutrophil gelatinase-associated lipocalin (NGAL, enzyme-linked immunosorbent assay [ELISA]), lactate dehydrogenase (LDH, kinetic method), hematocrit (Hct, microhematocrit), fibrinogen (Fi, Klauss modified) and blinded renal histology (acute tubular necrosis score). PRINCIPAL FINDINGS: BV caused significant decreases in GFR, RBF, UO, HcT and Fi; significant increases in RVR, NGAL and LDH; and acute tubular necrosis. SP did not prevent these changes; instead, it caused a significant decrease in GFR when used alone. CONCLUSION: SP administered simultaneously with BV, in an approximate 10∶1 concentration, did not prevent BV-induced AKI, hemolysis and fibrinogen consumption. SP used alone caused a decrease in GFR.

Acute oxalate nephropathy associated with Clostridium difficile colitis.

We report the case of a 69-year-old man who presented with acute kidney injury in the setting of community-acquired Clostridium difficile-associated diarrhea and biopsy-proven acute oxalate nephropathy. We discuss potential mechanisms, including increased colonic permeability to oxalate. We conclude that C difficile-associated diarrhea is a potential cause of acute oxalate nephropathy.

Preconditioning with triiodothyronine improves the clinical signs and acute tubular necrosis induced by ischemia/reperfusion in rats.

BACKGROUND: Renal ischemia/reperfusion (I/R) injury is manifested by acute renal failure (ARF) and acute tubular necrosis (ATN). The aim of this study was to evaluate the effectiveness of preconditioning with 3, 3, 5 triiodothyronine (T3) to prevent I/R renal injury. METHODOLOGY/PRINCIPAL FINDINGS: The rats were divided into four groups: sham-operated, placebo-treated (SO-P), sham-operated T3- treated (SO- T3), I/R-injured placebo-treated (IR-P), and I/R-injured T3-treated (IR- T3) groups. At 24 h before ischemia, the animals received a single dose of T3 (100 µg/kg). Renal function and plasma, urinary, and tissue variables were studied at 4, 24, and 48 h of reperfusion, including biochemical, oxidative stress, and inflammation variables, PARP-1 immunohistochemical expression, and ATN morphology. In comparison to the SO groups, the IR-P groups had higher plasma urea and creatinine levels and greater proteinuria (at all reperfusion times) and also showed: increased oxidative stress-related plasma, urinary, and tissue variables; higher plasma levels of IL6 (proinflammatory cytokine); increased glomerular and tubular nuclear PARP-1 expression; and a greater degree of ATN. The IR-T3 group showed a marked reduction in all of these variables, especially at 48 h of reperfusion. No significant differences were observed between SO-P and SO-T3 groups. CONCLUSIONS: This study demonstrates that preconditioning rats with a single dose of T3 improves the clinical signs and ATN of renal I/R injury. These beneficial effects are accompanied by reductions in oxidative stress, inflammation, and renal PARP-1 expression, indicating that this sequence of factors plays an important role in the ATN induced by I/R injury.

Kielin/chordin-like protein attenuates both acute and chronic renal injury.

The secreted kielin/chordin-like (KCP) protein, one of a family of cysteine-rich proteins, suppresses TGF-ß signaling by sequestering the ligand from its receptor, but it enhances bone morphogenetic protein (BMP) signaling by promoting ligand-receptor interactions. Given the critical roles for TGF-ß and BMP proteins in enhancing or suppressing renal interstitial fibrosis, respectively, we examined whether secreted KCP could attenuate renal fibrosis in mouse models of chronic and acute disease. Transgenic mice that express KCP in adult kidneys showed significantly less expression of collagen IV, α-smooth muscle actin, and other markers of disease progression in the unilateral ureteral obstruction model of renal interstitial fibrosis. In the folic acid nephrotoxicity model of acute tubular necrosis, mice expressing KCP survived high doses of folic acid that were lethal for wild-type mice. With a lower dose of folic acid, mice expressing KCP exhibited improved renal recovery compared with wild-type mice. Thus, these data suggest that extracellular regulation of the TGF-ß/BMP signaling axis by KCP, and by extension possibly other cysteine-rich domain proteins, can attenuate both acute and chronic renal injury.

