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1.  Proliferative Capacity of Stem/Progenitor-like Cells in the Kidney may Associate with the Outcome of Patients with Acute Tubular Necrosis 
Human pathology  2011;42(8):1132-1141.
Animal studies indicate that adult renal stem/progenitor cells can undergo rapid proliferation in response to renal injury, but whether the same is true in humans is largely unknown. To examine the profile of renal stem/progenitor cells responsible for acute tubular necrosis in human kidney, double- and triple-immunostaining was performed using proliferative marker and stem/progenitor protein markers on sections from ten kidneys with acute tubular necrosis and four normal adult kidneys. The immunopositive cells were recorded using two-photon confocal laser scanning microscopy. We found that dividing cells were present in the tubules of the cortex and medulla, as well as the glomerulus in normal human kidney. Proliferative cells in the parietal layer of Bowman’s capsule expressed CD133, and dividing cells in the tubules expressed immature cell protein markers paired box gene 2, vimentin and nestin. After acute tubular necrosis, Ki67-positive cells in the cortex tubules significantly increased compared to normal adult kidney. These Ki67-positive cells expressed CD133 and paired box gene 2, but not the cell death marker, activated caspase-3. In addition, the number of dividing cells increased significantly in patients with acute tubular necrosis, who subsequently recovered, compared to patients with acute tubular necrosis, who consequently developed protracted acute tubular necrosis or died. Our data suggest that renal stem/progenitor cells may reside not only in the parietal layer of Bowman’s capsule, but also in the cortex and medulla in normal human kidney, and the proliferative capacity of renal stem/progenitor cells after acute tubular necrosis may be an important determinant of a patient’s outcome.
PMCID: PMC3135674  PMID: 21315412
ATN; kidney; progenitor cells; stem cells; outcome; proliferation
2.  Acute kidney injury after hepatic ischemia and reperfusion injury in mice 
Hepatic ischemia reperfusion (IR) is the leading cause of acute liver failure (ALF) during the perioperative period and patients with ALF frequently develop acute kidney injury (AKI). There is no effective therapy for AKI associated with ALF because pathomechanisms are incompletely characterized, in part due to the lack of an animal model. In this study, we characterize a novel murine model of AKI following hepatic IR. Mice subjected to ~70% liver IR not only developed acute liver dysfunction, but also developed severe AKI 24 hr after liver injury. Mice subjected to liver IR developed histological changes of acute tubular injury including focal proximal tubular cell necrosis involving the S3 segment, cortical tubular ectasia, focal tubular simplification and granular bile/heme cast formation. In addition, there was focal interstitial edema and hyperplasia of the juxtaglomerular apparatus. Inflammatory changes in the kidney after hepatic IR included neutrophil infiltration of the interstitium and upregulation of several pro-inflammatory mRNAs (tumor necrosis factor-α, keratinocyte derived cytokine, monocyte chemotactic protein-1, macrophage inflammatory protein-2, intercellular adhesion molecule-1). In addition, marked renal endothelial cell apoptosis was detected involving peritubular interstitial capillaries, accompanied by increased renal vascular permeability. Finally, there was severe disruption of renal proximal tubule epithelial filamentous-actin. Our results show that AKI rapidly and reproducibly develops in mice after hepatic IR and is characterized by renal tubular necrosis, inflammatory changes and interstitial capillary endothelial apoptosis. Our murine model of AKI after liver injury closely mimics human AKI associated with ALF and may be useful in delineating the mechanisms and potential therapies for this common clinical condition.
PMCID: PMC2632727  PMID: 19079326
acute renal failure; apoptosis; endothelium; hepatic ischemia; inflammation; necrosis; neutrophil
3.  Proximal tubular cells contain a phenotypically distinct, scattered cell population involved in tubular regeneration 
The Journal of pathology  2013;229(5):645-659.
Regeneration of injured tubular cells occurs after acute tubular necrosis primarily from intrinsic renal cells. This may occur from a pre-existing intratubular stem/progenitor cell population or from any surviving proximal tubular cell. In this study, we characterize a CD24-, CD133-, and vimentin-positive subpopulation of cells scattered throughout the proximal tubule in normal human kidney. Compared to adjacent ‘normal’ proximal tubular cells, these CD24-positive cells contained less cytoplasm, fewer mitochondria, and no brush border. In addition, 49 marker proteins are described that are expressed within the proximal tubules in a similar scattered pattern. For eight of these markers, we confirmed co-localization with CD24. In human biopsies of patients with acute tubular necrosis (ATN), the number of CD24-positive tubular cells was increased. In both normal human kidneys and the ATN biopsies, around 85% of proliferating cells were CD24-positive – indicating that this cell population participates in tubular regeneration. In healthy rat kidneys, the novel cell subpopulation was absent. However, upon unilateral ureteral obstruction (UUO), the novel cell population was detected in significant amounts in the injured kidney. In summary, in human renal biopsies, the CD24-positive cells represent tubular cells with a deviant phenotype, characterized by a distinct morphology and marker expression. After acute tubular injury, these cells become more numerous. In healthy rat kidneys, these cells are not detectable, whereas after UUO, they appeared de novo – arguing against the notion that these cells represent a pre-existing progenitor cell population. Our data indicate rather that these cells represent transiently dedifferentiated tubular cells involved in regeneration.
PMCID: PMC3951144  PMID: 23124355
proximal tubules; progenitor cell; regeneration; acute tubular necrosis
4.  Acute Tubular Necrosis and Renal Failure in Patients with Glomerular Disease 
Renal Failure  2012;34(10):1252-1257.
