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N Perico

Publications and source records attributed to N Perico.

At least 37 records · Page 2Linked to original sources

Application of newer clearance techniques for the determination of glomerular filtration rate.

Glomerular filtration rate (GFR) is the standard measure of renal function and is critical for the management of renal diseases. Rigorous assessment of GFR requires the measurement of renal clearance of a filtration marker, such as inulin. This method, however, is not suitable for routine clinical practice. Labelled compounds as alternative filtration markers provide accurate and precise GFR measurement, but their use may be limited for safety reasons. Thus investigators have proposed clearance procedures using minute doses of non-radioactive contrast agents, including iothalamate and iohexol. Their renal clearance provides similar accuracy as inulin clearance in GFR estimation, but the need of urine collection again poses certain limitations to the procedure. Thus, plasma clearance of suitable exogenous markers, such X-ray contrast media, has been suggested for measuring renal function, in which the elimination rate of the tracer after a single intravenous injection is evaluated. Plasma clearance of these markers estimated by multiple blood samples provides precise information, but repeated sampling makes this method cumbersome. Abbreviated kinetic profiles have been proposed to predict GFR from the plasma disappearance curve. The simplified method that uses a one-compartment model corrected by the Bröchner-Mortensen formula gives an excellent correlation with inulin clearance and is currently employed for measuring GFR in multi-centre clinical trials.

Contrast Media↗

Chronic allograft nephropathy in the rat is improved by angiotensin II receptor blockade but not by calcium channel antagonism.

Functional and structural changes of chronic renal allograft failure share similarities with other chronic nephropathies with low nephron number. In models of reduced nephron number, angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers prevented proteinuria and retarded renal lesions. This study investigates whether blockade of angiotensin II activity prevented chronic allograft injury in the Fisher 344 --> Lewis rat kidney transplant model, and compares its effect with that of calcium channel blockers, the main antihypertensive agents used in transplant patients to control BP. Transplanted rats received either no treatment (control), the type 1 angiotensin II receptor antagonist losartan, or the calcium channel blocker lacidipine. Rats received cyclosporine for the first 10 d posttransplant to prevent acute rejection. Doses of antihypertensive drugs were adjusted to achieve a comparable level of BP control throughout the study. Awake systolic BP was comparable in animals given losartan or lacidipine during the 6-mo observation period. Daily treatment with losartan but not lacidipine resulted in a significant decrease in the amount of proteinuria, preserved glomerular and tubulointerstitial structure, and improved graft survival compared with corresponding parameters in control untreated rats. GFR, measured as inulin and p-aminohippurate clearances, respectively, in rats surviving the 6-mo follow-up, was numerically but not significantly higher in losartan-treated animals than in all other groups. Thus, at comparable levels of BP control, losartan but not lacidipine effectively protects animals from chronic allograft injury and allows long-term survival.

Analysis of Variance↗

The antiproteinuric effect of angiotensin antagonism in human IgA nephropathy is potentiated by indomethacin.

Evidence is available from animal and human studies that protein traffic through the glomerular capillary has a pathogenetic role in subsequent renal damage and that angiotensin-converting enzyme (ACE) inhibitors appear superior to other drugs in lowering proteinuria and the rate of renal function decline. This study compares the effect of ACE inhibition or angiotensin II (AngII) receptor blockade on urinary protein excretion and renal hemodynamics in 20 patients with IgA glomerulonephritis randomized to receive enalapril (20 mg/d) or irbesartan (100 mg/d) for 28 d in a double-blind study with two parallel groups. This study also evaluated whether addition of indomethacin (75 mg twice a day) to each of the two treatments resulted in a more potent antiproteinuric effect. Enalapril alone reduced total protein excretion (61% change from baseline) and fractional clearance of albumin without changes in GFR and minor elevation in renal plasma flow. Also, patients randomized to receive the AngII receptor antagonist irbesartan for 28 d had lower proteinuria (55% change from baseline) and fractional clearance of albumin at the end of the treatment period with similar renal hemodynamic changes. When indomethacin was added to enalapril treatment, a further significant reduction in urinary proteins and fractional albumin clearance was observed. In patients given irbesartan, the addition of indomethacin further reduced proteinuria and fractional clearance of albumin. The combined therapy with enalapril or irbesartan and indomethacin did not significantly affect GFR and renal plasma flow compared with baseline. These findings indicate that in patients with IgA glomerulonephritis the antiproteinuric effect of blocking AngII activity by either ACE inhibitors or AngII receptor antagonists is potentiated by indomethacin, an effect that occurred without impairment of renal function.

