Nephrotoxic Acute Tubular Necrosis Research Articles

Mechanisms of Drug-Induced Interstitial Nephritis.

Drug-induced acute interstitial nephritis (DI-AIN) is a drug hypersensitivity reaction (DHR) that manifests 7 to 10days after exposure to the culprit drug. DHRs account for fewer than 15% of reported adverse drug reactions. The kidneys are susceptible to DHR because: (1) the high renal blood flow whereby antigens are filtered, secreted, or concentrated, and (2) it is a major site of excretion for drugs and drug metabolites. More than 250 different drugs from various classes have been incriminated as causative agents of DI-AIN, the third most common cause of acute kidney injury in the hospital. DI-AIN must be differentiated from drug-induced nephrotoxic acute tubular necrosis because of their differing pathophysiology and treatment. DI-AIN begins with antigen processing and presentation to local dendritic cells. The dendritic cells activate T cells, and the subsequent effector phase of the immune response is mediated by various cytokines. Incriminated antigenic mechanisms include response to a conjugation product of the drug or its metabolite with a host protein (eg, beta-lactam or sulfonamide antibiotic) or the direct binding of the drug to a particular host allele to elicit a hypersensitivity response (eg, certain anti-epileptic drugs). If the offending drug is not identified and discontinued in a timely manner, irreversible fibrosis and chronic kidney disease will occur. The core structure of each drug or its metabolite is an antigenic determinant, and the host interaction is termed the structure-activity relationship. Differing structure-activity relationships accounts for effect, hypersensitivity, and cross-reactivity among and between classes. The essence of management of DI-AIN lies with the four sequential steps: anticipation, diagnosis, treatment, and prevention. Corticosteroids are used in the treatment of DI-AIN because of their potent anti-inflammatory effects on T cells and eosinophils. Anticipation and prevention require notifying the patient that DI-AIN is an idiosyncratic, hypersensitivity reaction that recurs on re-exposure, and the drug should be avoided.

Soluble Human Leukocyte Antigen-G in Pediatric Renal Transplantation

Soluble Human Leukocyte Antigen-G in Pediatric Renal Transplantation

Clinical cause of presumed acute tubular necrosis requiring renal replacement therapy and outcome of critically ill patients: post hoc analysis of a prospective 7-year cohort study

Acute kidney injury (AKI) secondary to acute tubular necrosis (ATN) is common in critically ill patients, and causes significant morbidity and mortality. The underlying etiology of ATN can be divided into pure ischemic, pure nephrotoxic, and mixed causes. This post-hoc analysis of a prospective cohort study aimed to investigate whether the cause (pure vs. mixed) of ATN affects the short- and long-term outcome of critically-ill patients. A total of 425 critically-ill patients with AKI secondary to clinically diagnosed ATN were divided into three groups according to the cause of ATN. Of these patients, 215 had mixed ATN, 203 had pure ischemic ATN, and seven had pure nephrotoxic ATN. All patients had one episode of AKI only. No patient had pre-existing chronic kidney disease. Patients were followed throughout their hospital stay (mortality rate, recovery of renal function at discharge) and up to 7years thereafter. The three patient groups differed in their demographic and clinical characteristics. The in-hospital mortality rates were 55% in the presumably mixed-cause ATN group, 39% in the pure ischemic group, and 29% in the pure nephrotoxic group. Complete renal recovery at discharge was documented in five out of five surviving patients with nephrotoxic ATN (100%) and in 92 out of 124 surviving patients with pure ischemic ATN (74%), but only in 29 out of 97 patients with mixed ATN (30%). None of the surviving patients was lost during the 7-year follow-up. At the end of the observation period, 60% of the survivors of pure ATN, compared with 22% of the survivors of mixed ATN, were alive. After 7years, 6% of the living patients with pure ATN had mild-to-moderate chronic kidney disease, whereas 38% of the mixed group patients had advanced CKD or end-stage renal disease. The cause of presumed ATN has a profound impact on short- as well as long-term outcomes of critically-ill patients with AKI requiring renal replacement therapy. The challenge for intensivists is to avoid further injury to the kidneys of these patients.