Renal failure is common in patients with glomerular disease. Although renal failure may result from the glomerular lesion itself, it is also observed in patients with minimal glomerular alterations. Degenerative changes and necrosis of the tubular epithelium are common findings in kidney biopsies from these patients. The aim of this work is to examine the association between acute tubular necrosis (ATN) and renal failure in patients with glomerulopathy and to estimate the relationship between the degree of ATN and renal failure in these patients. Data on age, sex, presence of nephrotic syndrome, and renal failure were recorded for 149 patients, who underwent a renal biopsy for the diagnosis of glomerulopathy. The biopsies were reviewed, and ATN, when present, was classified as one of four grades depending on its intensity. The mean age of the patients was 21 ± 16 years. Eighty patients (54%) were male, 43 (42%) had renal failure, 104 (72%) had nephrotic syndrome, and 66 (45%) had minimal change disease or focal segmental glomerulosclerosis. ATN was present in 115 (77%) patients. The frequency of renal failure was directly correlated with the intensity of ATN [odds ratio (OR) of 26.0 for patients with grade 2 lesions and OR of 45.5 for patients with grade 3 lesions]. ATN is a common finding in the biopsies of patients with glomerulopathy. The severity of ATN is directly associated with the frequency of renal failure in these patients.
PMCID: PMC3496189  PMID: 23002699
acute kidney injury; acute tubular necrosis; glomerular disease; nephrotic syndrome; histological score; histopathology
5.  Loxosceles gaucho Venom-Induced Acute Kidney Injury – In Vivo and In Vitro Studies 
Accidents caused by Loxosceles spider may cause severe systemic reactions, including acute kidney injury (AKI). There are few experimental studies assessing Loxosceles venom effects on kidney function in vivo.
Methodology/Principal Findings
In order to test Loxosceles gaucho venom (LV) nephrotoxicity and to assess some of the possible mechanisms of renal injury, rats were studied up to 60 minutes after LV 0.24 mg/kg or saline IV injection (control). LV caused a sharp and significant drop in glomerular filtration rate, renal blood flow and urinary output and increased renal vascular resistance, without changing blood pressure. Venom infusion increased significantly serum creatine kinase and aspartate aminotransferase. In the LV group renal histology analysis found acute epithelial tubular cells degenerative changes, presence of cell debris and detached epithelial cells in tubular lumen without glomerular or vascular changes. Immunohistochemistry disclosed renal deposition of myoglobin and hemoglobin. LV did not cause injury to a suspension of fresh proximal tubules isolated from rats.
Loxosceles gaucho venom injection caused early AKI, which occurred without blood pressure variation. Changes in glomerular function occurred likely due to renal vasoconstriction and rhabdomyolysis. Direct nephrotoxicity could not be demonstrated in vitro. The development of a consistent model of Loxosceles venom-induced AKI and a better understanding of the mechanisms involved in the renal injury may allow more efficient ways to prevent or attenuate the systemic injury after Loxosceles bite.
Author Summary
Loxosceles (recluse or brown spider) is the most important spider genus causing human envenomation. In Brazil Loxosceles spiders were responsible for approximately 7,000 cases of spider envenomation per year. The brown spider accidents may cause late cutaneous necrosis at the bite site, intravascular hemolysis, rhabdomyolysis, coagulation system changes and acute kidney injury (AKI). Even patients with mild cutaneous lesion may develop severe hemolysis and AKI, which is the main cause of death after these accidents. The mechanisms causing kidney injury are poorly understood. In this manuscript we described a consistent rodent model of Loxosceles gaucho venom-induced AKI and studied some of the possible mechanisms of the renal lesion. The results of this research showed that kidney injury may occur independently of the cutaneous lesion and without changes in the systemic blood pressure. Kidney dysfunction occurred likely due to intra-renal vasoconstriction and rhabdomyolysis, although a direct toxic effect of the venom on the proximal tubules cannot be ruled out.
PMCID: PMC3104973  PMID: 21655312
6.  Determining the mechanisms underlying augmented renal drug clearance in the critically ill: use of exogenous marker compounds 
Critical Care  2014;18(6):657.
The aim of this study was to explore changes in glomerular filtration (GFR) and renal tubular function in critically ill patients at risk of augmented renal clearance (ARC), using exogenous marker compounds.
This prospective, observational pharmacokinetic (PK) study was performed in a university-affiliated, tertiary-level, adult intensive care unit (ICU). Patients aged less than or equal to 60 years, manifesting a systemic inflammatory response, with an expected ICU length of stay more than 24 hours, no evidence of acute renal impairment (plasma creatinine concentration <120 μmol/L) and no history of chronic kidney disease or renal replacement therapy were eligible for inclusion. The following study markers were administered concurrently: sinistrin 2,500 mg (Inutest; Laevosan, Linz, Austria), p-aminohippuric acid (PAH) 440 mg (4% p-aminohippuric acid sodium salt; CFM Oskar Tropitzsch, Marktredwitz, Germany), rac-pindolol 5 or 15 mg (Barbloc; Alphapharm, Millers Point, NSW, Australia) and fluconazole 100 mg (Diflucan; Pfizer Australia Pty Ltd, West Ryde, NSW, Australia). Plasma concentrations were then measured at 5, 10, 15, 30, 60 and 120 minutes and 4, 6, 12 and 24 hours post-administration. Non-compartmental PK analysis was used to quantify GFR, tubular secretion and tubular reabsorption.
