Marzo Aprile 2025 - In depth review

Is Iohexol a Possible Method for Estimating Glomerular Filtration Rate?

Posted on Tuesday April 1st, 2025Scarica PDF

Fabrizio Cristiano

DOI: 10.69097/42-02-2025-03

Fabrizio Cristiano^1,2, Guillermo Rosa Diez⁴, Carlos Guido Musso^3,4, Jenny Cristiano⁵

1 UOSD Nefrologia e Dialisi Ospedale di Ortona, Asl 2 Lanciano Vasto Chieti
2 Department of Neuroscience, Imaging and Clinical Science, University "G. d'Annunzio" Chieti - Pescara, 66100 Chieti, Italy
3 Servicio de Nefrología, Hospital Italiano, Buenos Aires, Argentina
4 Research Department, Hospital Italiano de Buenos Aires. Buenos Aires, Argentina
5 UOC Farmacia Ospedaliera – Ospedale Clinicizzato di Chieti – Asl 2 Lanciano Vasto Chieti

Corresponding author:
Fabrizio Cristiano
UOSD Nefrologia e Dialisi Ospedale di Ortona, Asl 2 Lanciano Vasto Chieti
Department of Neuroscience, Imaging and Clinical Science, University "G. d'Annunzio" Chieti - Pescara, 66100 Chieti, Italy
E-mail: fabrizio.cristiano@asl2abruzzo.it

Abstract

The measurement of glomerular filtration rate (GFR) is essential in diagnosing and managing chronic kidney disease (CKD) and autosomal dominant polycystic kidney disease (ADPKD), both requiring precise renal function assessment. Traditionally, GFR has been estimated using endogenous markers like creatinine and cystatin C, though these can be inaccurate due to factors unrelated to kidney function, such as muscle mass and diet. The iohexol clearance method provides a more accurate and less invasive alternative to traditional markers like inulin or radioactive markers. Iohexol, a non-ionic, water-soluble contrast agent, is exclusively eliminated by glomerular filtration, making it highly suitable for direct GFR estimation. This paper describes procedures for iohexol clearance, involving defined-interval blood samples after intravenous administration. In patients with normal renal function, sampling intervals are more frequent, while in advanced CKD patients, including those with ADPKD, slower iohexol elimination requires wider intervals to ensure accurate clearance analysis. Iohexol has demonstrated high precision and reproducibility, even compared to other markers. Research supports using iohexol to monitor CKD and ADPKD progression effectively. Particularly in ADPKD, iohexol detects subtle but clinically significant GFR changes, even in early disease stages, making it valuable for evaluating targeted therapies. However, iohexol use is limited to specialized centers due to high costs and strict protocols. Its implementation in advanced European healthcare facilities underscores its efficacy, providing reliable GFR estimates that enhance nephrology practice, despite some limitations.

Keywords: glomerular filtration rate, iohexol, CKD

Introduction

Glomerular filtration rate (GFR) assessment is a parameter in the diagnosis and management of chronic kidney disease (CKD), allowing an accurate estimation of renal function. Several methods have been proposed to measure GFR, including endogenous markers such as serum creatinine and cystatin C, as well as methods based on exogenous markers that are administered and subsequently quantified in plasma or urine [1]. Among exogenous markers, iohexol has recently gained attention due to its reliability, safety and accuracy in determining GFR. Iohexol is a nonionic, water-soluble, low-osmolal contrast agent, which has ideal characteristics for the assessment of GFR. Its elimination exclusively by the kidney, through glomerular filtration, makes it particularly suitable for this purpose [2].

GFR Analysis Methodology

The iohexol clearance method is a widely accepted approach to estimate glomerular filtration rate (GFR) due to its high accuracy and reproducibility. This method involves the administration of an exogenous tracer (iohexol) followed by serial blood sampling to monitor its plasma clearance. Below is a step-by-step description of the method. Iohexol is intravenously injected as a 5% solution (50 mg/mL), with the dose ranging from 5 to 10 mL (approximately 250 mg of iohexol). The precise dose is adjusted according to the patient’s body weight and renal function. Blood samples are collected at predetermined intervals based on the patient’s renal function. In patients with normal or mildly impaired renal function, blood samples are collected at shorter intervals, typically at 2, 4, and 6 hours. Patients with moderately to severely impaired renal function require extended sampling intervals, such as 2, 4, 6, 12, and 24 hours, to account for slower iohexol elimination. Plasma iohexol concentrations are measured using spectrophotometry or high-performance liquid chromatography (HPLC). The clearance rate of iohexol, directly proportional to GFR, is calculated from the plasma concentration decay curve. GFR is estimated using models such as the Brøchner-Mortensen formula, which considers the volume of distribution and elimination kinetics of iohexol. Protocol Adaptations: Specific protocols (e.g., 2-point or multi-point sampling) are tailored to optimize accuracy while reducing patient burden. Adjustments are made for variables like age, body mass, and comorbidities. This structured approach ensures a reliable estimation of GFR while accommodating physiological and pathological variations among patients. The iohexol clearance method has proven effective in clinical settings, particularly for patients with chronic kidney disease (CKD) and autosomal dominant polycystic kidney disease (ADPKD), where precise GFR monitoring is crucial.