Biopsy-Proven Acute Tubular Necrosis due to Vancomycin Toxicity

Vancomycin (VAN) has been associated with acute kidney injury (AKI) since it has been put into clinical use in the 1950's. Early reports of AKI were likely linked to the impurities of the VAN preparation. With the advent of the more purified forms of VAN, the incidence of AKI related to VAN were limited to acute interstitial nephritis (AIN) or as a potentiating agent to other nephrotoxins such as Aminoglycosides. VAN as the sole etiologic factor for nephrotoxic acute tubular necrosis (ATN) has not been described. Here, we report a case of biopsy-proven ATN resulting from VAN.

Acute renal failure due to multiple stings by Africanized bees. Report on 43 cases

This study reports on acute renal failure (ARF) due to multiple stings by Africanized bees (AB) occurring in 43 cases collected between 1982 and 2007 (at the Nephrology Section, University of Antioquia School of Medicine and San Vicente de Paul University Hospital, Medellin, Colombia). No intervention on patient care was performed except for responding the Nephrology consult and prescribing dialysis. Data obtained from the medical records included demography; clinical presentation; laboratory results on admission; evolution of renal function to document improvement and normalization; intervals between stings and outcomes; number of dialysis sessions; length of follow-up and hospitalization; survival; and mortality. Not all patients had complete data and therefore, the number of observations is included where required. Mean age was 56 ± 26 yr (range 2-96); 37 (86%) were men; 38 (of 41 cases) came from rural areas (91%); 22 (of 39) were farmers (56.4%); 33 (of 41) lived in Medellin or in the department of Antioquia (80.5%). Number of stings per patient: ~ 900. Interval between stings and ARF < 48 hours: in 31 cases (72.1%; mean 2.6 ± 2.6 days; range 1-12); 37 (of 43) required dialysis (86%); mean number of sessions: 4.7 ± 3.3 (range 1-12). Survival occurred in 36 cases (83.7%) and mortality, in 7, all > 60 yr (16.3%). At last follow-up, renal function improvement was documented in 36 (83.7%) and normalization in 15 of them (41.7%). Interval until initiation of diuresis: 10.6 ± 6.8 days (range 1-25). Duration of hospitalization: 16.9 ± 8.7 days (range 1-39). 25.2 ± 18.3 days (range 1-75). Hematuria and oliguria occurred before 24 hours; there was an increase of CPK in 90%, of ALT in 96%, of AST in 89%, of DHL in 95%, and of BUN and creatinine in 100%. Based on our findings and on the review of the available information, we propose that this type of ARF occurs as a result of rhabdomyolysis with subsequent myoglobinuria, which lead to nephrotoxic acute tubular necrosis; a variable degree of direct nephrotoxicity, not quantifiable with current diagnostic methods, is also probably involved. A better knowledge of this entity by the medical community could improve care and prognosis of the patients who develop it.

Expression of HLA-G and MICA mRNA in renal allograft

HLA-G is a nonclassical MHC class I antigen that displays tolerogenic functions; MICA is a stress-regulated molecule recognized by NKG2D cytotoxicity-activating receptor expressed by NK and T cells subsets. We evaluated HLA-G isoforms and MICA mRNA levels in peripheral blood mononuclear cells (PBMCs) and in biopsies from kidney allograft recipients with acute rejection (AR), chronic rejection (CR), and stable graft evolution (SE). HLA-G1 was the only transcript resulted from amplification, both in PBMCs as in biopsy samples. HLA-G1 mRNA levels in PBMCs from 9/10 patients with CR, 7/9 with AR and 8/10 healthy volunteers were below the median value of SE patients. The analysis of biopsies revealed that patients with AR ( n = 6), who overcame rejection had a tendency towards higher HLA-G1 levels than those with nephrotoxic acute tubular necrosis (ATN) ( n = 3). Similar levels of MICA expression were observed in PBMCs from AR, CR, SE and C groups; MICA expression levels were similar also in biopsy specimens from AR and nephrotoxic ATN patients. No correlation was found between MICA expression and the graft state. These preliminary results suggest that HLA-G1 isoforms, but not MICA mRNA levels, may provide a marker for measuring the state of kidney allograft, and be the basis for further studies that may establish the influence of these molecules in renal allograft rejection or acceptance.