Age sensitizes the kidney to heme protein-induced acute kidney injury.

Age increases the risk for ischemic acute kidney injury (AKI). We questioned whether a similar age-dependent injury occurs following exposure to hemoglobin, a known nephrotoxin. Old mice (~16 mo old), but not young mice (~6 mo old), when administered hemoglobin, exhibited marked elevation in blood urea nitrogen (BUN) and serum creatinine, and acute tubular necrosis with prominent tubular cast formation. The aged kidney exhibited induction of heme oxygenase-1 (HO-1) and other genes/proteins that may protect against heme-mediated renal injury, including ferritin, ferroportin, haptoglobin, and hemopexin. Old mice did not evince induction of HO-2 mRNA by hemoglobin, whereas a modest induction of HO-2 mRNA was observed in young mice. To determine the functional significance of HO-2 in heme protein-induced AKI, we administered hemoglobin to relatively young HO-2(+/+) and HO-2(-/-) mice: HO-2(-/-) mice, compared with HO-2(+/+) mice, exhibited greater renal dysfunction and histologic injury when administered hemoglobin. In addition to failing to elicit a protective system such as HO-2 in response to hemoglobin, old mice exhibited an exaggerated maladaptive response typified by markedly greater induction of the nephrotoxic cytokine IL-6 (130-fold increase vs. 10-fold increase in mRNA in young mice). We conclude that aged mice, unlike relatively younger mice, are exquisitely sensitive to the nephrotoxicity of hemoglobin, an effect attended by a failure to induce HO-2 mRNA and a fulminant upregulation of IL-6. Age thus markedly augments the sensitivity of the kidney to heme proteins, and HO-2 confers resistance to such insults.

Montelukast abrogates rhabdomyolysis-induced acute renal failure via rectifying detrimental changes in antioxidant profile and systemic cytokines and apoptotic factors production.

In addition to antiasthmatic effect, the cysteinyl leukotriene receptor 1 (CysLT1) antagonist montelukast shows renoprotective effect during ischemia/reperfusion and cyclosporine-induced renal damage. Here, we proposed that montelukast protects against rhabdomyolysis-induced acute renal failure. Compared with saline-treated rats, at 48 h following the induction of rhabdomyolysis using intramuscular glycerol (10 ml 50% glycerol/kg), significant elevations in serum levels of urea, creatinine, phosphate and acute renal tubular necrosis were observed. This was associated with elevations in serum Fas, interleukin-10, tumor necrotic factor-alpha, and transforming growth factor-beta1 and renal malondialdehyde and nitrite and detrimental reductions in renal catalase and superoxide dismutase activities. The effects of rhabdomyolysis on renal functional, biochemical and structural integrity and the associated changes in cytokines and Fas levels were abolished upon concurrent administration of montelukast (10 mg/kg i.p.) for 3 days (1 day before and 2 days after induction of rhabdomyolysis). Alternatively, administration of the anti-oxidant, α-tocopherol (400 mg/kg i.m.) for 3 days, succeeded in alleviating renal oxidative stress, but had no significant effect on the circulating levels of most cytokines and partially restored kidney functional and structural damage. Serum level of interleukin-6 was not altered by rhabdomyolysis but showed significant elevations in rats treated with montelukast or α-tocopherol. Collectively, motelukast abrogated functional and structural renal damage induced by rhabdomyolysis via ameliorating renal oxidative stress and modulation of systemic cytokines and apoptotic factors production. The results of this work are expected to open new avenues for early prevention of rhabdomyolysis-induced acute renal failure using selective CysLT1 antagonists such as montelukast.

Diagnosis and treatment of hyper-delayed graft function after renal transplantation.