Adult↗

Precision of plasma clearance of iohexol for estimation of GFR in patients with renal disease.

The choice of the optimal method for the measurement of renal function is based on the accuracy and the precision of the technique. The plasma clearance of nonradioactive iohexol has been proposed as a reliable alternative to renal clearance of inulin for estimation of GFR. However, the precision of this method in estimating GFR in patients with renal disease has not been determined so far. This issue was assessed by determining plasma clearance of iohexol on three different occasions during a 12-d period in 24 patients with renal disease and a wide range of renal function (creatinine clearance: 14 to 104 ml/min per 1.73 m2). Overall, the mean intraindividual coefficient of variation was 5.59%, and the reproducibility was 6.28%. The precision of the method also applied to the subgroup of patients with moderate-to-severe renal insufficiency, because a low coefficient of variation (5.71%) and a high reproducibility (6.57%) were found in patients with GFR < or =40 ml/min per 1.73 m2. It was also shown that the precision of GFR measurement by the plasma clearance of iohexol is not affected by the gender. These findings indicate that the method of plasma clearance of iohexol allows a good precision in the estimation of GFR in patients with normal renal function and different degrees of renal dysfunction.

Adult↗

How to convert from traditional cyclosporine to the microemulsion formulation in stable renal transplant patients?

How to convert from traditional cyclosporine (CsA) to the microemulsion formulation in stable renal transplant patients is still a matter of debate. The present study was designed to evaluate the effects of changeover from traditional Sandimmune to Neoral formulation at two dose-ratio conversions on CsA pharmacokinetics, safety and tolerability particularly in terms of renal function. Thirty outpatients regularly followed at our Clinical Research Center were randomized to 1:1 or 1:0.75 dose-ratio conversion and assigned to the two groups according to a comparable renal function and time post-transplant. Patients underwent CsA pharmacokinetic evaluation and renal function measurements (GFR and RPF) before, at day 15, and at month 6 after conversion to Neoral formulation. More consistent CsA concentration-time profiles with Neoral than traditional formulation were obtained at the two time points of evaluation after conversion. At 1:1 dose-ratio conversion an increased absorption rate, reflected by a shorter time to maximum blood CsA concentration (Tmax), and a greater bioavailability, as shown by an increase in the peak CsA concentration (Cmax) and the 12-h exposure to drug defined by the area under the time-concentration curve (AUC0-->12 h) was found 15 d and 6 months after conversion to Neoral formulation. A similar AUC as compared with traditional Sandimmune was observed in those patients randomized to receive a 25% lower dose of Neoral formulation. All of patients defined as 'low' absorbers became 'high' absorbers as early as 15 d after conversion to Neoral formulation at 1:1 or 0.75 dose-ratio regimen. Overall mean GFR was unchanged in both conversion regimens during the 6 months of follow-up. However, there was a tendency to lower GFR even in some patients randomized to 1:0.75 conversion but mostly in those with 1:1 conversion. A limited sampling strategy utilizing three blood samples (0, 1, 3 h post-dosing of Neoral formulation) provided an excellent correlation with actual drug exposure (r = 0.977). Enhanced CsA absorption with the microemulsion formulation results in increased drug exposure that may reduce GFR in some patients who undergo 1:1 dose-ratio conversion. The Neoral formulation that permits a more effective, consistent, and predictable absorption of CsA may represent a great advantage in order to prevent acute and possibly chronic rejections. Efforts have to be made to find optimal therapeutic range and dosing schedule for this new formulation, which may be facilitated by using the limited sampling approach to predict AUC after only three-point sampling.

Administration, Oral↗

Sequential monitoring of urine-soluble interleukin 2 receptor and interleukin 6 predicts acute rejection of human renal allografts before clinical or laboratory signs of renal dysfunction.