This is necessary to capture the slower elimination and obtain adequate data to correctly calculate the clearance [3]. Each patient may present physiological variations that affect the pharmacokinetics of iohexol, so protocols may be adapted based on factors such as age and body mass (e.g., elderly or underweight patients eliminate the tracer more slowly) and comorbid conditions (e.g., liver disease). These adjustments are aimed at obtaining a detailed and accurate profile of GFR, especially in patients with impaired renal function or significant physiological variability [4]. The concentration of iohexol is determined in the laboratory by spectrophotometry or chromatography, and the data obtained are used to calculate the plasma clearance of iohexol. The clearance of iohexol (i.e. the rate at which it is eliminated from the plasma) is proportional to the GFR. In practice, the GFR can be calculated with formulas that consider the volume of distribution and the elimination time of iohexol [5].

Renal Function Level	Tracer Dose	Sampling Times	Additional Notes
Normal renal function	5-10 mL (250 mg)	2, 4, 6 hours	Frequent sampling captures rapid elimination
Mildly impaired function	5-10 mL (250 mg)	2, 4, 6 hours	Protocols remain similar to normal function
Moderate impairment	5-10 mL (250 mg)	2, 4, 6, 12 hours	Sampling extended to account for slower elimination
Severe impairment	5-10 mL (250 mg)	2, 4, 6, 12, 24 hours	Comprehensive sampling ensures accurate calculation over prolonged clearance
Special populations	Adjusted by weight	Variable intervals	Tailored protocols based on age, comorbidities (e.g., liver disease), and body mass

Table 1. Detailed description of the iohexol Method for GFR Estimation. Iohexol Sampling protocols based on renal function.

GFR Measurement: The Standard in Renal Functionality Assessment

Unlike other previously used contrast agents, such as inulin or 125I-iothalamate, iohexol has fewer side effects, is easy to handle, and does not require a specialized center for radioactivity management, as is the case with radioactive markers. Numerous studies have shown that iohexol offers high accuracy in estimating GFR. For example, comparison of iohexol clearance with inulin confirmed the accuracy of iohexol as a valid and less invasive alternative. GFR measurement with iohexol is based on blood sampling after marker injection and calculations that take into account the concentration of the marker in the plasma at defined intervals. Iohexol clearance has been shown to be useful in patients for whom creatinine is not always accurate in estimating renal function, particularly in conditions such as CKD, acute renal failure, and in pediatric patients or those with significant comorbidities, as this method is less influenced by variables such as muscle mass, age, and diet [6].

The ability to standardize a formula for accurate estimation of GFR and to use specific formulas for interpretation of clearance values has reduced errors related to GFR measurement. However, the criticality of measuring GFR with iohexol is represented by rigorous protocols for blood sampling and laboratory analysis. Errors in sampling times and measurement techniques can influence the precision of the results. Many laboratories have adopted standardized protocols to minimize these fluctuations, making the use of iohexol more common and widespread in order to consolidate its role in clinical practice and in nephrology research, especially for those particulars that may present variability in estimating GFR [7].

