Mechanisms of amphotericin B-induced reduction of the glomerular filtration rate: a micropuncture study

Amphotericin B infusions cause acute reductions in renal plasma flow and glomerular filtration rate. The exact mechanism by which these changes occur has not been identified fully, nor have the effects of the drug on the renal microcirculation been studied adequately. In this study, we examined the effect of intrarenal amphotericin B infusions (0.05 mg/kg/min) on glomerular hemodynamics in the anesthetized rat. Amphotericin B did not affect systemic blood pressure and slightly increased hematocrit (5%), but significantly decreased renal blood flow and glomerular filtration rate by 40 and 35%, respectively. Glomerular micropuncture revealed decreases in single nephron plasma flow and glomerular filtration rate (from 142 +/- 12 to 89 +/- 14 and from 35.3 +/- 2.2 to 22.8 +/- 2.8 nl/min, respectively). These changes were due to significant increases in pre- and postglomerular resistances (from 1.91 +/- 0.17 to 3.95 +/- 0.38 and from 1.30 +/- 0.10 to 2.08 +/- 0.12 10(10) dyn.sec.cm-5, respectively), and to a significant decrease in the glomerular capillary ultrafiltration coefficient which fell from 0.043 +/- 0.008 to 0.032 +/- 0.009 nl/(sec.mm Hg). These results provide further insight into the mechanisms of the acute renal effects of amphotericin B, and suggest possible mediators that may be involved in these effects.     

Renal function--estimation of glomerular filtration rate.

Assessment and follow-up of renal dysfunction is important in the early detection and management of chronic kidney disease. The glomerular filtration rate (GFR) is the most accurate measurement of kidney disease and is reduced before the onset of clinical symptoms. Drawbacks to the measurement of GFR include the high cost and incompatibility with routine laboratory monitoring. Serum creatinine determination is a mainstay in the routine laboratory profile of renal function. The measurement of serum cystatin C has been proposed as a more sensitive marker for GFR. According to National Kidney Foundation-K/DOQ1 clinical guidelines for chronic kidney disease, serum markers should not be used alone to assess GFR. Based on prediction equations, clinical laboratories should report an estimate of GFR, in addition to reporting the serum value. In this article, information is presented on how best to estimate GFR using prediction equations for adults and for children. Using serum creatinine concentration with the Modification of Diet in Renal Disease (MDRD) study equation offers a suitable estimation of GFR in adults. The cystatin C prediction equation with the use of a prepubertal factor seems superior to creatinine-based prediction equations in children of <14 years.     

Direct vasoconstriction as a possible cause for amphotericin B-induced nephrotoxicity in rats.

In anesthetized rats we tested the hypothesis that amphotericin B (AmB) reduces glomerular filtration rate (GFR) by activating the tubuloglomerular feedback (TGF) mechanism. Infusion of 1 mg/kg AmB over 50 min was followed by a reduction in kidney GFR (from 0.47 +/- 0.03 to 0.39 +/- 0.02 ml/min per 100 g body wt during the second hour after infusion; P less than 0.05) and by an increase in urine flow and urinary chloride excretion. Single-nephron GFR (SNGFR) measured in proximal (TGF interrupted) or distal tubules (TGF intact) decreased to a similar degree from 33.4 +/- 1.8 and 30.6 +/- 1.2 nl/min in the control period to 19.7 +/- 1.9 and 21.2 +/- 1.6 nl/min during the second hour after AmB infusion (P less than 0.05). Distal chloride concentrations and TGF responses to changes in loop of Henle flow rate were not significantly altered by AmB. AmB at 10(-5) M reduced the diameter of isolated perfused afferent arterioles from rabbit kidneys. In isometrically contracting rings of rabbit aorta and renal artery in vitro AmB produced endothelium-independent constriction, with half-maximal contraction (EC50) being achieved by 1.8 x 10(-6) and 2.6 x 10(-6) M in intact vessels and 1.3 x 10(-6) and 1.7 x 10(-6) M in endothelium-denuded vessels respectively. Tension development did not occur in Ca-free media or in the presence of Ca channel blockers. Pretreatment with ouabain or Bay K 8644 potentiated the effect of AmB. The vasoconstrictive effect of AmB was counteracted by aminophylline and atrial natriuretic peptide. We conclude that the AmB-induced reduction in GFR is not caused by TGF activation and that AmB has a direct vasoconstrictor effect that is probably initiated by depolarization-induced opening of Ca channels. This effect may be an important component of the nephrotoxic actions of AmB.     

The estimated glomerular filtration rate in outpatients

The glomerular filtration rate (GFR) calculated by the MDRD formula was estimated in a population of outpatients aged over 18 years. Serum creatinine concentrations were measured, by using 5 analytical systems: Abbott Architect (n = 9054), Roche Modular (n = 22947), Roche Integra 400 (n = 2748), Roche Integra 700 (n = 8350), and Roche Hitachi (n = 20196). For 4 systems, the distribution of GFR differed little. The exception was the Roche Hitachi analytical system where TE and bias were higher than the acceptable requirements. Therefore, with this system, the proportion of outpatients with a GFR of < 60 ml/min per 1.73 m2 was twice higher than that with the use other analytical systems. Such publications should contain data on the analytical quality of measurement of serum creatinine concentrations in the range of 88 to 140 micromol/l. The estimated GFR may be clinically used provided that the performance of this test will be better than the acceptable analytical quality requirements established by the working NKDEP group.     