Twenty patients were included in the study. Marker administration was well tolerated, with no adverse events reported. Sinistrin clearance as a marker of GFR was significantly elevated (mean, 180 (95% confidence interval (CI), 141 to 219) ml/min) and correlated well with creatinine clearance (r =0.70, P <0.01). Net tubular secretion of PAH, a marker of tubular anion secretion, was also elevated (mean, 428 (95% CI, 306 to 550) ml/min), as was net tubular reabsorption of fluconazole (mean, 135 (95% CI, 100 to 169) ml/min). Net tubular secretion of (S)- and (R)-pinodolol, a marker of tubular cation secretion, was impaired.
In critically ill patients at risk of ARC, significant alterations in glomerular filtration, renal tubular secretion and tubular reabsorption are apparent. This has implications for accurate dosing of renally eliminated drugs.
PMCID: PMC4271452  PMID: 25432141
7.  An Iranian experience on renal allograft diseases* 
Renal transplantation is the treatment of choice for most patients with end stage renal disease. In addition, renal biopsy is the gold standard to assess the causes of renal allograft dysfunction. This study was designed to evaluate and designate renal lesions according to Banff schema.
In this cross-sectional study, all renal allograft biopsies obtained from renal transplant patients at Alzahra and Noor referral hospitals in Isfahan during 2006-2008 were studied. Evaluations were made according to the Banff classification 2009. Clinical data was collected from the pathology database and analyzed using SPSS.
A total number of 161 specimens were studied from 68% male and 32% female subjects. The donor source was living unrelated in 85%, living related 9.9% and cadaveric in 5% of cases. Pathologic results showed 22.4% acute tubular necrosis (ATN), 13.7% interstitial fibrosis and tubular atrophy (IF/TA) grade II, 9.9% IF/TA (Grade III), 6.8% acute T-cell mediated rejection (TCMR-IA), 5.6% TCMR-IB, 5% borderline change, 5% infarction, 4.3% TCMR-IIA, 4.3% TA/IF (Grade I), 3.7% acute antibody-mediated rejection (ABMR), 1.9% TCMR-IIB and 17.4% other lesions.
The commonest causes of graft dysfunction after kidney transplant were IF/TA, no evidence of any specific etiology (NOS) and ATN. Living donors were found to be important sources for kidney transplantation in Iran.
PMCID: PMC3434898  PMID: 22973365
Kidney Transplantation; Kidney Allograft; Transplantation Results; Renal Biopsy
8.  Nephrotic Syndrome and Acute Renal Failure Apparently Induced by Sunitinib 
Case Reports in Oncology  2009;2(3):172-176.
We report a case of nephrotic syndrome and acute renal failure apparently induced by sunitinib. A 67-year-old man with a history of metastatic renal cell carcinoma presented with progressive kidney dysfunction with proteinuria, general edema, and body weight gain of 21 kg after undergoing 3 weeks of sunitinib therapy. The patient had taken no other over-the-counter medications, and all other possible causes of nephrotic syndrome were excluded. The Naranjo Adverse Drug Reaction Probability Scale score for this event was 6, indicating a high probability that the observed presentations were associated with use of the drug. However, despite the discontinuation of sunitinib, his condition deteriorated, and hemodialysis was initiated for respiratory distress. A renal biopsy was performed, which revealed ischemic acute tubular necrosis with minimal change nephropathy. In conclusion, nephrologists and oncologists should be aware that nephrotic syndrome with ischemic acute tubular necrosis is a possible adverse effect of sunitinib. For early diagnosis of this condition and to avoid renal damage, we recommend differential diagnosis of serum creatinine and proteinuria in patients undergoing sunitinib therapy.
PMCID: PMC2914378  PMID: 20737033
Sunitinib; Nephrotic syndrome; Ischemic acute tubular necrosis
9.  The first description of severe anemia associated with acute kidney injury and adult minimal change disease: a case report 
Acute kidney injury in the setting of adult minimal change disease is associated with proteinuria, hypertension and hyperlipidemia but anemia is usually absent. Renal biopsies exhibit foot process effacement as well as tubular interstitial inflammation, acute tubular necrosis or intratubular obstruction. We recently managed a patient with unique clinical and pathological features of minimal change disease, who presented with severe anemia and acute kidney injury, an association not previously reported in the literature.
Case presentation
A 60-year-old Indian-American woman with a history of hypertension and diabetes mellitus for 10 years presented with progressive oliguria over 2 days. Laboratory data revealed severe hyperkalemia, azotemia, heavy proteinuria and progressively worsening anemia. Urine eosinophils were not seen. Emergent hemodialysis, erythropoietin and blood transfusion were initiated. Serologic tests for hepatitis B, hepatitis C, anti-nuclear antibodies, anti-glomerular basement membrane antibodies and anti-neutrophil cytoplasmic antibodies were negative. Complement levels (C3, C4 and CH50) were normal. Renal biopsy unexpectedly displayed 100% foot process effacement. A 24-hour urine collection detected 6.38 g of protein. Proteinuria and anemia resolved during six weeks of steroid therapy. Renal function recovered completely. No signs of relapse were observed at 8-month follow-up.
Adult minimal change disease should be considered when a patient presents with proteinuria and severe acute kidney injury even when accompanied by severe anemia. This report adds to a growing body of literature suggesting that in addition to steroid therapy, prompt initiation of erythropoietin therapy may facilitate full recovery of renal function in acute kidney injury.
PMCID: PMC2636832  PMID: 19166584
10.  Shiga Toxin 1 Causes Direct Renal Injury in Rats  
Infection and Immunity  2005;73(11):7099-7106.