Glomerular filtration rate (GFR) is the gold standard measure of kidney function and is critical to the diagnosis and management of kidney disease. An adequate estimation of GFR requires the measurement of renal clearance of an exogenous marker with the characteristic of being filtered by the kidney and that is not subject to reabsorption, metabolism or secretion. Although inulin represents an ideal marker of glomerular filtration, it cannot be used in clinical practice to estimate glomerular filtration. 125I-iothalamate and 99mTc-diethylenetriaminepentaacetic acid (DTPA) can represent an alternative, however, being difficult to handle and with safety limits, they cannot also be used in clinical practice. A possible alternative for estimating glomerular filtration could be represented by the use of non-radioactive contrast agents such as iothalamate (ionic) [8], which in terms of estimation and precision are comparable to inulin. However, they have limitations mainly represented by the collection method of urine and potential errors affected by delayed bladder emptying, such as obstructive causes in male patients or an excessive water load. The use of an appropriate exogenous marker (51Cr-EDTA, 125I-iothalamate, iohexol) has the advantage of estimating glomerular filtration precisely by evaluating the rate of elimination of the tracer after an intravenous infusion [9] and with blood samples repeated at intervals over time, however the procedure is complicated to implement. Thanks to the Bröchner-Mortensen formula it was possible to correlate iohexol with inulin clearance with data analysis with a simplified model with analysis of six blood samples (Figure 1). This method is currently used to measure GFR in multicenter clinical trials [10]. The Bröchner-Mortensen formula is used to estimate creatinine clearance (or glomerular filtration rate, GFR) using iohexol, a contrast agent used in nuclear medicine and radiology to assess renal function. This method is useful for calculating GFR on a blood sample collected after iohexol administration [11].

Figure 1. GFR correction with iohexol using Bröchner-Mortensen formula.

Iohexol for CKD Patients

In order to give an accurate estimate of GFR, iohexol is considered a valid alternative to inulin but presents practical difficulties in the estimation and accuracy of the results. The accuracy of GFR estimation with iohexol was evaluated by administering the marker on three different occasions to 24 patients and measuring its plasma clearance. The results show a low intraindividual variability (5.59%) and a high reproducibility (6.28%), demonstrating that iohexol is reliable even in patients with moderate or severe renal insufficiency (GFR < 40 mL/min/1.73 m²) [12].

The accuracy of iohexol clearance is high and is not affected by gender and stage of chronic kidney disease, making the method applicable to different types of patients. Simplified iohexol clearance measurement methods exist to measure GFR in patients with CKD, comparing their accuracy with that of the standard 10-hour two-compartment method. The study evaluates the performance of several simplified models, including a population pharmacokinetic (popPK) model and 5-, 6-, and 7-hour single-compartment models, to reduce the complexity and cost of measurements [13].

The results indicate that compared to the 8-hour reference method, the abbreviated models tend to overestimate GFR, especially in patients with an eGFR less than 40 mL/min/1.73 m². Furthermore, the popPK model is less precise and less reliable in patients with advanced CKD (stage III-IV), while the 6- and 7-hour monocompartmental models provide a more accurate estimate but show limitations compared to the standard method [8].

Iohexol represents a valid alternative to inulin for the estimation of GFR, without the need for continuous infusion or urine collection required for inulin. The iohexol plasma clearance method initially requires multiple blood samples to accurately estimate GFR. However, abbreviated methods using a single plasma sample have also been developed, which certainly simplifies the procedure but may reduce accuracy for some patients, particularly those with advanced renal failure [14].

The reliability of the single-sample method has been evaluated. Their study demonstrated that, despite a strong correlation between the multiple and single clearance methods, the accuracy of the single sample method varies significantly according to the patient’s GFR, with acceptable results for approximately 75% of patients and more significant deviations for the remaining 25% [15].

Iohexol for ADPKD patients

Due to its unique characteristics, iohexol has been studied as a marker of GFR in patients with ADPKD. Iohexol clearance, measured by plasma sampling at specific times after contrast injection, represents a valid alternative to inulin and other traditional markers and has allowed to examine the progression of the disease and the effect of potential therapies in reducing the rate of GFR decline. ADPKD is characterized by a gradual replacement of the renal parenchyma with cystic formations resulting in a progressive decrease in GFR; accurate monitoring of this decline with iohexol allows a reliable estimate of residual renal function [16]. Iohexol is particularly useful in patients with ADPKD because it allows repeatable and reliable measurements with an accurate estimate of GFR over time, essential to monitor the evolution of the disease. It also detects changes in GFR even in the early stages of the disease, when creatinine values are not yet significant [17]. Iohexol is an accurate marker for measuring GFR in patients with CKD and ADPKD. Due to its high accuracy, reliability and ease of use compared to traditional markers such as inulin, iohexol allows for accurate monitoring of the progression of chronic kidney disease. Iohexol clearance-based methods, including simplified protocols, reduce the need for extensive sampling, making the process less invasive and more suitable for frequent clinical use [18].