BACKGROUND: The significance of noninvasive techniques to the early diagnosis of acute rejection in kidney transplants remains elusive. In this study, we examined whether an early posttransplant increase in serum- and urine-soluble interleukin (IL) 2 receptor (sIL-2R) and IL-6 levels predicted acute rejection. METHODS: Sequential determinations of serum and urine sIL-2R and IL-6 were performed in the first 30 postoperative days in 40 renal transplant patients. Changes during the posttransplant period observed in 26 patients who had one or more episodes of acute rejection (group A) were compared with those recorded in 14 patients who did not experience acute rejection of their graft (group B). RESULTS: Serum sIL-2R was higher than normal in patients of groups A and B without statistical differences between the two groups. In the first 3 days after transplantation, urinary sIL-2R was higher than normal in group A but not in group B. Urinary sIL-2R at days 2 and 3 was significantly higher (P<0.05) in group A than in group B. In the first 5 days after transplantation, urinary IL-6 was persistently higher than normal in group A, whereas it progressively decreased to normal value on day 4 in group B. Sudden increases (doubling within 24 hr) in urine IL-6 preceded clinical diagnosis of acute rejection by a mean period of 2 days, with an 87% sensitivity and a 64% specificity, and also predicted recurrent rejection episodes. CONCLUSIONS: Sequential monitoring of urinary sIL-2R and IL-6 levels does allow very early diagnosis of rejection without invasive procedures. Specifically, high urinary sIL-2R in the first 5 posttransplant days identifies the subgroup of patients at risk. In the subsequent days, a sudden increase in urinary IL-6 occurs in those of the above patients who will indeed reject their graft.

Acute Disease↗

Acquired transplant tolerance.

Increasing the acceptance rate of organs is the central goal of transplantation research. Long-term survival of vascularized organs without chronic immunosuppressive therapy has been achieved in experimental animals. In humans, the possibility of achieving immunological tolerance and a drug-free state has been reported occasionally in patients who after withdrawal of immunosuppressants because of major toxicity still carry a functioning graft. It has been proposed that organ transplant implies a migratory flux of donor 'passenger' leukocytes out of the graft into the recipient tissue or organs, to establish a persistent condition of 'microchimerism'. Although there is evidence that the same migratory mechanisms apply to all organ grafts, migration of 'passenger' leukocytes is less in kidney and heart than in liver. To enhance the acceptance of organs less tolerogenic than liver, perioperative infusion of donor bone marrow has been attempted to increase the donor 'passenger' leukocyte load. It has been suggested that the established microchimerism is not only associated with long-term acceptance of the graft, but it also plays an active role in induction and maintenance of donor-specific unresponsiveness. However, the intimate mechanism(s) responsible for prolonged graft survival in this setting remain speculative. Experimental evidence is also available that the thymus plays a major role in the development of self-tolerance and is critical in the induction of acquired tolerance to exogenous antigens. It has been reported that after intrathymic injection of donor cells clonal deletion of maturing thymocytes occurs and is the major mechanism in the induction of donor-specific tolerance, since peripheral T-cell component would be devoid of alloreactive population. Studies are warranted in the near future to explore whether the thymus technique can be employed to prolong survival or induce tolerance to allograft in humans. An interesting novel strategy for transplant tolerance is also the oral administration of alloantigens, which has been recently applied to the cardiac transplant model in rat. All these approaches will have a major impact in the near future on transplant medicine, opening new perspectives to obtain indefinite graft survival.

Animals↗

Prediction of cyclosporine area under the curve using a three-point sampling strategy after Neoral administration.

Accurate monitoring of cyclosporine (CsA) dosage is still a problem, because measurement of the area under the curve (AUC)--the most appropriate indicator of exposure to CsA--requires a number of blood samples to be taken over 12 h, which makes monitoring difficult in day-to-day clinical practice. This study investigated whether a limited sampling strategy in human kidney transplantation reflected the actual AUC better in patients given Neoral than in those being treated with Sandimmune. Stepwise multiple regression analysis of CsA blood levels recorded after Neoral administration to 20 renal transplant patients showed the best results in AUC prediction with three sampling points (1.5, 8, 11 h after Neoral dosing; r = 0.992 with an associated error in AUC prediction ranging from -8.0 to 8.8%). Because blood sampling at 8 and 11 h is not feasible in routine clinical practice, sample points from 0 to 3 h after Neoral dosing, i.e., up to the time of maximum mean blood CsA concentration plus 2 SD, were considered. The best results were obtained with a three-point strategy (0, 1, and 3 h after Neoral dosing; error in prediction: -9.0 to 7.2%), which gave an excellent correlation between measured and predicted AUC (r = 0.989). A similar analysis after Sandimmune given to the same patients always resulted in poor AUC prediction with a wide associated error. These findings indicate that with Neoral, but not Sandimmune, a limited strategy of three-point sampling taken early after dosing allows an excellent and perfectly reliable prediction of the actual AUC.

