Renal subcapsular transplantation of hepatocyte growth factor-producing mesothelial cell sheets improves ischemia-reperfusion injury.

Ischemia-reperfusion injury (IRI) is a clinically important cause of acute kidney injury leading to chronic kidney disease. Furthermore, IRI in renal transplantation still remains a risk factor for delayed graft function. Previous studies on IRI have had some limitations, and few of the studied therapies have been clinically applicable. Therefore, a new method for treating renal IRI is needed. We examined the effects of human mesothelial cell (MC) sheets and hepatocyte growth factor (HGF)-transgenic MC (tg MC) sheets transplanted under the renal capsule in an IRI rat model and compared these two treatments with the intravenous administration of HGF protein and no treatment through serum, histological, and mRNA analyses over 28 days. MC sheets and HGF-tg MC sheets produced HGF protein and significantly improved acute renal dysfunction, acute tubular necrosis, and survival rate. The improvement in necrosis was likely due to the cell sheets promoting the migration and proliferation of renal tubular cells, as observed in vitro. Expression of α-smooth muscle actin at day 14 and renal fibrosis at day 28 after IRI were significantly suppressed in MC sheet and HGF-tg MC sheet treatment groups compared with the other groups, and these effects tended to be reinforced by the HGF-tg MC sheets. These results suggest that the cell sheets locally and continuously affect renal paracrine factors, such as HGF, and support recovery from acute tubular necrosis and improvement of renal fibrosis in chronic disease.

Application of new acute kidney injury biomarkers in human randomized controlled trials.

The use of novel biomarkers of acute kidney injury (AKI) in clinical trials may help evaluate treatments for AKI. Here we explore potential applications of biomarkers in simulated clinical trials of AKI using data from the TRIBE-AKI multicenter, prospective cohort study of patients undergoing cardiac surgery. First, in a hypothetical trial of an effective therapy at the time of acute tubular necrosis to prevent kidney injury progression, use of an indirect kidney injury marker such as creatinine compared to a new direct biomarker of kidney injury reduces the proportion of true acute tubular necrosis cases enrolled. The result is a lower observed relative risk reduction with the therapy, and lower statistical power to detect a therapy effect at a given sample size. Second, the addition of AKI biomarkers (interleukin-18 and NGAL) to clinical risk factors as eligibility criteria for trial enrollment in early AKI has the potential to increase the proportion of patients who will experience AKI progression and reduce trial cost. Third, we examine AKI biomarkers as outcome measures for the purposes of identifying therapies that warrant further testing in larger, multicenter, multi-country trials. In the hypothetical trial of lower cardiopulmonary bypass time to reduce the risk of postoperative AKI, the sample size required to detect a reduction in AKI is lower if new biomarkers are used to define AKI rather than serum creatinine. Thus, incorporation of new biomarkers of AKI has the potential to increase statistical power, decrease the sample size, and lower the cost of AKI trials.

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.

Retooling the creatinine clearance equation to estimate kinetic GFR when the plasma creatinine is changing acutely.

It is often desirable to estimate the GFR (eGFR) at the bedside to assess AKI or renal recovery. Current eGFR equations estimate kidney function when the plasma creatinine is stable, but do not work if the plasma creatinine is changing rapidly. To analyze kidney function in the acute setting, a simple formula is proposed that requires only a modest number of inputs that are readily obtainable from clinical laboratory data. The so-called kinetic eGFR (KeGFR) formula is derived from the initial creatinine content, volume of distribution, creatinine production rate, and the quantitative difference between consecutive plasma creatinines over a given time. For that period, the deciphered creatinine excretion then yields the creatinine clearance rate. The additional formula variables needed are any steady-state plasma creatinine, the corresponding eGFR by an empirical formula, and the maximum increase in creatinine per day if anuric. The kinetic formula complements clinical intuition but also adds a quantitative and visual dimension to the assessment of kidney function, demonstrated by its analysis of GFRs underlying the plasma creatinine fluctuations in several scenarios of AKI or renal recovery. Deduced from first principles regarding the physiology of creatinine balance, the KeGFR formula enhances the fundamental clearance equation with the power and versatility to estimate the kidney function when the plasma creatinine is varying acutely.

Acute kidney injury due to acute cortical necrosis following a single wasp sting.