Developments in the assessment of glomerular filtration rate

The assessment of the glomerular filtration rate (GFR) is the most commonly used test of renal function. The accepted reference procedure employs an exogenous clearance marker whilst the most popular test is that of serum or plasma creatinine. All of these tests have limitations, although the surrogate endogenous markers are the most practical. Cystatin C, a low molecular weight protein which can be measured by light scattering immunoassay, possesses many of the attributes required of the ideal GFR marker. Data on reference ranges indicate that circulating cystatin C levels reflect the variation in GFR throughout life and the marker demonstrates a better correlation with the reference procedure than serum creatinine.     

肾小球滤过率评估方程在不同人群中的适用性

目前基于普通人群所开发的通用估算肾小球滤过率（ eGFR）评估公式在临床广泛使用,但某些特定人群由于其自身特点的影响,其eGFR评估公式亦会与普通人群有所不同。文章就eGFR评估公式的发展过程及在不同人群中的适用性作一综述,主要包括中国人群、儿童、糖尿病患者、心力衰竭患者、老年人。在临床研究及应用中应需注意肌酐与半胱氨酸蛋白酶抑制剂 C检测方法的标准化以及eGFR评估公式的差异化和本土化使用。     

Heparin-binding EGF-like growth factor contributes to reduced glomerular filtration rate during glomerulonephritis in rats

Heparin-binding epidermal growth factor-like growth factor (HB-EGF), a member of the epidermal growth factor (EGF) family, is expressed during inflammatory and pathological conditions. We have cloned the rat HB-EGF and followed the expression of HB-EGF in rat kidneys treated with anti- glomerular basement membrane (anti-GBM) antibody (Ab) to induce glomerulonephritis (GN). We observed glomerular HB-EGF mRNA and protein within 30 minutes of Ab administration and showed by in situ hybridization that glomerular HB-EGF mRNA expression was predominantly in mesangial and epithelial cells. Expression of HB-EGF correlated with the onset of decreased renal function in this model. To test the direct effect of HB-EGF on renal function, we infused the renal cortex with active rHB-EGF, prepared from transfected Drosophila melanogaster cells. This treatment induced a significant decrease in single nephron GFR (SNGFR), single nephron plasma flow, and glomerular ultrafiltration coefficient and an increase in the glomerular capillary hydrostatic pressure gradient. In addition, anti-HB-EGF Ab administered just before anti-GBM Ab blocked the fall in SNGFR and GFR at 90 minutes without any change in the glomerular histologic response. These studies suggest that HB-EGF expressed early in the anti-GBM Ab GN model contributes to the observed acute glomerular hemodynamic alterations.     

The effect of amiloride on amphotericin B-induced hypokalaemia.

Amiloride was administered to 19 oncology patients exhibiting marked amphotericin B-induced electrolyte wasting. Mean serum potassium concentrations increased in the 5 days preceding and following administration (3.4 +/- 0.5 versus 3.9 +/- 0.8 mmol/L, P = 0.002). A trend towards decreased potassium supplementation was also observed (48.0 +/- 66.5 versus 29.4 +/- 43.2 mmol/day, P = 0.12). Amiloride is a therapeutic option to decrease potassium wasting in patients being treated with amphotericin B.     

Dietary protein suppresses feedback control of glomerular filtration in rats.

We have examined the possibility that changes in glomerular filtration rate (GFR) after changes in dietary protein intake may depend on altered function of the tubuloglomerular (TG) feedback system. We studied male Sprague-Dawley rats after dietary pretreatment for 9.6 +/- 3.6 (SD) d with isocaloric diets containing either 6% or 40% casein. We found that GFR in rats fed the high protein diet was 24-29% higher than in rats fed the low protein diet. Simultaneous measurements of single nephron GFR (SNGFR) in the distal tubule were 6.3 nl/min or 21% higher in the rats fed the high protein diet whereas proximally measured SNGFR was not statistically different in the two groups. The higher distally measured SNGFR of rats receiving the high protein diet was associated with a 4.2 nl/min or 50% smaller suppression of SNGFR by TG feedback (-4.3 vs. -8.5 nl/min, P less than 0.001). Loop perfusion experiments demonstrated that in rats fed the high protein diet the TG feedback mechanism was less sensitive than in rats fed the low protein diet. The TG feedback response in rats fed the low protein diet, as assessed by reductions in stop-flow pressure and SNGFR, was half-maximal at flows of 14-15 nl/min. In contrast, the TG feedback response in rats fed the high protein diet was half-maximal at 22-24 nl/min. Maximal suppression of stop-flow pressure and SNGFR and the slope of the TG feedback response to increasing loop flow rates were not different in the two groups. We conclude that the sensing mechanism of the TG feedback system is rendered less responsive by a high protein intake, and that this change permits GFR to increase.     