Ambulatory Care↗

Platelet-activating factor mediates angiotensin II-induced proteinuria in isolated perfused rat kidney.

Isolated kidney preparations (IPK) from male Sprague Dawley rats perfused at constant pressure were used to evaluate the effect of angiotensin II (AII) and platelet-activating factor (PAF) on renal function and urinary protein excretion. Compared with basal, intrarenal infusion of AII at 8 ng/min caused a progressive increase in protein excretion (11 +/- 6 versus 73 +/- 21 micrograms/min) in parallel with a decline in renal perfusate flow (RPF) (29 +/- 3 versus 18 +/- 3 ml/min). Addition to the perfusate of PAF at 50 nM final concentration also induced proteinuria (9 +/- 4 versus 55 +/- 14 micrograms/min) but did not change RPF (29 +/- 3 versus 30 +/- 3 ml/min). Preexposure of isolated kidneys to the PAF receptor antagonist WEB 2086 prevented the increase in urinary protein excretion induced by AII infusion (basal: 13 +/- 6; post-AII: 12 +/- 7 micrograms/min) but failed to prevent the vasoactive effect of AII (RPF, basal: 30 +/- 2; post-AII: 21 +/- 3 ml/min). In additional experiments, dexamethasone reduced the proteinuric effect of PAF remarkably. These results indicate that in isolated kidney preparation: (1) AII infusion induced proteinuria and decreased RPF; and (2) the effect of AII in enhancing urinary protein excretion was completely prevented by a specific PAF receptor antagonist, which, however, did not influence the AII-induced fall in RPF. It is suggested that PAF plays a major role in AII-induced changes in the permselective function of the glomerular capillary barrier.

Angiotensin II↗

Prevention of transplant rejection: current treatment guidelines and future developments.

In the past 2 decades, progressive improvements in the results of organ transplantation as a therapeutic strategy for patients with end-stage organ disease have been achieved due to greater insight into the immunobiology of graft rejection and better measures for surgical and medical management. It is now known that T cells play a central role in the specific immune response of acute allograft rejection. Strategies to prevent T cell activation or effector function are thus all potentially useful for immunosuppression. Standard immunosuppressive therapy in renal transplantation consists of baseline therapy to prevent rejection and short courses of high-dose corticosteroids or monoclonal or polyclonal antibodies as treatment of ongoing rejection episodes. Triple-drug therapy with the combination of cyclosporin, corticosteroids and azathioprine is now the most frequently used immunosuppressive drug regimen in cadaveric kidney recipients. The continuing search for more selective and specific agents has become, in the past decade, one of the priorities for transplant medicine. Some of these compounds are now entering routine clinical practice: among them are tacrolimus (which has a mechanism of action similar to that of cyclosporin), mycophenolate mofetil and mizoribine (which selectively inhibit the enzyme inosine monophosphate dehydrogenase, the rate-limiting enzyme for de novo purine synthesis during cell division), and sirolimus (rapamycin) [which acts on and inhibits kinase homologues required for cell-cycle progression in response to growth factors, like interleukin-2 (IL-2)]. Other new pharmacological strategies and innovative approaches to organ transplantation are also under development. Application of this technology will offer enormous potential not only for the investigation of mechanisms and mediators of graft rejection but also for therapeutic intervention.

Animals↗

Measurement of glomerular filtration rate.

