Haemodynamic or metabolic stimulation tests to reveal the renal functional response: requiem or revival?

Haemodynamic or metabolic stimulation tests to reveal the renal functional response: requiem or... Clinical Kidney Journal, 2018, 1–32 doi: 10.1093/ckj/sfy022 CKJ Review CK J R E V I E W Haemodynamic or metabolic stimulation tests to reveal the renal functional response: requiem or revival? 1,2 2 1 2 Bart De Moor , Johan F. Vanwalleghem , Quirine Swennen , Koen J. Stas 3,4 and Bjo ¨ rn K. I. Meijers 1 2 Faculty of Medicine and Life Sciences, University of Hasselt, Diepenbeek, Belgium, Department of Nephrology, Jessa Hospital of Hasselt, Hasselt, Belgium, Department of Nephrology, Universitair Ziekenhuis Leuven, Leuven, Belgium and Department of Immunology and Microbiology, Faculty of Medicine, Katholieke Universiteit Leuven, Leuven, Belgium Correspondence and offprint requests to: Bart De Moor; E-mail: bart.demoor@uhasselt.be ABSTRACT Renal stimulation tests document the dynamic response of the glomerular filtration rate (GFR) after a single or a combination of stimuli, such as an intravenous infusion of dopamine or amino acids or an oral protein meal. The increment of the GFR above the unstimulated state has formerly been called the renal functional reserve (RFR). Although the concept of a renal reserve capacity has not withstood scientific scrutiny, the literature documenting renal stimulation merits renewed interest. An absent or a blunted response of the GFR after a stimulus indicates lost or diseased nephrons. This information is valuable in preventing, diagnosing and prognosticating acute kidney injury and pregnancy-related renal events as well as chronic kidney disease. However, before renal function testing is universally practiced, some shortcomings must be addressed. First, a common nomenclature should be decided upon. The expression of RFR should be replaced by renal functional response. Second, a simple protocol must be developed and propagated. Third, we suggest designing prospective studies linking a defective stimulatory response to emergence of renal injury biomarkers, to histological or morphological renal abnormalities and to adverse renal outcomes in different renal syndromes. Keywords: protein stimulation test, renal functional reserve, renal functional response, renal stimulation test, renal stress test practice, clinicians usually rely on estimated GFR (eGFR) calcu- INTRODUCTION lated from a single serum marker measurement, mostly creatin- Glomerular filtration rate (GFR) is considered the best overall ine. However, such estimates have several limitations. Estimating index of kidney function. It is dependent on age, gender, ethni- equations are valid only in steady-state conditions. Moreover, city, body composition and diet [1] aswell asnephron endow- analytical variation of serum creatinine measurements (2% for ment [2]. GFR is determined by the measured clearance of certain enzymatic assays), variation in tubular secretion and dependency exogenous markers or endogenous waste products. In everyday on muscle mass [3] should be factored in. Received: 2.11.2017. Editorial decision: 26.2.2018 V C The Author(s) 2018. Published by Oxford University Press on behalf of ERA-EDTA. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/ licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com Downloaded from https://academic.oup.com/ckj/advance-article-abstract/doi/10.1093/ckj/sfy022/4969997 by Ed 'DeepDyve' Gillespie user on 12 July 2018 2| B. De Moor et al. Table 1. Suggested terminology and alternatives in the context of a Often ignored, GFR is not constant, as the kidneys do not renal stimulation test continuously function at maximum filtration capacity [4]. It is estimated that in healthy subjects, kidneys usually operate at Unstimulated GFR Random GFR Stimulated GFR 75% of their maximal GFR. Renal function is influenced by di- urnal cycles [5] and is stimulated by protein-containing meals. Unstressed GFR Uncontrolled GFR Stressed GFR Thus, single-point assessments of renal function ignore varying Basal GFR Actual GFR Peak GFR rates of glomerular filtration, as kidneys are capable of adjusting Baseline GFR Reference GFR Maximal or maximized GFR their performance to haemodynamic and metabolic demands. Resting GFR Maximal filtration capacity In 1930, Verney mentioned the reserve forces of the kidney Minimal GFR [6]. In analogy with myocardial and pulmonary function, a re- Renal functional response¼ stimulated GFR – baseline GFR (either in mL/min or dundant or dormant renal reserve was hypothesized, intended in percentage of baseline GFR), i.e. renal functional reserve, renal reserve cap- to cope with extraordinary haemodynamic and metabolic de- acity, renal reserve filtration capacity. mands. Fifty years later, Bosch called this the renal functional reserve (RFR), defined as the difference between the baseline protein intake of the subject. This can be derived from the urea GFR and the stimulated GFR, measured 2 h after a protein meal [7]. nitrogen level in timed urine collection. Coincidentally, patients Over the years, enthusiasm for the RFR concept abated [8– with CKD often follow a low-protein diet. This increases the 12], until Ronco and colleagues [4, 13–15] and Molitoris [16] re- value of a stimulatory test. cently revived interest in this concept. They postulate that di- The stimulated or stressed GFR is the measured GFR follow- minished RFR contributes to the susceptibility for recurrent ing a stimulus, including an oral protein load, an intravenous acute kidney injury (AKI). These authors argue that evaluation amino acid (AA) solution, a glucagon infusion or a dopamine of the degree of functional recovery post-AKI is not only clouded drip [22]. Rodrı ´guez-Iturbe et al. [23] defined a tubular stress test, by the loss of muscle mass but also by stimulated single-neph- describing the tubular secretion of intravenously injected cre- ron GFR to compensate for nephron loss. Testing the renal func- atinine. Regretfully, a creatinine solution marketed for intraven- tional response in these recovered patients could possibly ous use in human experiments is currently not available unveil this undetected loss of functional units and could iden- (personal inquiry). As creatinine is readily absorbed by the tify patients at risk for progression to chronic kidney disease gastrointestinal tract, an oral creatinine load is safer and might (CKD). This hypothesis was discussed and reviewed at the Fifth result in a comparable tubular challenge [24]. Recently a fur- International Conference of the French Society of Intensive Care osemide stress test was applied to patients with progressive [17, 18]. AKI, discriminating recovery from progression [25]. Thus renal Additionally, a deficit in RFR has been incriminated in stimuli are either of a metabolic or haemodynamic nature. A pregnancy-related kidney disease [19]. Further, study of the protein meal, when composed of cooked meat, challenges the diagnostic and prognostic utility of RFR has been mentioned in kidney with both AA and creatinine. This stimulus can be con- the roadmap for global kidney health 2017, issued by the sidered a combination of both a metabolic and a tubular International Society of Nephrology [20]. Finally, the promotion stimulus. of high-protein diets to lose weight stimulated renewed atten- Descriptions of the numerous alternative tubular challenges tion to the postprandial behaviour of the GFR. (sodium, potassium, phosphorus, acid, water deprivation and Reviewing the literature on RFR is impeded by a myriad of water loading) is beyond the scope of this review. definitions and stimulatory tests. This article aims to propose a After stimulation and in healthy subjects, the GFR can reach synthesizing lexicon and tries to offer a variety of protocols for 180–200 mL/min. Some authors refer to GFR in this range as future directions of research. hyperfiltration. Cachat et al. [26] reviewed the literature in 2015 and Tonneijck et al. [27] recently described the mechanisms of diabetic hyperfiltration. These authors correctly differentiate LEXICON between whole kidney function as opposed to single-nephron The RFR (also referred to as renal reserve capacity) is defined as function. On a single-nephron level, hyperfiltration is assumed the difference between the stimulated GFR and the baseline when the intraglomerular pressure is elevated, causing albu- GFR. This difference can be expressed in absolute terms (mL/ minuria and in the long-term leading to progressive glomerulo- min) or in relative terms (percentage of increment relative to sclerosis. Single-nephron hyperfiltration does not automatically the baseline GFR). Although a straightforward and simple defin- translate into whole-kidney hyperfiltration, quite the opposite: ition at first sight, terminologies and definitions are quite con- glomerular hyperfiltration is often intended to preserve a wan- fusing. Table 1 proposes a revised nomenclature in the context ing whole-kidney GFR in the face of a diminishing nephron of renal functional testing. The expression of RFR should be number [28]. More recently, high GFR values were also noted in replaced by renal functional response. septic intensive care unit (ICU) and post-operative patients. We The baseline or basal GFR is sometimes referred to as un- advocate the use of augmented renal clearance for seemingly stimulated GFR (as opposed to stimulated GFR) or unstressed physiological adaptations and the use of stimulated GFR in the GFR (to better differentiate it from the GFR in stressed circum- context of RFR. stances) and finally resting GFR. While the resting GFR is the lowest normal GFR, it is not identical to the baseline GFR used in the context of AKI, which is usually defined as the best or PHYSIOLOGY OF METABOLIC RENAL highest GFR preceding an AKI episode [17, 21]. STIMULATION To maximally guarantee an unstimulated (lowest) GFR, pa- tients are often instructed to adhere to a low-protein or vegetar- For a more extensive overview of the functional compensation ian diet in preparation for a renal stimulation test. If the person after a protein meal, we refer the reader to excellent reviews by is not instructed to do so, the test results (actual GFR and max- Gabbai [29], Bankir et al. [30], Helal et al. [31], King and Levey [1] imal increase) should be interpreted in the light of the usual and Premen [32]. Downloaded from https://academic.oup.com/ckj/advance-article-abstract/doi/10.1093/ckj/sfy022/4969997 by Ed 'DeepDyve' Gillespie user on 12 July 2018 Haemodynamic or metabolic stimulation tests | 3 Any metabolic stimulus triggers the kidneys to increase the oral fluids. Hypovolaemia also blunts the renal response after GFR primarily by reducing the overall renal vascular resistance stimulation [38]. Second, the body must remain in the fasting (RVR) and inducing a postprandial renal hyperaemia. This in- state for at least 8 h (overnight fasting). A low-protein or vegetar- crease of the renal blood flow results from systemic mediators ian diet for 10 days preceding the test is advised by some authors as well as paracrine factors, both acting on the whole kidney to ascertain a true unstimulated GFR. Doubt remains if this inter- level as on the single-nephron GFR. Initially, recruitment of qui- val succeeds in normalizing glomerular hypertrophy caused by a escent glomeruli in ill-perfused regions was hypothesized, chronically high-protein diet. If the investigator does not advo- hence the term ‘renal functional reserve’ [7, 33]. Later it was cate this preparatory phase, habitual protein intake can be esti- concluded that the increased GFR results from a higher filtra- mated from urea nitrogen in a 24-h urine collection [41] and the tion effort of all single nephrons, almost exclusively attributed extent of GFR stimulation must be interpreted with this know- to a higher effective renal plasma flow (ERPF). ledge. Finally, besides a thorough non-pharmacological prepar- The feed-forward stimulus after a protein load or an increase ation, some drugs must be paused, as they interfere with renal in AA plasma levels originates from the pancreas and the liver vascular adaptation. These include non-steroidal anti- [30]. A higher ratio of glucagon to insulin stimulates the liver in inflammatory drugs (NSAIDs) [42], ACE inhibitors and angioten- favour of nitrogen handling and helps the kidneys in the sin receptor blockers. disposal of urea. The hepatic production of cyclic adenosine monophosphate (cAMP) operates as a second messenger. On Selecting the proper stimulus the single-nephron level, glucagon and cAMP cooperate to re- duce the tubular solute concentration at the macula densa. In Measuring the stimulated GFR requires maximal recruitment of this way, the tubuloglomerular feedback is downregulated. As a the so-called reserve GFR. Several approaches have been advo- result, vasodilation of the pre-glomerular arteries and arterioles cated, which—broadly speaking—can be divided into haemody- induces an increase in the single-nephron GFR. Intrinsic renal namic and metabolic stimuli. autoregulation with nitric oxide, vasodilating prostaglandins In humans, a significant increase of the GFR has been and kinins is responsible for this action. Inhibition of renal described with glucagon infusions at a rate of 10–20 ng/kg/min. autocrine prostaglandin synthesis with indomethacin counter- More frequently, dopamine is used. This vasoactive drug aug- acts the vasodilatory effects of AAs. The hypothalamic–hypo- ments the ERPF and hence the GFR without affecting cardiac physeal axis contributes to this process. Vasopressin or the output or systemic vascular resistance. The FF usually drops antidiuretic hormone (ADH) is also active in stimulating the GFR slightly when dopamine is infused at a dose of 2.0 mg/kg/min. after a protein meal. Together with glucagon, this hormone This is the result of afferent and preferentially efferent arteri- helps in the processing of protein metabolites. The role of olar dilation [43]. At the single-nephron level, the increased fil- growth hormone seems of less importance, as a protein meal tration seems totally attributable to higher plasma flow in equally elicits a functional renal response in growth hormone– combination with lower transcapillary pressure. Sometimes deficient patients [34, 35]. dopamine is the only renal stimulus used, for instance, in a In the long term, the afferent arteriole is evidently the weak dopamine-induced glomerular response test [44]. spot in these consecutive events, as this site harbours the first Dopamine provocation may be combined with a metabolic signs of hypertensive hyalinosis, impeding maximal relaxation stimulus. When combined with an AA infusion, the effects are [36]. Arterial stiffness proved to be an independent predictor of additive [45]. During the AA infusion, ERPF and GFR increase adaptive glomerular hyperfiltration after kidney donation [37]. proportionally with a predominant afferent arteriolar dilation If the ERPF is not able to keep pace with the increased demands, resulting in a constant FF. The composition of the AA