Tenofovir-associated renal and bone toxicity.

OBJECTIVES: The aims of the study were to describe the clinical presentation and renal and bone abnormalities in a case series of HIV-infected patients receiving treatment with tenofovir (TDF), and to recommend appropriate screening for toxicity related to TDF. METHODS: Patients were identified from referrals to a specialist HIV renal clinic. Patients were included if treatment with TDF was assessed as the primary cause of the renal function impairment and clinical data were available prior to and following discontinuation of TDF treatment. Data were collected from case note review and clinic databases. RESULTS: Twenty-two patients (1.6% of all those who received TDF) were identified with TDF-associated renal toxicity. All had normal serum creatinine prior to TDF therapy. All presented with proteinuria. On stopping TDF, renal function improved. Eight patients had confirmed Fanconi syndrome. Twelve patients presented with bone pain and osteomalacia was confirmed on an isotope bone scan in seven of these patients. The findings (in those patients tested) of tubular proteinuria, reduced tubular transport maximum of phosphate (TmP), and glycosuria were all consistent with the proximal tubule being the site of toxicity. CONCLUSION: Renal toxicity remains a concern in patients treated with TDF. Clinical presentation may be with renal dysfunction, Fanconi syndrome or osteomalacia. Our investigations suggest proximal tubular toxicity as a common pathogenic mechanism.

Renal amyloidosis in intravenous drug users.

BACKGROUND: Intravenous drug abuse is associated with a wide variety of acute and chronic medical complications. The increased longevity of drug users has seen the emergence of new diseases as a result of chronic bacterial and viral infection. We recently observed an increase in the number of cases of renal amyloidosis among intravenous drug users in central London. AIM: To describe here the demographic and clinical characteristics of such patients. METHODS: Patients were identified retrospectively from computerized patient renal biopsy records at University College London and Royal Free Hospitals from 1990-2005. Clinical information was collected from patient hospital records. RESULTS: We identified 20 cases of AA amyloidosis; 65% occurred between January 2000 and September 2005. All were proteinuric (mean 7.3 g/l, range 0.5-14.8 g/l) and 13 required dialysis within 1 month of diagnosis. Of the remaining seven, four developed end-stage renal failure after mean follow-up of 16 months (range 6-30). Nine died, with median survival of 19 months (range 1-62); all deaths were due to sepsis. DISCUSSION: Secondary AA amyloidosis is a serious complication of chronic soft tissue infection in intravenous drug users in central London. Affected individuals invariably presented with nephrotic range proteinuria and advanced renal failure. Treatment options are limited and the outcome for such patients on renal replacement was poor. Cross-disciplinary strategies are needed to prevent this serious complication of long-term intravenous drug abuse.

Rac regulates vascular endothelial growth factor stimulated motility.

During angiogenesis endothelial cells migrate towards a chemotactic stimulus. Understanding the mechanism of endothelial cell migration is critical to the therapeutic manipulation of angiogenesis and ultimately cancer prevention. Vascular endothelial growth factor (VEGF) is a potent chemotactic stimulus of endothelial cells during angiogenesis. The endothelial cell signal transduction pathway of VEGF represents a potential target for cancer therapy, but the mechanisms of post-receptor signal transduction including the roles of rho family GTPases in regulating the cytoskeletal effects of VEGF in endothelial cells are not understood. Here we analyze the mechanisms of cell migration in the mouse brain endothelial cell line (bEND3). Stable transfectants containing a tetracycline repressible expression vector were used to induce expression of Rac mutants. Endothelial cell haptotaxis was stimulated by constitutively active V12Rac on collagen and vitronectin coated supports, and chemotaxis was further stimulated by VEGF. Osteopontin coated supports were the most stimulatory to bEND3 haptotaxis, but VEGF was not effective in further increasing migration on osteopontin coated supports. Haptotaxis on support coated with collagen, vitronectin, and to a lesser degree osteopontin was inhibited by N17 Rac. N17 Rac expression blocked stimulation of endothelial cell chemotaxis by VEGF. As part of the chemotactic stimulation, VEGF caused a loss of actin organization at areas of cell-cell contact and increased stress fiber expression in endothelial cells which were directed towards pores in the transwell membrane. N17 Rac prevented the stimulation of cell-cell contact disruption and the stress fiber stimulation by VEGF. These data demonstrate two pathways of regulating endothelial cell motility, one in which Rac is activated by matrix/integrin stimulation and is a crucial modulator of endothelial cell haptotaxis. The other pathway, in the presence of osteopontin, is Rac independent. VEGF stimulated chemotaxis, is critically dependent on Rac activation. Osteopontin was a potent matrix activator of motility, and perhaps one explanation for the absence of a VEGF plus osteopontin effect is that osteopontin stimulated motility was inhibitory to the Rac pathway.

