Acute renal failure with sodium-glucose-cotransporter-2 inhibitors: Analysis of the FDA adverse event report system database.

BACKGROUND AND AIMS: Sodium-glucose-cotransporter-2 (SGLT2) inhibitors have recently been approved for the treatment of type II diabetes mellitus (T2DM). It has been proposed that these agents could induce acute renal failure (ARF) under certain conditions. This study aimed to evaluate the association between SGLT2-inhibitors and ARF in the FDA adverse event report system (FAERS) database. METHODS AND RESULTS: We analyzed adverse event cases submitted to FAERS between January 2013 and September 2016. ARF cases were identified using a structured medical query. Medications were identified using both brand and generic names. During the period evaluated, 18,915 reports (out of a total of 3,832,015 registered in FAERS) involved the use of SGLT2-inhibitors. SGLT2-inhibitors were reportedly associated with ARF in 1224 of these cases (6.4%), and were defined as the "primary" or "secondary" cause of the adverse event in 96.8% of these cases. The proportion of reports with ARF among reports with SGLT2 inhibitor was almost three-fold higher compared to reports without these drugs (ROR 2.88, 95% CI 2.71-3.05, p < 0.001). The proportion of ARF reports among cases with SGLT2-inhibitors was significantly greater than the proportion of ARF among cases with T2DM without SGLT2-inhibitors (ROR 1.68, 95% CI 1.57-1.8, p < 0.001). Among the SGLT2-inhibitors, canagliflozin was associated with a higher proportion of reports of renal failure (7.3%), compared to empagliflozin and dapagliflozin (4.7% and 4.8% respectively, p < 0.001). CONCLUSION: SGLT2-inhibitors are associated with an increase in the proportion of reports of ARF compared to other medications. SGLT2-inhibitor agents may differ from one another in their respective risk for ARF.

Erythema ab igne of shins: a kerosene stove-induced prototype in diabetics.

A patient with erythema ab igne of shins is presented, caused by repeated thermal injury induced by a heating stove placed between the knees. This injury pattern has been repeatedly identified in diabetic patients involved in similar heating practice, underscoring a possible predisposition related to diabetic neuropathy.

Diabetes and radiocontrast media increase endothelin converting enzyme-1 in the kidney.

Plasma endothelin-1 levels rise in diabetes and after exposure to contrast media suggesting a role in progressive diabetic and acute radiocontrast nephropathies. Here we studied individual and combined effects of streptozotocin-induced diabetes and contrast media on renal endothelin converting enzyme-1 levels in the rat. In vivo, medullary (but not cortical) endothelin converting enzyme protein gradually increased 4 to 5-fold following the induction of diabetes or after the administration of contrast media but rose 15-fold when diabetic rats were given contrast media. Changes in mRNA expression paralleled those of the protein. Immunohistochemistry confirmed that increased tubular and endothelial cell endothelin converting enzyme-1 were most pronounced in the medulla. In vitro, endothelin-1 levels increased 3-fold following incubation of endothelial cells with media high in glucose or with contrast and 4-fold with their combination. Endothelin converting enzyme-1 protein and mRNA expression changed in a similar pattern while prepro endothelin-1 mRNA increased with each insult but not in an additive way. Our study shows that diabetes and contrast media up-regulate renal medullary endothelin converting enzyme-1 expression and synthesis.

Cyclosporine A induces endothelin-converting enzyme-1: Studies in vivo and in vitro.