BACKGROUND: Renal transplant recipients may experience delayed graft function (DGF), but recovery can take many months, a condition we define as hyper-delayed graft function (HDGF). METHODS: A retrospective review of 50 renal transplant recipients who had HDGF and comparison with patients who had immediate graft function (IGF) and DGF. RESULTS: Acute renal tube necrosis (ATN) during or soon after surgery was the most common cause of HDGF. Following standard treatment, 48 HDGF patients transitioned from oliguria to polyuria in 45 days (± 3) and renal function of the kidney fully recovered in 73 days (± 1). These HDGF patients had similar overall survival and kidney survival rates as IGF and DGF patients who were matched for age, sex, primary underlying disease, tissue matching, warm and cold ischemia time, and surgery time. CONCLUSIONS: Appropriate care and monitoring of HDGF patients allows them to regain normal renal function and to achieve patient and renal survival rates similar to those of IGF and DGF patients.

Inhibition of glycogen synthase kinase-3ß prevents NSAID-induced acute kidney injury.

Clinical use of nonsteroidal anti-inflammatory drugs (NSAIDs) like diclofenac (DCLF) is limited by multiple adverse effects, including renal toxicity leading to acute kidney injury. In mice with DCLF-induced nephrotoxicity, TDZD-8, a selective glycogen synthase kinase (GSK)3ß inhibitor, improved acute kidney dysfunction and ameliorated tubular necrosis and apoptosis associated with induced cortical expression of cyclooxygenase-2 (COX-2) and prostaglandin E2. This renoprotective effect was blunted but still largely preserved in COX-2-null mice, suggesting that other GSK3ß targets beyond COX-2 functioned in renal protection. Indeed, TDZD-8 diminished the mitochondrial permeability transition in DCLF-injured kidneys. In vitro, GSK3ß inhibition reinstated viability and suppressed necrosis and apoptosis in DCLF-stimulated tubular epithelial cells. DCLF elicited oxidative stress, enhanced the activity of the redox-sensitive GSK3ß, and promoted a mitochondrial permeability transition by interacting with cyclophilin D, a key component of the mitochondrial permeability transition pore. TDZD-8 blocked GSK3ß activity and prevented GSK3ß-mediated cyclophilin D phosphorylation and the ensuing mitochondrial permeability transition, concomitant with normalization of intracellular ATP. Conversely, ectopic expression of a constitutively active GSK3ß abolished the effects of TDZD-8. Hence, inhibition of GSK3ß ameliorates NSAID-induced acute kidney injury by induction of renal cortical COX-2 and direct inhibition of the mitochondrial permeability transition.

An integrative view of the pathophysiological events leading to cisplatin nephrotoxicity.

Cisplatin is among the most effective chemotherapeutic agents against solid tumors. Nephrotoxicity is the most common side effect of cisplatin chemotherapy, which limits the clinical use of cisplatin and seriously worsens the quality of life of cancer patients resulting in dosage reduction and discontinuation of treatment. Cisplatin involves a complex multifactorial process, as it has direct toxic effect on cells of the renal tubules, vasculature and glomeruli, and causes alterations in renal blood flow and glomerular filtration rate. Indirectly, cisplatin also induces inflammation of the renal interstitium, which contributes to the acute damage and may lead to chronic interstitial fibrosis, indicative of irreversible renal damage. This review presents an integrative view of the pathophysiological effects of cisplatin on tubular, vascular, glomerular, and interstitial function and the interplay among these actions. Moreover, it reviewed human clinical trials of the last ten years in order to evaluate the incidence and severity of the renal injury induced by cisplatin at the doses and therapeutic guidelines used in the clinical practice.

Tubular epithelial injury and inflammation after ischemia and reperfusion in human kidney transplantation.

OBJECTIVE: To provide an integrated insight into the kinetics of tubular injury, inflammation, and oxidative stress after human kidney transplantation. BACKGROUND: Tissue injury due to ischemia and reperfusion is an inevitable consequence of kidney transplantation. Tubular epithelial injury, inflammation, and oxidative stress play major roles in the pathophysiology of acute kidney injury in small animals, but it remains to be established whether this paradigm holds true for human kidney transplantation. METHODS: Markers of tubular injury, inflammation, and oxidative stress were compared between recipients of kidneys from donors after cardiac death (DCD; N = 8) with prolonged ischemia and recipients of living donor kidneys with minimal ischemia (N = 8). RESULTS: In the early postoperative period, creatinine clearance and tubular sodium reabsorption were profoundly reduced in DCD kidneys, coinciding with significantly increased urinary concentrations of tubular injury markers (neutrophil gelatinase-associated lipocalin, N-acetyl-ß--glucosaminidase, and cystatin C) and an 18-fold increase in renal production of cytokeratin-18, indicating extensive necrotic cell death. Tubular injury in DCD kidneys was followed by greater systemic inflammatory activity and oxidative stress in the postoperative period (measured with 17-plex cytokine arrays and as plasma F2-isoprostanes, respectively). In contrast, no evidence of oxidative damage to either of the 2 kidney types was found in the early reperfusion period. CONCLUSIONS: These findings establish the relevance of observations in animal models for human kidney transplantation and form the basis for development of novel therapies to improve early graft function and expand the use of donor kidneys with prolonged ischemia.