solution the efferent vasoconstriction gradually prevails, leading to a depends on local availability, but gluconeogenic AA should be higher intraglomerular pressure and filtration fraction (FF). This present [46], whereas branched-chain AAs do not alter GFR or additive mechanism, triggered by the renin–angiotensin system FF [47]. The infusion rates reported in the literature are dispar- with thromboxane A2 and endothelin-1 as cofactors, leads to a ate. The AA infusion can begin the night before the test day, cascade of negative events. In the long run, a higher FF might but the GFR response is already present after a 1- or 2-h infu- lead to glomerular as well as tubular injury and a loss of neph- sion time. A dose–response curve for AA stimulus was con- rons. Treatment with an angiotensin-converting enzyme (ACE) structed by Giordano et al. [48]. Within the physiological range, inhibitor has been shown to restore the GFR response after a incremental AA concentrations cause a stepwise increase in protein stimulation [38]. the GFR, whereas this effect levels off in the pharmacological range. The administration of a single AA to elicit a change in GFR is METHODOLOGY OF RENAL STIMULATION also reported. Arginine [49, 50] and glycine have been used, TESTS each acting via different pathways. Arginine causes systemic and renal vasodilation, while glycine operates via the N- Table 2 provides an overview of the chronology and methodology methyl-D-aspartate glutamate receptor (NMDA-R) [29]. This re- of a renal stimulation test. The numerous stimuli and modes of ceptor is localized in the proximal tubule and functions as a cal- GFR measurements are described in the following paragraph. cium channel, causing local vasodilation. A more natural approach is to stimulate the GFR by a protein Measurement of unstimulated GFR meal. This short-term oral protein loading should consist of at Several factors may influence the unstimulated GFR. First, hydra- least 1 g/kg of protein [51]. Rodrı ´guez-Iturbe et al. [52] studied tion status [39] is a very important confounding variable. Spinelli three quantities of protein meals: 1.3, 1.1 and 0.55 g/kg. The fil- et al. [40] advise the use of bio-impedance measurements to iden- tration fraction rose significantly with the moderate and large tify dehydrated subjects. For this reason, most protocols adopt a protein load but not with the lower protein load. strict oral hydration policy, starting with 10–20 mL/kg plain water Animal proteins are preferred, so most centres prepare a and replacing each voided urine sample with an equal amount of cooked beef hamburger. Red meat, however, contains 3.5–5 mg/g Downloaded from https://academic.oup.com/ckj/advance-article-abstract/doi/10.1093/ckj/sfy022/4969997 by Ed 'DeepDyve' Gillespie user on 12 July 2018 4| B. De Moor et al. Table 2. How to perform a renal stimulation test? Preparatory phase: Test day: Part 1, Test day: Part 3, instruction and informed measuring unstimulated measuring stimu- Variables consent GFR Test day: Part 2, stimulus lated GFR Location Home Hospital: recumbent position Duration 1 day: starting urine 2–4 h 30–60 min to cover inges- 2–4 h collection tion and digestion 2–3 days: when CACrC is opted 10 days: when a low-protein diet is advised Diet Diet 1: habitual diet until Fasting for at least 8 h the night before RFR testing Diet 2: controlled low-pro- Fasting for at least 8 h tein diet for at least 10 days before RFR Fluids Drinking according to thirst Drinking is stimulated: Drinking in equal amounts Drinking in equal 10–20 mL/kg at start to match diuresis amounts to match diuresis PO Start cimetidine (when Stimulus option 1: 1 g/kg CACrC is chosen) accord- protein offered as cooked ing to the Hilbrands meat (containing protocol creatinine) Stop NSAID, preferentially Stimulus option 2: 1 g/kg pause ACE i or angioten- protein offered as egg sin receptor blocker whites or a commercial protein solution (not con- taining creatinine) IV Introduce two separate IV Stimulus option 3: a 10% IV lines AA solution at a rate of 4 mL/kg/h during 3 h Stimulus option 4: IV dopa- mine at a rate of 2 mg/kg/ min (can be combined with stimulus 3) Stimulus option 5: IV gluca- gon at a rate of 10–20 ng/ kg/min during 1 h Clinical exam Weight, height, hydration Blood pressure and heart status, blood pressure rate at regular intervals Blood as well as 24-h urine collection for ref- GFR option 1: plasma or urine samples in erence creatinine clear- urinary clearance of an combination with ance, sodium excretion exogenous marker timed urine and urea nitrogen Urine collections and sam- collections appearance ples: every 30–60 min bracketed with serum samples GFR option 2: urinary CrC Urine collections (with or without cimeti- and samples every dine correction) 30–60 min brack- Urine collections and sam- eted with serum ples: every 30–60 minutes samples bracketed with serum samples Result Unstimulated GFR or Stimulated GFR or CrC: Stimulated CrC: mean of at least three highest of at measurements least three measurements PO, by mouth; IV, intravenous. Downloaded from https://academic.oup.com/ckj/advance-article-abstract/doi/10.1093/ckj/sfy022/4969997 by Ed 'DeepDyve' Gillespie user on 12 July 2018 Haemodynamic or metabolic stimulation tests | 5 creatine. By cooking, a non-metabolic conversion of creatine to sulfamethoxazole, cimetidine and possibly fenofibrate). On the creatinine occurs [53]. This metabolite is easily absorbed and other hand, when the investigator wants to capture solely the the rising serum levels result in increased tubular secretion until dynamics of glomerular filtration, tubular secretion of creatin- the tubular transport maximum is reached [54]. Accordingly, the ine can be blocked by cimetidine. This results in the cimetidine- more pronounced response (after a protein challenge) of creatin- aided CrC (CACrC). In the publication by Hilbrands et al. [66], ci- ine clearance (CrC) compared with inulin clearance is due to a metidine was started 1–4 days prior to the GFR stimulus accord- higher input and increased tubular secretion of creatinine. ing to a dosing protocol determined by the actual renal function. Alternatives for animal protein are dairy products and egg- Irrespective of the methodology, investigators must ascer- white proteins. These are more practical in paediatric subjects tain complete voiding or resort to placing a bladder catheter [55]. Vegetable proteins, for instance soy products or bean curd, (mostly done in children, which increases the invasiveness of are less effective in stimulating the GFR [56]. Many reasons for the test). this difference have been postulated, including a different AA We do not advocate GFR estimating formulas (Chronic Kidney mixture, less sulphur-containing AA, less oxidative stress or Disease Epidemiology Collaboration formula or Cockcroft–Gault acid load, lower maximal AA serum levels, faster internalization formula] to document the renal functional response. Some au- in the cells due to a different insulin/glucagon surge, less so- thors propose cystatin C measurements [67, 68]. The kinetics of dium and more potassium content. An elaborate description of this functional biomarker have been tested after protein meals, the renal benefits attributed to a vegetarian diet is beyond the with conflicting results [69, 70]. scope of this article. The reader is referred to excellent reviews Alternative possibilities for measuring the GFR before by Kalantar-Zadeh et al. [57] and Snelson and Fouque [58]. and after a stimulus are urinary or plasma clearances of The renal response after a haemodynamic stimulus is im- isotopes, e.g. Cr-labeled ethylenediaminetetra-acetic acid 125 99m mediate while the maximal effect of a metabolic stimulus is (Cr-EDTA), I-labeled iothalamate [45]and Tc-labeled noted after 1–3 h. Recent evidence shows that in obese non- diethylenetriaminepenta-acetic acid (Tc-DTPA) (see Tables 4 diabetic subjects, the maximal rise in GFR after a protein stimu- and 5 for references). Most protocols choose the urinary clear- lus is postponed [59]. ance of a subcutaneously injected or continuously infused Over the years, no major side effects of renal stimulation tests radioisotope. Alternatively, calculation of the GFR by decaying have been observed. In the different studies, blood pressure and plasma levels after an intravenous bolus can be performed. heart rate were carefully monitored, especially when dopamine However, this technique requires the investigator to invite the was used as a stimulating agent. After the stimulus has waned test person on two separate days, one for an unstimulated renal function returns to its unstimulated state. Intravenous per- GFR test and one for a stimulated GFR test. Other drawbacks fusion of a hyperosmolar AA solution has been found to cause are the exposure to radiation and the additional costs. local pain and phlebitis. No increase in urinary neutrophil gelati- Recently an elegant technique of urinary clearance of iohexol nase-associated lipocalin or proteinuria has been documented in was tested in an ICU population with varying GFRs [71]. The the protein stimulation experiments performed by Sharma et al. protocol describes a bolus injection followed by a continuous [51]. N-acetyl glucosaminidase (NAG) has been studied in immu- infusion of a low dose of iohexol combined with regular noglobulin A nephropathy (IgAN) during RFR testing [60], but the plasma and urine sampling. This technique seems applicable serial documentation of damage biomarkers, including albumin- in renal function testing. uria, remains largely unexplored. In the meantime, progress is being made in the development and validation of fluorescent markers for GFR determination. These intravenously injected compounds behave as an ideal Measuring GFR during renal stimulation tests renal filtration marker. Their plasma disappearance curves match glomerular filtration and can be read transdermally The Achilles heel of renal function testing is the method used thanks to their fluorescent properties. In this way, an almost for GFR determination [61]. Urinary inulin clearance remains real-time GFR evaluation is possible [72, 73]. the most extensively reported method in renal stimulation Table 3 describes in more detail the advantages and disad- tests. This classic mode of GFR measurement is often combined vantages of the numerous options. with para-aminohippuric acid (PAH) clearance to document the ERPF. Delanaye et al. [62] delineates the difficulties of this technique, including costs, variances in lab techniques and Alternatives to GFR measurements availability. Zitta et al. [44] succeeded in studying GFR behav- iour after AA infusion via the plasma kinetics of sinistrin and Magnetic resonance imaging (MRI) holds great promise, as it hippurate supplied to a two-compartment computer model. allows for simultaneous measurements of both the GFR and The advantage of this technique is the elimination of urine renal plasma flow (RPF) [74], as well as providing estimates of collections. single-nephron GFR. Additionally, MRI could be used to quantify The easiest alternative for the use of inulin is to monitor renal fibrosis, as recent evidence suggests [75]. urinary CrC by timed urine collections (30 or 60 min), consider- Doppler ultrasound can detect the decrease in RVR occurring ing known caveats when using this biomarker. At least three in healthy kidneys after a protein challenge [76, 77]. This has led clearance calculations are advised. The CrC overestimates true investigators to study the renal resistive index variation (RRIV) GFR because of additive tubular secretion, leading to a mean before and after an AA infusion. A similar decrease in RVR can bias of 14 mL/min or 25% [63]. The overestimation depends on be documented when pressure is applied to the retroperitoneal baseline kidney function. However, when subjects are asked to vasculature. This autoregulatory reflex is intended to preserve adhere to a low-protein diet of 0.5 g/kg/day, calculated CrCs are the GFR. Maximal renal vasodilation was recorded when a sa- similar to inulin clearance [64, 65]. When urinary CrC is used line bag representing 10% of the body weight was placed on the not only as a GFR estimator but also to track accessory tubular abdomen. The maximal RRIV observed in these experiments secretion, the intake of drugs that inhibit the tubular secretion correlated with the RFR, thus offering a non-invasive real-time of creatinine must be avoided (e.g. trimethoprim– evaluation of the changing RVR [78]. Downloaded from https://academic.oup.com/ckj/advance-article-abstract/doi/10.1093/ckj/sfy022/4969997 by Ed 'DeepDyve' Gillespie user on 12 July 2018 6| B. De Moor et al. Tabe 3. Advantages and disadvantages of the different options mentioned in Table 1 Option Pros Cons Evaluation Diet 1: habitual diet Easiest protocol. Protein intake can be Unstimulated GFR is influenced by the Simplicity: high evaluated by the urinary nitrogen protein content of the habitual diet. Duration: low appearance The renal response may be lower Costs: low Validity: lower Diet 2: 10 days of Best guarantee of approaching unstimu- Requires the effort of a dietician and the Simplicity: low low-protein or lated or resting GFR subject’s compliance Duration: long vegetarian diet Costs: higher Validity: higher Stimulus option 1: Easiest to prepare. Oldest and most exten- Subjects must ingest the meal in 30 min. Simplicity: high oral protein load sively documented challenge In case of gastric emptying disorders, Duration: low in the form of digestion can be slower Costs: low cooked meat Validity: neutral Stimulus option 2: The taste can be adapted to subjective Requires the effort of a dietician to com- Simplicity: neutral oral protein load wishes. Can be used in children pose the meal. The tubular secretion of Duration: low without creatinine creatinine is missed Costs: low Validity: neutral Stimulus option 3: IV Low-dose dopamine augments the renal Only offering a haemodynamic stimulus. Simplicity: low dopamine plasma flow more than the GFR Mostly used in combination with an AA Duration: low infusion. Requires an extra IV line and Costs: high clinical follow-up. Dopamine has fallen Validity: lower into disuse Stimulus option 4: IV If AA plasma levels are more than tripled, AA composition must match those used Simplicity: low AA infusion this stimulus offers the best guarantee in literature. Infusing AA may cause Duration: high of maximal GFR simulation phlebitis Costs: high Validity: highest Stimulus option 5: IV Shortest stimulus. Physiologically logical Requires glycaemic controls. Misses sim- Simplicity: low glucagon stimulus ultaneous insulin secretion as in normal Duration: low physiology. Less experience and litera- Costs: high ture support Validity: lower GFR option 1: ex- Best GFR measurement. Current literature In case of a single bolus injection: un- Simplicity: low ogenous marker proposes a bolus/continuous infusion stimulated and stimulated GFR meas- Duration: neutral protocol for the evaluation of unstable urements must be scheduled on two Costs: high renal function separate days. Validity: highest GFR option 2: cre- Easiest protocol. Evaluates glomerular fil- CrC overestimates true GFR Simplicity: high atinine clearance tration as well as tubular secretion Duration: neutral Costs: low Validity: neutral GFR option 2: If tubular inhibition is maximal, CACrC Maximal tubular inhibition of creatinine Simplicity: lower CACrC matches measured GFR secretion cannot be guaranteed. Duration: higher Potential side effects of cimetidine (al- Costs: higher lergy and tolerance). The tubular contri- Validity: high bution to overall clearance is blocked IV, intravenous. The first studies were performed in healthy individuals CLINICAL SUPPORT OF RENAL STIMULATION (Table 4). Several different stimuli were used. It was shown that TESTING inulin clearances could rise to 130–150 mL/min while CrCs Over the last three decades, numerous publications have reached 160–180 mL/min [7]. These studies also demonstrated reported on the renal stimulation test in various healthy and that the protein content of the habitual diet influences un- diseased populations (summarized in Tables 4 and 5). An ex- stimulated GFR and determines the absolute extent of the GFR haustive literature search of RFR testing proves very challenging increase after a protein load [80–82]. Hypovolaemia is an appre- because of the heterogeneous nomenclature, necessitating ciated cause of a blunted response [38]. Healthy elderly individ- several surveys and meticulous scrutiny of the references. uals show a lower GFR and less effect after stimulation, most Surprisingly, only a minor fraction of studies investigated >50 probably because they rely on fewer nephrons [83–85]. Recently subjects. Molina et al. [79] decided on a sample size of 384 Denic et al. [86] demonstrated that the single-nephron GFR (in children, considering a standard deviation of the GFR of unstimulated circumstances) remained remarkably stable in a 620 mL/min to find a pre–post difference of at least 2 mL/min. large cohort of living kidney donors until the age of 70 years. Despite this fundamental statistical consideration, most The age-dependent decline of the GFR in elderly donors was papers omit biological variance and inter-person variability in attributed to a lower nephron count and a lower metabolic need their discussions. without the presence of kidney disease. Downloaded from https://academic.oup.com/ckj/advance-article-abstract/doi/10.1093/ckj/sfy022/4969997 by Ed 'DeepDyve' Gillespie user on 12 July 2018 Haemodynamic or metabolic stimulation tests | 7 Downloaded from https://academic.oup.com/ckj/advance-article-abstract/doi/10.1093/ckj/sfy022/4969997 by Ed 'DeepDyve' Gillespie user on 12 July 2018 Table 4. Current experience with renal stimulation testing in subjects without kidney disease (for reference list, see Supplementary material) Type of Type of GFR stimulus measurement Urinary inulin Confounding Amino Protein Creatinine (þ PAH) Urinary Exogenous variables Reference Number Dopamine acids meal IV clearance CrC marker Summary of the results Bosch 1983 5: normal protein X X X GFR reached a maximal level of diet 1716 7.7 mL/min after 150 min. 8: vegetarian diet In patients with reduced num- ber of nephrons, RFR may be di- minished or absent Graf 1983 5 receiving paren- X X Endogenous CrC increases during teral nutrition infusion of AA Bosch 1984 16 X X CrC increases from 1236 13 to 1576 13 mL/min Rodriguez-Iturbe 44 X X CrC increases from 108.56 6.45 to 1985 161.56 9.39 mL/min ter Wee 1986 9X X IOTH 1 Infusion of AA and dopamine show additive effects: dopamine lowers FF, while during AA infu- sion the FF remains unchanged Hostetter 1986 10 X X GFR increases from 1016 7to 1146 6 mL/min. RVR decreases Castellino 1986 13 X X GFR increases from 1076 5to 1286 4 mL/min. Somatostatine blocks this increase Bosch 1986 7 X X GFR increases from 1226 10 to 1516 15 mL/min Solling 1986 Healthy male phys- X IOTH 1 Eight subjects received a meat icians and meal while seven were chal- students lenged with an AA infusion. GFR and RPF increased and FF as well as albumin excretion remained unchanged Mansy 1987 X X X Same increase of CrC after AA, 80 g meat and 80 g milk protein Rodriguez-Iturbe 37 X X Subjects were given, three quanti- 1988 ties of protein load: mild protein load, 0.55 g/kg; moderate protein load, 1.08 g/kg; high protein load, 1.35 g/kg. The effect on the GFR was incre- mental: the largest increase of GFR was observed when a high protein load was served. To ac- complish this GFR increase, the (continued) 8| B. De Moor et al. Downloaded from https://academic.oup.com/ckj/advance-article-abstract/doi/10.1093/ckj/sfy022/4969997 by Ed 'DeepDyve' Gillespie user on 12 July 2018 Table 4. Continued Type of Type of GFR stimulus measurement Urinary inulin Confounding Amino Protein Creatinine (þ PAH) Urinary Exogenous variables Reference Number Dopamine acids meal IV clearance CrC marker Summary of the results filtration fraction was signifi- cantly increased Rodriguez-Iturbe 10 X X A protein meal and not a carbohy- 1988 drate meal stimulates the CrC and is associated with a parallel increase (doubling) in plasma immunoreactive ANF Hirschberg 12 subjects (Glucagon) X (Arg) X Glucagon and IV infusion of argin- 1988 ine induce an increase in GFR that is blunted by NSAIDs Castellino 1988 18 X X The renal haemodynamic re- sponse following AA infusion is dependent on insulin/glucagon/ growth hormone replacement and can be blocked by somatostatin Laville 1989 9 X X X Simultaneous measurements of GFR and CrC showed a peak in GFR after 127 min and a max- imal CrC after 189 min. This was caused by a subsequent increase of tubular secretion of creatinine (contributing 15%) Olsen 1990 12 volunteers X EDTA 1 AA increased GFR by a primary ef- fect on renal haemodynamics or, less likely, by reducing the signal to the TGF. The increase in proximal tubular outflow was compensated for in the distal tubules Tam 1990 12 healthy medical X X Three protein meals were offered students and compared with a control meal. Regardless of the protein content, an increase in CrC is observed Braendle 1990 10 X X Oral protein concentrate and an oral mixture of AA induce a similar increase in GFR Wada 1991 7 normal subjects X X Branched-chain AA induces no tested twice with increase of CrC, while a mixture of AA elicits the expected (continued) Haemodynamic or metabolic stimulation tests | 9 Downloaded from https://academic.oup.com/ckj/advance-article-abstract/doi/10.1093/ckj/sfy022/4969997 by Ed 'DeepDyve' Gillespie user on 12 July 2018 Table 4. Continued Type of Type of GFR stimulus measurement Urinary inulin Confounding Amino Protein Creatinine (þ PAH) Urinary Exogenous variables Reference Number Dopamine acids meal IV clearance CrC marker Summary of the results a different AA functional response. Only the in- compositoin fusion of a mixture of AA is accompanied by an increase in serum glucagon levels Cirillo 1998 25 healthy adults X X GFR and urinary sodium excretion increase over baseline after a protein meal of 2 g/kg. A net de- crease in sodium balance is observed Luipold 2000 12 volunteers X X AA infusion increases GFR and RPF. Pretreatment with domperi- done marginally influences while sulpiride completely blocks the renal response. Sulpiride acts as a centrally and peripherally acting D -like re- ceptor antagonist Barai 2008 109 kidney donor X DTPA 1 Lower mean GFR in healthy adult candidates Indians than whites. No differ- ence between sexes. Similar in- crement of the GFR after AA stimulation: 27.3 6 10.01% Bird 2008 20 X EDTA 2 Comparison of iohexol with Cr- EDTA. Fasting and non-fasting. BSA versus ECV. The only sig- nificant increase of GFR was observed when GFR/BSA was considered Sharma 2016 18 X X Similar increase of CrC after 1 and 2 g/kg protein load and 1 g/kg protein powder. No appearance of urinary NGAL Rodenbach 18 X X with cimetidine IOH 1 Protein loading stimulates iohexol 2017 clearance and CACrC after a beef-or milk-based meal. Cystatin C eGFR changes are smaller Age Fliser 1993 10, median age 70 X X Lower GFR and ERPF in elderly. The years (up to 80 median percent increase (17%) years) was not different from younger controls. Higher RVR and FF in the elderly (continued) 10 | B. De Moor et al. Downloaded from https://academic.oup.com/ckj/advance-article-abstract/doi/10.1093/ckj/sfy022/4969997 by Ed 'DeepDyve' Gillespie user on 12 July 2018 Table 4. Continued Type of Type of GFR stimulus measurement Urinary inulin Confounding Amino Protein Creatinine (þ PAH) Urinary Exogenous variables Reference Number Dopamine acids meal IV clearance CrC marker Summary of the results Bo ¨ hler 1993 12 non-renal pa- X X Baseline GFR is lower in the elderly tients ages 60–80 compared with young adults. years However, RFR is well maintained in elderly human subjects Pecly 1999 13: 20–39 years X X Ageing decreases the increment of 13: 40–59 CrC. Increased bradykinin seems 11: 60–68 responsible for the GFR adaptation Fuiano 2001 10 young X X X In older subjects, GFR is lower. 11: 65–76 years After combined stimulus, a 15 young donors smaller increase was seen in 11 older donors older subjects. More arterioscler- osis and interstitial fibrosis in older patients. Esposito 2007 6 (25–37 years) X X X GFR and RPF were slightly reduced 6 (44–74 years) in elderly individuals, which re- 7 (81–96 years) sulted in increased FF. In the elderly as opposed to young and middle-aged subjects, neither GFR nor RPF increased after maximal stimulation Musso 2011 5: 20–40 years X X with cimetidine Renal functional response was pre- 6: 64–74 years sent in all age groups. Its magni- 5: > 74 years tude was significantly higher in healthy compared with older subjects Gender No data Ethnicity No data Diet [low protein Bosch 1984 10 (LP¼ 0.7–0.8 g/kg/d, X X CrC on low protein (LP) diet is (LP), normal NP 1.0–1.5 g/kg/d) lower: 976 34 versus 1096 37 protein (NP), mL/min. Peak GFR is similar at high protein 1226 45 mL/min (HP)] Castellino 6 (LP¼ 40 g/d, X X GFR is lower on LP diet. Increment NP 1.2–1.5 g/kg/d) after stimulus is equal Viberti 1987 6 (LP: 43 g/d, X X GFR is lower on LP diet: more rela- NP: 75 g/d) tive increment but not reaching peak GFR on normal protein diet. Unchanged FF (continued) Haemodynamic or metabolic stimulation tests | 11 Downloaded from https://academic.oup.com/ckj/advance-article-abstract/doi/10.1093/ckj/sfy022/4969997 by Ed 'DeepDyve' Gillespie user on 12 July 2018 Table 4. Continued Type of Type of GFR stimulus measurement Urinary inulin Confounding Amino Protein Creatinine (þ PAH) Urinary Exogenous variables Reference Number Dopamine acids meal IV clearance CrC marker Summary of the results Kontessis 1990 17 healthy subjects X X GFR is lower after a 3-week course (3 weeks vegetar- of vegetarian protein. Soy pro- ian versus animal teins induce less GFR increase protein) than meat proteins while serum AA levels are comparable. A meal containing animal protein induces a higher and more sus- tained increase in glucagon levels Nakamura 1993 6 healthy females X IOTH 1 Comparison with 0.7 g/kg tuna fish and 6 type 2 and the same or double amount diabetics of boiled egg white. GFR in- creases only after ingestion of tuna fish both in normal con- trols and diabetics. Only AA Gly and Ala rose differently after this meal Nakamura 1989 11 healthy X X Comparison with 1.0 g/kg tuna fish 20 diabetics versus bean curd. Vegetable pro- tein could not induce an in- crease of the CrC in healthy subjects or in diabetics. Nakamura 1990 10 healthy X X Comparison with 0.7 g/kg tuna fish volunteers versus boiled egg white, cheese 6 type 2 diabetics of tofu (bean curd). An increased GFR was only observed after tuna fish. This was accompanied by an increase in glucagon and growth hormone as well as three AAs (alanine, glycine and arginine) Simon 1998 8 healthy volunteers X X A chicken or equivalent beef meal induces identical GFR and RPF response. RVR decreases as GFR and RPF increase. FF remains unchanged Orita 2004 6 healthy male X X Offering a beefsteak or the same subjects amount of skim soy with soy sauce results in an identical en- hancement of GFR. AA analysis revealed no differences between the two protein challenges (continued) 12 | B. De Moor et al. Downloaded from https://academic.oup.com/ckj/advance-article-abstract/doi/10.1093/ckj/sfy022/4969997 by Ed 'DeepDyve' Gillespie user on 12 July 2018 Table 4. Continued Type of Type of GFR stimulus measurement Urinary inulin Confounding Amino Protein Creatinine (þ PAH) Urinary Exogenous variables Reference Number Dopamine acids meal IV clearance CrC marker Summary of the results Low sodium diet Ruilope 1986 11 X X No increment of GFR when salt- (20 mmol/d depleted. Recovery when capto- and furosem- pril is given. No recovery under ide 80 mg indomethacine once) Low sodium diet Memoli 1991 8 paired X X X In control conditions, both GFR (0.5 g) and fur- observations and RPF increase (þ31.5% and osemide 25 mg þ41%) after dopamine and AA for at least 3 stimulation. After salt depletion, days GFR and RPF are impaired mainly by an increased vascular resist- ance. After dopamine and AA, both GFR and RPF increase (þ37% and þ31%) Low hydration/ Hadj-Aissa 10 paired observa- X X High hydration resulting in a low high hydration 1992 tions. High hydra- urinary osmolality blunts a pro- tion: 1st h 10 mL/ tein-induced response of GFR kg, 2nd h 7.5 mL/ kg and 5 mL/kg/30 min Claris-Appiani 7 adults tested 6 X X The renal haemodynamic re- 1999 times sponse is blunted when hypo- tonic saline is infused (0.23– 0.45%) Anastasio 2001 12 paired observa- X X High hydration lowers GFR and tions. High hydra- preserves response versus low tion means 5 mL/ hydration (with a higher un- kg/30 min. Low stimulated GFR and lower hydration means response) 0.5 mL/kg/30 min Medication Krishna 1988 9: tested 3 times X X GFR increased from 1016 7to (placebo, indome- 1186 4 mL/min. Smaller in- thacine, enalapril crease after indomethacine. No effect of enalapril Herrera 1988 10 healthy subjects, X X A protein load induces an increase twice stimulated in GFR from 107.26 6.05 to without and with 146.46 6.79 mL/min/1.73 m and indometacine an increase in RBF. No effect of indomethacine Vanrenterghem 6 subjects X X Indomethacine blunts the GFR 1988 increase (continued) Haemodynamic or metabolic stimulation tests | 13 Downloaded from https://academic.oup.com/ckj/advance-article-abstract/doi/10.1093/ckj/sfy022/4969997 by Ed 'DeepDyve' Gillespie user on 12 July 2018 Table 4. Continued Type of Type of GFR stimulus measurement Urinary inulin Confounding Amino Protein Creatinine (þ PAH) Urinary Exogenous variables Reference Number Dopamine acids meal IV clearance CrC marker Summary of the results Chagnac 1989 12 healthy subjects X X CrC increases from 114.36 4.5 to before and after 137.1 mL/’/1.73 m after a pro- enalapril tein load. On the enalapril intake day, the increase of CrC was lower Mizuiri 1994 6 controls X (L-Arg) X L-arginine infusion leads to a sig- 10 controls and 10 nificant decrease in RVR and a IgAN patients be- significant increase in RPF and fore and after GFR in all groups. An increase in captopril plasma glucagon levels was observed. Captopril pretreat- ment in healthy subjects attenu- ates this effect Pritchard 1997 23 patients with X X X Tandolapril 2 mg and indometha- hypertension cine 3 times 25 mg: no effect on (four-way GFR or ERPF after dopamine and crossover) AA Body Deibert 2011 10 male patients X X The obese subjects show a higher composition with the metabolic baseline GFR and RPF. The pro- syndrome tein load induced a significant 10 controls increase in GFR and RPF in healthy controls and even more in patients with metabolic syndrome Anastasio 2017 28 obese X X Delayed glomerular response in 20 controls obese patients Time of day Buzio 1988 7 X X Best CrC stimulatory effect when protein load is administered at lunch (instead of supper) Buzio 1989 10 X X Circadian rhythm. No effect of pla- cebo when given in the evening 125 125 IOTH 1 ( I-iothalamate): IV bolus followed by a continuous infusion. Urinary and plasma clearances (to correct for incomplete voiding). HPLC measurement (in later studies); IOTH 2 ( I-iothalamate): single subcutaneous injection. Plasma clearances. Gamma counter measurement; IOH 1 (iohexol): IV bolus followed by a continuous infusion. Plasma clearances. HPLC measurement; EDTA 1 ( Cr-EDTA): IV bolus followed by a continuous infusion. Urinary clear- 51 99m ances; EDTA 2 ( Cr-EDTA): single IV bolus. Plasma clearances; DTPA 1 ( Tc-DTPA): single IV bolus. Plasma clearances. BSA, body surface area; HPLC, high-performance liquid chromatography; IV, intravenous; NGAL, neutro- phil gelatinase-associated lipocalin. 