AIM: Cyclosporine A (CsA) induces renal vasoconstriction and hypoxia and enhances the expression of endothelin-1 (ET-1) pro-hormone (pre-pro-ET-1), plausibly leading to a feed-forward loop of renal vasoconstriction, hypoxia and enhanced synthesis of the potent vasoconstrictor ET-1. Endothelin-converting enzyme (ECE)-1 cleaves big endothelin to generate endothelin (ET)-1 and is upregulated by hypoxia via hypoxia-inducible factor (HIF). We hypothesized that in addition to the direct induction of ET-1 synthesis, CsA might also intensify renal ECE-1 expression, thus contributing to enhanced ET-1 synthesis following CsA. METHODS: CsA was administered to Sprague Dawley rats (120 mg/kg/SC) for 4 days, and renal HIF and ECE-1 expression were assessed with Western blots and immunostaining. Human umbilical vein endothelial cells (HUVEC) and proximal tubular cell line (HK-2) were subjected to CsA, and ECE-1 induction was evaluated using real-time mRNA PCR and Western blots. RESULTS: Cyclosporine A intensified renal parenchymal ECE-1 expression in the rat kidney, particularly in distal nephron segments, along with renal hypoxia (detected by pimonidazole adducts) and HIF expression, in line with our recent observations showing episodic hypoxia in mice subjected to CsA. Furthermore, in cultured normoxic HUVEC and HK-2 cells, CsA dose-dependently induced both pre-pro-ET-1 and ECE-1 mRNA and protein expression, with enhanced ET-1 generation. CONCLUSION: CsA induces ECE-1 via both hypoxic and non-hypoxic pathways. ECE-1 may contribute to increased renal ET-1 generation following CsA, participating in a feed-forward loop of renal parenchymal hypoxia and ET synthesis.

Role of nitric oxide in renal medullary oxygenation. Studies in isolated and intact rat kidneys.

We investigated the role of the endothelial-derived relaxing factor nitric oxide (NO) in the homeostasis of O2 supply to the renal medulla, a region normally operating on the verge of hypoxia. Sensitive Clark-type O2 microelectrodes were inserted into renal cortex and medulla of anesthetized rats. The inhibitor of NO formation, L-NG-monomethylarginine (LNMMA), while increasing blood pressure and reducing renal blood flow, decreased medullary pO2 from 23 +/- 3 mmHg to 12 +/- 3 (P less than 0.001), with no change in the cortex. These responses were promptly reversed by L-arginine, which bypasses the LNMMA blockade. In isolated rat kidneys, LNMMA reduced perfusion flow without altering glomerular filtration rate, and augmented deep medullary hypoxic injury to thick ascending limbs from 68 to 90% of the tubules (P less than 0.02). These changes were prevented by L-arginine. Nitroprusside had a protective effect upon thick limb injury. Finally, in a previously reported model of radiocontrast nephropathy (1988. J. Clin. Invest. 82:401), LNMMA increased the severity of renal failure (final plasma creatinine from 2.3 +/- 2 mg% to 3.4 +/- 3, P less than 0.005) and the proportion of damaged thick limbs (from 24 +/- 6% to 53 +/- 9, P less than 0.01). Nitrovasodilatation may participate in the balance of renal medullary oxygenation and play an important role in the prevention of medullary hypoxic injury.

Acute renal failure with selective medullary injury in the rat.

Since human acute renal failure (ARF) is frequently the result of multiple rather than single insults, we used a combination of treatments to induce ARF in rats. Uninephrectomized, salt-depleted rats injected with indomethacin developed ARF after administration of radiocontrast. After 24 h, the plasma creatine rose from 103 +/- 3 to 211 +/- 22 mumol/liter (mean +/- SE) and the creatinine clearance dropped from 0.7 +/- 0.1 to 0.2 +/- 0.04 ml/min (P less than 0.001). Severe injury was confined to the outer medulla and comprised necrosis of medullary thick ascending limbs (mTALs), tubular collapse, and casts. Other nephron segments were free of damage except for the proximal convoluted tubules which showed vacuole formation originating from lateral limiting membranes that resembled changes reported in human contrast nephropathy. Cell damage to mTALs included mitochondrial swelling, nuclear pyknosis, and cytoplasmic disruption with superimposed calcification; these changes were most severe in the deepest areas of the outer medulla, away from vasa recta in zones remote from oxygen supply. The fraction of mTALs with severe damage was 30 +/- 7% (range 2-68) and the extent of injury was correlated with a rise in plasma creatinine (r = 0.8, P less than 0.001). Thus, the nature of mTAL injury was similar to the selective lesions observed in isolated kidneys perfused with cell-free medium and was shown to derive from an imbalance between high oxygen demand by actively transporting mTALs and the meager oxygen supply to the renal medulla. Combined multiple renal insults in the rat produce ARF that resembles the clinical syndrome of contrast nephropathy and is characterized by selective mTAL injury conditioned by medullary hypoxia.

