Renal artery stenosis following nilotinib administration in a patient with chronic myelogenous leukemia.

A 63-year-old male was diagnosed as having chronic phase CML in 2001. He obtained a major molecular response with imatinib (IM). In 2012, amulodipin was started for hypertension. In January 2013, IM was switched to nilotinib (NIL) in a clinical trial, and in February 2015, NIL was discontinued because MR4.5 had been maintained for two years. One month later, he was admitted to our hospital because of headache and high blood pressure (194/108 mmHg). His urine test showed protein 3+ and occult blood 2+. His eGFR rapidly deteriorated from 45.6 to 28.5 after admission. MR angiography showed left renal artery stenosis. He thus underwent angioplasty of the left renal artery with a stent implantation. His renal function subsequently improved. Cardiovascular events such as PAOD (peripheral artery occlusive disease) during NIL treatment were recently reported. However, to date, only four cases including our present patient with renal artery stenosis associated with NIL have been reported. These observations suggest assessment of risk factors for cardiovascular events at the start of NIL and careful monitoring to be important during tyrosine kinase inhibitor treatment of CML patients.

Endothelial progenitor cells homing and renal repair in experimental renovascular disease.

Tissue injury triggers reparative processes that often involve endothelial progenitor cells (EPCs) recruitment. We hypothesized that atherosclerotic renal artery stenosis (ARAS) activates homing signals that would be detectable in both the kidney and EPCs, and attenuated on renal repair using selective cell-based therapy. Pigs were treated with intrarenal autologous EPC after 6 weeks of ARAS. Four weeks later, expression of homing-related signals in EPC and kidney, single kidney function, microvascular (MV) density, and morphology were compared with untreated ARAS and normal control pigs (n = 7 each). Compared with normal EPC, EPC from ARAS pigs showed increased stromal cell-derived factor (SDF)-1, angiopoietin-1, Tie-2, and c-kit expression, but downregulation of erythropoietin (EPO) and its receptor. The ARAS kidney released the c-kit-ligand stem cell factor, uric acid, and EPO, and upregulated integrin beta2, suggesting activation of corresponding homing signaling. However, angiopoietin-1 and SDF-1/CXCR4 were not elevated. Administration of EPC into the stenotic kidney restored angiogenic activity, improved MV density, renal hemodynamics and function, decreased fibrosis and oxidative stress, and attenuated endogenous injury signals. The ARAS kidney releases specific homing signals corresponding to cognate receptors expressed by EPC. EPC show plasticity for organ-specific recruitment strategies, which are upregulated in early atherosclerosis. EPC are renoprotective as they attenuated renal dysfunction and damage in chronic ARAS, and consequently decreased the injury signals. Importantly, manipulation of homing signals may potentially allow therapeutic opportunities to increase endogenous EPC recruitment.

Renal failure and concurrent RAAS blockade in older CKD patients with renal artery stenosis: an extended Mayo Clinic prospective 63-month experience.

Concerns have been raised regarding a possible link between the increasing utilization of RAAS blocking strategies in the United States and the increasing ESRD epidemic. Most reports of accelerated renal failure in CKD patients with renal artery stenosis on RAAS blockade are retrospective. We hypothesized that this syndrome is therefore poorly understood, may be under-recognized, and demanded prospective analysis. As part of a larger cohort of 100 CKD patients on RAAS blockade presenting with worsening renal failure (>25% increased serum creatinine from baseline) while concurrently on an ACE inhibitor and/or an angiotensin receptor blocker, 26 patients (26%) enrolled between September 2002 and February 2005 had hemodynamically significant renal artery stenosis. RAAS blockade was discontinued, standard nephrology care applied, and eGFR by MDRD monitored. They consisted of 26 Caucasian patients, M:F = 10:16, age 75.3 +/- 6.4 (63-87) years. Mean follow-up was 26.4 +/- 16.4 (1-49) months. Duration of RAAS blockade prior to enrollment was 20.2 +/- 16.4 (0.5-48) months. Contrary to previous reports, precipitating factors were often absent (15/26), unilateral RAS lesions in patients with dual kidneys was common (19/26), and progression to ESRD was frequent (5/26). Four-fifths of the ESRD patients were dead after 5.5 +/- 4.1 (1-11) months. A fifth patient with improved eGFR died after 14 months from metastatic gastric cancer. Excluding five patients who progressed to ESRD and two patients lost early to follow-up, in 19 patients, eGFR increased from 27.8 +/- 9.5 (11-47) to 36.7 +/- 16 (14-68) mL/min/1.73 m(2) BSA (p = 0.014) after 34.8 +/- 10.1 (14-49) months of follow-up. This improvement in eGFR was evident after weeks to months of stopping RAAS blockade in these patients with and without renal PTA and stenting. Nevertheless, renal PTA/stenting further improved eGFR in selected patients. We conclude that renal failure/ESRD associated with concurrent RAAS blockade in older CKD patients with renal stenosis remains poorly understood and mostly unrecognized. Unilateral lesions in patients with dual kidneys, absent precipitating factors, and progression to ESRD with high mortality, despite discontinuation of RAAS blockade, are more common than previously thought. Lower baseline eGFR (<35) predicted ESRD. Our findings call for a larger prospective study, especially given growing concerns of iatrogenic renal failure from RAAS blockade in the aging U.S. population. An aging U.S. population further raises the probability of the presence of increasing and unrecognized renal artery stenosis in our CKD patient population.