HIV-associated renal disease in London hospitals.

We report experience from London hospitals which further illustrates the heterogeneous nature of HIV-associated nephropathy (HIVAN). Nineteen HIV-positive patients underwent renal biopsy from 1992 to 1994. Fourteen were male, five female. Eleven were Afro-Caribbean, 7 Caucasian and 1 Asian. Eleven patients had classical HIVAN with proteinuria, rapidly progressive renal failure and features of focal and segmental glomerulosclerosis (FSGS) on renal biopsy, and three of these had associated tubulo-interstitial nephritis (TIN). One further patient had TIN and tubular changes suggestive of HIVAN but no glomeruli were present in the biopsy. Other biopsy findings were of focal proliferative glomerulonephritis and TIN (1 patient), pauci-immune crescentic glomerulonephritis and TIN (1 patient), membranous nephropathy (1 patient), membranoproliferative nephropathy (1 patient) and haemolytic uraemic syndrome (2 patients). Of 11 patients with FSGS, seven died with median survival of 8 months (range 23 days-46 months) and five are still alive after median follow-up of 18 months (range 10-22 months). Of patients with glomerular disease other than FSGS, five died, with median survival of 3 months (range 1-27 months) and two have survived (10 and 27 months, respectively). Thirteen patients had renal failure, 10 of whom had FSGS. In 10 cases renal failure was acute and in two was the presenting feature of HIV infection. Thirteen patients underwent renal replacement therapy. Four received haemodialysis, and all died within one month. Nine patients received CAPD. Two were able to discontinue dialysis. Of the remaining seven, five died with median survival of 8 months (range 1.3-40 months) and two are alive 1 and 10 months after beginning dialysis.(ABSTRACT TRUNCATED AT 250 WORDS)

Presentation, clinical features and outcome in different patterns of atherosclerotic renovascular disease.

Atherosclerotic renovascular disease (ARD) is an increasingly important cause of renal failure. However, important features of the clinical presentation are not fully described, and the outcome after intervention by angioplasty remains controversial. Ninety-four patients with ARD diagnosed at angiography were reviewed. Twenty-four patients were diabetic. Thirty-nine patients had unilateral renal artery stenosis or occlusion (group A), 28 had bilateral stenosis (group B), and 27 had unilateral occlusion plus contralateral occlusion or stenosis (group C). Two years after presentation, actuarial patient survival was 96%, 74.3% and 47.1% in groups A, B and C, respectively (p < 0.001 for all differences); actuarial renal survival in surviving patients was 97.3%, 82.4% and 44.7%, respectively (p < 0.001 for all differences). Percutaneous transluminal balloon angioplasty (PCTA) was performed in 74 patients. Renal function improved in only a minority of cases, but was stable in 73% of nondiabetic patients 12 months after PCTA. Angioplasty was less effective in diabetic subjects, with only 53.3% having stable renal function at 12 months follow-up. Renal and patient survival were strongly related to the initial angiographic findings. In non-diabetic subjects, PCTA resulted in stabilization of renal function for at least one year in nearly three-quarters of cases, which suggests a benefit from intervention in this disease whose natural history is otherwise of progression.

Alkalinization and hemodialysis in severe salicylate poisoning: comparison of elimination techniques in the same patient.