Glomerular filtration rate (GFR) is the standard measure of renal function and is critical for the diagnosis and management of renal diseases. Rigorous assessment of GFR requires the measurement of renal clearance of an exogenous marker that is freely filtered by the kidney, and that does not undergo metabolism, tubular secretion or absorption, such as inulin. While its clearance provides the most accurate method of measuring GFR, it is not suitable for routine clinical practice. Labeled compounds as alternative filtration markers, including 125I-iothalamate and 99mTc-diethylenetriaminepenta-acetic acid (DTPA), provide accurate and precise GFR measurements, but their use may be limited for safety reasons. To avoid exposing patients to radiation, investigators have proposed clearance procedures using minute doses of non-radioactive contrast agents, including iothalamate (ionic) and iohexol (non-ionic). This approach provides similar accuracy to inulin clearance. The most important limitation of all renal clearance methods is that urine is collected by spontaneous voiding, stimulated by water loading, and thus subject to errors due to incomplete emptying of the bladder. Thus, plasma clearance of a suitable exogenous marker (51Cr-EDTA, 125I-iothalamate, iohexol) has been suggested for measuring renal function, in which the elimination rate of the tracer after a single intravenous injection is evaluated. Plasma clearance of these markers estimated by multiple blood samples provides more precise information, but repeated sampling makes this method cumbersome. To overcome this drawback, abbreviated kinetic profiles have been proposed to predict GFR from the plasma disappearance curve (elimination phase). On analyzing the data with a simplified method that uses a one-compartment model (six blood samples only in the elimination phase), corrected with the Bröchner-Mortensen formula, an excellent correlation was found with inulin clearance. This method is currently employed for measuring GFR in multicenter clinical trials.

Animals↗

Recovery of blood mononuclear cell calcineurin activity segregates two populations of renal transplant patients with different sensitivities to cyclosporine inhibition.

In vitro studies have shown that the immunosuppressive property of cyclosporine (CsA) depends on its ability to inhibit the phosphatase activity of calcineurin, a critical enzyme for T cell activation. Here we sought to investigate whether measurement of calcineurin activity in peripheral blood mononuclear cells (PBMC) from 30 renal transplant patients given CsA as a part of their immunosuppressive regimen would help in optimizing CsA therapy. We first documented that in PBMC from these patients complete inhibition of calcineurin phosphatase activity by in vitro addition of CsA occurs at concentrations that are easily achieved in vivo for a dose as low as 3 mg/kg/day orally, which corresponds to trough CsA blood levels of 100-150 ng/ml. However, ex vivo, at a blood CsA trough level of 250 ng/ml, calcineurin activity in PBMC was only inhibited from 40% to 70% as compared with controls. Patients on higher doses of CsA had a further inhibition of baseline calcineurin activity, although a complete suppression was never reached. A significant correlation was found between trough CsA concentration and the basal calcineurin activity (r=0.48; P=0.0085). To clarify the relationship between the daily exposure of patients to CsA and changes in the enzyme activity of calcineurin, we then correlated the pharmacokinetic profile of CsA in these patients with different CsA dosing (<4, 4-6, >6-8, >8 mg/kg/day) with the profile of calcineurin activity at different intervals from dosing. Each of the above CsA doses suddenly reduced calcineurin activity, with a nadir at 2 hr after maximum blood concentration. The degree of the inhibition was not a function of peak CsA blood levels. In all patients, CsA blood level returned to basal values 10 hr after dosing. By contrast, only in 50-70% of patients (depending on the dose) did calcineurin activity return to baseline at the same time point after dosing. In summary we have shown that (1) inhibition of calcineurin activity measured ex vivo in PBMC taken from CsA-treated transplanted recipients reflects the blood CsA trough level; (2) after CsA the time-course of inhibition of enzyme activity is relatively independent from CsA pharmacokinetics; (3) the rate of recovery of calcineurin activity 10 hr after CsA dosing segregates two populations of transplanted recipients -- one with complete recovery of the enzyme activity and another that never returns to the baseline calcineurin level.

Calcineurin↗

Cyclosporine induces glomerulosclerosis: three-dimensional definition of the lesions in a rat model of renal transplant.