Cyclosporin a induces renal episodic hypoxia.

AIM: Cyclosporin A (CsA) causes renal toxicity. The underlying mechanisms are incompletely understood, but may involve renal hypoxia and hypoxia-inducible factors (Hifs). We sought for hypoxia and Hif in mouse kidneys with CsA-induced toxicity, assessed their time course, Hif-mediated responses and the impact of interventional Hif upregulation. METHODS: Mice received CsA or its solvent cremophore for up to 6 weeks. Low salt diet (Na+ ↓) was given in combination with CsA to enhance toxicity. We assessed fine morphology, renal function, blood oxygen level-dependent magnetic resonance imaging under room air and following changes in breathing gas composition which correlate with vascular reactivity, pimonidazole adducts (which indicate O2 tensions below 10 mmHg), Hif-α proteins, as well as expression of Hif target genes. Stable Hif upregulation was achieved by inducible, Pax8-rtTA-based knockout of von Hippel-Lindau protein (Vhl-KO), which is crucial for Hif-α degradation. RESULTS: Cyclosporin A transiently increased renal deoxyhaemoglobin (R2*). Augmented vascular reactivity was observed at 2 h, but decreased at 24 h after CsA treatment. Na+ ↓/CsA provoked chronic renal failure with tubular degeneration and interstitial fibrosis. Nephron segments at risk for injury accumulated pimonidazole adducts, as well as Hif-α proteins. Remarkably, Hif target gene expression remained unchanged, while factor-inhibiting Hif (Fih) was enhanced. Na+ ↓/CsA/Vhl-KO aggravated morpho-functional outcome of chronic renal CsA toxicity. CONCLUSIONS: Cyclosporin A provokes episodic hypoxia in nephron segments most susceptible to chronic CsA toxicity. Fih is upregulated and likely blocks further Hif activity. Continuous tubular Hif upregulation via Vhl-KO worsens the outcome of chronic CsA-induced renal toxicity.

Adaptive response to hypoxia and remote ischaemia pre-conditioning: a new hypoxia-inducible factors era in clinical medicine.

Transient ischaemia leads to tolerance to subsequent protracted ischaemia. This 'ischaemia pre-conditioning' results from the induction of numerous protective genes, involved in cell metabolism, proliferation and survival, in antioxidant capacity, angiogenesis, vascular tone and erythropoiesis. Hypoxia-inducible factors (HIF) play a pivotal role in this transcriptional adaptive response. HIF prolyl hydroxylases (PHDs), serving as oxygen sensors, control HIFα degradation. HIF-mediated ischaemic pre-conditioning can be achieved with the administration of PHD inhibitors, with the attenuation of organ injury under various hypoxic and toxic insults. Clinical trials are currently under way, evaluating PHD inhibitors as inducers of erythropoietin. Once their safety is established, their potential use might be further tested in clinical trials in various forms of acute ischaemic and toxic organ damage. Repeated transient limb ischaemia was also found to attenuate ischaemic injury in remote organs. This 'remote ischaemic pre-conditioning' phenomenon (RIP) has been extensively studied recently in small clinical trials, preceding, or in parallel with an abrupt insult, such as myocardial infarction, cardiac surgery or radiocontrast administration. Initial results are promising, suggesting organ protection. Large-scale multi-centre studies are currently under way, evaluating the protective potential of RIP in cardiac surgery, in the management of myocardial infarction and in organ transplantation. The mechanisms of organ protection provided by RIP are poorly understood, but HIF seemingly play a role as well. Thus, Inhibition of HIF degradation with PHD inhibitors, as well as RIP (in part through HIF), might develop into novel clinical interventions in organ protection in the near future.

The effect of ketotifen on nitric oxide synthase activity.