14 | B. De Moor et al. Downloaded from https://academic.oup.com/ckj/advance-article-abstract/doi/10.1093/ckj/sfy022/4969997 by Ed 'DeepDyve' Gillespie user on 12 July 2018 Table 5. Current experience with renal stimulation testing in subjects with kidney disease (for reference list, see Supplementary material) Type of stimulus Type of GFR measurement Result Urinary Inulin Clinical Protein Creatinine (þ PAH) Urinary Exogenous context Condition Ref Number Dopamine AA meal IV clearance CrC marker Hyperechogenicity Potential kidney Fouda 2011 34 potential kidney X X MAG 3 The renal reserve is comparable in donors donors with Grade 1 the two groups. In 41% of 17 biop- hyperechogenicity, 10 sies of the donors with abnormal matched healthy ultrasound, morphologic abnor- donors malities are present, compared with only 1 of 8 biopsied controls Single kidney Post-donation Bosch 1984 5 X X CrC increases from 706 14 to 836 4 mL/min Iturbe 1985 25 X X CrC increases from 115.46 11.6 to 137.46 11.6 mL/min ter Wee 1986 9 X X IOTH 1 GFR shows only increment on double stimulation Solling 1986 8 meat meal X X X Short-term protein load and AA, 7 amino acid increased RPF and GFR and decreased RVR. The permselectiv- ity of the GBM was unchanged ter Wee 1987 18 after X IOTH 1 GFR increases 4.5% versus 10% in uninephrectomy, controls. After donation in paired 10 kidney donors (pre observations, the GFR increase and post) decreases from 12.4% before to 5.9% after nephrectomy Cassidy 1988 12 X X Lower CrC in donor group but com- parable increase on placebo. Amore 1988 6 patients after unilat- X X Patients with single kidneys show eral nephrectomy albuminuria at baseline, while 8 healthy subjects their CrC is normal. After a protein load, albuminuria increases while their CrC response is lower than in controls ter Wee 1990 20 pre and post X X IOTH 1 After donation: 65% of pre-donation observations GFR, lower FF. Dopamine: increase of GFR, with 13.8% before versus 5.3% after donation. AA-induced increase: 11.2% before versus 9.6% after. Combined: 20% increase be- fore versus 12.6% after donation. ERPF helps maintain GFR Heering 1994 8 controls X X A RFR is shown in healthy controls 8 renal graft but a grossly diminished response recipients is seen in patients with a single 8 after nephrectomy kidney (continued) Haemodynamic or metabolic stimulation tests | 15 Downloaded from https://academic.oup.com/ckj/advance-article-abstract/doi/10.1093/ckj/sfy022/4969997 by Ed 'DeepDyve' Gillespie user on 12 July 2018 Table 5. Continued Type of stimulus Type of GFR measurement Result Urinary Inulin Clinical Protein Creatinine (þ PAH) Urinary Exogenous context Condition Ref Number Dopamine AA meal IV clearance CrC marker ter Wee 1994 15 pairs (donor/ X X IOTH 1 Preserved increase in GFR on AA recipient) stimulus, less after dopamine. 12 long-term follow-up Long-term RFR is preserved, less due to increased ERPF than to glomerular hypertrophy Rodriguez-Iturbe 14 normal controls X X IOTH 2 An IV bolus of creatinine stimulated 2001 7 donors tubular secretion in controls (11.3 11 after kidney times), in donors (4.3 times) and in transplantation transplanted patients (2.5 times) Rook 2006 125 kidney donors 120 X X IOTH 1 GFR post-donation was predicted by days before and 57 GFR , GFR and age pre max days after donation Rook 2008 178 kidney donors, 4 X IOTH 1 Dopamine-induced increase in GFR months before and 2 was reduced from 11 to 5% after months after nephrectomy. Dopamine-induced donation increase correlated negatively with donor age and BMI Spinelli 2017 7 pairs donor/recipient X X Sum of stimulated CrC of donor and recipient equals pre-donation stimulated CrC Van London 2018 105 female kidney X IOTH 1 Donors were tested 4 months before donors ages <45 years and 2 months after donation. Female 51 donors with a BMI donors with a BMI >25 kg/m >25 kg/m showed an absent functional response. BMI correlated with RFR After resection of Bhisitkul 1991 12 X X No differences in CrC before and after Wilms tumour oral protein load in single kidneys versus controls Regazzoni 1998 37 after nephrectomy in X X Long-term follow-up shows stable childhood GFR but decreasing increase of GFR after oral protein load Donckerwolcke 11 patients after X X GFR and ERPF are well preserved. At 2001 nephrectomy rest, tubular secretion of creatin- ine is stimulated. Two patients show maladaptation with loss of RFR Renal agenesis De Santo 1997 21 adults with unilateral X X X Higher blood pressure and protein- renal agenesis uria in patients with lowest GFR. (3 groups with declin- Normal response after protein ing GFR) load in all groups. CrC overesti- mated GFR by 32.7% Renal transplantation Cairns 1988 9 renal transplants on X X EDTA 1 After a protein load, azathioprine- cyclosporine treated renal transplantation (continued) 16 | B. De Moor et al. Downloaded from https://academic.oup.com/ckj/advance-article-abstract/doi/10.1093/ckj/sfy022/4969997 by Ed 'DeepDyve' Gillespie user on 12 July 2018 Table 5. Continued Type of stimulus Type of GFR measurement Result Urinary Inulin Clinical Protein Creatinine (þ PAH) Urinary Exogenous context Condition Ref Number Dopamine AA meal IV clearance CrC marker 9 azathioprine-treated showed a significant increase of renal transplants GFR and ERPF compared with cyclosporine treated renal transplants Nunley 1991 6 RT on cyclosporine X X Cyclosporine alters the renal re- 7 RT on azathioprine sponse to a protein meal Rondeau 1993 18 X X RFR: increase from 50 to 60 mL/min. No effect of ACE inhibitors. Less RFR if cyclosporine treatment Ader 1994 12 patients studied at X X Renal transplant patients show a GFR 20 days and 7.6 months increase after AA stimulus 8 single kidneys 12 controls Shokeir 1994 152 donor/recipient X X DTPA 2 The GFR of paediatric recipients is pairs: 40 paediatric significantly lower. The functional recipients, 112 adult response of the transplanted kid- recipients ney was assessed after 4–8 months. Also, graft functional re- serve proved lower in paediatric recipients Chagnac 1995 6 on cyclosporine before X X High-dose nifedipine increases renal and after 2 weeks perfusion, decreases FF and RVR with high-dose but RFR remains absent nifedipine Hansen 1995 9 healthy volunteers X DTPA 1 A 10-week dietary supplementation 9 on cyclosporine with fish oil did not induce signifi- 9 without cyclosporine cant renal function improvement. On low-dose cyclosporine, a well- preserved renal response is demonstrated Pluvio 1996 16 transplanted patients X X No renal functional response on on cyclosporine cyclosporine treatment, both trans- 6 nephrectomy patients planted and non-renal patients. 7 on cyclosporine Basal GFR correlates with renal 9 controls allograft volume (measured by ultrasound) Hansen 1996 8 on cyclosporine X X DTPA 1 Low-dose cyclosporine A does not at- 8 on azathioprine tenuate the renal response after dopamine or AA infusion Englund 1996 36 renal transplanted X X Baseline GFR and ERPF is lower in children, 15 donors transplanted patients. Increases and 15 single kidneys are similar. Stimulated GFR and ERPF correlated with kidney length (continued) Haemodynamic or metabolic stimulation tests | 17 Downloaded from https://academic.oup.com/ckj/advance-article-abstract/doi/10.1093/ckj/sfy022/4969997 by Ed 'DeepDyve' Gillespie user on 12 July 2018 Table 5. Continued Type of stimulus Type of GFR measurement Result Urinary Inulin Clinical Protein Creatinine (þ PAH) Urinary Exogenous context Condition Ref Number Dopamine AA meal IV clearance CrC marker Maranes 1998 11 patients with ‘en X X Patients having received an ‘en bloc’ bloc’ transplantation pediatric kidney transplantation 10 controls (single kid- show a greater renal response (and ney transplants) a lesser risk of hyperfiltration) Fagugli 1998 25 kidney transplanted X X A group of renal transplants shows patients no RFR but rather a reduction of 8 controls GFR, a higher FF and a high level of thromboxane Zhang 1999 5 normal volunteers X (L-Arg) X L-Arg increased GFR from 1036 9to 21 renal transplants on 1226 7 mL/min/1.73 m in control cyclosporine (10 with subjects. In transplanted patients, normal renal no increase of GFR was observed function) Englund 2000 30 children X X Stable GFR and preserved increase on 7 recipient/donor pairs repeated measurements. Donors tend to show a higher response. Max GFR is related to kidney volume Bertoni 2001 40 grafted with a kidney X CrC increases at 6 months and after 1 younger than 55 years year. The increase in the CrC is 40 grafted with a kidney higher in kidneys from younger older than 55 years donors. This increase is inversely related to donor baseline GFR Delclaux 2001 11 out of 14 patients, X X EDTA 1 7 of 11 patients show an RFR that is >20 years after lower than median. No correlation transplantation was found with morphological data (unless a slightly higher glo- merulosclerosis rate in this popu- lation). In 4 of 11 patients a functional response is present, even >20 years after renal transplantation Fulladosa 2003 32 transplanted patients X X X Correlation of renal response with on cyclosporine renal biopsy. The presence of ar- terial hyalinosis is the only histo- logical parameter associated with impaired renal response Kamar 2006 10 patients on FK and X X Similar GFR and renal functional re- sirolimus sponse after 6 and 12 months 7 patients on FK and post-transplantation. No correl- MMF ation with histology. Saurina 2006 14 patients before and 8 X DTPA 1 More proteinuria and higher calcu- months after conver- lated glomerular filtration pressure sion to sirolimus after conversion of CNI to sirolimus (continued) 18 | B. De Moor et al. Downloaded from https://academic.oup.com/ckj/advance-article-abstract/doi/10.1093/ckj/sfy022/4969997 by Ed 'DeepDyve' Gillespie user on 12 July 2018 Table 5. Continued Type of stimulus Type of GFR measurement Result Urinary Inulin Clinical Protein Creatinine (þ PAH) Urinary Exogenous context Condition Ref Number Dopamine AA meal IV clearance CrC marker Heart transplantation Ader 1996 12 renal and 13 heart X X Maximal increase of GFR after heart transplants transplantation (7 months) is 8 single K and 12 lower than in controls. No increase controls in ERPF was seen in heart trans- planted patients Heart Failure Magri 1998 10 (mild HF, X X No vasodilatory response on AA in compensated) mild HF. Restored response after treatment with RAS blocker Frangiosa 1999 9 patients with end- X X GFR and ERPF are higher in normal stage HF (ACE inhibi- controls, but the percentage in- tors, diuretics) crease after a protein load is con- 18 controls served (27%) in HF patients, although they show a high FF (35%) Coronary artery disease Fuiano 2005 15 patients with an indi- X X Unstimulated: lower ERPF in CAD, cation for coronary higher FF. Lower RPF dependent on angiography severity of CAD 15 kidney donors as a After AA infusion: no increase of GFR control group in CAD. After 2 years: decrease in GFR and RPF. Unchanged response to AA. Cardiac surgery Mazzarella 1991 11 adult patients sched- X X Patients were tested before, as well uled for coronary ar- as 9 days and 6 months after car- tery bypass graft diac surgery. At 9 days, no signifi- cant renal response could be shown. The renal response was restored at 6 months Pregnancy Ronco 1988 29 pregnant subjects X X X Resting CrC increases during preg- were tested at differ- nancy. Increment in CrC decreases ent stages during pregnancy. Peak GFR is 160 mL/min Late gestation com- Barron 1995 14: protein challenge X X GFR is higher during gestation and pared with 3 8: carbohydrate even higher than post-protein load months post- challenge in post-partum women. Placebo partum during pregnancy is less effective Early and late gesta- Sturgiss 1996 14: AA infusion X X GFR increases in early and late preg- tion compared 7: crystalloid nancy. Percentage increase is not with 3 months different from post-partum. post-partum Unstimulated GFR is 40% higher during pregnancy Heguile ´ n 2001 8 pregnant women (15 X X Pregnant women still show an weeks) increased CrC on protein loading 5 controls Mid-term Heguile ´ n 2007 8 hypertensive preg- X X After protein challenge, hypertensive nant, 5 non-hyper- pregnant women show a lesser in- tensive, 8 controls crease of CrC than normal preg- nant women (continued) Haemodynamic or metabolic stimulation tests | 19 Downloaded from https://academic.oup.com/ckj/advance-article-abstract/doi/10.1093/ckj/sfy022/4969997 by Ed 'DeepDyve' Gillespie user on 12 July 2018 Table 5. Continued Type of stimulus Type of GFR measurement Result Urinary Inulin Clinical Protein Creatinine (þ PAH) Urinary Exogenous context Condition Ref Number Dopamine AA meal IV clearance CrC marker Cohen 2012 Healthy pregnancy ¼ 15 X X In controls, baseline CrC increases Pregnancy and CKD ¼ 25 from 99.86 2.9 to 1496 4 mL/min. Non-pregnant In healthy pregnancy, baseline CrC women ¼ 8 increases from 118.56 3.2 to 223.46 5.2 mL/min, a 90% increase. In CKD pregnancy, baseline CrC in- creases from 1326 7.6 to 1866 10.3 mL/min, a 40% increase Liver cirrhosis Hirschberg 1984 8 X X No increase of the GFR after a protein load Rodriquez 1999 10 patients with Child A X X GFR and ERPF are lower in patients liver cirrhosis with cirrhosis. The functional re- 10 controls serve is similar. Higher levels in cGMP and NO were seen in pa- tients, probably to compensate for angiotensine II effects Woitas 2002 22 patients with decom- X X Baseline GFR and ERPF were low. pensated liver cirrho- After AA infusion the GFR in- sis and ascites creases by 67% and ERPF by 29% Woitas 1997 12 patients with liver X X Baseline GFR and ERPF were lower. In cirrhosis