Degradable gelatin microspheres as an embolic agent: an experimental study in a rabbit renal model.

OBJECTIVE: To investigate the basic characteristics of degradable gelatin microspheres (GMSs), including their embolic behavior and degradation periods when they are used as embolic materials in the renal arteries of rabbit models. MATERIALS AND METHODS: Based on the GMS particle size, 24 kidneys were divided into 3 groups of eight kidneys, and each group was embolized with a different GMS particle size (group 1: 35-100 microm, group 2: 100-200 microm, and group 3: 200-300 microm). From each group, two rabbits were sacrificed immediately after embolization (day 0), and a pair of rabbits from each group underwent an angiogram and were sacrificed on days 3, 7, and 14, respectively, after embolization. The level of arterial occlusion, the pathological changes in the renal parenchyma, and the degradation of the GMSs were evaluated angiographically and histologically. RESULTS: A follow-up angiogram on days 0, 3, 7, and 14 revealed the presence of wedge-shaped poorly-enhanced areas in the parenchymal phase as seen in all groups. The size of these areas tended to increase with the particle diameter, and persisted up to day 14. On days 3, 7, and 14, parenchymal infarctions were observed histologically in all cases, and this observation corresponded with the parenchyma being supplied by the embolized arteries. GMSs of group 1 mainly reached the interlobular arteries, while those of group 3 mainly reached the interlobar arteries. In all but two cases, the GMSs were identified histologically even on day 14, and sequential degradation was histologically identified in all GMS groups. CONCLUSION: GMSs can be used as degradable embolic materials which can control the level of embolization.

Does this patient have hypertensive encephalopathy?

A 63-year-old man was admitted to our hospital for further investigation and management of brain metastases. The patient was initially presented with a 4-day history of confusion. On the day of admission, the patient was confused, agitated, disorientated in place and time, and had visual disturbances. His blood pressure was repeatedly recorded high, with levels of systolic blood pressure between 170-210 mm Hg. A brain magnetic resonance imaging showed areas of high signal on T2 and fluid-attenuated inversion recovery images, located bilaterally in the white matter of the occipital regions and unilateral in the left frontal lobe, suggestive of posterior reversible encephalopathy syndrome. Aggressive treatment of hypertension resulted in complete resolution of the clinical and radiologic features of the syndrome.

Arterial embolization using poly-N-acetyl glucosamine gel in a rat kidney model.

Aqueous solutions of poly-N-acetyl glucosamine (p-GlcNAc) exhibit a liquid-gel transition at physiological pH and temperature. This feature inspired the authors to conduct a study to evaluate the macro- and histological changes of rat kidneys after embolization using either p-GlcNAc gel injection into the renal artery or ligation of the renal artery. The procedures were performed in 46 rats through open abdominal surgeries. Animals were sacrificed at 3 days and at 1, 3, 5, and 8 weeks postoperatively. The results of both macro-observation and histological study showed that p-GlcNAc gels were effective in causing necrosis and subsequent fibrosis in all embolized kidneys. The data indicate that p-GlcNAc gel may have promise as an effective agent for therapeutic embolization.