Discussion

The use of iohexol to measure GFR has several advantages over other methods, particularly those based on creatinine. Iohexol clearance provides an accurate and direct measurement of GFR without the limitations of factors unrelated to renal function (e.g. muscle mass) that influence creatinine. This makes it particularly useful for patients with variable characteristics, such as the elderly and children, or those with impaired muscle mass [19]. Unlike traditional methods such as inulin, which require continuous infusion and multiple urine collections, iohexol measurement is less invasive and more convenient for patients, as it requires only blood samples. Iohexol has low intraindividual variability, which makes repeat GFR measurements reliable over time, allowing effective monitoring of renal function in patients with chronic or progressive renal failure. The iohexol method is used in many European centers and is integrated into guidelines for GFR monitoring. In some countries, such as Sweden, it is used as part of standard care, demonstrating the efficacy and applicability of this technique at the clinical level. These advantages make iohexol a preferable choice for measuring GFR in clinical situations where greater accuracy is needed than creatinine-based estimates [20]. The use of iohexol has been particularly effective for comparing GFR data with other parameters, such as total kidney and cyst volume, allowing a holistic assessment of disease progression. Due to the accuracy of the iohexol-based method, it has been possible to demonstrate that some experimental drug treatments were able to slow down disease progression in selected patients [21]. However, this method still has some disadvantages. Iohexol itself and the analytical processes involved (e.g., spectrophotometry, chromatography) are costly. The method requires multiple blood samples, advanced laboratory equipment, and trained personnel, which increases operational costs.

The procedure presents a considerable complexity represented by sampling rigidity, because accurate GFR estimation depends on precise timing of blood samples. Even minor deviations in sampling times can lead to errors in clearance calculation; specialized training is required, because laboratory personnel need expertise in handling iohexol and analyzing plasma concentrations, which may not be available in all healthcare settings.

The method is often restricted to tertiary care centers or research facilities due to the need for specific equipment and expertise and regions with limited healthcare infrastructure may lack the resources to implement this method. The requirement for several blood samples over time makes the method invasive and potentially uncomfortable for patients. Elderly or pediatric patients, as well as those with compromised venous access, may face difficulties with repeated sampling. It is a method that is exposed to potential errors represented by a variability in the measurement, inconsistent sampling times or variations in laboratory analysis can affect the accuracy of the results. Following a precise protocol is essential, but this may not always be feasible in high-volume clinical settings. Differences in age, body weight, comorbidities (e.g., liver disease), and body composition can affect iohexol pharmacokinetics, necessitating protocol adjustments. In patients with severely impaired renal function, prolonged clearance times require extended sampling intervals, increasing the complexity and inconvenience. Although rare, the use of iohexol may pose risks, such as allergic reactions or mild nephrotoxicity in vulnerable patients. Close monitoring is necessary to minimize adverse effects, adding to the procedural demands. Methods like creatinine- or cystatin C-based eGFR estimates, while less accurate, are more practical for routine clinical use due to lower cost and invasiveness.

Newer non-invasive or minimally invasive approaches may overshadow iohexol clearance in certain settings [22]. To reduce the complexity, abbreviated kinetic profiles have been proposed, but these tend to decrease the precision of the results, especially in patients with advanced stages of CKD, as emerged from comparative studies between standard and simplified methods (iohexol).

Conclusions

The iohexol clearance method is a gold standard for GFR estimation in specific clinical and research contexts, providing unmatched accuracy. However, its high costs, procedural complexity, invasiveness, and dependency on specialized resources significantly limit its applicability in routine healthcare.

Simplified protocols and further technological advancements could help mitigate these barriers, broadening its accessibility. GFR estimation with iohexol involves some secondary difficulties, both in terms of high costs and the need to procure specific materials and handle a significant number of blood samples [23]. This limits the methodology to research settings or specialized centers. Unlike the gold standard creatinine-based method, which is less expensive and practicable in all healthcare settings, the use of iohexol requires advanced equipment and specifically trained personnel. The iohexol method, if not performed correctly, tends to overestimate GFR in patients with stage III and IV chronic kidney disease (eGFR < 40 mL/min/1.73 m²). Although iohexol is currently used in several research centers and specialized clinics in Europe, it remains poorly available in many healthcare settings due to staff training requirements. This logistical limitation reduces the applicability of the method in routine clinical settings, making regular monitoring of GFR with iohexol difficult in many peripheral regions. Countries such as Sweden have integrated the method as part of standard care, demonstrating the effectiveness of this approach in an advanced healthcare setting, but its use is still limited to specific cases or large clinical studies (iohexol). In conclusion, although the iohexol method is accurate and represents a valid alternative to traditional markers such as inulin, it still has significant disadvantages that limit its large-scale adoption, especially in settings with limited resources or in the absence of specialized laboratory technical staff.

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