and portal both groups GFR and ERPF are hypertension increased after AA infusion. The degree of ERPF increase is higher in cirrhotic patients Liver transplantation Badalamenti 1995 13 treated with fish oil X (L-arg) X Two months treatment with fish oil 13 with corn oil, during improves renal hemodynamics, no 2 months effect on RFR. Nephrotoxicity Occupational expos- Roels 1994 76 male lead workers X X Both controls and lead workers ure to lead showed a significant increase in CrC of 15%. Baseline and stimu- lated CrC is higher in lead workers Genetic risk of essential O’Connor 2001 26 normotensives with X X X RFR is already blunted in still normo- hypertension positive familial risk tensive subjects at genetic risk of of hypertension hypertension. Potential explan- 13 controls ations: insulin resistance to the amino acid–translocating effects of this hormone, baseline hyperfil- tration and decreased proximal tubular reabsorption during amino acid infusion Hypertension Losito 1988 34 mild to moderate HT X X Less increase in CrC after AA infu- (22 controls) sion. Some patients show no RFR: CrC correlates with albuminuria in these patients (continued) 20 | B. De Moor et al. Downloaded from https://academic.oup.com/ckj/advance-article-abstract/doi/10.1093/ckj/sfy022/4969997 by Ed 'DeepDyve' Gillespie user on 12 July 2018 Table 5. Continued Type of stimulus Type of GFR measurement Result Urinary Inulin Clinical Protein Creatinine (þ PAH) Urinary Exogenous context Condition Ref Number Dopamine AA meal IV clearance CrC marker Valvo 1990 15 hypertensives X IOTH 2 RFR is identical to controls. ACE 12 healthy subjects inhibitor does not influence the amount of RFR Buzio 1994 16 hypertensives with X IOTH 1 Nifedipine increases GFR, ERPF as apparently normal well as urinary excretion of pro- GFR with and without teins after a protein load, while nifedipine and captopril decreases GFR and captopril proteinuria Cottone 1994 16 newly diagnosed pa- X X Among 16 patients, 13 showed an tients with essential increased CrC after AA infusion. hypertension No correlation was found with 10 healthy controls plasma renin activity, aldosterone concentration, circulating norepin- ephrine and endothelin-1 Tietze 1997 12 controls X X GFR increases in healthy controls 14 patients with essen- with and without ramipril. In tial hypertension hypertensive patients, ramipril in- hibits the increase in RPF. Long- term treatment with ACE inhibitor blunts the response of GFR and RPF Belsha 1998 33 normotensive X X Normal functional response in hyper- adolescents tensive adolescents. No renal 29 hypertensive pathology even with left ventricu- adolescents lar hypertrophy Zitta 2000 15 controls, 16 hyperten- X X No increase of GFR in hypertensive sive patients patients unless partial recovery after carvedilol and not after fosi- nopril treatment Obesity þ Pecly 2006 14 obese and AHT X X In obese patients, GFR and RPF are hypertension 9 lean and AHT higher. Response after protein load is lower Teunissen- Out of 79 overweight in- X X Greater decrease in FF after a protein Beekman 2016 dividuals with un- supplemented breakfast following treated hypertension a 4-week course of protein and normal GFR, supplementation 27 on maltodextrin and 25 on protein mix participated Gaipov 2016 10 hypertensive X X Lower RFR in hypertensive patients. nephropathy Correlation with renal resistive 14 hypertensive without index and proteinuria nephropathy 11 controls ADPKD Harrap 1992 19 ADPKD X X Lower ERPF in ADPKD patients, also 20 controles stimulated renin–angiotensin sys- tem and higher body sodium load. Non-significant increase in GFR after oral protein load (continued) Haemodynamic or metabolic stimulation tests | 21 Downloaded from https://academic.oup.com/ckj/advance-article-abstract/doi/10.1093/ckj/sfy022/4969997 by Ed 'DeepDyve' Gillespie user on 12 July 2018 Table 5. Continued Type of stimulus Type of GFR measurement Result Urinary Inulin Clinical Protein Creatinine (þ PAH) Urinary Exogenous context Condition Ref Number Dopamine AA meal IV clearance CrC marker Scleroderma Livi 2002 21 scleroderma patients X X Unstimulated: lower CrC with normal Stimulated: less increase of CrC. The creatinine response is dependent on MAP and 10 controls unstimulated CrC Livi 2011 28 normotensive sclero- X X 19 patients had an RFR defect and 9 derma patients showed a normal RFR. Those pa- tients had a lower BP. After 5 years: 13 of 19 showed a reduction of CrC >2mL/min/year Amin 2012 30 patients with X DTPA 2 High prevalence of lower RFR in scleroderma scleroderma patients. Pulmonary 30 controls hypertension correlated with ab- normal RFR SLE No CKD Khusnutdinova 30 versus 40 controls X X RFR was 41% in controls and lower in 2014 SLE Poststreptococcal GN No CKD on follow- Iturbe 1985 35 patients X X CrC rose from 82.06 6.45 to 90.36 5.3 up mL/min Chronic No CKD Tietze 1994 13 biopsied CGN X IOTH 1 Renal response and glomerulo-tubu- glomerulonephritis 13 controls lar balance are intact. Abnormal lack of suppression of the renin– angiontensin–aldosterone system after AA infusion IgA nephropathy Bach 1994 7 with modest X X GFR and ERPF increased in controls impairment and patients without nephrotic 2 nephrotic syndrome. No increase in the two 9 controls nephrotic patients Beukhof 1985 32 X IOTH 1 Dopamine induces GFR-only effect when baseline GFR > 73 mL/min/ 1.73 m GFR 64 mL/min,Diet: Pluvio 1996 7 stage II, 8 stage III-IV X X RFR 20% in Stage II comparable to 0.9–1.3 g/kg/d and 12 controls normals. No RFR in Stages III–IV protein De Santo 1997 10 proteinuric IgAN X X X GFR was lower and FF was higher at patients baseline in patients. GFR increase 20 controls following protein load was comparable Sulikowska 2004 20 patients before and 1 X X Omega-3 polyunsaturated acids im- year after treatment prove dopamine-induced GFR re- with Omega-3 sponse and lower proteinuria and NAG excretion Sulikowska 2008 50 X X Less response on dopamine, higher 15 controls NAG and FeUA Sulikowska 2012 46 patients X X Lower DIR in patients. Correlation of 15 controls EPO with uric acid clearance: more EPO and reduced urate clearance (continued) 22 | B. De Moor et al. Downloaded from https://academic.oup.com/ckj/advance-article-abstract/doi/10.1093/ckj/sfy022/4969997 by Ed 'DeepDyve' Gillespie user on 12 July 2018 Table 5. Continued Type of stimulus Type of GFR measurement Result Urinary Inulin Clinical Protein Creatinine (þ PAH) Urinary Exogenous context Condition Ref Number Dopamine AA meal IV clearance CrC marker Sulikowska 2015 46 non-nephrotic IgAN X X IgAN patients were separated in sub- patients jects showing a decrease in EPO lev- 15 controls els versus those showing an increase in EPO levels. A decreasing EPO level was associated with a pre- served CrC response, less protein- uria, less NAG and lower uric acid and blood pressure while kidney bi- opsy findings were comparable HIV nephropathy Marques 1998 6 healthy X X CrC increases in healthy subjects. In 9 asymptomatic carriers HIV carriers a lower response is of HIV observed Sickle Cell anaemia Herrera 2002 16 sickle cell A X X IOTH 2 SCA patients have a higher GFR at 20 controls baseline, but no increase in tubu- lar secretion of creatinine CKD Altered renal Bosch 1983 6 X X Some have RFR while others not function CKD1a, CKD1b, Bosch 1984 CKD1a (4), CKD1b (13), X X X CKD1a: from 1496 12 to 1656 13 mL/ CKD2, CKD4 CKD2 (9), CKD4 (5) min CKD1b: from 1096 8 to 1246 16 mL/ min CKD2: from 706 14 to 866 12 ml/min CKD4: from 226 6to 246 6 ml/min CKD 1, CKD 2-3, CKD ter Wee 1985 CKD 1: 9 X X IOTH 1 4 CKD 2–3: 11 CKD 4: 7 Variable GFR Bosch 1986 10 X X GFR increases from 636 29 to 766 37 mL/min dependent on severity Colome 1987 16 controls (13 adults X X No response if clearance is <40 mL/ and 3 children) min and in patients with acquired 31 patients (22 adults or congenital solitary kidney. The and 9 children) presence of proteinuria is not associated CGN Chan 1988 12 patients X X No acute effect on glomerular barrier 12 controls size selectivity Reduced number of Zuccala 1989 20 with 15–70% sclerotic X X RFR is not necessarily reduced or ab- functioning glomeruli sent in patients with a reduced glomeruli 10 with acquired single number of functioning glomeruli kidney 5 with surgical ablation of >50% of renal mass 24 controls CKD Krishna 1991 15 CKD X X Preserved renal reserve in CKD pa- tients not influenced by enalapril Uemasu 1991 8 healthy subjects glucagon THIO Normal controls show an increase in 9 subjects with CGN and GFR and ERPF. CGN with preserved baseline GFR >90 mL/ GFR showed no increase in ERPF, min while patients with lower GFR 8 subjects with baseline showed no effect on GFR while GFR between 40 and ERPF increases 90 mL/min (continued) Haemodynamic or metabolic stimulation tests | 23 Downloaded from https://academic.oup.com/ckj/advance-article-abstract/doi/10.1093/ckj/sfy022/4969997 by Ed 'DeepDyve' Gillespie user on 12 July 2018 Table 5. Continued Type of stimulus Type of GFR measurement Result Urinary Inulin Clinical Protein Creatinine (þ PAH) Urinary Exogenous context Condition Ref Number Dopamine AA meal IV clearance CrC marker Loo 1994 32 with CKD X X Renal response in healthy subjects 19 post-transplantation was 31 mL/min. Lower response in 12 kidney donors CKD patients: 13.5 mL/min. Same 62 healthy controls response in transplant recipients. Lower response in donors: 5.4 mL/ min De Santo 1997 10 healthy subjects X X Similar increase of GFR in healthy 10 CKD patients (GFR ¼ and CKD patients. Renal tubules 40 mL/min) contribute to the acid/base balance in both groups by reabsorbing most of the bicarbonate load CKD on low protein Cianciaruso 1994 14 X X X Lower effect of stimulus in patients diet even after low-protein diet, while in controls an increased effect is seen on a low-protein diet CKD 1-2CKD 3CKD 4 De Santo 1995 CKD 1–2 ¼ 115 X X Compared with 85 healthy subjects, CKD 3 ¼ 85 renal disease patients peak later CKD 4 ¼ 73 after a protein meal. Cumulative GFR increase is less in renal disease Herrera 1998 12 controls X X X Comparison of inuline and CrC re- 7 donors veals that there is a limited tubular 8 CKD secretion of creatinine dependent on renal mass De Nicola 1999 21 proteinuric CKD pa- X X No improvement of 6 months treat- tients: 11 for 6 ment with arginine supplementa- months on L-arginine tion on renal functional response and 10 controls Barai 2010 25 controls X DTPA 1 Control mean renal reserve ¼ 23.4% 100 CKD CKD 1 ¼ 19.08% CDK 2 ¼ 15.4% CKD 3 ¼ 8.9% CKD 4 ¼ 6.7% Diabetes Bosch 1986 18 X X GFR decreases from 1186 46 to 1026 37 mL/min Insulin-dependent ter Wee 1987 14 X X IOTH 1 130 mL/min baseline GFR, lesser (type 1) increase after AA than controls de- pendent on baseline GFR (negative correlation) Type 2 DM Nakamura 1989 A: no albuminuria X X No albuminuria: normal GFR in- B: micro crease. Microalbuminuria: no GFR C: macro increase. Macro: GFR decreases after placebo Type 1 DM Nosadini 1989 15 IDDM (>9 years), 8 X EDTA 1 Comparison of AA and ketone body with and 7 without infusion shows that renal re- albuminuria sponse in long-standing DM type 1 8 controls patients is not present (continued) 24 | B. De Moor et al. Downloaded from https://academic.oup.com/ckj/advance-article-abstract/doi/10.1093/ckj/sfy022/4969997 by Ed 'DeepDyve' Gillespie user on 12 July 2018 Table 5. Continued Type of stimulus Type of GFR measurement Result Urinary Inulin Clinical Protein Creatinine (þ PAH) Urinary Exogenous context Condition Ref Number Dopamine AA meal IV clearance CrC marker Type 2 DM with Brouhard 1990 8 patients on low- X X RFR measured at 6-month intervals nephropathy protein (0.6 g/kg/d) during 1 year decreased as well as and 7 on normal diet resting GFR in patients on normal diet Type 1 DM Dedov 1991 10 patients with type 1 X X Patients with normal RFR show a DM without diabetic lower baseline GFR. Patients with nephropathy no RFR have a higher resting GFR 7 healthy controls and demonstrate hilar glomerular lesions with severely expanded mesangium, apparently preceding overt nephropathy Type 2 DM Tuttle 1992 12 diabetic patients X X Diabetics show a higher baseline GFR without insulin and ERPF, as well as a more prom- treatment inent RFR. This does not change 9 normal subjects after 36 h of insulin infusion. A 3- week course of insulin therapy diminishes the exaggerated renal response and the volume of the right kidney without normalizing it Sackmann 1998 33 patients: 14 early X X Early stage (at high GFR) and late stage, 10 microalbu- stage (proteinuric and lower GFR) minuric, 9 late stage show less response 12 controls Type 1 DM Sackmann 2000 10 with nephropathy, 10 X X Less increase of GFR in patients with without nephropathy (proteinuria and 15 controls hypertension) even when GFR is preserved Type 2 DM Guizar 2001 181 recently diagnosed X X 75% of patients show microalbumi- type 2 -> 28 studied, nuria. Studied microalbuminuric 7 controls patients lose response on protein load Type 2 DM Earle 2001 9 African-Asian diabetes X X Less response in patients of African- 9 white patients Asian descent due to defective NO production or bioavailability Type 1 DM Assan 2002 285 IDDM treated with X X 10–12% functional response, con- cyclosporine served even after 7 and 10 years of 100 IDDM not treated low-dose cyclosporine treatment with cyclosporine Type 1 DM Tuttle 2002 12 DM type 1 X X Diabetics have a higher GFR and FF. 12 controls AA and glucagon induce GFR to rise via a different pathway. Glucagon can be inhibited by indomethacine (continued) Haemodynamic or metabolic stimulation tests | 25 Downloaded from https://academic.oup.com/ckj/advance-article-abstract/doi/10.1093/ckj/sfy022/4969997 by Ed 'DeepDyve' Gillespie user on 12 July 2018 Table 5. Continued Type of stimulus Type of GFR measurement Result Urinary Inulin Clinical Protein Creatinine (þ PAH) Urinary Exogenous context Condition Ref Number Dopamine AA meal IV clearance CrC marker Type 1 DM Zaletel 2004 22 patients without X X Renal response is inversely related to renal disease CRP, linking endothelial dysfunc- tion with renal haemodynamic behaviour Type 1 DM Sulikowska 2007 30 sulodexide and 13 X X Sulodexide helps in improving dopa- not mine-induced GFR response and lowering of NAG Mueller 2009 28 diabetic patients X X Preserved RFR in 6 of 28 patients. No correlation with cystatin C Children (< 18 years) Hellerstein 2004 89 studies in 78 children X X þ cimetidine Follow-up of CACrC after a meat-free protein meal is non-invasive and inexpensive Solitary kidneys Peco-Antic 2012 22 patients XX þ cimetidine CACrC and cystatin C were com- 30 controls pared. Half of the patients had decreased RFR. Cystatin C was a strong predictor. Also, blood pres- sure was a determinant CKD Molina 1988 Normal: 386 X X X A normogram was constructed with CKD: 21 p10 and p90. Negative correlation of stimulated GFR with unstimulated De Santo 1990 Normal: 11 X X Earlier peak GFR in healthy children. 