Infection with Shiga toxin (Stx)-producing Escherichia coli has been implicated to cause hemolytic uremic syndrome, which is characterized by histological abnormalities such as microvascular thrombi and tubular cell damage in the kidney. Although Stx is known to be the major virulence factor of the pathogen, it is still unclear whether Stx directly impairs renal cells in vivo to cause such histological changes and deterioration of renal function. To assess the consequence of the direct action of Stx on renal cells, left kidneys of rats were perfused with Stx1 from the renal artery through the renal vein and then revascularized. Kidneys of control animals were perfused with the vehicle alone. On day 1, apoptosis and induction of tumor necrosis factor alpha gene expression were noticed to occur in the medulla of the Stx1-perfused kidneys. On day 3, extensive tubular injuries were observed by light microscopy: aggregated platelets and monocytic infiltrates in both glomeruli and the medullary interstitium were detected by immunostaining. Tubular changes were more extensive on day 9, with areas of infarction seen in the cortex and medulla. These changes were not found to occur in the sham-operated kidneys. No obvious glomerular changes were detected by light microscopy at any time point. When nonperfused right kidneys were removed after the Stx1 perfusion of the left kidneys, the serum creatinine and blood urea nitrogen levels were increased from day 2, and acute renal failure followed on day 3. These results indicate that Stx1 caused glomerular platelet aggregation, tubular damage, and acute deterioration of renal function by acting directly on renal cells.
PMCID: PMC1273854  PMID: 16239503
11.  Histopathologic patterns of adult renal disease in Kermanshah, Iran: A 6-year review of two referral centers 
Background: The pattern of glomerular diseases in northwest Iran is unknown. This study was conducted to evaluate the histological pattern of renal diseases in this region.
Methods: We retrospectively studied the reports of 266 native adult renal biopsies at the Imam Reza and Taleghani Hospitals from June 2007 to June 2012. Pathological findings include minimal change disease (MCD), focal segmental glomerulosclerosis (FSGS), mesangioproliferative glomerulonephritis (MPGN), mesangiocapillary glomerulonephritis (MCGN), post streptococcal proliferative glomerulonephritis (PSPGN), membranous glomerulonephritis (MGN), hypertensive nephropathy (HN), crescentic glomerulonephritis or rapid progressive glomerulonephritis (CGN or RPGN), chronic tubular interstitial necrosis (CTIN), chronic sclerosing glomerulonephritis (CGN), Alport syndrome, acute tubular necrosis (ATN), lupus nephritis, renal amyloidosis. The data were collected and analyzed.
Results: The mean age of the patients was 37.41±15.78 years. Nephrotic syndrome was observed in 155 (58.3%) cases which was higher in frequency in females (61.9%) (p<0.005), followed by renal insufficiency in 87 (32.7%) cases. Totally, 187 (70.3%) had primary glomerulonephritis (GN) whereas, 79 (29.7%) had secondary GN. MCD was found to be the most common histological pattern (44%) and CGN (1.12%) was the least common. The frequencies of secondary glomerulonephritis (GN) include lupus nephritis to be the most frequent (41.8%) followed by chronic tubulo interstitial nephritis (38%) and type II diabetic nephropathy (19%).
Conclusion: The results showed that minimal change disease ranked first followed by focal segmental glomerulosclerosis. We hope that this will form the basis for developing a renal biopsy registry across the continent in Iran.
PMCID: PMC3755843  PMID: 24009967
Renal biopsy; Adult renal disease; kermanshah
12.  Sustained Oxidative Stress Causes Late Acute Renal Failure via Duplex Regulation on p38 MAPK and Akt Phosphorylation in Severely Burned Rats 
PLoS ONE  2013;8(1):e54593.
Clinical evidence indicates that late acute renal failure (ARF) predicts high mortality in severely burned patients but the pathophysiology of late ARF remains undefined. This study was designed to test the hypothesis that sustained reactive oxygen species (ROS) induced late ARF in a severely burned rat model and to investigate the signaling mechanisms involved.
Materials and Methods
Rats were exposed to 100°C bath for 15 s to induce severe burn injury (40% of total body surface area). Renal function, ROS generation, tubular necrosis and apoptosis, and phosphorylation of MAPK and Akt were measured during 72 hours after burn.
Renal function as assessed by serum creatinine and blood urea nitrogen deteriorated significantly at 3 h after burn, alleviated at 6 h but worsened at 48 h and 72 h, indicating a late ARF was induced. Apoptotic cells and cleavage caspase-3 in the kidney went up slowly and turned into significant at 48 h and 72 h. Tubular cell ROS production shot up at 6 h and continuously rose during the 72-h experiment. Scavenging ROS with tempol markedly attenuated tubular apoptosis and renal dysfunction at 72 h after burn. Interestingly, renal p38 MAPK phosphorylation elevated in a time dependent manner whereas Akt phosphorylation increased during the first 24 h but decreased at 48 h after burn. The p38 MAPK specific inhibitor SB203580 alleviated whereas Akt inhibitor exacerbated burn-induced tubular apoptosis and renal dysfunction. Furthermore, tempol treatment exerted a duplex regulation through inhibiting p38 MAPK phosphorylation but further increasing Akt phosphorylation at 72 h postburn.
These results demonstrate that sustained renal ROS overproduction induces continuous tubular cell apoptosis and thus a late ARF at 72 h after burn in severely burned rats, which may result from ROS-mediated activation of p38 MAPK but a late inhibition of Akt phosphorylation.