1. We studied the effect of ketotifen, a second generation H1-receptor antagonist on nitric oxide synthase (NOS) activity in colonic mucosa and in renal tissues, and on rat renal haemodynamics in vivo. 2. Ketotifen (100 micrograms ml-1) increased human colonic NOS activity from 3.7 +/- 0.6 to 14.5 +/- 1.3 nmol g-1 min-1 (P < 0.005, ANOVA). In rat renal cortical and medullary tissues ketotifen increased NOS activity by 55% and 86%, respectively (P < 0.001). The stimulation of NOS activity was attenuated by NADPH deletion and by the addition of N omega nitro-L-arginine methyl ester (L-NAME) or aminoguanidine, but not by [Ca2+] deprivation. NOS activity was unaffected by two other H1-antagonists, diphenhydramine and astemizole, or by the structurally related cyproheptadine. Renal cortical NOS activity was also significantly stimulated 90 min after intravenous administration of ketotifen to anaesthetized rats. 3. Ketotifen administration to anaesthetized rats induced modest declines in blood pressure and reduced total renal, cortical and outer medullary vascular resistance. This is in contrast to diphenhydramine, which did not induce renal vasodilatation. 4. We conclude that ketotifen stimulates NOS activity by mechanisms other than H1-receptor antagonism. The association of this effect with therapeutic characteristics of ketotifen and the clinical implications of these findings are yet to be defined.

Pathophysiology of radiocontrast nephropathy: a role for medullary hypoxia.

Recent experimental data underlies the role of hypoxic tubular injury in the pathophysiology of radiocontrast nephropathy. Although systemic transient hypoxemia, increased blood viscosity, and a leftward shift of the oxygen-hemoglobin dissociation curve may all contribute to intrarenal hypoxia, imbalance between oxygen demand and supply plays a major role in radiocontrast-induced outer medullary hypoxic damage. Low oxygen tension normally exists in this renal region, reflecting the precarious regional oxygen supply and a high local metabolic rate and oxygen requirement, resulting from active salt reabsorption by medullary thick ascending limbs of Henle's loop. Radiologic contrast agents markedly aggravate outer medullary physiologic hypoxia. This results from enhanced metabolic activity and oxygen consumption (as a result of osmotic diuresis and increased salt delivery to the distal nephron) because the regional blood flow and the oxygen supply actually increase. The latter effect may result in part from the activation of various regulatory mediators of outer medullary blood flow to ensure maximal regional oxygen supply. Low-osmolar radiocontrast agents may be less nephrotoxic because of the smaller osmotic load and vasomotor alterations. Experimental radiocontrast-induced renal failure requires preconditioning of animals with various insults (for example, congestive heart failure, reduced renal mass, salt depletion, or inhibition of nitric oxide and prostaglandin synthesis). In all these perturbations, which resemble clinical conditions that predispose to contrast nephropathy, outer medullary hypoxic injury results from insufficiency or inactivation of mechanisms designed to preserve regional oxygen balance. This underlines the importance of identifying and ameliorating predisposing factors in the prevention of this iatrogenic disease.

Experimental nephrotoxicity of the radiocontrast agents iohexol, ioxaglate, and iothalamate. An in vitro and in vivo study.

The authors compared the renal toxicity of the low osmolality radiocontrast agents, iohexol and ioxaglate, and the ionic agent, iothalamate, at equivalent iodine dose, using experimental models in vitro and in vivo. In isolated perfused rat kidneys, all agents induced comparable biphasic hemodynamic changes, associated with similar declines in glomerular filtration rate (GFR) and tubular necrosis. In two different in vivo models (using multiple insults combined with the administration of radiocontrast), iothalamate appeared to induce more severe morphologic injury. Despite similar nephrotoxic potential in vitro, the newer radiocontrast agents, iohexol and ioxaglate, cause in vivo less renal injury than iothalamate in the experimental models.

Effects of ioversol versus iothalamate on endothelin release and radiocontrast nephropathy.