10 children with mean Greater increase of GFR and RPF in creatinine 2.6 mg/dL diseased children Offspring of hyper- Grunfeld 1990 21 X X Lack of GFR increment in offspring of tensive parents hypertensive parents is associated with higher albuminuria Type 1 DM Semiz 1998 22 patients (11 with >5 X X Renal functional response is lower years of diabetes, 11 after a longer duration of diabetes. with shorter duration) This pathology is present without 15 healthy controls albuminuria Raes 2007 51 diabetic children X X Unstimulated GFR is similar, 34 controls increased FF. Lower RFR in patients Previous post-strep- Cleper 1997 36 patients (5–21 years X X Similar basal CrC. The functional re- tococcal GN old) without renal sponse is lower in patients after a function anomalies post-streptococcal GN 12 controls (2–12 years old) Previous HUS Perelstein 1990 17: previous HUS X X Children with a history of HUS show 11: single kidney an abnormal RFR 15: controls Tufro 1991 16 X X Protein content in the diet influences CrC (continued) 26 | B. De Moor et al. Downloaded from https://academic.oup.com/ckj/advance-article-abstract/doi/10.1093/ckj/sfy022/4969997 by Ed 'DeepDyve' Gillespie user on 12 July 2018 Table 5. Continued Type of stimulus Type of GFR measurement Result Urinary Inulin Clinical Protein Creatinine (þ PAH) Urinary Exogenous context Condition Ref Number Dopamine AA meal IV clearance CrC marker Dieguez 2004 26: tested two times XX þ cimetidine CACrC rises after a protein load in 15 controls both patients and controls. When distinction is made between re- sponders (> 36% increase) and not, non-responders develop protein- uria. They had a longer oliguria period during their HUS Bruno 2012 33 children with previ- X EDTA 2 Half of the children showed a GFR in- ous HUS (18 males, 15 crease of at least 20%, judged as a females) with normal normal response CrC Reflux nephropathy Coppo 1993 28 children with surgi- X Children with severe renal parenchy- cally corrected bilat- mal scarring had greater albumin- eral vesico-ureteric uria and beta-2 microglobuline in reflux basal conditions. Both increased after AA infusions. CrC increases also Matsuoka 2009 35 patients with reflux X THIO When glomerular size was normal, nephropathy, glom- DIR was good and ERPF was erular size evaluated unchanged on renal biopsy When GS was enlarged, GFR and ERPF increased both When GS was extremely enlarged, both GFR and ERPF remained unchanged Unilateral uretero- Montini 2000 4 boys and 1 girl after X X GFR at baseline was greater in normal pelvic junction pyeloplasty with than in surgically treated kidney. obstruction contralateral kidney Aspirin decreases GFR in operated as control kidneys. Lower GFR increase after protein loads in operated kidneys Posterior urethral Ansari 2011 25 patients, at least 6 X DTPA 1 In more than a third of patients, RFR valve weeks after fulgur- is depleted. They had more blad- ation of posterior ur- der dysfunction and more severe ethral valve vesicoureteral reflux 125 125 IOTH 1 ( I-iothalamate): IV bolus followed by a continuous infusion. Urinary and plasma clearances (to correct for incomplete voiding). HPLC measurement (in later studies);IOTH 2 ( I-iothalamate): single SC injection. Plasma clearances. Gamma counter measurement; IOH 1 (iohexol): IV bolus followed by a continuous infusion. Plasma clearances. HPLC measurement; IOH 2 (iohexol): single IV bolus. Plasma clearances. HPLC measurement; EDTA 1 ( Cr- 51 99m 99m EDTA): IV bolus followed by a continuous infusion. Urinary clearances; EDTA 2 ( Cr-EDTA): single IV bolus. Plasma clearances; DTPA 1 ( Tc-DTPA): single IV bolus. Plasma clearances; DTPA 2 ( Tc-DTPA): single IV bolus. Isotope 99m renography; MAG 3 ( Tc MAG 3): single IV bolus. Isotope renography; THIO (thiosulfate sodium): IV bolus followed by a continuous infusion. Urinary clearances. Measurement by the method of Brun. GN: glomerulonephritis; HUS, Haemolytic uraemic syndrome. Haemodynamic or metabolic stimulation tests | 27 Overweight people show an increased unstimulated GFR Diabetic patients with overt proteinuria fail to respond with a and less exploitable filtration capacity [87]. GFR increase when challenged with a protein meal [100–103]. Kidney donors as well as patients with a congenital single In pregnancy, the induced augmented renal clearance (we kidney were extensively studied (Table 5). The expected re- deliberately avoid using the phrase ‘hyperfiltration’) is observed sponse after a fixed protein meal or an AA infusion is generally because of an increased ERPF thanks to relaxin, a vasodilating preserved in single kidneys, even several years after nephrec- hormone produced by a healthy placenta. Pregnancy offers the tomy. Dopamine accomplishes less stimulatory effect, as ERPF most extensive increment of GFR [104]. The filtration fraction of is already maximally increased [45]. Long-term follow-up re- kidneys in pregnancy is normal or decreased [105]. Only normo- veals that the gradual increase in the GFR in the post-transplant tensive gravida display a functional response [106]. Failure to period is achieved by glomerular hypertrophy instead of an fully dilate the afferent arteriole and augment ERPF may lead to increased ERPF [88]. Regazzoni et al. [89] described an unchanged pre-eclampsia or pregnancy-related hypertension [104]. Hence GFR several years after a nephrectomy in childhood. However, the interest in examining the RFR in women with kidney dis- an oral protein load proved gradually less effective in evoking orders consulting with a pregnancy wish. an adequate response. Transplanted kidneys show less re- sponse to a protein stimulus when treated with cyclosporine CRITICAL APPRAISAL OF RENAL STIMULATION compared with patients treated with a calcineurin-free regi- TESTING men, mostly azathioprine [90]. The extent of the GFR increment after a stimulus correlated with kidney size (i.e. length or vol- The idea of a dormant and exhaustible RFR was flawed as soon ume). Kidneys from younger donors exhibited a better renal re- as it became obvious that single and transplanted kidneys still sponse after a stimulus and this was dependent upon the show a functional improvement after a protein load [10]. This unstimulated GFR of the donor [91]. The native kidneys of pa- observation led to waning interest in renal function testing and tients after a heart transplantation tended to show less re- resulted in incomplete scientific explorations: not all renal syn- sponse than the single transplanted kidney [92]. This was dromes have been thoroughly tested. Correlations with histolo- attributed to pre-existent cardiovascular damage, absence of gical findings are hardly reported. Moreover, there are no renal denervation or a slightly higher cyclosporine trough level. reference data in sickness or in health. Furthermore, longitu- Hypertensive patients challenged with a protein meal, dinal data linking a decreased stimulatory effect to unfavour- demonstrate a weaker or absent renal response. The presence able outcomes are scarce. Today, the use of RFR measurements of albuminuria indicates subclinical damage with abolished has no place in routine clinical care. filtration reserve. A significant negative correlation was shown A second criticism is the missing of a renal distress signal, between the renal response and the renal resistive indices, making renal and cardiac stress testing hard to compare. An ab- evaluated by ultrasound [77]. In the offspring of hypertensive sent functional response and/or the demonstration of a higher parents, the RFR proved lower and was associated with albu- filtration fraction could be viewed as a surrogate for renal mal- minuria [93]. Fifteen patients planned for a coronary angiog- adaptation, potentially leading to progressive nephron loss. raphy were matched with as many healthy peers. Their ERPF This parameter can only be documented when renal clearances was lower and correlated with the extent of coronary lesions of a filtration and a perfusion marker (PAH or I-hippuran or [94]. No response on AA infusion could be documented in pa- 99 Tc-mercaptoacetyltriglycine) are followed simultaneously. tients with coronary artery disease. Without the emergence of injury biomarkers, a normal renal IgAN cases were studied after AA and dopamine infusions. A response after a protein load implies normal protein tolerance. diminished renal response was present in patients with more In contrast to cardiac stress testing providing the clinician prominent histological lesions (with >50% of the glomeruli with an early diagnosis allowing for targeted treatment, renal showing proliferation and >15% of the glomeruli with crescents function testing offers the clinician a suggestion of subclinical or segmental lesions) [95]. Another study correlated a lower GFR pathology, but without therapeutic consequences. increase to injury biomarkers such as proteinuria and NAG ex- A concern is the terminology used. The literature is with cretion [60]. confounding nomenclature and consensus definitions are Livi et al. [96] studied patients suffering from systemic sclerosis missing. and found that they displayed a lower stimulated GFR. Followed Renewed interest in renal function testing has been stimu- for 5 years, scleroderma patients without increasing GFR at the lated by nephrologists involved in AKI care. A metabolic challenge startlostkidney function ata faster rate of >2 mL/min/year. This could be valuable in assessment of the renal recovery. However, study is one of the rare prospective reports. Children tested after a the causative link of diminished renal protein tolerance to a previous episode of haemolytic uremic syndrome showed variable higher susceptibility for recurrent AKI remains debatable. response after a protein meal. Low responders (<36% increase) de- Finally, renal function testing is relatively labour intensive veloped proteinuria later in life [97]. and requires the allocation of resources. Because the test re- When renal function is decreasing, the amount of exploitable mains in the experimental context, it is not reimbursed. Spinelli filtration capacity decreases but stays measurable even in pa- et al. [40] performed a cost calculation of a simple RFR test using tients with Stage 4 CKD [98]. This contrasts with the former the- cooked beef as a stimulus and four urine CrC measurements ory of RFR, claiming that the reserve capacity is fully utilized added to 8 h of a nurse’s workload. The total cost was e91 for a before the GFR drops below 50 mL/min [80]. single RFR estimation. Costs were predominantly driven by the In a small study, 10 compensated patients with mild heart nursing workload, so actual costs may vary substantially failure showed no vasodilatory response after AA infusion. The between different regions of the world. response was restored after initiation of an ACE inhibitors [99]. A higher GFR is observed in diabetics with hyperglycaemia. FUTURE DIRECTIONS OF RESEARCH In these circumstances, the renal blood flow and the filtration fraction are increased, resulting in a higher intraglomerular The first step to be taken is deciding on a common vocabulary. pressure. This leads to transient or permanent albuminuria [27]. We propose to use the terminology of unstimulated GFR (when Downloaded from https://academic.oup.com/ckj/advance-article-abstract/doi/10.1093/ckj/sfy022/4969997 by Ed 'DeepDyve' Gillespie user on 12 July 2018 28 | B. De Moor et al. Table 6. Suggested research topics for renal stimulation testing (adapted and complemented from Molitoris [16]) Clinical category Specific situation Diagnostic information 1. Prior to renal mass reduc- Before kidney donation Risk of CKD post-donation ing surgery Before nephrectomy for other reasons Need for nephron-sparing surgery or alternative therapies (e.g. radiofrequency ablation) 2. In case of congenital or Congenital anomalies of the kidney and urinary Long-term prognosis acquired lower renal tract mass After kidney transplantation Long-term prognosis After kidney donation Risk of progressive renal failure 3. In case of suspected renal Before major surgery Risk of AKI frailty Before pregnancy in high-risk situations Risk of gestational hypertension and pre- eclampsia Before or during chemotherapy or treatment Early nephrotoxicity? Need for dose reduction or with nephrotoxic drugs change of therapy? In high-risk patients (cardiovascular disease, Early diagnosis of CKD COPD, OSAS, diabetes, scleroderma, etc.) In geriatric patients Discerning renal ageing from genuine CKD In patients after cystectomy and urinary Early diagnosis of tubulointerstitial nephritis diversion In patients with the cardiorenal syndrome Distinction between worsening renal function and true AKI Follow-up after an AKI episode Fully recovered or not Follow-up after inflammatory Fully recovered or not glomerulonephritis 4. In case of suspected Obesity Maladaptive hyperfiltration or not whole kidney Diabetes type 1 and type 2 Maladaptive hyperfiltration or not hyperfiltration Septic patients Augmented renal clearance resulting in alterna- tive dosing of antibiotics COPD, chronic obstructive pulmonary disease; OSAS, obstructive sleep apnoea syndrome. all confounding variables are controlled for), random GFR and as a higher GFR have been associated with increased cardiovas- stimulated GFR. We also advocate rephrasing the terminology cular risk [109]. No renal response might indicate single-neph- of RFR, although firmly embedded in the literature, to renal ron hyperfiltration in both circumstances. functional response. The complexity of the stimulation protocol should match Second, two standard protocols of renal function testing can the importance of the anticipated result. Hence the study of kid- be proposed, varying in complexity from an elaborate research ney donor candidates might receive the greatest attention: methodology (encompassing exogenous markers) to a simple maximal stimulus (dopamine in combination with an AA infu- scheme with calculated renal CrCs by the means of timed urine sion) combined with measured GFR by an exogenous marker. collections. However, recent evidence points to the important Women at high risk for pre-eclampsia or pregnancy-induced contribution of tubular secretion in the clearance of protein- hypertension might be solicited to participate in a simple pro- bound retention products [107]. The tubular contribution to tein challenge study with urinary CrC. Also, patients applying overall renal clearance can be evaluated by simultaneously for bariatric surgery might be tested: an absent functional re- measuring the clearance of creatinine and an exogenous filtra- sponse could provide the multidisciplinary team with a sense of tion marker, either after a protein meal or a creatinine load. urgency. Will these patients regain their glomerular reactivity Alternative stimuli should be explored, for instance serelaxin along with the expected reduction of proteinuria [110]? Tubular [108]. function testing can be interesting in patients with chronic ob- Third, prospective studies in different disease entities are structive pulmonary disease or obstructive sleep apnea, with necessary to link an abnormal renal response to major adverse both showing a high prevalence of kidney disease. Can RFR test- renal endpoints and provide us with reference values. In Table 6 ing before and after starting nocturnal continuous positive air- we present four clinical situations in which the absent response way pressure sort out the questions in this syndrome regarding after stimulation might yield meaningful diagnostic and prog- cause, effect or merely association? Post-AKI patients can be nostic information: subjects before kidney mass reducing sur- evaluated before they leave the ICU by means of an AA infusion gery or known to have a diminished number of nephrons, and timed urinary CrCs. In this way, their renal recovery status patients in which renal disease is assumed and individuals with is better documented and can be correlated with future events. an augmented renal clearance. When the eGFR is low, a signifi- Doig et al. [111] published a randomized controlled trial in an cant stimulatory response indicates a sufficient nephron quan- ICU population of an AA infusion as a preventive strategy for tity. In the case of a diminished or absent increase, CKD can be AKI: the primary endpoint was negative but eGFR and urine pro- ascertained. Subjects at high cardiovascular risk may present duction increased. Repetitive testing of the glomerular and with a preserved eGFR. If a renal stimulation test fails to induce tubular reserve by a protein load in patients after cystectomy an increment of glomerular filtration, these patients can be and urinary diversion, might elucidate progressive tubulointer- diagnosed as having subclinical kidney disease. A lower as well stitial damage even before serum creatinine rises. Downloaded from https://academic.oup.com/ckj/advance-article-abstract/doi/10.1093/ckj/sfy022/4969997 by Ed 'DeepDyve' Gillespie user on 12 July 2018 Haemodynamic or metabolic stimulation tests | 29 Finally, to broaden the scientific foundation of renal function CONFLICT OF INTEREST STATEMENT testing, studying the behaviour of renal damage biomarkers None declared. during renal stimulation might offer more insight into glomeru- lar and tubular adaptation. Moreover, functional data should be coupled to histological information. Morphological details REFERENCES acquired by MRI or ultrasound can provide additional elements. 