Interaction of endothelin with renal nerves modulates kidney function in spontaneously hypertensive rats

BACKGROUND AND METHODS: We investigated kidney function, renal endothelin-1 concentration, prepro-endothelin-1 mRNA as well as endothelin receptor A and B mRNA expression and receptor properties in normotensive Wistar-Kyoto (WKY) rats and spontaneously hypertensive rats (SHR) with intact renal nerves and 7 days after renal denervation. In addition, responses of renal function to the non-selective ETA/ETB receptor blocker bosentan (10 mg/kg i.v. bolus injection) were studied. RESULTS: In SHR, renal papillary prepro-endothelin-1 mRNA expression, endothelin-1 tissue concentrations and endothelin receptor density were significantly lower than in normotensive rats. Renal denervation was associated with a decrease in papillary tissue prepro-endothelin-1 mRNA and in WKY rats also with a significant reduction in papillary endothelin-1 content without affecting ET receptor density. Bosentan did not alter renal blood flow or glomerular filtration rate but decreased urine flow rate in both intact normotensive and hypertensive rats, whereas it decreased urine sodium and potassium excretion only in intact WKY. Bosentan had no effects on renal function in renal denervated rats. CONCLUSION: Since renal papillary endothelin-1 appears to counteract the fluid and sodium retaining effects of renal nerve activity, an impaired renal endothelin-1 synthesis in SHR may contribute to excessive sodium retention and thus to the pathogenesis of hypertension in SHR.     

Acute Kidney Injury in Immunoglobulin A Nephropathy: Potential Role of Macroscopic Hematuria and Acute Tubulointerstitial Injury

The aim of our retrospective study was to analyze the clinical course and outcome of patients with immunoglobulin A (IgA) nephropathy who presented with macroscopic hematuria and acute kidney injury (AKI). During the period from 1990 to 2005, seven out of 584 adult patients with IgA nephropathy (1.2%) fulfilled the criteria for macroscopic hematuria‐induced AKI. There was an equal gender distribution among our patients, and a rather high average age at presentation (55.7 ± 10.9 years). Four patients who were oliguric upon admission to hospital needed hemodialysis treatment. The average serum creatinine at the time of kidney biopsy was 429.8 ± 377 µmol/L (median value 378). The percutaneous kidney needle biopsies showed focal proliferative crescentic glomerulonephritis of subclass III, according to the Haas scheme, associated with prominent red blood cell tubular casts and acute tubulointerstitial nephritis. Four patients with the most prominent crescents and tubulointerstitial involvement were treated with methylprednisolone. All patients, treated and untreated, recovered their kidney function (the serum creatinine at a median follow‐up of 15 months was 111.7 ± 38 µmol/L). In conclusion, AKI in IgA nephropathy accompanied by macroscopic hematuria appears to have been a reversible condition in our series of patients. Regarding pathogenesis, the kidney biopsy study points to the important role of glomerular bleeding with consequent, widespread obstructive red blood cell tubular casts accompanied by tubular injury and interstitial nephritis.     

No association between immunization and Guillain-Barré syndrome in the United Kingdom, 1992 to 2000

BACKGROUND: Our goal was to determine whether immunization is associated with the incidence of Guillain-Barré syndrome (GBS). METHODS: We analyzed data for all patients registered with 253 general practices in the United Kingdom General Practice Research Database from 1992 to 2000, with a mean of 1.8 million registered patients. We identified new occurrences of GBS and estimated age- and sex-specific and age-standardized incidence rates. We then determined whether the date of diagnosis was made within 42 days of any immunization and estimated the relative risk of diagnosis following immunization after adjusting for age and sex. RESULTS: There were 228 incident cases of GBS, including 107 women and 121 men. The age-standardized incidence rate per 100 000 person-years was 1.22 (95% confidence interval [CI], 0.98-1.46) in women and 1.45 (95% CI, 1.19-1.72) in men. Age-specific incidence rates per 100 000 person-years were highest in men aged 65 to 74 years (3.86; 95% CI, 2.50-5.70) and women aged 75 to 84 years (2.54; 95% CI, 1.39-4.27). There were 7 cases (3.1%) in which the onset occurred within 42 days of any immunization; 3 of the 7 cases occurred after influenza immunization. There were 221 cases (97.0%) that were not associated with immunization. The adjusted relative risk during the 42 days after immunization was 1.03 (95% CI, 0.48-2.18; P = .94). CONCLUSIONS: There is either minimal or no risk of GBS associated with routine immunization practice in the United Kingdom. Obtaining a precise estimate of any potential risk associated with an individual vaccine would require a study with more GBS cases.     