Acute kidney injury (AKI) can develop after multiple wasp or bee stings. The etiology is the acute tubular necrosis secondary to shock, pigment toxicity, interstitial nephritis, or direct nephrotoxicity of venom. We report a 40-year-old female who presented with oliguric AKI after a single wasp sting on her hand. Her history, examination, and investigations did not support any of the established causes of AKI in such settings. She did not improve with supportive management and dialysis, and kidney biopsy showed acute cortical necrosis (ACN). This is the first report of ACN after a single wasp sting.

Low cefepime concentrations during high blood and dialysate flow continuous venovenous hemodialysis.

Dosing of cefepime during high blood flow (Qb; 300 ml/min), high dialysate flow (Qd; 3 liter/h) continuous venovenous hemodialysis (CVVHD) is undefined. Six patients on CVVHD had serum and effluent cefepime concentrations measured at 0.5, 1, 2, 6, and 12 h after dosing. Three patients had cefepime concentrations less than the MIC for Pseudomonas aeruginosa. A dose of 2,000 mg every 12 h or 1,000 mg every 8 h may increase time at a therapeutic concentration.

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.

Pathological Features of Recovery or Progression in Acute Tubular Necrosis: Single Centre Study.

Acute tubular necrosis (ATN) is the most important and frequent cause of acute kidney injury (AKI). Controversy exists concerning the role of renal biopsy in the evaluation of ATN prognosis. We aim in our study to evaluate the role of renal biopsy for the detection of recovery and progression and rate of recovery of ATN. The study was designed to include all biopsies with the diagnosis in ATN in adults >21-year-old, from January 2016 to December 2018. Biopsies were recruited retrospectively and were reviewed by three pathologists and quantitated. Four histological ATN features were evaluated. Flattening cells, distension or dilatation, debris, and vacuolation and for each a score were attributed as follows: 0 = less than 5% of section, 1 = 6%-25%, 2 = 26%-50%, 3 = >50%. Thirty-five patients with 35 renal biopsies were analyzed. Flattening was seen <5% in nine patients, 6%-25% in 15 patients, 26%-50% in six patients. and >50% in five patients. Dilatation was seen <5% in 11 patient, 6%-25% in 10 patients, 26%-50% seen in six patients, and >50% in eight patients. The presence of debris was seen in <5% in 12 patients, 6%-25% in 12 patients, 26%-50% seen in six patients, and >50% seen in five patient. Vacuolation was seen in 5% in eight patients, 6%-25% in 14 patients, 26%-50% in seven patients, and >50% in six patients. It was found that flattening <5% and dilatation <5% and dilatation >50% in renal biopsy are the good indicators for recovery and good prognosis of cases of ATN, in addition debris <5% and >50% and vacuolation <5% are also good indicators for recovery and good prognosis of cases of ATN. On the other hand, flattening from 6% to 25% and from 26% to 50%, dilatation from 6% to 25%, debris from 26% to 50% and vacuolation >50% are also indicators for delayed recovery and poor prognosis of cases of ATN. Renal biopsy in AKI with the diagnosis of ATN with scoring system of flattening, dilatation, debris, and vacuolation can point to indication of recovery or progression of these cases.

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

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.

Acute dialysis in HIV-positive patients in Cape Town, South Africa.

AIM: The prognosis for HIV patients needing acute dialysis is uncertain. The aim of this study was to describe the clinical presentation, renal diagnoses and outcomes of HIV patients who underwent acute haemodialysis at Groote Schuur Hospital in the period 2002-2007. METHODS: A retrospective review of case records of HIV patients who underwent acute haemodialysis was conducted. RESULTS: One hundred and seventeen patients were reviewed (median age 34.0 years (29.0-40.0) 53.8% men, 93.2% black Africans) and 33 had a renal biopsy. Acute tubular necrosis (ATN) was diagnosed in 68 patients. Recovery of renal function occurred in 33.3% of all patients while in 25.7% treatment was withdrawn and 41.0% died in hospital. Suspected ATN was the commonest cause of renal disease in those who recovered renal function (82.1%). A higher CD4 count (odds ratio (OR)=0.994, P=0.007), lower pre-dialysis serum creatinine (<1230 µmol/L) and longer hospitalization (OR=0.93, P=0.006) significantly correlated with survival. CONCLUSION: There is a good chance of survival for HIV patients needing acute dialysis when the diagnosis is ATN, and when the CD4 count is more than 200 cells/mm3.

[Therapeutics for acute tubular necrosis in 2020]. / Prise en charge de la nécrose tubulaire aiguë en 2020.