1. King AJ, Levey AS. Dietary protein and renal function. JAm Obviously these lines of research will greatly amplify the cost of renal function testing and can only be initiated in the context of Soc Nephrol 1993; 3: 1723–1737 2. The Low Birth Weight and Nephron Number Working a study. 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Haemodynamic or metabolic stimulation tests to reveal the renal functional response: requiem or revival?

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Abstract

Clinical Kidney Journal, 2018, 1–32 doi: 10.1093/ckj/sfy022 CKJ Review CK J R E V I E W Haemodynamic or metabolic stimulation tests to reveal the renal functional response: requiem or revival? 1,2 2 1 2 Bart De Moor , Johan F. Vanwalleghem , Quirine Swennen , Koen J. Stas 3,4 and Bjo ¨ rn K. I. Meijers 1 2 Faculty of Medicine and Life Sciences, University of Hasselt, Diepenbeek, Belgium, Department of Nephrology, Jessa Hospital of Hasselt, Hasselt, Belgium, Department of Nephrology, Universitair Ziekenhuis Leuven, Leuven, Belgium and Department of Immunology and Microbiology, Faculty of Medicine, Katholieke Universiteit Leuven, Leuven, Belgium Correspondence and offprint requests to: Bart De Moor; E-mail: bart.demoor@uhasselt.be ABSTRACT Renal stimulation tests document the dynamic response of the glomerular filtration rate (GFR) after a single or a combination of stimuli, such as an intravenous infusion of dopamine or amino acids or an oral protein meal. The increment of the GFR above the unstimulated state has formerly been called the renal functional reserve (RFR). Although the concept of a renal reserve capacity has not withstood scientific scrutiny, the literature documenting renal stimulation merits renewed interest. An absent or a blunted response of the GFR after a stimulus indicates lost or diseased nephrons. This information is valuable in preventing, diagnosing and prognosticating acute kidney injury and pregnancy-related renal events as well as chronic kidney disease. However, before renal function testing is universally practiced, some shortcomings must be addressed. First, a common nomenclature should be decided upon. The expression of RFR should be replaced by renal functional response. Second, a simple protocol must be developed and propagated. Third, we suggest designing prospective studies linking a defective stimulatory response to emergence of renal injury biomarkers, to histological or morphological renal abnormalities and to adverse renal outcomes in different renal syndromes. Keywords: protein stimulation test, renal functional reserve, renal functional response, renal stimulation test, renal stress test practice, clinicians usually rely on estimated GFR (eGFR) calcu- INTRODUCTION lated from a single serum marker measurement, mostly creatin- Glomerular filtration rate (GFR) is considered the best overall ine. However, such estimates have several limitations. Estimating index of kidney function. It is dependent on age, gender, ethni- equations are valid only in steady-state conditions. Moreover, city, body composition and diet [1] aswell asnephron endow- analytical variation of serum creatinine measurements (2% for ment [2]. GFR is determined by the measured clearance of certain enzymatic assays), variation in tubular secretion and dependency exogenous markers or endogenous waste products. In everyday on muscle mass [3] should be factored in. Received: 2.11.2017. Editorial decision: 26.2.2018 V C The Author(s) 2018. Published by Oxford University Press on behalf of ERA-EDTA. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/ licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com Downloaded from https://academic.oup.com/ckj/advance-article-abstract/doi/10.1093/ckj/sfy022/4969997 by Ed 'DeepDyve' Gillespie user on 12 July 2018 2| B. De Moor et al. Table 1. Suggested terminology and alternatives in the context of a Often ignored, GFR is not constant, as the kidneys do not renal stimulation test continuously function at maximum filtration capacity [4]. It is estimated that in healthy subjects, kidneys usually operate at Unstimulated GFR Random GFR Stimulated GFR 75% of their maximal GFR. Renal function is influenced by di- urnal cycles [5] and is stimulated by protein-containing meals. Unstressed GFR Uncontrolled GFR Stressed GFR Thus, single-point assessments of renal function ignore varying Basal GFR Actual GFR Peak GFR rates of glomerular filtration, as kidneys are capable of adjusting Baseline GFR Reference GFR Maximal or maximized GFR their performance to haemodynamic and metabolic demands. Resting GFR Maximal filtration capacity In 1930, Verney mentioned the reserve forces of the kidney Minimal GFR [6]. In analogy with myocardial and pulmonary function, a re- Renal functional response¼ stimulated GFR – baseline GFR (either in mL/min or dundant or dormant renal reserve was hypothesized, intended in percentage of baseline GFR), i.e. renal functional reserve, renal reserve cap- to cope with extraordinary haemodynamic and metabolic de- acity, renal reserve filtration capacity. mands. Fifty years later, Bosch called this the renal functional reserve (RFR), defined as the difference between the baseline protein intake of the subject. This can be derived from the urea GFR and the stimulated GFR, measured 2 h after a protein meal [7]. nitrogen level in timed urine collection. Coincidentally, patients Over the years, enthusiasm for the RFR concept abated [8– with CKD often follow a low-protein diet. This increases the 12], until Ronco and colleagues [4, 13–15] and Molitoris [16] re- value of a stimulatory test. cently revived interest in this concept. They postulate that di- The stimulated or stressed GFR is the measured GFR follow- minished RFR contributes to the susceptibility for recurrent ing a stimulus, including an oral protein load, an intravenous acute kidney injury (AKI). These authors argue that evaluation amino acid (AA) solution, a glucagon infusion or a dopamine of the degree of functional recovery post-AKI is not only clouded drip [22]. Rodrı ´guez-Iturbe et al. [23] defined a tubular stress test, by the loss of muscle mass but also by stimulated single-neph- describing the tubular secretion of intravenously injected cre- ron GFR to compensate for nephron loss. Testing the renal func- atinine. Regretfully, a creatinine solution marketed for intraven- tional response in these recovered patients could possibly ous use in human experiments is currently not available unveil this undetected loss of functional units and could iden- (personal inquiry). As creatinine is readily absorbed by the tify patients at risk for progression to chronic kidney disease gastrointestinal tract, an oral creatinine load is safer and might (CKD). This hypothesis was discussed and reviewed at the Fifth result in a comparable tubular challenge [24]. Recently a fur- International Conference of the French Society of Intensive Care osemide stress test was applied to patients with progressive [17, 18]. AKI, discriminating recovery from progression [25]. Thus renal Additionally, a deficit in RFR has been incriminated in stimuli are either of a metabolic or haemodynamic nature. A pregnancy-related kidney disease [19]. Further, study of the protein meal, when composed of cooked meat, challenges the diagnostic and prognostic utility of RFR has been mentioned in kidney with both AA and creatinine. This stimulus can be con- the roadmap for global kidney health 2017, issued by the sidered a combination of both a metabolic and a tubular International Society of Nephrology [20]. Finally, the promotion stimulus. of high-protein diets to lose weight stimulated renewed atten- Descriptions of the numerous alternative tubular challenges tion to the postprandial behaviour of the GFR. (sodium, potassium, phosphorus, acid, water deprivation and Reviewing the literature on RFR is impeded by a myriad of water loading) is beyond the scope of this review. definitions and stimulatory tests. This article aims to propose a After stimulation and in healthy subjects, the GFR can reach synthesizing lexicon and tries to offer a variety of protocols for 180–200 mL/min. Some authors refer to GFR in this range as future directions of research. hyperfiltration. Cachat et al. [26] reviewed the literature in 2015 and Tonneijck et al. [27] recently described the mechanisms of diabetic hyperfiltration. These authors correctly differentiate LEXICON between whole kidney function as opposed to single-nephron The RFR (also referred to as renal reserve capacity) is defined as function. On a single-nephron level, hyperfiltration is assumed the difference between the stimulated GFR and the baseline when the intraglomerular pressure is elevated, causing albu- GFR. This difference can be expressed in absolute terms (mL/ minuria and in the long-term leading to progressive glomerulo- min) or in relative terms (percentage of increment relative to sclerosis. Single-nephron hyperfiltration does not automatically the baseline GFR). Although a straightforward and simple defin- translate into whole-kidney hyperfiltration, quite the opposite: ition at first sight, terminologies and definitions are quite con- glomerular hyperfiltration is often intended to preserve a wan- fusing. Table 1 proposes a revised nomenclature in the context ing whole-kidney GFR in the face of a diminishing nephron of renal functional testing. The expression of RFR should be number [28]. More recently, high GFR values were also noted in replaced by renal functional response. septic intensive care unit (ICU) and post-operative patients. We The baseline or basal GFR is sometimes referred to as un- advocate the use of augmented renal clearance for seemingly stimulated GFR (as opposed to stimulated GFR) or unstressed physiological adaptations and the use of stimulated GFR in the GFR (to better differentiate it from the GFR in stressed circum- context of RFR. stances) and finally resting GFR. While the resting GFR is the lowest normal GFR, it is not identical to the baseline GFR used in the context of AKI, which is usually defined as the best or PHYSIOLOGY OF METABOLIC RENAL highest GFR preceding an AKI episode [17, 21]. STIMULATION To maximally guarantee an unstimulated (lowest) GFR, pa- tients are often instructed to adhere to a low-protein or vegetar- For a more extensive overview of the functional compensation ian diet in preparation for a renal stimulation test. If the person after a protein meal, we refer the reader to excellent reviews by is not instructed to do so, the test results (actual GFR and max- Gabbai [29], Bankir et al. [30], Helal et al. [31], King and Levey [1] imal increase) should be interpreted in the light of the usual and Premen [32]. Downloaded from https://academic.oup.com/ckj/advance-article-abstract/doi/10.1093/ckj/sfy022/4969997 by Ed 'DeepDyve' Gillespie user on 12 July 2018 Haemodynamic or metabolic stimulation tests | 3 Any metabolic stimulus triggers the kidneys to increase the oral fluids. Hypovolaemia also blunts the renal response after GFR primarily by reducing the overall renal vascular resistance stimulation [38]. Second, the body must remain in the fasting (RVR) and inducing a postprandial renal hyperaemia. This in- state for at least 8 h (overnight fasting). A low-protein or vegetar- crease of the renal blood flow results from systemic mediators ian diet for 10 days preceding the test is advised by some authors as well as paracrine factors, both acting on the whole kidney to ascertain a true unstimulated GFR. Doubt remains if this inter- level as on the single-nephron GFR. Initially, recruitment of qui- val succeeds in normalizing glomerular hypertrophy caused by a escent glomeruli in ill-perfused regions was hypothesized, chronically high-protein diet. If the investigator does not advo- hence the term ‘renal functional reserve’ [7, 33]. Later it was cate this preparatory phase, habitual protein intake can be esti- concluded that the increased GFR results from a higher filtra- mated from urea nitrogen in a 24-h urine collection [41] and the tion effort of all single nephrons, almost exclusively attributed extent of GFR stimulation must be interpreted with this know- to a higher effective renal plasma flow (ERPF). ledge. Finally, besides a thorough non-pharmacological prepar- The feed-forward stimulus after a protein load or an increase ation, some drugs must be paused, as they interfere with renal in AA plasma levels originates from the pancreas and the liver vascular adaptation. These include non-steroidal anti- [30]. A higher ratio of glucagon to insulin stimulates the liver in inflammatory drugs (NSAIDs) [42], ACE inhibitors and angioten- favour of nitrogen handling and helps the kidneys in the sin receptor blockers. disposal of urea. The hepatic production of cyclic adenosine monophosphate (cAMP) operates as a second messenger. On Selecting the proper stimulus the single-nephron level, glucagon and cAMP cooperate to re- duce the tubular solute concentration at the macula densa. In