Renal artery stenosis emerged after angiotensin-converting enzyme inhibitor treatment for myocardial infarction: a case report.

A 76-year-old woman with acute myocardial infarction underwent percutaneous coronary angioplasty followed by treatment with an angiotensin-converting enzyme (ACE) inhibitor, lisinopril. Her renal function deteriorated after the administration of lisinopril, so it was changed to another ACE inhibitor, temocapril. Renography suggested a complication of severe right renal artery stenosis, and renal angiography revealed bilateral renal artery stenoses. Her renal hemodynamics were assessed by (99m)Tc-Mercaptoacetyltriglycine ((99m)Tc-MAG(3))-renography before and after withdrawal of temocapril. The authors concluded the patient had essential hypertension complicated by atherosclerotic renovascular disease. In the treatment of elderly patients with heart disease, hypertension, or both, with ACE inhibitor, the possibility of coexisting renal artery stenosis should be considered. Renography is recommended as a reliable tool for detecting renal artery stenosis.

Mechanism of deterioration in renal function in patients with renovascular hypertension treated with enalapril.

Azotemia produced by converting enzyme inhibition in renovascular hypertension was studied in six patients by measurement of glomerular filtration rate (GFR) and effective renal plasma flow (ERPF). Patients with unilateral renovascular hypertension lowered GFR acutely to 40% of control values at 4 hours, but after 4 days it only returned to 75% of control even though ERPF exceeded control values. Calculated filtration fraction (GFR/ERPF) decreased from 0.31 to 0.19 in 4 hours (p less than 0.05) and remained at 0.20 after 4 days of treatment despite increases in GFR and ERPF. In bilateral renovascular hypertension, neither the decreased GFR nor lowered ERPF induced by enalapril showed any tendency to return toward normal with continued treatment. These data are consistent with selective glomerular efferent arteriolar dilation in response to enalapril and suggest that angiotensin converting-enzyme inhibition interferes with the autoregulatory capacity of the kidney in the presence of severe renovascular hypertension.

Renal vascular lesions after chemotherapy with vinblastine, bleomycin, and cisplatin.

A 30 year old man with metastatic embryonal carcinoma became hypertensive during vinblastine, bleomycin, and cisplatin therapy. Three months after completion of therapy, accelerated hypertension occurred (blood pressure 210/140 mm Hg). Nitroprusside failed to control the hypertension, but captopril resulted in a prompt and sustained normalization of the blood pressure. The plasma renin activity was markedly elevated before therapy. Renal biopsy disclosed "onionskin" narrowing of the interlobular arteries and fibrin thrombosis of a majority of the afferent arterioles. A form of drug-induced renovascular hypertension is suggested.

Changes in coagulation and fibrinolysis in the postoperative period immediately after kidney transplantation in patients receiving OKT3 or cyclosporine A as induction therapy.

Different immunosuppressive agents, in particular OKT3, have been implicated as causative factors in the risk for renal thrombosis in the period immediately after kidney transplantation. Also, in different types of vascular surgery, a state similar to hypercoagulation has been reported. To assess the extent to which OKT3, cyclosporine A (CsA), and surgery itself affect coagulation and fibrinolysis, a study was conducted of 20 patients divided into two groups: group A, 10 patients received OKT3 (first dose during the induction of anesthesia); and group B, 10 patients received CsA (first dose at least 2 hours before transplantation). Basal determinations and determinations at 2, 4, and 24 hours after the induction of anesthesia were made. No differences were found between the groups with respect to the clinical and usual coagulation parameters. The following were studied in both groups: (1) markers of coagulation activity (prekallikrein [PKK] levels and formation of thrombin-antithrombin complexes [TATc]), (2) inhibitors and suppressors of hemostasis (antithrombin III [AT-III] and protein C [PC] activity), (3) markers of fibrinolysis activation (levels of plasminogen [PLG] and of alpha2-antiplasmin [alpha2-APL]), and (4) markers of endothelial damage (tissue plasminogen activator [TPA] and thrombomodulin [TMD]). In both groups, an important formation of TATc was observed early, together with a decrease in PKK levels and consumption of both AT-III and PC, which reached their lowest levels at 24 hours. This points to an activation of coagulation through the intrinsic route and a secondary consumption of hemostasis inhibitors, both possibly caused by surgery. A consumption of PLG and alpha2-APL was also observed, reflecting stimulation of the fibrinolytic system and a physiological response to the activation of coagulation. A greater release of endothelial TPA was only observed in the patients receiving OKT3 (P < 0.0001), possibly signaling endothelial activation. It is concluded that surgical stress could be the major factor triggering the alterations seen in hemostasis and their possible consequences.