Block copolymer micelles as delivery vehicles of hydrophobic drugs: Micelle–cell interactions

One-third of drugs in development are water insoluble and one-half fail in trials because of poor pharmacokinetics. Block copolymer micelles are nanosized particles that can solubilize hydrophobic drugs and alter their kinetics in vitro and in vivo. However, block copolymer micelles are not solely passive drug containers that simply solubilize hydrophobic drugs; cells internalize micelles. To facilitate the development of advanced, controlled, micellar drug delivery vehicles, we have to understand the fate of micelles and micelle-incorporated drugs in cells and in vivo. With micelle-based drug formulations recently reaching clinical trials, the impetus for answers is ever so strong and detailed studies of interactions of micelles and cells are starting to emerge. Most notably, the question arises: Is the internalization of block copolymer micelles carrying small molecular weight drugs an undesired side effect or a useful means of improving the effectiveness of the incorporated drugs?     

Impaired response of the denervated kidney to endothelin receptor blockade in normotensive and spontaneously hypertensive rats

BACKGROUND: As yet, there are only limited data available on the exact role of endothelin (ET) acting through endothelin-A (ETA) receptors in renal sodium and water regulation and the potential functional implications of an interaction of the renal ET system with renal nerves in normotensive and spontaneously hypertensive rats. METHODS: Experiments were carried out in 64 male conscious spontaneously hypertensive rats and in 56 normotensive Wistar-Kyoto (WKY) rats. Bilateral renal denervation (BRD) was performed in 32 spontaneously hypertensive rats and 28 WKY rats 7 days before the experiments. The ETA receptor antagonist, BQ-123 (16.4 nmol/kg x min intravenously) or the endothelin-B (ETB) receptor antagonist, BQ-788 (25 nmol/kg x min intravenously) were infused at a rate of 25 microL/min for 50 minutes. RESULTS: Renal papillary ET-1 concentration in intact spontaneously hypertensive rats was 67.8% lower than in intact WKY rats (154 +/- 40 fmol/mg protein vs. 478 +/- 62 fmol/mg protein, P < 0.01). BRD decreased papillary ET-1 by 73.5% in WKY rats to 127 +/- 19 fmol/mg protein (P < 0.001), but had no effect in spontaneously hypertensive rats (122 +/- 37 fmol/mg protein). BRD, BQ-123, or BQ-788 did not affect glomerular filtration rate (GFR) or renal blood flow (RBF) in any of the groups. In intact WKY, BQ-123 decreased urine flow rate (V) from 4.65 +/- 0.44 microL/min.100 g body weight to 2.44 +/- 0.35 microL/min.100 g body weight (P < 0.01), urinary excretion of sodium (UNaV) from 238.2 +/- 27.4 to 100.2 +/- 17.0 (P < 0.01) and potassium (UKV) from 532.1 +/- 62.6 nmol/min.100 g body weight to 243.0 +/- 34.2 nmol/min.100 g body weight (P < 0.001), whereas BQ-788 decreased only V and UNaV. In renal denervated WKY, BQ-123 or BQ-788 did not alter V, UNaV, or UKV. In intact spontaneously hypertensive rats BQ-123 but not BQ-788 decreased V from 3.94 +/- 0.48 microL/min.100 g body weight to 2.55 +/- 0.44 microL/min.100 g body weight (P < 0.05). In renal denervated spontaneously hypertensive rats neither BQ-123 nor BQ-788 affected V, UNaV, or UKV. CONCLUSION: An interaction between ET and renal nerves is involved in the control of renal function. Moreover, renal nerves participate in the regulation of ET-1 production within the kidney. Finally, decreased synthesis of ET-1 in the renal papilla of spontaneously hypertensive rats may contribute to development and/or maintenance of hypertension due to modulation of renal excretory function.     

Therapeutic Approach in Patients with a Floating Thrombus in the Right Heart

Background

The occurrence of a floating thrombus in the right heart, although rare, is a life-threatening condition requiring a specific approach. In most cases, these thrombi are a result of embolization from deep venous thrombosis, and have lodged temporarily in the right heart. The management of this condition is variable, depending on whether or not there is a thrombus entrapped within a foramen ovale (FO).

Objectives

To present the management of 2 patients with a free-floating thrombus in the right heart, and a third patient with an entrapped thrombus in the FO.

Case Reports

Two patients with a free-floating thrombus in the right atrium who were treated with thrombolytic therapy had an immediate excellent outcome. The patient with a thrombus entrapped within the FO was scheduled for surgical removal of the thrombus due to an unacceptable risk of systemic embolization if treated with thrombolytic and anticoagulant therapy. Unfortunately, he developed an ischemic stroke on the fifth day of presentation, just a few hours before the scheduled surgery, despite meticulous monitoring of continuous heparin infusion with activated partial thromboplastin time.

Conclusion

Thrombolytic therapy is recommended in patients with a free-floating thrombus in the right heart. However, in patients with a thrombus entrapped within an FO, delaying surgical removal of the thrombus may be deleterious due to unpredictable systemic embolization.