PMCID: PMC3547934  PMID: 23349934
13.  Renal haemodynamic, microcirculatory, metabolic and histopathological responses to peritonitis-induced septic shock in pigs 
Critical Care  2008;12(6):R164.
Our understanding of septic acute kidney injury (AKI) remains incomplete. A fundamental step is the use of animal models designed to meet the criteria of human sepsis. Therefore, we dynamically assessed renal haemodynamic, microvascular and metabolic responses to, and ultrastructural sequelae of, sepsis in a porcine model of faecal peritonitis-induced progressive hyperdynamic sepsis.
In eight anaesthetised and mechanically ventilated pigs, faecal peritonitis was induced by inoculating autologous faeces. Six sham-operated animals served as time-matched controls. Noradrenaline was administered to maintain mean arterial pressure (MAP) greater than or equal to 65 mmHg. Before and at 12, 18 and 22 hours of peritonitis systemic haemodynamics, total renal (ultrasound Doppler) and cortex microvascular (laser Doppler) blood flow, oxygen transport and renal venous pressure, acid base balance and lactate/pyruvate ratios were measured. Postmortem histological analysis of kidney tissue was performed.
All septic pigs developed hyperdynamic shock with AKI as evidenced by a 30% increase in plasma creatinine levels. Kidney blood flow remained well-preserved and renal vascular resistance did not change either. Renal perfusion pressure significantly decreased in the AKI group as a result of gradually increased renal venous pressure. In parallel with a significant decrease in renal cortex microvascular perfusion, progressive renal venous acidosis and an increase in lactate/pyruvate ratio developed, while renal oxygen consumption remained unchanged. Renal histology revealed only subtle changes without signs of acute tubular necrosis.
The results of this experimental study argue against the concept of renal vasoconstriction and tubular necrosis as physiological and morphological substrates of early septic AKI. Renal venous congestion might be a hidden and clinically unrecognised contributor to the development of kidney dysfunction.
PMCID: PMC2646329  PMID: 19108740
14.  Percutaneous ultrasound-guided renal biopsy in children: a single centre experience 
Hippokratia  2011;15(3):258-261.
Background and aim: The contribution of renal biopsy is of major importance in many renal diseases in children. In our study we aimed to evaluate retrospectively the indications, safety, efficacy and the spectrum of histopathological findings of percutaneous ultrasound-guided renal (PRB) biopsy during a 7 year period as well as to analyze specific groups of renal patients.
Patients and Methods: A total of 84 renal biopsies were performed in 81 children. Demographic data, clinical symptoms at presentation, indications for renal biopsy, laboratory findings, complications of the procedure and histological diagnosis were obtained from all patients who underwent PRB.
Results: The commonest indication for biopsy accounted was steroid resistant, steroid dependent or frequent relapsing idiopathic nephrotic syndrome (INS). Subcapsular hematoma presented 11% of the patients, but none of them needed blood transfusion. Adequate renal tissue sample was obtained in 97.7% of the renal biopsies. In 80% the histopathology revealed glomerular diseases. The most frequent types of biopsy-proven renal diseases were: focal segmental glomerulosclerosis (FSGS) (15%), IgA nephropathy (13.5%), minimal change disease (10%), various stages of lupus nephritis (8.5%), Henoch-Schonlein nephritis (7.5%), membranous glomerulonephritis (7.5%), mesangioproliferative glomerulonephritis (6%), post-infectious glomerulonephritis (6%), hemolytic uremic syndrome (5%), tubulointerstitial nephropathies (3.5%), acute tubular necrosis 2.5%. Among the 28 cases of INS, FSGS accounted for 43%. The leading histopathological pattern found in patients with recurrent episodes of gross haematuria was IgAN (84.5%). Among 7 cases of lupus nephritis, the observed histological types were: IV+V in 3/7, IIIA in 3/7 (43%) and IIB in 1/7.
Conclusions: Our study shows that percutaneous ultrasound-guided renal biopsy is a safe, reliable and effective technique in children. It also provides updated information for childhood renal disease pattern.
PMCID: PMC3306034  PMID: 22435025
Percutaneous ultrasound-guided renal biopsy; renal diseases; children
15.  Activation of the miR-17 Family and miR-21 During Murine Kidney Ischemia-Reperfusion Injury 
Nucleic Acid Therapeutics  2013;23(5):344-354.
Ischemia-reperfusion (I/R) is the main cause of acute kidney injury (AKI) in patients. We investigated renal microRNA (miRNA) expression profiles and the time course of changes in selected miRNA expressions after renal I/R to characterize the miRNA network activated during development and recovery from AKI.
Methods and Results
One day after lethal (30 minutes) and sublethal (20 minutes) renal ischemia, AKI was verified by renal histology (tubular necrosis, regeneration), blood urea nitrogen (BUN) level, renal mRNA expression, and plasma concentration of neutrophil gelatinase-associated lipocalin (NGAL) in C57BL/6J mice. On the first day after 30-minute, lethal I/R miR-21, miR-17-5p, and miR-106a were elevated out of the 21 miRNAs successfully profiled on the Luminex multiplex assay. After 20-minute, sublethal I/R, renal miR-17-5p and miR-106a expressions were elevated on the first and second days of reperfusion, while miR-21 expression increased later and lasted longer. Renal miR-17-5p and miR-21 expressions correlated with each other. Renal function returned to normal on the fourth day after sublethal I/R.