Disease Severity Adversely Affects Delivery of Dialysis in Acute Renal Failure

Background/Aims: Methods of intermittent hemodialysis (IHD) dose quantification in acute renal failure (ARF) are not well defined. This observational study was designed to evaluate the impact of disease activity on delivered single pool Kt/V_urea in ARF patients. Methods: 100 patients with severe ARF (acute intrinsic renal disease in 18 patients, nephrotoxic acute tubular necrosis in 38 patients, and septic ARF in 44 patients) were analyzed during four consecutive sessions of IHD, performed for 3.5–5 h every other day or daily. Target IHD dose was a single pool Kt/V_urea of 1.2 or more per dialysis session for all patients. Prescribed Kt/V_urea was calculated from desired dialyzer clearance (K), desired treatment time (t) and anthropometric estimates for urea distribution volume (V). The desired clearance (K) was estimated from prescribed blood flow rate and manufacturer’s charts of in vivo data obtained in maintenance dialysis patients. Delivered single pool Kt/V_urea was calculated using the Daugirdas equation. Results: None of the patients had prescription failure of the target dose. The delivered IHD doses were substantially lower than the prescribed Kt/V values, particularly in ARF patients with sepsis/septic shock. Stratification according to disease severity revealed that all patients with isolated ARF, but none with 3 or more organ failures and none who needed vasopressive support received the target dose. Conclusion: Prescription of target IHD dose by single pool Kt/V_urea resulted in suboptimal dialysis dose delivery in critically ill patients. Numerous patient-related and treatment-immanent factors acting in concert reduced the delivered dose.

Nephronectin expression in nephrotoxic acute tubular necrosis

Acute tubular necrosis (ATN) is characterized by an initiation phase, followed by an extension phase, and a maintenance and recovery phase, the latter of which involves increased regeneration of tubular cells. Nephronectin (NPNT), a ligand for alpha8beta1 integrin, is expressed in the ureteric bud epithelium during kidney morphogenesis. However, little is known about the potential involvement of NPNT in the regeneration phase of ATN. cDNA microarray, real-time polymerase chain reaction, in situ hybridization, immunohistochemistry, immuno-electron microscopy and immunoassay (for urine) were used to identify the time-course NPNT expression in a murine model of ATN. The gene transcript of NPNT was examined during a 14-day course of ATN by a cursory cDNA microarray analysis. Although NPNT was observed focally in normal renal tubular epithelium, it was greatly expressed in regenerating tubular cells during the maintenance and recovery phases of ATN. As early as day 1 following onset of ATN, NPNT was already present in the urine. Importantly, NPNT expression preceded proliferating cell nuclear antigen protein expression in regenerating renal tubular epithelial cells, as demonstrated by double immunohistochemistry. The present study was the first to identify an enhanced expression of NPNT in regenerating tubular epithelium in an experimental model of ATN. NPNT may play a crucial role in the regenerating process of nephrotoxic ATN. Our data also suggest that NPNT may provide a useful tissue and urine biomarker for both the development and evolution of nephrotoxic acute renal injury.

野鳥のコリンエステラーゼ阻害剤中毒

A total of 43 wild birds (crows and hawfinches) in seven separate incidents were found dead during the spring from 2004 to 2006 in Iwate Prefecture. Pathological, toxicological and pathogenic examinations of the birds showed miosis and lacrimation. Observed pathological changes were characterized by severe congestion in the lungs, kidneys, liver and optical choroids, nephrotoxic acute tubular necrosis and hypersecretion of the mucous glandular epithelia of digestive tracts. The gizzard contents contained organophosphates from the birds in five incidents and chemicals suggestive of carbamates from those in two incidents. Neither hemagglutinative viruses nor significant bacteria were isolated from the affected birds. Based on the results, the disease was diagnosed as poisoning caused by the detected chemicals.