Measuring the stimulated GFR requires maximal recruitment of this way, the tubuloglomerular feedback is downregulated. As a the so-called reserve GFR. Several approaches have been advo- result, vasodilation of the pre-glomerular arteries and arterioles cated, which—broadly speaking—can be divided into haemody- induces an increase in the single-nephron GFR. Intrinsic renal namic and metabolic stimuli. autoregulation with nitric oxide, vasodilating prostaglandins In humans, a significant increase of the GFR has been and kinins is responsible for this action. Inhibition of renal described with glucagon infusions at a rate of 10–20 ng/kg/min. autocrine prostaglandin synthesis with indomethacin counter- More frequently, dopamine is used. This vasoactive drug aug- acts the vasodilatory effects of AAs. The hypothalamic–hypo- ments the ERPF and hence the GFR without affecting cardiac physeal axis contributes to this process. Vasopressin or the output or systemic vascular resistance. The FF usually drops antidiuretic hormone (ADH) is also active in stimulating the GFR slightly when dopamine is infused at a dose of 2.0 mg/kg/min. after a protein meal. Together with glucagon, this hormone This is the result of afferent and preferentially efferent arteri- helps in the processing of protein metabolites. The role of olar dilation [43]. At the single-nephron level, the increased fil- growth hormone seems of less importance, as a protein meal tration seems totally attributable to higher plasma flow in equally elicits a functional renal response in growth hormone– combination with lower transcapillary pressure. Sometimes deficient patients [34, 35]. dopamine is the only renal stimulus used, for instance, in a In the long term, the afferent arteriole is evidently the weak dopamine-induced glomerular response test [44]. spot in these consecutive events, as this site harbours the first Dopamine provocation may be combined with a metabolic signs of hypertensive hyalinosis, impeding maximal relaxation stimulus. When combined with an AA infusion, the effects are [36]. Arterial stiffness proved to be an independent predictor of additive [45]. During the AA infusion, ERPF and GFR increase adaptive glomerular hyperfiltration after kidney donation [37]. proportionally with a predominant afferent arteriolar dilation If the ERPF is not able to keep pace with the increased demands, resulting in a constant FF. The composition of the AA solution the efferent vasoconstriction gradually prevails, leading to a depends on local availability, but gluconeogenic AA should be higher intraglomerular pressure and filtration fraction (FF). This present [46], whereas branched-chain AAs do not alter GFR or additive mechanism, triggered by the renin–angiotensin system FF [47]. The infusion rates reported in the literature are dispar- with thromboxane A2 and endothelin-1 as cofactors, leads to a ate. The AA infusion can begin the night before the test day, cascade of negative events. In the long run, a higher FF might but the GFR response is already present after a 1- or 2-h infu- lead to glomerular as well as tubular injury and a loss of neph- sion time. A dose–response curve for AA stimulus was con- rons. Treatment with an angiotensin-converting enzyme (ACE) structed by Giordano et al. [48]. Within the physiological range, inhibitor has been shown to restore the GFR response after a incremental AA concentrations cause a stepwise increase in protein stimulation [38]. the GFR, whereas this effect levels off in the pharmacological range. The administration of a single AA to elicit a change in GFR is METHODOLOGY OF RENAL STIMULATION also reported. Arginine [49, 50] and glycine have been used, TESTS each acting via different pathways. Arginine causes systemic and renal vasodilation, while glycine operates via the N- Table 2 provides an overview of the chronology and methodology methyl-D-aspartate glutamate receptor (NMDA-R) [29]. This re- of a renal stimulation test. The numerous stimuli and modes of ceptor is localized in the proximal tubule and functions as a cal- GFR measurements are described in the following paragraph. cium channel, causing local vasodilation. A more natural approach is to stimulate the GFR by a protein Measurement of unstimulated GFR meal. This short-term oral protein loading should consist of at Several factors may influence the unstimulated GFR. First, hydra- least 1 g/kg of protein [51]. Rodrı ´guez-Iturbe et al. [52] studied tion status [39] is a very important confounding variable. Spinelli three quantities of protein meals: 1.3, 1.1 and 0.55 g/kg. The fil- et al. [40] advise the use of bio-impedance measurements to iden- tration fraction rose significantly with the moderate and large tify dehydrated subjects. For this reason, most protocols adopt a protein load but not with the lower protein load. strict oral hydration policy, starting with 10–20 mL/kg plain water Animal proteins are preferred, so most centres prepare a and replacing each voided urine sample with an equal amount of cooked beef hamburger. Red meat, however, contains 3.5–5 mg/g Downloaded from https://academic.oup.com/ckj/advance-article-abstract/doi/10.1093/ckj/sfy022/4969997 by Ed 'DeepDyve' Gillespie user on 12 July 2018 4| B. De Moor et al. Table 2. How to perform a renal stimulation test? Preparatory phase: Test day: Part 1, Test day: Part 3, instruction and informed measuring unstimulated measuring stimu- Variables consent GFR Test day: Part 2, stimulus lated GFR Location Home Hospital: recumbent position Duration 1 day: starting urine 2–4 h 30–60 min to cover inges- 2–4 h collection tion and digestion 2–3 days: when CACrC is opted 10 days: when a low-protein diet is advised Diet Diet 1: habitual diet until Fasting for at least 8 h the night before RFR testing Diet 2: controlled low-pro- Fasting for at least 8 h tein diet for at least 10 days before RFR Fluids Drinking according to thirst Drinking is stimulated: Drinking in equal amounts Drinking in equal 10–20 mL/kg at start to match diuresis amounts to match diuresis PO Start cimetidine (when Stimulus option 1: 1 g/kg CACrC is chosen) accord- protein offered as cooked ing to the Hilbrands meat (containing protocol creatinine) Stop NSAID, preferentially Stimulus option 2: 1 g/kg pause ACE i or angioten- protein offered as egg sin receptor blocker whites or a commercial protein solution (not con- taining creatinine) IV Introduce two separate IV Stimulus option 3: a 10% IV lines AA solution at a rate of 4 mL/kg/h during 3 h Stimulus option 4: IV dopa- mine at a rate of 2 mg/kg/ min (can be combined with stimulus 3) Stimulus option 5: IV gluca- gon at a rate of 10–20 ng/ kg/min during 1 h Clinical exam Weight, height, hydration Blood pressure and heart status, blood pressure rate at regular intervals Blood as well as 24-h urine collection for ref- GFR option 1: plasma or urine samples in erence creatinine clear- urinary clearance of an combination with ance, sodium excretion exogenous marker timed urine and urea nitrogen Urine collections and sam- collections appearance ples: every 30–60 min bracketed with serum samples GFR option 2: urinary CrC Urine collections (with or without cimeti- and samples every dine correction) 30–60 min brack- Urine collections and sam- eted with serum ples: every 30–60 minutes samples bracketed with serum samples Result Unstimulated GFR or Stimulated GFR or CrC: Stimulated CrC: mean of at least three highest of at measurements least three measurements PO, by mouth; IV, intravenous. Downloaded from https://academic.oup.com/ckj/advance-article-abstract/doi/10.1093/ckj/sfy022/4969997 by Ed 'DeepDyve' Gillespie user on 12 July 2018 Haemodynamic or metabolic stimulation tests | 5 creatine. By cooking, a non-metabolic conversion of creatine to sulfamethoxazole, cimetidine and possibly fenofibrate). On the creatinine occurs [53]. This metabolite is easily absorbed and other hand, when the investigator wants to capture solely the the rising serum levels result in increased tubular secretion until dynamics of glomerular filtration, tubular secretion of creatin- the tubular transport maximum is reached [54]. Accordingly, the ine can be blocked by cimetidine. This results in the cimetidine- more pronounced response (after a protein challenge) of creatin- aided CrC (CACrC). In the publication by Hilbrands et al. [66], ci- ine clearance (CrC) compared with inulin clearance is due to a metidine was started 1–4 days prior to the GFR stimulus accord- higher input and increased tubular secretion of creatinine. ing to a dosing protocol determined by the actual renal function. Alternatives for animal protein are dairy products and egg- Irrespective of the methodology, investigators must ascer- white proteins. These are more practical in paediatric subjects tain complete voiding or resort to placing a bladder catheter [55]. Vegetable proteins, for instance soy products or bean curd, (mostly done in children, which increases the invasiveness of are less effective in stimulating the GFR [56]. Many reasons for the test). this difference have been postulated, including a different AA We do not advocate GFR estimating formulas (Chronic Kidney mixture, less sulphur-containing AA, less oxidative stress or Disease Epidemiology Collaboration formula or Cockcroft–Gault acid load, lower maximal AA serum levels, faster internalization formula] to document the renal functional response. Some au- in the cells due to a different insulin/glucagon surge, less so- thors propose cystatin C measurements [67, 68]. The kinetics of dium and more potassium content. An elaborate description of this functional biomarker have been tested after protein meals, the renal benefits attributed to a vegetarian diet is beyond the with conflicting results [69, 70]. scope of this article. The reader is referred to excellent reviews Alternative possibilities for measuring the GFR before by Kalantar-Zadeh et al. [57] and Snelson and Fouque [58]. and after a stimulus are urinary or plasma clearances of The renal response after a haemodynamic stimulus is im- isotopes, e.g. Cr-labeled ethylenediaminetetra-acetic acid 125 99m mediate while the maximal effect of a metabolic stimulus is (Cr-EDTA), I-labeled iothalamate [45]and Tc-labeled noted after 1–3 h. Recent evidence shows that in obese non- diethylenetriaminepenta-acetic acid (Tc-DTPA) (see Tables 4 diabetic subjects, the maximal rise in GFR after a protein stimu- and 5 for references). Most protocols choose the urinary clear- lus is postponed [59]. ance of a subcutaneously injected or continuously infused Over the years, no major side effects of renal stimulation tests radioisotope. Alternatively, calculation of the GFR by decaying have been observed. In the different studies, blood pressure and plasma levels after an intravenous bolus can be performed. heart rate were carefully monitored, especially when dopamine However, this technique requires the investigator to invite the was used as a stimulating agent. After the stimulus has waned test person on two separate days, one for an unstimulated renal function returns to its unstimulated state. Intravenous per- GFR test and one for a stimulated GFR test. Other drawbacks fusion of a hyperosmolar AA solution has been found to cause are the exposure to radiation and the additional costs. local pain and phlebitis. No increase in urinary neutrophil gelati- Recently an elegant technique of urinary clearance of iohexol nase-associated lipocalin or proteinuria has been documented in was tested in an ICU population with varying GFRs [71]. The the protein stimulation experiments performed by Sharma et al. protocol describes a bolus injection followed by a continuous [51]. N-acetyl glucosaminidase (NAG) has been studied in immu- infusion of a low dose of iohexol combined with regular noglobulin A nephropathy (IgAN) during RFR testing [60], but the plasma and urine sampling. This technique seems applicable serial documentation of damage biomarkers, including albumin- in renal function testing. uria, remains largely unexplored. In the meantime, progress is being made in the development and validation of fluorescent markers for GFR determination. These intravenously injected compounds behave as an ideal Measuring GFR during renal stimulation tests renal filtration marker. Their plasma disappearance curves match glomerular filtration and can be read transdermally The Achilles heel of renal function testing is the method used thanks to their fluorescent properties. In this way, an almost for GFR determination [61]. Urinary inulin clearance remains real-time GFR evaluation is possible [72, 73]. the most extensively reported method in renal stimulation Table 3 describes in more detail the advantages and disad- tests. This classic mode of GFR measurement is often combined vantages of the numerous options. with para-aminohippuric acid (PAH) clearance to document the ERPF. Delanaye et al. [62] delineates the difficulties of this technique, including costs, variances in lab techniques and Alternatives to GFR measurements availability. Zitta et al. [44] succeeded in studying GFR behav- iour after AA infusion via the plasma kinetics of sinistrin and Magnetic resonance imaging (MRI) holds great promise, as it hippurate supplied to a two-compartment computer model. allows for simultaneous measurements of both the GFR and The advantage of this technique is the elimination of urine renal plasma flow (RPF) [74], as well as providing estimates of collections. single-nephron GFR. Additionally, MRI could be used to quantify The easiest alternative for the use of inulin is to monitor renal fibrosis, as recent evidence suggests [75]. urinary CrC by timed urine collections (30 or 60 min), consider- Doppler ultrasound can detect the decrease in RVR occurring ing known caveats when using this biomarker. At least three in healthy kidneys after a protein challenge [76, 77]. This has led clearance calculations are advised. The CrC overestimates true investigators to study the renal resistive index variation (RRIV) GFR because of additive tubular secretion, leading to a mean before and after an AA infusion. A similar decrease in RVR can bias of 14 mL/min or 25% [63]. The overestimation depends on be documented when pressure is applied to the retroperitoneal baseline kidney function. However, when subjects are asked to vasculature. This autoregulatory reflex is intended to preserve adhere to a low-protein diet of 0.5 g/kg/day, calculated CrCs are the GFR. Maximal renal vasodilation was recorded when a sa- similar to inulin clearance [64, 65]. When urinary CrC is used line bag representing 10% of the body weight was placed on the not only as a GFR estimator but also to track accessory tubular abdomen. The maximal RRIV observed in these experiments secretion, the intake of drugs that inhibit the tubular secretion correlated with the RFR, thus offering a non-invasive real-time of creatinine must be avoided (e.g. trimethoprim– evaluation of the changing RVR [78]. Downloaded from https://academic.oup.com/ckj/advance-article-abstract/doi/10.1093/ckj/sfy022/4969997 by Ed 'DeepDyve' Gillespie user on 12 July 2018 6| B. De Moor