Our results demonstrate that besides miR-21, miR-17-5p, and miR-106a are additionally activated during the maintenance and recovery phases of renal I/R injury. Furthermore, a correlation between renal miR-17-5p and miR-21 expressions warrants further investigation of how they may influence each other and the outcome of renal ischemia-reperfusion injury.
PMCID: PMC3760057  PMID: 23988020
16.  Renal failure in fulminant hepatic failure and terminal cirrhosis: a comparison between incidence, types, and prognosis. 
Gut  1981;22(7):585-591.
Forty patients with terminal cirrhosis and 40 patients with fulminant hepatic failure-all consecutively admitted-were studied with regard to incidence, types, and prognosis of complicating renal insufficiency. Renal failure was considered present when the serum creatinine was greater than 0.20 mmol/l. Of the patients with cirrhosis 26 (65%) developed renal failure. In 15 the type was functional, in three due to acute tubular necrosis, and in eight indeterminable. Of the patients with fulminant hepatic failure 22 (55%) had renal insufficiency; of these 13 had functional renal failure, five acute tubular necrosis, and in four the type was indeterminable. In both categories of patients, renal failure was equally frequent among patients with or without gastrointestinal bleeding and with or without ascites or diuretic therapy. The biochemical tests of liver function were similar in patients with or without renal failure in both categories. The mean renal blood flow in seven unselected patients with fulminant hepatic failure was reduced in the same order as previously observed in patients with cirrhosis. In terminal cirrhosis the mortality rate was 88% in the presence of renal failure, 71% in its absence (p greater than 0.05), while the same figures in fulminant hepatic failure were 100% and 67% (p less than 0.05). The incidence, relative frequency, and prognosis of renal failure were not different in the two conditions, indicating identical pathophysiological circumstances.
PMCID: PMC1419318  PMID: 7262632
17.  The histopathology of septic acute kidney injury: a systematic review 
Critical Care  2008;12(2):R38.
Sepsis is the most common trigger of acute kidney injury (AKI) in critically ill patients; understanding the structural changes associated with its occurrence is therefore important. Accordingly, we systematically reviewed the literature to assess current knowledge on the histopathology of septic AKI.
A systematic review of the MEDLINE, EMBASE and CINHAL databases and bibliographies of the retrieved articles was performed for all studies describing kidney histopathology in septic AKI.
We found six studies reporting the histopathology of septic AKI for a total of only 184 patients. Among these patients, only 26 (22%) had features suggestive of acute tubular necrosis (ATN). We found four primate studies. In these, seven out of 19 (37%) cases showed features of ATN. We also found 13 rodent studies of septic AKI. In total, 23% showed evidence of ATN. In two additional studies performed in a dog model and a sheep model there was no evidence of ATN on histopathologic examination. Overall, when ATN was absent, studies reported a wide variety of kidney morphologic changes in septic AKI – ranging from normal (in most cases) to marked cortical tubular necrosis.
There are no consistent renal histopathological changes in human or experimental septic AKI. The majority of studies reported normal histology or only mild, nonspecific changes. ATN was relatively uncommon.
PMCID: PMC2447560  PMID: 18325092
18.  Detection of renal allograft rejection using blood oxygen level-dependent and diffusion weighted magnetic resonance imaging: a retrospective study 
BMC Nephrology  2014;15(1):158.
Acute rejection (AR) and acute tubular necrosis (ATN) are main causes of early renal allograft dysfunction. Blood oxygen level-dependent magnetic resonance imaging (BOLD MRI) and Diffusion weighted (DW) MRI can provide valuable information about changes of oxygen bioavailability and water diffusion by measuring R2* or apparent diffusion coefficient (ADC) respectively. We aimed to determine the value of BOLD MRI and DW MRI in detecting causes for early allograft dysfunction in renal allograft recipients.
Fifty patients received renal allografts from deceased donors were analyzed, including 35 patients with normal renal function (control group), 10 AR patients and 5 ATN patients. Cortical R2* (CR2*) and medullary R2* (MR2*) were measured by BOLD MRI. Ten diffusion gradient b values (0, 5, 10, 20, 50, 100, 200, 400, 800, 1200s/mm2) were used in DW MRI. ADC values were measured in renal cortex (CADC) and medulla (MADC). CADCl and MADCl were measured under low b values (b ≤ 200 s/mm2), while CADCh and MADCh were measured under high b values (b > 200 s/mm2).
MR2* was significantly lower in AR group (18.2 ± 1.5/s) than control group (23.8 ± 5.0/s, p = 0.001) and ATN group (25.8 ± 5.0/s, p = 0.004). There was a tendency of lower levels on CADCl, MADCl, CADCh or MADCh in AR group than in control group. There were no differences on ADC values between AR group and ATN group.
BOLD MRI was a valuable method in detection of renal allografts with acute rejection.
PMCID: PMC4192395  PMID: 25270976
19.  Renal failure in otherwise uncomplicated acute viral hepatitis. 
British Medical Journal  1978;2(6133):338-341.
Twelve patients with otherwise uncomplicated acute viral hepatitis (two were HBsAg-positive) developed renal failure. Apart from dehydration due to repeated vomiting in one patient, no factor responsible for precipitating renal failure could be identified. The clinical course was characterised by renal failure with plasma urea concentrations reaching maximum values of 26-69 mmol/l (175-416 mg/100 ml). Ten patients needed dialysis for up to two weeks. Seven patients recovered completely, while the other five died from sepsis. The types of renal failure were similar to those described in fulminant hepatic failure and cirrhosis--namely, functional renal failure in five patients and acute tubular necrosis in seven. Two of the patients with functional renal failure later developed tubular necrosis. The mechanism responsible for renal failure in acute viral hepatitis is uncertain, though endotoxaemia may contribute.
