Role of the monoclonal kappa chain V domain and reversibility of renal damage in a transgenic model of acquired Fanconi syndrome

Acquired Fanconi syndrome (FS) is a complication of monoclonal gammopathies featuring a generalized dysfunction of the proximal tubule of the kidney, due to the storage within proximal tubular cells of a monoclonal immunoglobulin light chain. We engineered transgenic mice in which the endogenous mouse Jkappa cluster was replaced by a human VkappaJkappa rearranged gene cloned from a patient with smoldering myeloma-associated FS. The V region belonged to the VkappaI subgroup and was related to the O2-O12 germ-line gene, a V segment previously found associated with FS and light-chain crystallization in several patients with myeloma. Association of the human VkappaI domain with a mouse kappa constant domain in transgenic animals yielded a nephrotoxicity pattern similar to that observed in patients, strongly suggesting that the whole pathogenic effect of FS light chains can be ascribed to a peculiar structure of the V domain. Morphologic alterations of the kidney tubular cells, which contained rhomboid-shape crystals, were observed in mice, together with alterations of the proximal tubule reabsorption function. Moreover, the number of renal crystalline inclusions was dramatically reduced after conditional deletion of the human VkappaI transgene, showing that proximal tubular lesions are reversible upon suppression of the nephrotoxic light chain secretion.     

The effect of renal impairment on the pharmacokinetics of oxcarbazepine and its metabolites

We have studied the effect of renal impairment on the pharmacokinetics of oxcarbazepine, its active monohydroxy-metabolite (which predominates in plasma), their glucuronides, and the inactive dihydroxy-metabolite after a single oral dose of oxcarbazepine (300 mg). Six subjects with normal renal function and 20 patients with various degrees of renal impairment participated.The mean areas under the plasma concentration-time curves of oxcarbazepine and its monohydroxy-metabolite were 2–2.5-times higher in patients with severe renal impairment (CL_CR<10 ml·min^–1) than in healthy subjects. The apparent elimination half-life of the monohydroxy-metabolite [19 (SD 3) h] in these patients was about twice that in healthy subjects.The effect of renal impairment on the plasma concentrations of glucuronides was more marked. The renal clearances of the unconjugated monohydroxy-metabolite and its glucuronides (the main compounds recovered in urine) correlated well with creatinine clearance.The maximum target dose in patients with slight renal impairment (CL_CR>30 ml·min^–1) should not be changed. In patients with moderate renal impairment (CL_CR10–30 ml·min^–1) it should be reduced by 50%. In patients with severe renal impairment (CL_CR<10 ml·min^–1), the glucuronides of oxcarbazepine and its monohydroxy-metabolite are likely to accumulate during repeated administration, and dosage adjustment of oxcarbazepine in these patients could not be proposed from this single administration study.     

Protection of Renal Function with ACE Inhibitors: Experience with Benazepril

Research into progressive renal scarring has been closely linked over the last two decades with angiotensin II (AII). This has led to a better understanding of the mechanisms underlying the development of glomerulosclerosis and tubulointerstitial scarring. AII appears to play an important role in the pathogenesis of both; this may be because of either a direct proliferative and fibrogenic effect of AII or an indirect effect mediated by growth factors such as platelet-derived growth factor (PDGF) and transforming growth factor (TGF(beta1)). These findings have led to significant therapeutic advances as ACE inhibition prevents the progression of experimental renal scarring and attenuates the progression of chronic renal failure in humans. Benazepril, through its metabolite benazeprilat, is a non-sulfhydryl orally active ACE inhibitor. The kinetics of benazeprilat are substantially affected by severe renal impairment; for patients with a creatinine clearance of <30 ml/min the initial recommended daily dose is 5mg. The angiotensin converting enzyme inhibition in a progressive renal insufficiency (AIPRI) study confirmed that benazepril provides protection against the progression of renal insufficiency in patients with various renal diseases and that this treatment is well tolerated.     