Insuficiência renal aguda em pacientes com doença glomerular: aspectos histológicos e papel da necrose tubular aguda / aspectos histológicos e papel da necrose tubular aguda / Acute renal failure in patients with glomerular diseases: histological and role of acute tubular necrosis

A insuficiência renal aguda é comum em pacientes com síndrome nefrótica, podendo requerer terapia de substituição renal e ser irreversível. A insuficiência renal aguda nesses pacientes pode ser precipitada por processos infecciosos, hipovolemia, drogas nefrotóxicas; entretanto na maioria dos casos a etiologia não é identificada e a insuficiência renal aguda é considerada idiopática. A necrose tubular aguda foi associada à insuficiência renal aguda em adultos com lesão mínima. O objetivo deste estudo é avaliar a correlação entre a necrose tubular aguda definida histologicamente com insuficiência renal aguda em pacientes com doença glomerular. Biópsias renais de pacientes com glomerulopatia foram analisadas quanto à intensidade da necrose tubular aguda e esses dados correlacionados com os dados clínicos e presença de insuficiência renal aguda. A análise foi realizada em duas amostras e a intensidade de necrose tubular aguda graduada de duas formas: na primeira amostra a intensidade de necrose tubular aguda foi graduada em cinco níveis de intensidade; na segunda amostra foi feita uma estimativa em percentual da área da cortical acometida. A acurácia da análise semiquantitativa na primeira amostra foi avaliada por meio da correlação com análise morfométrica relativa ao número de túbulos com características necróticas por área de cortical (Spearman r=0,88, P<0,0001) e ao percentual de área da cortical com necrose tubular aguda (Spearman r=0,93, P<0,0001). A reprodutibilidade da análise intraobservador foi regular (kappa=0,53, P<0,0001). A primeira amostra constou de 149 casos com idade média de 21±16 anos. A síndrome nefrótica esteve presente em 104 (72%) pacientes e os principais diagnósticos foram: doenças do espectro Lesão Mínima – Glomeruesclerose Segmentar e Focal (45%). Necrose tubular aguda foi observada em 114 (77%) pacientes. insuficiência renal aguda foi diagnosticada em 43 (42%) pacientes. Houve correlação positiva entre a intensidade da necrose tubular aguda e a presença de insuficiência renal (gamma=0,70, P<0,0001). A segunda amostra foi composta por 80 pacientes com idade média 32 ± 18 anos. Síndrome nefrótica foi diagnosticada em 72 (90%) casos e os principais diagnósticos foram as doenças do espectro lesão mínima-Glomeruloesclerose segmentar e focal (54, 68%). Necrose tubular aguda foi observada em 60 (75%) pacientes e insuficiência renal aguda foi diagnosticada em 28 (35%) casos. A intensidade de necrose tubular aguda foi maior nos pacientes com (29,1 ± 27,7) que nos pacientes sem insuficiência renal aguda (5.4 ± 5.1, P<0,0001). A presença de necrose tubular aguda apresentou alta especificidade para diagnóstico de insuficiência renal aguda quando estimada em 10% da cortical representada (especificidade 96,1%, curva ROC [AUC=0,832, P<0,0001]). Não houve diferença entre os grupos com e sem insuficiência renal aguda em relação ao sexo, proteinúria, doença renal e albumina sérica, colesterol e triglicérides. A freqüência de hipertensão arterial sistêmica foi maior no grupo com insuficiência renal aguda com idade mais elevada (P=0,015).