Previous description of chronic cyclosporine (CsA) renal toxicity commonly included vascular changes, tubular atrophy, and interstitial fibrosis. Glomerular injury was only occasionally documented and it is not clear whether glomerular changes may have an impact on the clinical syndrome of CsA toxicity observed in experimental animals and humans. At the moment the prevailing view is that when patients given CsA have glomerular lesions at a renal biopsy, these were due to concomitant chronic rejection or renal hypoperfusion rather than to CsA itself. As a follow-up of our previous work on the subject (abstract; J Am Soc Nephrol 2:1398, 1992) the present study was undertaken to clarify whether CsA is a direct cause of glomerular injury. We used a model of renal transplant among Lewis rats to better mimic the condition in which CsA is given to humans. Animals underwent kidney isografts and were given daily CsA or vehicle for as long as 12 months. At the end of the experiment specimens of renal tissue were analyzed by a serial section morphometric analysis technique, which allows precise evaluation at the individual glomerular level, glomerular volume and percentage of the capillary tuft affected by sclerosis. Among 85 glomeruli from CsA-treated rats, examined by three-dimensional morphometric analysis, only 12% were normal and 88% revealed segmental sclerosis. Data of single-section analysis compared with three-dimensional morphometric reconstruction showed that the former markedly underestimated the extent of glomerular injury. By three-dimensional analysis we showed that chronic CsA administration was associated with profound changes in glomerular capillary tuft volume distribution as compared to normal. Specifically, a subset of smaller than normal glomeruli emerged in CsA-treated animals in addition to a population of glomeruli which were larger than normal. No significant correlation was found between capillary tuft volume and sclerosis volume. These findings indicate that chronic administration of CsA induces in rats glomerular lesions comparable to the ones reported in human renal or heart transplant. Our present model may help investigating the mechanism(s) of chronic CsA renal toxicity, and will provide important clues for pharmacological manipulations aimed at reducing the long-term consequences of CsA on the kidney.

Animals↗

The kidney triggers graft-versus-host disease in experimental combined transplantation of kidney and stem cell-enriched peripheral leukocytes.

As a preclinical step to human studies with combined stem cell-enriched peripheral leukocytes and organ transplantation from the same donor, a series of studies in rats was undertaken. These studies indicated that Lewis rats infused intravenously with major histocompatibility complex-incompatible (from Brown-Norway rats), stem cell-enriched peripheral leukocyte preparation alone never developed graft-versus-host disease (GHVD). However, GVHD invariably manifested in all animals a few days after the kidney was transplanted in rats that had been previously primed with stem cell-enriched peripheral leukocytes from the same kidney donor strain. GVHD was prevented by substituting the crude preparation of stem cell-enriched peripheral leukocytes with a purified preparation that was almost completely free of T lymphocytes. However, in these latter experiments all rats rejected their kidney graft within 10 days from the surgery. In rats previously given the crude stem cell-enriched peripheral leukocyte preparation, perioperative administration of the fusion protein CTLA4lg also prevented GVHD and prolonged kidney graft survival up to 106 to 175 days. By contrast, animals with kidney transplants, which were given CTLA4lg without stem cells, rejected their grafts within 35 days. All together, these findings may possibly contribute to the creation of rationally designed strategies of combining organ and bone marrow from the same donor to enhance mixed chimerism and prolong survival after organ transplantation.

Abatacept↗

Glomerular filtration rate determined from a single plasma sample after intravenous iohexol injection: is it reliable?

The iohexol injection plasma clearance method is a good alternative to the inulin clearance method for determination of GFR, but requires multiple blood samples. To avoid this, methods have been developed which derive GFR from a formula that uses a single plasma concentration of the tracer and anthropometric data. The aim of this study was to evaluate whether a single plasma sample taken after iohexol injection allows reliable estimation of GFR. In this study, results of single-point determination were compared with those obtained by multiple-point plasma clearance. The GFR of 686 outpatients with different degrees of renal function were recalculated by use of the Jacobsson formula. The optimum time for sampling was found at 10 h after injection of the marker for clearances < 40 mL/min per 1.73 m2, 4 h for clearances between 40 and 99 mL/min per 1.73 m2, and 3 h for clearances > 100 mL/min per 1.73 m2. Results documented that for 75% of the patients, the simplified technique gave an error between -5% to +5% in the evaluation of GFR; for the remaining 25% of the patients, prediction error ranged from -22% to +40%. Furthermore, despite a highly significant correlation between multiple-point iohexol clearance (six plasma samples) and the single-point method (Y = 0.968X + 1.704, r2 = 0.988), the regression intercept was statistically different from 0 and the standard error of the slope estimate established that 95% confidence interval did not include 1.0 (the line of identity), thus indicating that the model can be rejected by the data at a significance level of 0.05. Thus the single-plasma-sample method to determine GFR after radiocontrast injection does not represent a real advantage over the multiple-point method and may lead to unacceptable errors in GFR calculation.

Adult↗