| Abstract|| |
Renal reserve (RR) is the ability of the kidneys to increase their basal glomerular filtration rate (GFR) by at least 20% after a protein overload. It has been documented that RR is preserved in healthy elderly people, and even in patients with chronic kidney disease, but its magnitude is significantly decreased with aging. Besides, RR has also been evaluated in kidney transplant patients who were on sirolimus or calcineurin inhibitors (CNI):cyclosporine or tacrolimus, and it was found that RR was lower in the CNI group compared to the sirolimus group, a phenomenon that could be attributed to the intra- renal vasoconstrictive effect of CNI. In conclusion, RR is a physiological variable which has its particular characteristics in different renal settings.
|How to cite this article:|
Musso CG. Renal reserve test: Its methodology and significance. Saudi J Kidney Dis Transpl 2011;22:990-3
| Introduction|| |
Renal reserve (RR) is the kidney's ability to increase its basal glomerular filtration rate (GFR) by at least 20% after a protein overload and a renal response lower than that is considered a decreased one. ,
A reliable GFR assessment is crucial for evaluating the RR. Classical creatinine clearance (Ccr) is not a reliable test for this purpose because a considerable part of creatinine excretion in the urine is due to tubular secretion while inulin clearance (gold standard) is neither practical nor cheap as GFR assessment test.  The most practical, low- cost, and reliable method for evaluating GFR seems to be the cimetidineaided creatinine clearance (CACC), especially that which uses oral doses of the drug. Since cimetidine inhibits creatinine secretion in the proximal tubules, the ratio of the CACC and GFR is about 1.1 ± 0.02. ,,
| Renal Reserve: Assessment with CACC|| |
Two weeks prior to performing the test, angiotensin converting enzyme inhibitors (ACEI) and angiotensin II receptor blocker (ARB) medication must be stopped.
If these drugs were prescribed for treating hypertension, and not just for a nephroprevention purpose, they could be replaced by calcium channel blocker or methyldopa for the period of the test.
The patient is given cimetidine (800 mg twice a day) for 48 hours before performing the GFR. At the end of this period, a blood sample is obtained for measuring basal serum creatinine and an oral hydration using tap water (20 mL/kg) is given for over 30 min. At the end of this 30-min period, patients are asked to void spontaneously (and they usually continue urinating every 30 min). Time and volume data obtained from each micturition are accurately documented from two periods (in order to obtain an average value). The volume of each voiding is replaced with an equal volume of tap water drink in order to maintain the obtained rate of micturition. Complete bladder voiding is documented by ultrasound. After the above- mentioned two micturitions are done, an oral protein load (1.5 g/kg) based on dairy products is supplied (30 min for ingestion and 40 min for digestion). At the end of this (70- min) period, urine samples during four 30- min micturition periods are obtained (representing around 120 min) in order to document the highest value of RR.
Creatinine clearance (Ccr) is calculated from these data applying the following formula:
creatinine clearance = urinary creatinine (mg/dL) × urinary volume (mL)/serum creatinine (mg/dL) × time (min). 
| Renal Reserve: Physiological Mechanism|| |
It is generally accepted that the amino acid components of the protein per se induce the renal response through local vasodilatation and hyperfiltration. The renal response to a protein or an amino acid load is attributed to a tubular- glomerular feedback (TGF) mechanism. An increase in plasma amino acid levels would result in an increase in the filtered load of amino acids at any given GFR and would provoke an increase in tubular amino acid reabsorption. Because amino acids and sodium are co- transported in the proximal tubule, proximal sodium chloride reabsorption would also increase, resulting in a decrease in sodium delivery to the distal tubule and macula densa, which induces the release of vasodilator autacoids. Thus, the TGF mechanism results in afferent arteriolar vasodilatation and a consequent increase in renal blood flow and GFR.  It has been proposed that this vasodilatation phenomenon is the result of a local release of prostaglandins, nitric oxide and kinins. ,,
Proximal tubule dysfunction (e.g. Fanconi syndrome) or blockage of the macula densa function (e.g. loop diuretics) does not lead to an increase in the GFR after a protein overload. This indicates that the normal RR response requires a normal proximal tubule and macula densa function. Moreover, several lines of evidence suggest that extrarenal factors are not required to enable hyperfiltration to take place.