Coingestion of cyclooxygenase inhibitors can worsen severe paracetamol poisoning by middle-sized and small arteries vasoconstriction.

OBJECTIVE: We report fatal cases of multifocal ischemic injuries occurring in patients awaiting liver transplantation after severe concomitant paracetamol and cyclooygenase inhibitors self-poisoning. DESIGN AND SETTING: Case report in an intensive care unit. PATIENTS: In addition to signs of acute liver failure with a systemic inflammatory response syndrome, these three previously healthy young women demonstrated cutaneous vasoconstriction. One patient displayed a sudden ST-segment elevation with ventricular fibrillation. INTERVENTIONS: Angiography, plasma endothelin concentrations measurements, and autopsy. RESULTS: Radiography showed diffuse vasospasm on mesenteric and renal arteries, transiently reversed by vasodilators. We measured tenfold higher plasma endothelin concentrations than in healthy controls. Autopsy revealed no atherosis (including coronary arteries); organs showed multifocal ischemic injuries without thrombosis. CONCLUSIONS: Such injuries subsequent to dramatic vasoconstriction suggest that cyclooygenase inhibition has specific deleterious vascular side effects once systemic inflammatory response syndrome is in progress during paracetamol poisoning.

Alcohol occlusion of segmental renal arteries as alternative to kidney resection.

Treatment of postoperative urine leakage after a lower pole resection by embolic occlusions of segmental arteries using pure ethanol in a thirty-four-year-old man is described. There were no postoperative complications, and follow-up examination at two years showed a functioning but small kidney in a patient without symptoms.

Reversibility of captopril-induced renal insufficiency after prolonged use in an unusual case of renovascular hypertension.

We report a case of severe hypertension with an occluded renal artery to a solitary kidney, who developed sudden deterioration of renal function following treatment with captopril. His renal function remained impaired but stable during 2 years' treatment with captopril but returned to pre-treatment levels soon after cessation of the drug. This indicates reversibility in captopril-induced renal failure even after its prolonged use and suggests that no organic damage occurs to glomerular arterioles following chronic ACE inhibition.

Occlusion of unilateral stenosed renal arteries--relation to medical treatment.

In 78 patients we studied retrospectively the occurrence of occlusion in unilateral renal artery stenosis during antihypertensive drug treatment. Complete occlusion occurred in 14 patients (18%). In a multivariate analysis the following characteristics were included: blood pressure, aetiology of the stenosis, serum creatinine, the degree of the stenosis, anti-hypertensive medication, standing renal vein renin ratio and age. In this analysis the combination of a diuretic and an ACE-inhibitor, during the observation period, showed an independent relation to the development of an occlusion (P less than 0.05). Also the ACE-inhibitor alone showed a relation (P = 0.06). In the 14 patients who developed an occlusion only three showed a significant rise in serum creatinine. We conclude that special attention should be given to the follow-up of patients with renal artery stenosis who have ACE-inhibitors in their treatment regimen, especially when in combination with a diuretic.

Multiple arterial occlusions and hypertension probably caused by an oral contraceptive: a patient in whom the development of renovascular hypertension has been followed.

An 18-year-old woman taking an oral contraceptive was admitted to hospital because of a stroke due to occlusion of three branches of the right middle cerebral artery. She later developed renovascular hypertension due to occlusion of one of two renal arteries on the right side. Occlusion of the ceoliac artery was also found. The circumstances suggest that the occlusions were caused by multiple emboli, the source of which could not be identified. The kidney with the circulatory disturbance was shown to have a persistent abnormal renin secretion three and six months after the stroke, but the peripheral renin level was lower at the second investigation. Cardiac function studies revealed an alarming degree of left ventricular hypertrophy, and satisfactory blood pressure control could not be maintained despite increasing antihypertensive therapy. Surgical corrrction of the circulatory disturbance promptly led to normotension without drugs, and the patient has remained normotensive during the postoperative observation period of twelve months. The oral contraceptive was probably responsible for precipitating the vascular occlusions, but no predisposing factors or warning symptoms were present to identify this patient as being at risk.

