Protein Diet and Estimated Glomerular Filtration Rate

Chronic kidney disease (CKD) is a common health problem worldwide. CKD staging or classification, together with patients’ prognosis and treatment plan depend on the patients’ kidney function which is assessed by measurement of glomerular filtration rate (GFR). Estimated GFR can be obtained using serum or plasma creatinine as a main variable in equations or formulae such as Cockcroft-Gault equation, MDRD equation (Modification of Diet in Renal Disease), the Schwartz and Counahan-Barratt formulae. These equations, though widely accepted, still have to be adjusted or validated among different groups of patients according to the variation in some factors such as race, diet, and genetic heterogenicity. Diet, especially the high protein load, can affect GFR representing the renal functional reserve. A high protein diet can cause an increase in GFR that lasts for many hours. Long-term consumption of vegetarian diet which is low in protein and contains only protein from plant sources can cause a low baseline GFR while the renal functional reserve is still preserved. This paper aims to remind of the role of protein diet effect on GFR measurement especially when assessing the renal function in vegetarians or individuals on long-term low-protein intake.


Introduction
Chronic kidney disease (CKD) is becoming an increasing health problem in many countries, its prevalence and staging were studied and reported from all over the globe including United States [1], Australia [2], European countries [3], the Republic of China [4], and Japan [5].In Thailand, the National Health Examination Survey 2004 found that the prevalence of CKD (compiling only those of stage 3, 4 and 5) in Thai adults was 8.45% [6].
These reports show that CKD is becoming a more serious problem worldwide as the patients with end stage renal disease (ESRD) need dialysis and/or transplantation which need complicate health care and also a high cost of health service.CKD stages were most often classified based on Kidney Disease Outcome Quality Initiatives (K/DOQI) which classified CKD patients into 5 stages according to their glomerular filtration rate (GFR) [7].So the measurement of GFR should be reliable and accurate.
Intake of cooked meat has a significant effect on serum creatinine concentration and GFR.Misclassification of CKD is possible if measurements are made after high protein diet [8], and in individuals with exceptional dietary intake such as vegetarian [9].

GFR Measurement: Clearance Technique
GFR provides the best index of overall kidney function especially glomerular function.GFR is not measured directly but can be assessed by clearance technique using creatinine, inulin, radionuclide-labeled markers, radiocontrast markers or other substances that are freely filtered but not transported in the renal tubules.Clearance (C) of a substance is the rate at which an indicator substance is removed from plasma per unit concentration, specifying a volume from which all of the substance is removed per unit time.Clearance can be calculated from the formula C = UV/P, where C is clearance in ml/min, U means the urine concentration of the substance in mg/mL, V means the urine volume in one minute and P means plasma concentration of the substance in mg/mL [10,11].

Estimated GFR (eGFR)
Clearance method needs accurate urine collection which is not easily accomplished, time consuming and can be cumbersome leading to inadequate compliance and unreliability.In 1976 Cockcroft and Gault proposed the prediction of creatinine clearance from serum creatinine (S cr ) [12].The principle has been accepted, modified, and called estimated GFR.
Other equations to estimate GFR from serum creatinine have come out and been widely used as well.Levey et al. [13]  Among children, the Schwartz [14] and Counahan-Barratt [15] formulae provide clinical useful estimates of GFR.
Manjunath et al. in 2001 stated that measurement of creatinine clearance using timed (e.g., 24-hour) urine collections does not improve the estimate of GFR over that provided by prediction equations.Anyhow, they indicated that a 24-hour urine sample provides useful information for GFR estimation in individuals with exceptional dietary intake (vegetarian diet, use of creatine supplements) or muscle mass (amputation, malnutrition, muscle wasting) [16].

Variation of Serum Creatinine
Creatinine has a molecular weight of 113 D. It is a break down product of creatine and phosphocreatine in muscle, and is usually produced at a rather constant rate in the body.Creatinine generation is proportional to muscle mass.The liver plays important role in formation of creatinine through methylation of guanidine aminoacetic acid [17].
Creatinine is freely filtered by the renal glomeruli.There is no renal tubular reabsorption of the substance, while approximately 3% of creatinine in the urine is secreted from the renal tubules.With a decrease in GFR, blood concentration of creatinine rises, presenting a reciprocal relationship between GFR and serum creatinine concentration.
In CKD patients with reduced glomerular and nephron function, serum creatinine rises and renal tubular secretion of creatinine is in relatively higher proportion.
Elevated level of serum creatinine usually indicates reduced GFR, but normal level does not exclude possibility of reduced GFR especially when renal damage is not immense.Renal clearance representing GFR is a more accurate method to measure kidney function.
Serum creatinine level can be affected by numerous factors.It is slightly increased just after ingestion of high meat diet, vigorous exercise, or due to some drugs that block tubular secretion of creatinine especially in CKD patients who already have high concentration of creatinine in the blood.Serum creatinine level is lower in individuals with muscle wasting, malnutrition, dietary protein restriction, and advanced liver disease.So in CKD patients with severe malnutrition and severe muscle wasting, serum creatinine might not be as high as in those with more muscle mass though their kidney functions are in the same level.

Protein Diet and GFR, Renal Functional Reserve
Intake of cooked meat has a significant effect on serum creatinine concentration and GFR [18,19].Proteins of different sources, for example animal protein vs vegetable protein, do not affect GFR at the same magnitude [20,21], The capacity of the kidney to increase its renal blood flow and GFR after a dietary protein load is called renal functional reserve [22].The increase in GFR after high protein diet can be due both to an increase in the serum creatinine concentration and the known postprandial increase of true GFR [8,22].Healthy vegetarians are known to have a statistically reduced baseline GFR [18] but the ability to increase the GFR after high protein diet is still maintained [23], unlike in patients with a reduced number of nephrons whose renal functional reserve may be diminished or absent [22].
Protein diet from animal source produced more increment in postprandial GFR compared to that from vegetable source [21].Kontessis et al. in 1995 reported that, after a high protein diet of animal source, plasma concentrations of valine, lysine, and IGF-I were higher than after a vegetable protein diet, while the plasma levels of growth hormone and glucagon did not differ significantly.The plasma valine was strongly correlated to the GFR [20].

The Classification of Chronic Kidney Disease in Vegetarian
Since the classification of chronic kidney disease is based on baseline GFR [7], and strict and long-term healthy vegetarians are known to have a statistically reduced baseline GFR [18], therefore physicians need to bear this in mind when dealing with diagnosis and classification of chronic kidney disease in vegetarians.Barai [25].They found lower GFR in vegans and lactovegetarians but higher mean urinary albumin excretion rate in the omnivores.
In Thailand, it is our Thai tradition to consume rice meals with more carbohydrate and local vegetables, with less meat than the western style, especially in the rural area.The effect of meat on baseline serum creatinine and GFR estimation may play some minor part when dealing with diagnosis and classification of chronic kidney disease.

Conclusion
Vegetarians and individuals consuming long-term lowprotein diet exhibit low baseline GFR though their renal functional reserve is still preserved.To assess renal function or survey of the prevalence of CKD using single measurement of baseline GFR, these low protein consumers may be mistaken as patients with early stages of CKD.
in 1999 presented a new prediction equation called the MDRD equation (Modification of Diet in Renal Disease) claimed to be more accurate especially in the black.eGFR = 170 × [S cr (mg/dL)] −0.999 × [age] −0.176 × [0.762 if patient is female] × [1.18 if patient is black].