PMCID: PMC1606474  PMID: 687905
20.  Predictors of outcome in idiopathic rapidly progressive glomerulonephritis (IRPGN) 
BMC Nephrology  2006;7:16.
Small vessel vasculitides are known to follow a devastating course towards end-stage renal disease, unless treated with immunosuppressive regiments. We investigated the value of clinical, histological and immunohistochemical parameters as predictors of outcome at diagnosis in patients with pauci immune necrotizing glomerulonephritis.
In 34 patients the percentage and evolution stage of crescents, the presence of glomerular necrosis, the degree or severity of arteriosclerosis, as well as the extent of tubulointerstitial infiltration, interstial fibrosis and tubular atrophy were assessed. Monoclonal antibodies were used to identify infiltrating macrophages, α-SMA(+) and PCNA(+) cells, the expression of integrins α3β1 and LFA-1β, the adhesion molecule ICAM-1, the growth factor TGF-β1 and the terminal complement component C5b-9.
24 pts (70.6%) showed a complete or partial response to the treatment. The follow-up period was 20 ± 22 months. At multivariate analysis, serum CRP (p = 0.024), the intensity of tubular expression of C5b-9 (p < 0.0001) as well as the extent of glomerular and tubular expression of α3β1 integrin (p = 0.001 and 0.008 respectively) independently predicted the response to treatment. The response rate was better in ANCA(+) pts (p = 0.008). The extent of interstitial infiltrate (p < 0.0001), the severity of tubulointerstitial fibrosis (p < 0.0001) and the severity of tubular TGF-β1 expression (p < 0.0001) were independent predictors of long term outcome of renal function.
Patients with ANCA-associated renal vasculitis seem to respond better to the treatment. Acute phase reactants, such as CRP, implying a more intense parenchymal inflammatory reaction, as well as the intensity of the de novo expression of C5b-9 and the glomerular and tubular expression of α3β1 integrin predict the response to therapy. The severity of TIN lesions and of the tubulo-interstitial TGF-β1 and C5b-9 expression predict an unfavourable outcome.
PMCID: PMC1660564  PMID: 17078867
21.  Protective effect and localization by optical imaging of human renal CD133+ progenitor cells in an acute kidney injury model 
Physiological Reports  2014;2(5):e12009.
Recent approaches of regenerative medicine can offer a therapeutic option for patients undergoing acute kidney injury. In particular, mesenchymal stem cells were shown to ameliorate renal function and recovery after acute damage. We here evaluated the protective effect and localization of CD133+ renal progenitors from the human inner medulla in a model of glycerol‐induced acute tubular damage and we compared the results with those obtained with bone marrow‐derived mesenchymal stem cells. We found that CD133+ progenitor cells promoted the recovery of renal function, preventing tubular cell necrosis and stimulating resident cell proliferation and survival, similar to mesenchymal stem cells. In addition, by optical imaging analysis, CD133+ progenitor cells accumulated within the renal tissue, and a reduced entrapment in lung, spleen, and liver was observed. Mesenchymal stem cells were detectable at similar levels in the renal tissue, but a higher signal was present in extrarenal organs. Both cell types produced several cytokines/growth factors, suggesting that a combination of different mediators is involved in their biological action. These results indicate that human CD133+ progenitor cells are renotropic and able to improve renal regeneration in acute kidney injury.
In the present study, we found that administration of human CD133+ renal progenitors promoted renal repair after murine AKI, similar to mesenchymal stem cells. In addition, these cells showed a high renal localization evaluated by optical imaging analysis, and the production of renoprotective factors. Mesenchymal stem cells were detectable at similar levels in the renal tissue, but a higher signal was present in extrarenal organs.
PMCID: PMC4098737  PMID: 24793983
AKI; biodistribution; mesenchymal stem cells; renal progenitor cells; stem cells
22.  NONOBSTRUCTIVE OLIGURIA—Differential Diagnosis 
California Medicine  1963;99(2):83-89.
A review is presented of ten years' experience with the differential diagnosis of oliguria, utilizing the standard tests of renal function with the addition of the phenolsulfonphthalein excretion and urinary chloride measurements. The histories of 60 patients seen in consultation because of 24-hour urinary volume of less than 400 ml were studied in order to clarify the value of these tests. Particular attention was given to the postoperative “dilution state,” the oliguria of which tends to mimic that of “acute tubular necrosis.”
In only 25 per cent of the 60 cases was “acute tubular necrosis” responsible for the oliguria. In the remaining 75 per cent of patients, oliguria was due either to the effects of simple dehydration without tubular damage, or to tubular dysfunction on a physiologic rather than an organic basis. Thus, three out of four patients with oliguria required aggressive and specific fluid-electrolyte therapy, often with the intensive use of potassium. One out of four required the opposite in therapy—controlled dehydration without added potassium and, on occasion, peritoneal or extracorporeal dialysis, in order to allow six to ten days for tubular repair.
PMCID: PMC1515215  PMID: 13931952
23.  Zebrafish usp39 Mutation Leads to rb1 mRNA Splicing Defect and Pituitary Lineage Expansion 
PLoS Genetics  2011;7(1):e1001271.