PIP: The case history of an 18-year-old patient, who had been taking oral contraceptives for 2 years (ethinylestradiol 50 mcg, megestrol acetate 4 mg) and who developed multiple arterial occlusions and hypertension, is reported. Occlusion of the ceoliac artery was also found. The circumstances suggest that the occlusions were caused by multiple emboli of unknown source. The affected kidney was shown to have an abnormal renin secretion 3 and 6 months after the stroke, but the peripheral renin level was lower at the 6 month investigation. A large degree of left ventricular hypertrophy was seen. Blood pressure was still uncontrolled despite antihypertensive therapy. Surgery was performed on the affected kidney and normal perfusion restored. The patient then became normotensive, and has remained so for a 12-month period. Oral contraceptives were probably responsible for precipitating the vascular occlusion. Predisposing factors or warning symptoms were absent in this patient.

Experimental models of nephrotoxic acute renal failure.

Table 1 summarizes the findings in these three models of nephrotoxic acute renal failure. As can be noted, leakage of filtrate across damaged tubular epithelium is a factor in each instance. Some degree of tubular obstruction is probably present in each model but is of major importance only with severe tubular injury. Hemodynamic alterations and a change in the ultrafiltration coefficient may also play a role in the renal functional impairment. It is not presently possible to quantitatively determine the significance of each of these abnormalities in a given experimental model.

Pathogenetic mechanisms of nephrotoxicity: insights into cyclosporine nephrotoxicity.

Drugs may produce acute renal failure by prerenal, intrarenal and obstructive (postrenal) mechanisms. Prerenal processes usually develop from an imbalance of the normal counterbalancing vasoconstrictor and vasodilatory substances regulating RBF, resulting in a predominant vasoconstrictive state. Intrarenal processes develop from toxic renal tubule epithelial cell injury. The pathogenesis of renal cell injury is a complex interplay among derangements in subcellular membrane functions and mediators of injurious processes. Plasma and subcellular membrane injury and resulting membrane dysfunction appear most important. Cyclosporine has the ability to interact with renal tubular cell membranes in a relatively specific manner and at low concentrations. Despite this interaction, the acute declines in renal excretory function produced by cyclosporine is due predominantly to functional declines in RBF rather than structural derangements in renal tubular cell integrity. Cyclosporine-induced acute renal failure, thus, appears to be due predominantly to prerenal, rather than intrarenal, processes in the experimental animal. Cyclosporine does, however, possess a limited toxic potential to injure renal cortical cells, so that a chronic tubulointerstitial nephropathy may develop with long-term use of this immunosuppressive agent.

Cocaine-induced renal artery dissection and thrombosis leading to renal infarction.

We present the case history of a 40-year-old man who developed renal artery dissection and thrombosis, probably due to cocaine use. The patient underwent exploratory laparotomy and thrombectomy. He remained asymptomatic and cocaine-free, and warfarin was discontinued 9 months after discharge. Approximately 12 months after discharge he returned to the hospital with symptoms very similar to previous episodes. He was found to have recurrent clot formation in the right renal artery. Further workup revealed a double heterozygous methyltetrahydrofolate reductase A1298C/C677T thermolabile polymorphism with an elevated serum homocysteine.

Unilateral renal artery stenosis with renal atrophy in a patient with metastatic papillary thyroid carcinoma treated with sorafenib.

Tyrosine kinase inhibitors (TKIs) have been recently introduced for treatment of different malignancies. Various cardiovascular toxicities have been reported with TKIs with hypertension being the most common adverse cardiovascular event. We report a case of a 60-year-old woman who developed left renal artery stenosis associated with renal atrophy in the context of metastatic papillary thyroid carcinoma treated with sorafenib. Renal atrophy was noticed during serial imaging studies to monitor cancer therapy. Clinically, she was asymptomatic without significant change in blood pressure. The glomerular filtration rate dropped from 88 ml/min/1.73 m(2) at baseline to 56 ml/min/1.73 ml/min and partially recovered to 71 ml/min/1.73 m(2) after renal artery stenting. To our knowledge, this will be the first known case of renal artery stenosis associated with TKI use. Physicians may need to investigate the possibility of developing renal artery stenosis in patients with unexplained worsening in kidney functions while on TKIs.