Dietary Acid Load and Glomerular Filtration Rate in Chronic Kidney Disease

Background: Kidney diseases are prevalencing rapidly. The nutritional transition has caused the diet of Iran community to increase the dietary acid load (DAL) and thus exacerbate metabolic disorders. Therefore, our goal was to determine the DAL of the diet in patients with Chronic Kidney Disease (CKD). Methods: In this cross-sectional study, the study population was composed of 90 patients with renal insuciency. DAL was included of Potential Renal Acid Load(PRAL), Net EndogeneusAcid Production(NEAP) and Net Acid Excretion(NAE) that were extracted using data of food frequency questionnaire and their correlation with anthropometric and biochemical indices such as Glomerular Filtration Rate (GFR) and creatinine were analyzed by SPSS v.26 software with a signicance level of < 0.05. Results: Mean of dietary acid load of participants were 17.15±9.85,-8.7±0.35 and 59.04±10.9 mEq/day for PRAL, NEAP and NAE respectively. Daily intake of energy (P<0.001) and protein percent of energy (P<0.01) in third tertile (T 3 ) of PRAL were signicant higher than rst tertile (T 1 ). Mean of age (P<0.05) and blood creatinine concentration (P<0.01) were signicant higher in T 1 than T 1 of NEAP index and GFR was signicant low (P<0.05). Daily energy intake (p<0.05), blood calcium concentration (p<0.05) and GFR (p<0.05) were signicantly more in higher tertiles of NAE index. Based on Crude General linear model, the higher tertiles of PRAL compared to rst tertile had signicant lower GFR (P<0.05). In adjustment model, T3 group had more not signicant GFR than T 1 group. Only in model II adjustment, T 2 group of NAE compared to T 1 , had higher GFR. Mean difference of GFR did not signicant across tertiles of NEAP index. In case of Creatinine, based

is measured by PRAL and the NEAP indexes which are based on dietary intakes of protein, calcium, magnesium, potassium and phosphorous (16). A part of the acid excreted by the kidneys can be considered equivalent to PRAL and a part as organic acid(OA), dependent on the body surface and permanently, is excreted from the kidneys (17). Considering the inappropriate diet pattern in Iranian families, such as low consumption of fruits and vegetables and high consumption of cereal and meat based foods, it is predictable that the Iranian diet will increase the acid load and thus exacerbate metabolic disorders (18).This type of diet, which is mostly the result of nutritional transition, can be associated with an increase in the acidic load of the diet and thus the aggravation of metabolic disorders; This condition is more dangerous in kidney patients, because these patients are restricted in consuming alkaline foods. In addition, because few studies have been done on the relationship between dietary acidity and kidney function (1,19), we estimated PRAL and NEAP and evaluated their association with sociodemographic and biochemical factors in general hospital, southwest of Iran.

Population and study design
In this cross-sectional study, 90 CKD patients with GFR 20-65ml/min (20) were enrolled by easy and accessible sampling method in 2018. The protocol of this study was reviewed and approved by the Ethics Committee of Yasuj University of Medical Sciences (Ethical code:IR.YUMS. REC.1396.29). Exclusion criteria were acute or chronic in ammatory disease, malignancy or known hematological dis order and recent severe hemorrhagic episode. Patients were informed the study goals and written consent was obtained .Demographic information was obtained during interviews with them. The weight of participants was measured with light clothing by a standard scale(Seca786, Germany) with 0.1 kg accracy.Patients's height was also measured in Standing without shoes position by no elastistic gauge plate(Seca786,Germany) with 0.5 cm accuracy. Body mass index(BMI) was calculated as weight(kg) divided by squared height(m 2 ). Four groups of BMI: lean (<18.5 kg / m 2 ), normal (18.5-24.9 kg / m 2 ) and overweight (25-29.9 kg / m 2 ) and obese (≥ 30 kg / m 2 ) (7). Food intake was obtained using a semiquantitive standard food frequency questionnaire (15,19).Cronbach's alpha coe cient for our FFQ was 0.932, so considering that it is higher than the cut of point of 0.7, it can be said that the FFQ used in this study has a very good validity and reliability. Amount and frequency of consumption of food items was as daily, weekly, monthly and seasonal. It should be noted that units of use for each item were standard units; For example, how much and how many a 240cc cup for milk? For fruits such as apples, the unit used was an average of 100 grams of apples. For different types of bread, the scale used is the palm of the hand (10 x 10 cm cut).Consumption of each food item was converted in to grams of food consumed per day using the illustrated guidebook of home scales. Since in Iran, most fats are consumed as cooking oil, a separate question was included in the questionnaire; "How many kilograms of cooking oil is bought for a household? How long is it generally enough? "Then, by knowing the number of household members, the approximate daily consumption of oil for each person can be calculated. Macronutrients and micronutrient content of each food was extracted using the Iranian food composition table. Blood samples were taken from patients after 12-14 hours of overnight fasting by an experienced nurse and biochemical tests were performed using the enzymatic colorimetric kits (bionic kit, Iran). Blood pressure is also measured by an experienced nurse using a standard mercry sphygmomanometer (DDM, Inc, Castelculier, France) after hospitalization and 15minutes of rest in seated position.