Angiotensin II contributes to glomerular hyperfiltration by stimulating efferent arteriolar vasoconstriction, in this way leading to an increase in the glomerular filtration fraction. Moreover, this hormone also induces sodium reabsorption in the proximal tubules by stimulating the sodium- proton anti- porter. As a result, the amount of luminal sodium detected in the macula densa diminishes, leading to vasodilatation of the afferent arteriole and consequently hyperfiltration. ,
| Renal Reserve in the Elderly|| |
In a recent study, we documented that RR was preserved in healthy, very old people, but its magnitude decreased significantly with aging. For instance, in the healthy, young group, basal glomerular filtration was 122.5 ± 25 mL/min/ 1.73 m 2 , while its highest value after protein load stimulus was 226.0 ± 49 mL/min/1.73 m2 , a RR of 84%. On the other hand, in the healthy, very old group, basal glomerular filtration was 51.6 ± 0.4 mL/min/1.73 m2 , while its highest value after protein load stimulus was 71.9 ± 1.1 mL/min/1.73 m2 , a RR of 39%. As explained above, RR response depends on the intervention of many variables (vasodilator autacoids release, GFR, thick ascending loop of Henle and proximal tubule function), many of which are diminished in the old, explaining why the magnitude of RR is reduced along the aging process. 
| Renal Reserve in Chronic Kidney Disease|| |
It is known that RR is usually preserved in CKD patients although its magnitude is reduced compared to RR in healthy people.
It was observed that there is no significant difference in RR characteristics between young and old patients with CKD (stages 2-3) with similar degree of kidney failure. However, a tendency for a reduced magnitude in RR response was observed in the stage 3 chronic renal disease elderly group compared to the young ones, but it was not statistically significant. It seems that even though the aging process and the non- severe chronic renal disease induce kidney dysfunction, the remaining nephron units are capable of keeping a positive RR response.  However, it seems that in elderly CKD stage 3 patients, there is a tendency to deliver a lower magnitude of RR response compared to the young. This phenomenon might be explained by the considerable structural and functional damage induced by the combination of senescence and moderate chronic renal disease. ,,
| Renal Reserve in Transplant Patients|| |
In a recent study, RR was evaluated in two groups of kidney transplant patients, who were on sirolimus in one group and on calcineurin inhibitors (CNI) (cyclosporine or tacrolimus) in the other group. The serum levels of those immunosuppressive drugs were within therapeutic range at the time of this study. General characteristics such as donor and receptor age, ischemia time, donor and receptor gender, and previous acute rejection episodes were similar between the groups, but the time since transplantation was longer in the sirolimus group compared to the CNI group. In this study, a significant lower baseline GFR was documented in the sirolimus group compared to the CNI one. The duration of post- transplantation period was longer among the patients on sirolimus, and to reduce the risk of chronic rejection, they had been switched to sirolimus as immunosuppressive drug for an average period of four years before the test (before this sirolimus period they had been on CNI). This longer duration of post- transplantation period among patients in the sirolimus group could explain their significantly lower GFR compared to the patients in the CNI group.
Additionally, the maximal GFR response after protein load, i.e. RR was significantly higher in the sirolimus group compared to the CNI group (P = 0.02) [Table 1]. The results documented significantly lower RR in the CNI group compared to the sirolimus one, despite their shorter post- transplantation period. This could be attributed to the vascular effect exerted by CNI that induces not only intrarenal vasoconstriction but also histological changes such as the arteriolar nodular hyalinosis. ,
|Table 1: Cimetidine-aided creatinine clearance (CACC) and renal reserve data.|
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In conclusion, RR is a physiological variable which has its particular characteristics in each renal scenario (healthy young, elderly, chronic renal disease, kidney transplant patients) and is a practical parameter to evaluate nephroprevention programs.
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Carlos G Musso
Nephrology Division, Hospital Italiano de Buenos Aires, Buenos Aires