Patients with ischaemic, mixed and nephrotoxic acute tubular necrosis in the intensive care unit – a homogeneous population?

IntroductionAcute tubular necrosis (ATN) is usually studied as a single entity, without distinguishing between ischaemic, nephrotoxic and mixed aetiologies. In the present study we evaluated the characteristics and outcomes of patients with ATN by aetiological group.MethodWe conducted a retrospective comparison of clinical features, mortality rates and risk factors for mortality for the three types of ATN in patients admitted to the general intensive care unit of a university hospital between 1997 and 2000.ResultsOf 593 patients with acute renal failure, 524 (88%) were classified as having ATN. Their mean age was 58 years, 68% were male and 52% were surgical patients. The overall mortality rate was 62%. A total of 265 patients (51%) had ischaemic ATN, 201 (38%) had mixed ATN, and 58 (11%) had nephrotoxic ATN. There were no differences among groups in terms of age, sex, APACHE II score and reason for ICU admission. Multiple organ failure was more frequent among patients with ischaemic (46%) and mixed ATN (55%) than in those with nephrotoxic ATN (7%; P < 0.0001). The complications of acute renal failure (such as, gastrointestinal bleeding, acidosis, oliguria and hypervolaemia) were more prevalent in ischaemic and mixed ATN patients. Mortality was higher for ischaemic (66%; P = 0.001) and mixed ATN (63%; P = 0.0001) than for nephrotoxic ATN (38%). When ischaemic ATN patients, mixed ATN patients and all patients combined were analyzed by multivariate logistic regression, the independent factors for mortality identified were different except for oliguria, which was the only variable universally associated with death (odds ratio [OR] 3.0, 95% confidence interval [CI] 1.64–5.49 [P = 0.0003] for ischaemic ATN; OR 1.96, 95% CI 1.04–3.68 [P = 0.036] for mixed ATN; and OR 2.53, 95% CI 1.60–3.76 [P < 0.001] for all patients combined]).ConclusionThe frequency of isolated nephrotoxic ATN was low, with ischaemic and mixed ATN accounting for almost 90% of cases. The three forms of ATN exhibited different clinical characteristics. Mortality was strikingly higher in ischaemic and mixed ATN than in nephrotoxic ATN. Although the type of ATN was not an independent predictor of death, the independent factors related to mortality were different for ischaemic, mixed and all patients combined. These data indicate that the three types of ATN represent different patient populations, which should be taken into consideration in future studies.

Fatal colchicine poisoning by accidental ingestion of meadow saffron-case report

A 62-year-old male died of colchicine poisoning after accidental ingestion of Colchicum autumnale (meadow saffron). He ate a salad of plant with green leaves regarded as wild garlic ( Allium ursinum). A few hours later he developed symptoms of gastroenteritis and was admitted to hospital. In spite of gastric lavage, activated charcoal and supportive measures, multi-organ system failure developed over the next two days. Laboratory analysis showed highly elevated blood concentrations of hepatic enzymes, creatine kinase, lactate dehydrogenase and blood urea nitrogen, as well as leukocytopenia and thrombocytopenia. Mechanical ventilation, dopamine, noradrenaline, crystalloid solutions and fresh frozen plasma were applied but despite treatment the patient died five days after the ingestion. Post-mortem examination revealed hepatic centrilobular necrosis, nephrotoxic acute tubular necrosis, petechial bleeding in fatty tissue, blunt and shortened intestinal villi and cerebral toxic edema. Botanical identification of incriminated plant gave Colchicum autumnale which confirmed colchicine poisoning. Although the accidental ingestion of Colchicum autumnale is rare and to our knowledge only five such cases have been described in detail, this is the second fatal case in Croatia described in the last 3 years.