Regression of existing glomerulosclerosis by inhibition of aldosterone

In this study, the effects of inhibition of aldosterone on regression of existing hypertension-related glomerulosclerosis were investigated. Adult male Sprague Dawley rats (220 to 250 g) underwent 5/6 nephrectomy (Nx). Severity of glomerulosclerosis was assessed by renal biopsy 8 wk later, and rats were divided into four groups with equal biopsy sclerosis and then randomized by group to 4-wk treatments as follows: Control with no further treatment (CONT; n = 6); spironolactone (SP) alone (200 mg/kg per d, by gavage, n = 6); or SP combined with nonspecific triple antihypertensive drugs (TRX; reserpine, hydralazine, and hydrochlorothiazide in drinking water; SP+TRX, n = 7) or with angiotensin type 1 receptor antagonist (AT1RA; losartan in drinking water; SP+AT1RA, n = 8). When the rats were killed 12 wk after Nx, autopsy glomerulosclerosis index (SI; 0 to 4+ scale) was compared with biopsy SI in the same rats. Systolic BP was increased at 8 wk after Nx and continued to increase at 12 wk after Nx in the CONT and SP groups but not in SP+TRX- or SP+AT1RA-treated rats. Serum creatinine at 12 wk was significantly decreased in all SP-treated groups versus CONT. CONT rats had on average a 157% increase in SI from biopsy to killing at 12 wk, compared with only 84% increase in SP rats, with regression of SI in some rats. The effects on glomerulosclerosis by SP were further enhanced (when systolic BP was controlled by TRX or by AT1RA). It is concluded that inhibition of aldosterone by SP not only slows development of glomerulosclerosis but also induces regression in some rats of existing glomerulosclerosis.     

Potential nephrotoxicity of intravenous infusions of naftidrofuryl oxalate

We report two cases of acute renal failure in patients witharteriosclerosis obliterans treated by intravenous infusionof naftidrofuryl oxalate. At renal biopsy the histological lesionswere identical with those found in ARF due to hyperoxaluriaof other causes, revealing tubular epithelial necrosis and massiveintra-tubular precipitation of calcium oxalate monohydrate (Cl)crystals. A second study was then conducted in four other patientswith arteriosclerosis obliterans to evaluate serum and urinarylevels of oxalate, and crystalluria during the intravenous administrationof 800 mg of naftidrofuryl oxalate per day for 10 days. Duringthe course of treatment, the serum and urinary oxalate levelswere found to increase substantially, with the gradual onsetof massive Cl crystalluria. These results indicate that naftidrofuryloxalate was responsible for the acute renal failure in the firsttwo patients. High intravenous doses of naftidrofuryl oxalatemust be used cautiously, with close surveillance of renal function.     

Diagnosis of left ventricular diastolic dysfunction in the setting of acute changes in loading conditions

Introduction  

Conventional pulsed wave Doppler parameters are known to be preload dependent, whereas newly proposed Doppler indices may be less influenced by variations in loading conditions. The aim of the present study was to evaluate the effects of haemodialysis-induced preload reduction on both conventional and new Doppler parameters for the assessment of left ventricular (LV) diastolic function.     

Dose dependency of captopril effects in severely hypertensive patients

In a double-blind randomized study, the dose response to captopril was studied in 12 severely hypertensive patients whose blood pressure had been previously controlled by this converting enzyme inhibitor, either in association with a diuretic (seven patients), or with a diuretic and a beta-blocker (five patients). All patients received in random sequence 32.5, 75, and 150 mg/day of captopril in three divided doses. Significant correlations were revealed between the dose administered and the levels of arterial blood pressure, plasma renin, plasma aldosterone and plasma potassium. Under the conditions of this study, dose-response curves were obtained for concentrations of captopril between 0.5 and 4 mg/day/kg body weight.     

Effect of beta-adrenergic receptors blockade on auricular natriuretic factor, aldosterone and renine blood activity during physical exercise

Physical exercise stimulates the renin-angiotensin-aldosterone system. However several factors affect the control of mineralocorticoid secretion. In this study, eight healthy volunteers performed maximal exercise on cycle ergometer after being pretreated for 3 days with placebo (P) or with a non selective beta-blocker (B) (pindolol 15 mg/day). Plasma reinin activity (PRA), aldosterone (ALD), atrial natriuretic factor (ANF), and kalemia (K+) were measured at rest (R) and during exercise until exhaustion (E). (table; see text) These results confirm the role of beta-adrenoceptor activation in the increased PRA during exercise. It appears an exercise-induced increase in plasma ANF which was more elevated in subjects treated with pindolol, but which had no inhibitory effect on ALD secretion in theses conditions. K+ rose during exercise and this hyperkalemia tended to be higher with a beta-blocker. It is suggested that K+ elevation counterbalance both PRA decrease and ANF increase to be responsible for the absence of change in plasma ALD during beta-blockade.     

Renal transplantation in the elderly: a survey

For ten years, an increase in the number of elderly patients on renal transplant waiting lists has occured. In an attempt to close the widening gap between supply and demand and because the demand for kidneys for younger patients already surpasses the supply, transplant physicians nowadays accept organs from older donors that might have been deemed inappropriate in the past. Programs of age matching between donors and recipients and of dual-kidneys transplantation have emerged. The initial results of these programs are encouraging with excellent patient and graft survival at one and three years.