We report the case of a man who took two overdoses of aspirin, on each occasion suffering a grand mal fit with blood levels of salicylate of over 5 mmol/l. The first event was treated with hemodialysis but without effective alkalinization, and the second with alkalinization but without hemodialysis. The rate of decline in salicylate concentration was faster with alkalinization in the first 4 hours. Similar salicylate levels were achieved with both techniques by 24 hours post-overdose. If a case of salicylate poisoning is to be treated with hemodialysis, treatment with alkalinization should still be given without delay, in order to prevent acidemia and to promote elimination of as much salicylate as possible via the kidneys.

Fulminant pregnancy-related Churg-Strauss syndrome.

Pregnancy has not hitherto been known to influence the course of Churg-Strauss syndrome. We describe a case where relapse occurred in four successive pregnancies. The disease proved fatal in the last pregnancy when aggressive treatment failed to reverse fulminant cardiac disease.

Rac is essential in the transformation of endothelial cells by polyoma middle T.

Expression of the Polyoma Middle T (PyMT) antigen in endothelial cells results in single-step transformation to hemangioma producing malignant cells. To study the mechanism of PyMT transformation, we used the PyMT induced mouse brain endothelial cell line, bEND.3, expressing constitutively active and dominant negative mutants of the small GTPase Rac. The bEND.3 cell phenotype of tumorigenesis, loss of normal growth control and formation of cysts rather than capillary tubes in fibrin gels was reversed by expression of dominant negative Rac. The mechanism of N17 Rac action in blocking the endothelial cell transformant, PyMT, did not involve effects of Rac on the actin cytoskeleton since this component of the bEND.3 cell phenotype was not affected. Furthermore, the PyMT induced activation of the plasminogen activator (PA)/plasmin system was not affected by Rac inhibition. Inhibition of the downstream effectors of Rac, phosphatidylinositol 3-kinase (PI3-K) and p70S6k, which are known to be constitutively activated by PyMT transformation, inhibited bEND.3 cell proliferation and cyst formation in fibrin gels even in cells expressing V12 constitutively active Rac, but they did not restore capillary tube formation. These results demonstrate that middle T antigen induced endothelial cell transformation requires signal transduction by Rac. The downstream Rac effectors, P13-K and p70S6k, mediate PyMT/Rac effects on cell proliferation and cyst formation, but other unknown effectors of PyMT are required for the cytoskeletal changes and activation of the PA/plasmin system.

Lipid profiles in patients with atherosclerotic renal artery stenosis.

BACKGROUND: Atherosclerotic renal artery stenosis (ARAS) is an important cause of renal disease in the elderly, and these patients have a high morbidity and mortality. There are no data on their blood lipid profiles. METHODS: The lipoprotein profiles were examined in patients with proven ARAS and compared with patients matched for age, gender, renal function and presence of diabetes. RESULTS: The profiles did not show any significant difference for apolipoprotein B (control 1.31 +/- 0.39 vs. ARAS 1.24 +/- 0.28; mean +/- SD), cholesterol (control 5.65 +/- 1.28 vs. ARAS 6.12 +/- 1.29), LDL cholesterol (control 3.72 +/- 1.03 vs. ARAS 4.06 +/- 1.18), fibrinogen (control 2.48 +/- 1.39 vs. ARAS 3.29 +/- 1.49), HDL cholesterol (control 1.16 +/- 0.38 vs. ARAS 1.00 +/- 0.26) and triglyceride (control 1.68 +/- 0.80 vs. ARAS 2.32 +/- 1.73) levels between the groups. Surprisingly lipoprotein(a) levels were higher in the control group (0.58 +/- 0.45) vs. ARAS (0.31 +/- 0.21). The most striking abnormality was the markedly lower apolipoprotein A1 levels in the ARAS group (control 2.09 +/- 0.55 vs. ARAS 0.95 +/- 0. 30) and apolipoprotein A1/B ratio (control 1.74 +/- 0.71 vs. ARAS 0. 78 +/- 0.24). CONCLUSION: The lipoprotein abnormality in ARAS mirrors that in other severe vascular diseases. Potential therapeutic interventions in patients with ARAS should consider treatments to modify the apolipoprotein A1 concentration rather than cholesterol alone.