RATIONALE AND OBJECTIVES: Certain radiocontrast agents, including iothalamate, iohexol, and ioxaglate, release the renal vasoconstrictor peptide endothelin from vascular endothelium in a way that might contribute to radiocontrast nephropathy. The effects of the nonionic, low osmolar agent, ioversol, on endothelin release and renal function are investigated. METHODS: Effects of ioversol were compared with equi-iodine doses of iothalamate when applied to cultured bovine aortic endothelial cells or injected into normal rats and rats preconditioned by uninephrectomy, salt depletion, and indomethacin (USIC) to develop radiocontrast nephropathy. RESULTS: In comparison with iothalamate, ioversol had a greatly reduced propensity to stimulate the release of endothelin, from cultured cells and when injected into anesthetized rats. Ioversol produced less renal vasoconstriction than did iothalamate, in control and in USIC rats, and the development of radiocontrast nephropathy, assessed by creatinine clearance and morphologic damage to the renal medulla, was largely avoided. CONCLUSIONS: These results strengthen the hypothesis that endothelin release induced by radiocontrast agents is correlated with their renal toxicity and therefore, may play a role in radiocontrast nephropathy.

Reduced amphotericin toxicity in an albumin vehicle.

Amphotericin B systemically infused into anesthetized rats at the rate of 0.4 mg/kg body weight over 20 min reproducibly induced renal vasoconstriction and renal cortical hypoxemia. By contrast, when infused with albumin (3 g/dl), amphotericin B did not reduce renal blood flow and did not affect renal cortical oxygenation. In vitro, hemolysis induced by amphotericin was also markedly reduced in the presence of albumin. Albumin did not appear to reduce the antibiotic effect of amphotericin in vitro. It was concluded that amphotericin B toxicity may be considerably reduced if administered in an albumin vehicle.

Meningococcal meningitis among Rwandan refugees: diagnosis, management, and outcome in a field hospital.

OBJECTIVE: To study the diagnostic process, clinical course, and outcome of Rwandan refugees with meningococcal meningitis, treated in an Israeli field hospital in Goma, Zaire, in the summer of 1994. METHODS: Patient hospital charts and laboratory records were reviewed with critical evaluation of clinical presentation and diagnostic tests. Patients were treated as part of a disaster relief effort in a refugee camp experiencing several coexisting lethal epidemics. RESULTS: A total of 65 patients were identified as having group A meningococcal meningitis. Latex agglutination test for Neisseria meningitidis soluble antigen in the cerebrospinal fluid was found to be a superior diagnostic tool, as compared to Gram stain, and at least as effective as culture. The mortality rate was 14%; mortality was markedly affected by co-morbidity (e.g., dysentery, pneumonia, and malnutrition). CONCLUSIONS: The outcome of patients with meningococcal meningitis, treated in referral centers within a disaster area may be favorable, despite overwhelming coexisting epidemics, and may be comparable to that achieved in advanced medical facilities. Encephalopathy may be a diagnostic pitfall in the perspective of coexisting epidemics, requiring a high index of suspicion and routine lumbar puncture. The latex agglutination test is highly useful in achieving prompt diagnosis of meningococcal meningitis, in particular when sample handling for culture and microscopy is suboptimal.

Primary hyperparathyroidism presenting as cervical myelopathy.

Quadriplegia as a presenting syndrome in a case of primary hyperparathyroidism is reported. The clinical picture was misdiagnosed as a space-occupying lesion in the cervical spinal canal, for which an unnecessary laminectomy was performed. The neurologic deficits disappeared following the removal of a parathyroid adenoma. The neurologic presentations of hyperparathyroidism are reviewed and discussed.

Airborne field hospital in disaster area: lessons from Armenia (1988) and Rwanda (1994).

The outcome of survivors within disaster areas largely depends upon the quick reallocation and operation of logistic and medical support systems. Enthusiastic media equipped with advanced communication systems, reveal mass human suffering in real time. But, the response period required for the organization of rescue systems is much slower and is most frustrating. In this article, we present our experience in quick deployment and operation of airborne field hospitals gained following the earthquake disaster in Armenia in 1988 and the civil war in Rwanda in 1994. Deployment of improvised, volunteer-based, military field hospitals was feasible within 24 hours after the decision was made. A multi-disciplinary structure enabled an effective, flexible mode of operation and reduced the dependency on mericulous, time-consuming assessments of requirements prior to deployment. These missions are a paradigm for the successful incorporation and integration within the capabilities of military infrastructure of volunteer professionals drafted from civil medical facilities. Such field hospitals could provide backup for primary care medical systems in disaster areas and substitute or take some pressure off of local hospitals, particularly when evacuation systems are insufficient.