Loss of retinoblastoma (Rb) tumor suppressor function is associated with human malignancies. Molecular and genetic mechanisms responsible for tumorigenic Rb downregulation are not fully defined. Through a forward genetic screen and positional cloning, we identified and characterized a zebrafish ubiquitin specific peptidase 39 (usp39) mutation, the yeast and human homolog of which encodes a component of RNA splicing machinery. Zebrafish usp39 mutants exhibit microcephaly and adenohypophyseal cell lineage expansion without apparent changes in major hypothalamic hormonal and regulatory signals. Gene expression profiling of usp39 mutants revealed decreased rb1 and increased e2f4, rbl2 (p130), and cdkn1a (p21) expression. Rb1 mRNA overexpression, or antisense morpholino knockdown of e2f4, partially reversed embryonic pituitary expansion in usp39 mutants. Analysis of pre-mRNA splicing status of critical cell cycle regulators showed misspliced Rb1 pre-mRNA resulting in a premature stop codon. These studies unravel a novel mechanism for rb1 regulation by a neuronal mRNA splicing factor, usp39. Zebrafish usp39 regulates embryonic pituitary homeostasis by targeting rb1 and e2f4 expression, respectively, contributing to increased adenohypophyseal sensitivity to these altered cell cycle regulators. These results provide a mechanism for dysregulated rb1 and e2f4 pathways that may result in pituitary tumorigenesis.
Author Summary
Previous studies have shown that Rb+/− mice develop pituitary adenomas; however, RB1 mutations have not been found in human pituitary tumors. In the present study, we uncovered a novel genetic pathway that may lead to Rb downregulation through RNA splicing mediated by usp39, a gene involved in assembly of the spliceosome. Our forward genetic study in zebrafish suggests that loss of usp39 results in aberrant rb1 mRNA splicing, which likely causes elevated expression of its target e2f4, a key regulator known to have oncogenic activity when overexpressed. We established that e2f4 upregulation is a main factor responsible for the adenohypophyseal cell lineage hyperplasia observed in the zebrafish usp39 mutant. It should be of interest to investigate if mutations or downregulation of USP39 would contribute to pituitary tumorigenesis in humans.
PMCID: PMC3020934  PMID: 21249182
24.  Prucalopride-associated acute tubular necrosis 
We report the first case of acute renal failure secondary to prucalopride, a novel agent for the treatment of chronic constipation. The 75 years old male patient was initiated on prucalopride after many failed treatments for constipation following a Whipple’s procedure for pancreatic cancer. Within four months of treatment his creatinine rose from 103 to 285 μmol/L (eGFR 61 decrease to 19 mL/min per 1.73 m2). He was initially treated with prednisone for presumed acute interstitial nephritis as white blood casts were seen on urine microscopy. When no improvement was detected, a core biopsy was performed and revealed interstitial fibrosis and tubular atrophy. The presence of oxalate and calcium phosphate crystals were also noted. These findings suggest acute tubular necrosis which may have been secondary to acute interstitial nephritis or hemodynamic insult. The use of prednisone may have suppressed signs of inflammation and therefore the clinical diagnosis was deemed acute interstitial nephritis causing acute tubular necrosis. There are no previous reports of prucalopride associated with acute renal failure from the literature, including previous Phase II and III trials.
PMCID: PMC4133431  PMID: 25133152
Prucalopride; Acute kidney tubular necrosis; Renal insufficiency; Constipation; Adverse drug event
25.  Radiofrequency ablation (RFA) of renal cell carcinoma (RCC): experience in 200 tumours 
Bju International  2013;113(3):416-428.
To evaluate our clinical experience with percutaneous image-guided radiofrequency ablation (RFA) of 200 renal tumours in a large tertiary referral university institution.
Patients and Methods
Image-guided RFA (ultrasonography or computed tomography [CT]) of 200 renal tumours in 165 patients from June 2004 to 2012 was prospectively evaluated. Institutional Review Board approval was granted.
The treatment response and technical success were defined by absence of contrast enhancement within the tumour on contrast enhanced CT or magnetic resonance imaging.
Both major and minor complications, glomerular filtration rate (GFR) before and after RFA, the management and outcomes of the complications, as well as oncological outcome were prospectively documented.
Multivariate analysis was used to determine variables associated with major complications and also the percentage GFR change after RFA.
The overall (OS), 5-year cancer-specific (CSS), local recurrence-free (LRFS) and metastasis-free survival (MFS) rates are presented using the Kaplan–Meier curves.
In all, 200 tumours were RF ablated with a mean (range) tumour size of 2.9 (1–5.6) cm and the mean (range) patient age was 67.7 (21–88.6) years with a mean follow-up period of 46.1 months.
The primary technical and overall technical success rate was 95.5% and 98.5%, respectively. Two independent predictors of successful RFA in a single sitting were tumour size (<3 cm) and exophytic location in multivariate logistic regression analysis.
Major complications included ureteric injury (six patients), calyceal-cutaneous fistula (one), acute tubular necrosis (one) and abscess (two). Two independent predictors of ureteric injury were central location and lower pole position.
Within this cohort of patients, only four patients developed significant renal function deterioration i.e. >25% decreased in GFR. In all, 161 (98%) patients of the 165 patients have preservation of renal function. Any change in renal function after RFA was not influenced by tumour factors or solitary kidney status.
In our clinical series, this yielded a 5-year OS, CSS, LRFS and MFS rates of 75.8%, 97.9%, 93.5% and 87.7% respectively.
Image-guided RFA is a safe, nephron sparing and effective treatment for small renal cell carcinoma (RCC) tumours with a low rate of recurrence and has good 5-year CSS and MFS rates.
PMCID: PMC4233988  PMID: 24053769
radiofrequency ablation; renal cell carcinoma; complication; survival rates

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