Acute kidney injury is a major cause of in-hospital morbidity and mortality because of the serious nature of the underlying illnesses and the high incidence of complications. The two major causes of acute kidney injury that occur in the hospital are prerenal disease and acute tubular necrosis. Acute tubular necrosis has a histological definition, even if a kidney biopsy is rarely performed. Kidney injuries occurring during acute tubular necrosis are underlined by different pathophysiological mechanisms that emphasize the role of hypoxia on the tubular cells such as apoptosis, cytoskeleton disruption, mitochondrial function and the inflammation mediated by innate immune cells. The microcirculation and the endothelial cells are also the targets of hypoxia-mediated impairment. Repair mechanisms are sometimes inadequate because of pro-fibrotic factors that will lead to chronic kidney disease. Despite all the potential therapeutic targets highlighted by the pathophysiological knowledge, further works remain necessary to find a way to prevent these injuries.

Tenofovir nephrotoxicity: acute tubular necrosis with distinctive clinical, pathological, and mitochondrial abnormalities.

Tenofovir, a widely prescribed antiretroviral medication for treatment of HIV-1 infection, is infrequently associated with renal dysfunction and biopsy findings of acute tubular necrosis. We examined the clinical and pathological findings in 13 cases of tenofovir nephrotoxicity (7 men and 6 women, mean age of 51.1±9.6 years). Patients received tenofovir therapy for a mean of 19.6 months (range, 3 weeks to 8 years; median 8 months). Nine patients presented with acute kidney injury, and four had mild renal insufficiency with subnephrotic proteinuria. Mean baseline serum creatinine was 1.3±0.3 mg/dl, reaching 5.7±4.0 mg/dl at the time of biopsy, with mean proteinuria of 1.6±0.3 g/day. Glycosuria was documented in seven patients, five of whom were normoglycemic. Renal biopsy revealed toxic acute tubular necrosis, with distinctive proximal tubular eosinophilic inclusions representing giant mitochondria visible by light microscopy. Electron microscopy showed mitochondrial enlargement, depletion, and dysmorphic changes. Clinical follow-up after tenofovir discontinuation was available for 11 of 13 patients (mean duration 13.6 months). Significant recovery of renal function occurred in all patients, including four who required transient hemodialysis. Our study shows that tenofovir nephrotoxicity is a largely reversible form of toxic acute tubular necrosis targeting proximal tubules and manifesting distinctive light microscopic and ultrastructural features of mitochondrial injury.

Tenofovir-induced kidney disease: an acquired renal tubular mitochondriopathy.

Tenofovir, used in combination with other antiretroviral agents, is an effective therapy for HIV infection. Although large clinical studies and post-marketing data support a benign renal profile for tenofovir, numerous cases of kidney injury raise concern for nephrotoxic potential. Early human studies and experimental evidence suggested that tenofovir itself was not associated with mitochondrial toxicity within the kidney. However, recent animal data demonstrate that tenofovir causes mitochondrial DNA depletion and mitochondrial toxicity. Herlitz et al. confirm the nephrotoxicity of tenofovir in humans. They describe its clinical consequences, histopathologic findings, and its mitochondrial toxicity in HIV+ patients.

Hemolysis and acute kidney failure.

Deposits of iron and hemosiderosis in the kidney have been observed in diseases with intravascular hemolysis, including paroxysmal nocturnal hemoglobinuria, and valvular heart diseases and prosthetic heart valve implants. However, the decrease in kidney function associated with hemolysis caused by cardiac valvular disease or prostheses is less well recognized. We present a case of intravascular hemolysis after repair and banding of the mitral valve that resulted in massive renal tubular deposition of hemosiderin with decreased kidney function. We discuss the pathophysiologic process of both acute and chronic tubular injury from heme and heme proteins, including injury to organelles resulting in autophagic vacuoles containing damaged organelles, such as mitochondria. We conclude that tubular injury resulting from heme proteins should be considered as a cause of decreased kidney function in all patients with a cardiac valvular disease or prosthesis.

Challenges in clinical-pathologic correlations: acute tubular necrosis in a patient with collapsing focal and segmental glomerulosclerosis mimicking rapidly progressive glomerulonephritis.

Herein, we report a case of acute kidney injury (AKI) due to diarrhea-induced acute tubular necrosis (ATN) in a patient with nephrotic syndrome secondary to biopsy-proven collapsing focal and segmental glomerulosclerosis (FSGS). The clinical picture mimicked rapidly progressive glomerulonephritis (RPGN) and motivated pulse therapy with methylprednisolone and cyclophosphamide. The case presentation is followed by a brief overview of the epidemiology of AKI in nephrotic syndrome as well as a discussion of its risk factors and potential mechanisms involved.