Maximizing Contrast to Noise with Inductively Coupled Implanted Coils

Magnetic resonance (MR) microscopy with inductively coupled implanted coils has been used previously to follow loss and return of intra-medullary contrast as a result of nephrotoxic acute tubular necrosis with 117 microns resolution over a 2000 microns thick slice. The purpose of the current study was to further investigate the capabilities of in vivo MR microscopy by combining the implanted coil imaging technique with spin echo pulse sequence optimization done through signal-to-noise ratio (SNR) and contrast-to-noise ratio (CNR) modeling. These models included consideration of the effects of T2* and sampling time on signal-to-noise and contrast-to-noise ratios. They were initially tested with GdCl3 and agar gel phantoms constructed to the relaxation time and spin density specifications of the intra-medullary junction which bridges the outer and inner stripe of the outer medulla. In vivo microscopy was performed using single turn radiofrequency (RF) coils that were surgically implanted around the left kidney of two rats and inductively coupled to an external "birdcage" body coil. The models revealed maximum CNR per unit imaging time at a TR of 800 msec. A TE of 16 msec proved to be the best compromise between loss of transverse magnetization and decreased bandwidth. These CNR predictions were supported by the gel phantom and in vivo data. Maximizing the CNR in the current study enabled us to improve the resolution of in vivo MR microscopy to 78 microns over a 1000 microns slice with an SNR of 40 and a CNR of eight in a total imaging time of 54 minutes.

Implanted coil MR microscopy of renal pathology.

Inductively coupled implanted coils have been shown to provide up to a 10-fold increase in signal-to-noise ratio when compared to whole-body imaging of small animals. The current study was designed to extend the implanted coil imaging technique to a rodent model of renal pathology. Resonant radiofrequency (RF) coils were implanted around the left kidney of four rats and inductively coupled from within a birdcage body coil. All images were acquired at 2 T using a T1-weighted spin-echo sequence with TR = 500 ms and TE = 20 ms. In vivo MR microscopy with voxels of 117 x 117 x 2000 microns demonstrated cortex, inner and outer medulla, and major vascular structures on baseline images. Mercuric chloride-induced nephrotoxic acute tubular necrosis (ATN) diminished cortico-medullary contrast at 24 h after dosing with pathologic evaluation demonstrating nephrotoxic changes in the inner cortex. The kidney regained a baseline MR appearance 360 h after dosing and resolution of the damage was confirmed with histology. T1 data were gathered on excised kidneys as an adjunct to the images to help correlate the loss and return of cortico-medullary contrast with the pathology and pathophysiology of nephrotoxic ATN. With implanted RF coils we were able to demonstrate renal pathology and follow its subsequent resolution. Specifically, loss and return of cortico-medullary contrast as a result of nephrotoxic ATN were serially documented in four rats. Such serial in vivo studies performed on single animals should further the use of MR microscopy by minimizing the number of animals required for adequate biostatistics.

Ligandinuria in nephrotoxic acute tubular necrosis

Ligandin (GSH-S-transferase B), an abundant intracellular soluble protein in rat proximal tubules, hepatocytes, and small intestinal mucosal cells, is believed to be a component of an organic anion transport system. Its presence in urine was determined immunologically and catalytically in adult, female, Sprague-Dawley rats that were given mercuric chloride or potassium dichromate. These nephrotoxic agents produce severe renal failure, with epithelial necrosis in the proximal tubule. Mercuric chloride perferentially injures the terminal part of the proximal tubule, while potassium dichromate damages more proximal segments. Ligandinuria was consistently detected immunologically and catalytically from 6 to 24 hr following injection of mercuric chloride. Potassium dichromate administration did not result in immunologically detectable liganduria; however, GSH-S-transferase activity, which provides a more sensitive assay, was frequently detected. The findings are consistent with immunofluorescent localization of ligandin in the proximal tubule. Immunologic or enzymatic measurement of ligandin in urine may provide a sensitive index of acute injury to the proximal tubule.