Takayasu's arteritis identified by computerized tomography: revealing the submerged portion of the iceberg?

BACKGROUND: Takayasu's arteritis is a rare, probably underdiagnosed disorder in Israel. OBJECTIVE: To evaluate the contribution of computerized tomography to the diagnosis of Takayasu's arteritis. METHODS: A retrospective analysis of the diagnostic process was recently conducted in three consecutive patients diagnosed over the last 3 years. RESULTS: Three females of Arab origin with Takayasu's arteritis were recently identified by CT. In two of the three patients the imaging procedure was performed for different working hypotheses, and the radiological findings (wall thickening, perivascular edema, and segmental intraluminal obliteration of the aorta and its major branches) were unexpected. In these two patients, repeated physical examination following the imaging procedure disclosed initially missed findings that could have led to an earlier consideration of Takayasu's arteritis (bruits above the epigastrium, subclavian and carotid arteries, and absent brachial pulses). Retrospective analysis of the patients' symptoms following CT revealed the true nature of the patients misinterpreted complaints (e.g., typical abdominal angina replaced a faulty obtained history compatible with renal colic or dyspepsia). In the third patient CT was performed for the evaluation of an epigastric bruit associated with constitutional complaints. The diagnosis of aortitis, based upon the presence of diffuse aortic wall thickening and edema of the surrounding fat, without intraluminal narrowing, could have been missed by angiography, the traditional "gold standard" diagnostic procedure. All three patients complained of ill-defined epigastric abdominal pain and had epigastric tenderness during examination. CONCLUSIONS: CT has the potential for detecting Takayasu's disease and may be superior to angiography, particularly at the early non-obliterative stage. Since the diagnosis of Takayasu's disease is rarely considered, the expanding use of CT and MRI technologies may reveal missed cases that are evaluated for other plausible diagnoses. The true incidence of Takayasu's arteritis in Israel may be much higher than reported, particularly in the Arab population. Our findings suggest that epigastric tenderness, originating from active inflammatory reaction in the abdominal aortic wall, should be considered as a diagnostic criterion of Takayasu's aortitis.

Emphysematous complications in dentistry, 1960-1993: an illustrative case and review of the literature.

Seventy-four reports of emphysematous complications in ambulatory dental patients, published in the English literature between the years 1960 and 1993, are reviewed, and an additional case of subcutaneous, retropharyngeal, and mediastinal emphysema following an impression-taking procedure for a crown preparation is presented. This rare complication occurred mainly in patients in the third and fifth decades of life, after dental procedures on the third molar, in particular during mandibular extractions and treatment on the right side. The use of an air syringe, high-speed handpieces, or their combination was reported in 71% of cases. Centripetal air dissection, with retropharyngeal and mediastinal emphysema, occurred in 35% of the patients, especially following extractions.

[The osmolar gap and the diagnosis of severe alcohol intoxication].

The calculated osmolar gap is a useful diagnostic tool in clinical toxicology whenever toxicologic screens are not available. In a case of severe intoxication with ethyl alcohol there was deep coma and a calculated osmolar gap of 208 mOsm, consistent with an ethanol plasma level of 958 mg/dl. The diagnosis of severe ethanol intoxication was confirmed later. Serial calculations of the osmolar gap served to assess the clinical course.

[Bilateral hydronephrosis and erythrocytosis].

A 36-year-old woman who developed extreme erythrocytosis following partial correction of severe bilateral hydronephrosis by bilateral ureterolithotomy is presented. Hydronephrosis appears to stimulate renal synthesis and release of erythropoietin. The mechanism could involve increase in medullary hypoxia by increased pressure of the renal pelvis on the medullary vasculature. This might be especially marked when the renal blood supply is compromised by concomitant atherosclerosis, as in this case.