Evolution of glomerular filtration rate in proteinuric NIDDM patients

OBJECTIVE: To evaluate, by means of a precise method, the rate of decline of glomerular filtration rate in proteinuric non-insulin-dependent diabetic (NIDDM) patients. RESEARCH DESIGN AND METHODS: The study was comprised of seven NIDDM patients who visited an outpatient clinic and had a 24-h urinary protein excretion rate greater than or equal to 500 mg in the absence of heart failure, urinary tract infection, or other nephropathies. RESULTS: Glomerular filtration rate (51Cr-labeled EDTA, single-injection protocol) and 24-h proteinuria (turbidimetric method) were assessed at periodic intervals (2-6 mo). Correlation of the measurements with time (Pearson's r, with Student's t test used to assess the significance, alpha = 0.05) was used to evaluate the trend of evolution of glomerular filtration rate. Renal biopsies were performed in four patients. In three of four patients, renal histopathology was consistent with the diagnosis of diabetic nephropathy (in the 4th patient measurements were not satisfactory). Neither glomerular filtration rate nor proteinuria correlated significantly with time, except in one patient who had multiple myeloma. CONCLUSIONS: The decline of glomerular filtration rate in proteinuric NIDDM patients is different from that observed in insulin-dependent diabetic patients, which is probably much slower.     

血肌酐检测和肾小球滤过率估计

准确估计肾脏功能有助于早期发现肾功能损害。血肌酐检测的标准化和一致性对估计肾小球滤过率（GFR）非常重要。应用国外的估计肾小球滤过率的公式时应注意是否适合中国人群。     

Evidence that insulin-like growth factor I increases renal plasma flow and glomerular filtration rate in fasted rats.

The mechanisms whereby growth hormone may increase renal plasma flow (RPF) and GFR are not known, but circumstantial evidence has implicated insulin-like growth factor I (IGF-I) as a mediator of this effect. This study examined whether an infusion of IGF-I will increase RPF and GFR, whether this effect occurs quickly, and if this effect is dependent on eicosanoids or peptide hormones known to affect renal function. Rats fasted for 3 d to reduce IGF-I and IGF-I plasma binding proteins were anesthetized; then the rats received an intravenous injection of 25 micrograms/kg IGF-I, and an infusion of 25 micrograms/kg IGF-I within 20 min. Controls received infusion of the vehicle. RPF (para-aminohippurate clearances), GFR (inulin clearances), renal vascular resistance (RVR), mean arterial blood pressure (MABP), plasma IGF-I, and glucose concentrations were measured repeatedly. At the end of the 20-min infusion, plasma IGF-I tended to be increased in the animals that received IGF-I (P = 0.069), but did not increase in the control rats. IGF-I induced a significant and sustained fall in RVR and rise in RPF and GFR without any change in MABP. A small, transient, but significant decrease in plasma glucose concentrations was observed during IGF-I but not during vehicle infusion. Indomethacin, but not somatostatin, blocked the renal response to IGF-I infusion. Thus, IGF-I infusion increases RPF and GFR and reduces RVR in fasted rats. This effect requires the presence of eicosanoids but does not seem to require other peptide hormones suppressed by somatostatin.     

Prediction of glomerular filtration rate from changes in serum creatinine

The glomerular filtration rate (GFR) was estimated from serum creatinine concentration in patients in whom the individual relation between GFR and serum creatinine had been previously determined. 51Cr-EDTA plasma clearance was used as reference method for GFR. The relation between 51Cr-EDTA clearance and estimated GFR was determined from 340 investigations in 197 adult patients with a variety of infectious and internal diseases. The imprecision of estimated GFR was 46% (1 CV) at 20 ml/min, 23% at 45 ml/min, 20% at 75 ml/min and 18% at 110 ml/min. This poor precision was probably due to the fact that many patients with acute infectious diseases, congestive heart failure, diabetes mellitus, etc., have an unstable renal function and therefore their creatinine distribution is not under steady state. This must always be considered when serum creatinine is used to estimate GFR.     

四种肾小球滤过功能测定方法的评估分析

目的 评估测定肾小球滤过功能的各种方法。方法 以^99mTc-DTPA清除率（CL^99mTc)为标准，用受试者工作特征曲线（ROC）分析及相关回归分析评定碘海醇清除率（CLIoh)、4小时内生肌酐清除率（4h Ccr)、生物电阻抗瘦体重法肌酐清除率（LBWCcr)、Cockcroft-Gault肌酐清除率（CkCcr)检测肾小球滤过功能的准确性。结果 35例患者结果显示CLIoh ROC曲线下面积平均为0.98；4hCcr ROC曲线下面积平均为0.91；LBWCcr ROC曲线下面积平均为0.94；CkCcr ROC曲线下面积平均为0.89。CLIoh、4hCcr、LBWCcr、LBWCcr、CkCcr与CL^99mTc相关系数分别为0.98、0.88、0.92、0.90，回归系数分别为1.03、0.71、0.95、0.91。结论 CLIoh准确性最好，LBWCcr准确性仅次于CLIoh并且简便、重复性好，4hCcr准确性居第三位，但结果偏高，CkCcr亦较准确、有一定的实用性并且最为简便。