De nitions
Dietary acid load was estimated using the Remer and Manz equation (17,20):

Discussion
The Iranian diet is thought to be relatively acidic due to its high consumption of re ned grains such as white rice and non-alcoholic beverages (18). This type of conception was partially con rmed in our study because the values of the PRALand NAE indices were inclined towards completely positive and acidic values. Of course, the average NAP values indicate the alkalinity of the diet of our patients. It should be noted that the PRAL index,despite its signi cant limitations, unlike the NEAP index, takes into account the amounts of potassium, magnesium and calcium in the diet. These ions play role in preventing acidi cation of the blood(24-26);Therefore, it seems that PRAL is more accurate.In Tehran Lipid and Glucose Study (16), mean of PRAL in subgroup CKD patients was -19.46±1.5mEq/day; Indicates that the diet of Tehranian CKD patients was alkaline. In other study (27), mean value of NEAP of CKD patients was 50.1±13.1mEq/day. In Brazilian study (28), the median value of PRAL was 6.8 mEq/day and of NEAP was 53.1 mEq/day for CKD patients. In African American CKD patient (15),Median estimated NEAP was estimated 71 mEq/d.Another study (29) showed that median value of estimated DAL, is 47.24 mEq/d .The study among Venezuelan CKD children (30) indicated that mean of PRAL is 16 ± 10.7 mEq/day. In study of American CKD patients (31) mean NEAP, PRAL, and NAE were 58.2 ± 24.3, 9.7 ± 18.4, and 32.1 ± 19.8 mEq/day, respectively. Despite all studies were on CKD patients, differences in the results of these studies can be attributed to differences in population food patterns, age groups, designs and number of participants, measuring methods and food intake estimating method and variation in confounder variables.
Todays, due to the industrialization of the food production process and easier access to food and changing the people's tastes, consumption of re ned carbohydrate-based foods, high sodium and protein foods, especially animal proteins has increased, while our ancestors ate plant-based foods and high ber and potassium (32).This transition has changed very rapidly over the past decades. In patients with chronic renal failure due to the inability of the renal tubules to excrete toxic acidic metabolic products (15), the metabolic disorders resulting from this nutritional transition are exacerbated.
In our study, daily intake of energy and protein percent of energy in T 3 group of PRAL index were signi cant more than T 1 ; Also, the mean of daily energy intake increased signi cantly across the tertiles of NAE index.
Other studies reported similar results (32). Eating protein-rich foods can increase the body's pool of amino acids and ultimately lead to an increase the free hydrogen ions in the body, which can lower the pH of the blood to an acidic state. It is also important to pay attention to the type of consumed protein. Protein from animal sources has high biological availability and is also high in phosphorus. The exception in animal sources is milk and dairy products, that the effect of high phosphorus, is neutralized by its high calcium content. In plant foods, phosphorus is mostly in the phytate form, which has low biological availability, so the acidifying effect of phosphorus in plant sources is greatly reduced (24)(25)(26).In addition, animal proteins are high in sulfurcontaining amino acids, methionine and cysteine, which are converted to sulfuric acid in the body, so animal foods can increase the acidic load of body uids through this physiological mechanism. Conversely, plantbased protein contains glutamine, Which is mostly known in the body as a consumer and recipient of hydrogen ions, so this is another mechanism for the positive effects of plant foods in improving acid -base balance in the body (24,33).Vegetables are also high in potassium, which binds to organic anions and converts them to bicarbonate, thus slowing down the production of endogenous acid compared to animal foods (34). In the countries with nutritional transition, including Iran, is estimated that the share of animal protein is more than vegetable protein in diet and even this ratio is twice (35); From this point of view, a good outlook is not predictable.
In our study, mean of GFR increased signi cantly across the tertiles of NAE and NEAP indexes; This relationship seems irrational; But this signi cance was lost in general linear model test, and it is interesting that based on Crude General linear model, the higher tertiles of PRAL compared to rst tertile had signi cant lower GFR. This difference was not signi cant in adjustment models; But, the third tertile of PRAL had less GFR than the rst tertile. correlation of creatinine concentration with DAL was not seen after in crude model; After adjusting, the mean creatinine concentration in T 3 group of NAE was signi cantly higher than the T 1; In the case of NAP, it was just the opposite; As the creatinine concentration decreased signi cantly across tertiles of NEAP(negative correlation). Other studies have shown that increasing the acid load of the diet is associated with low GFR and more reduction of it over the time and high Creatinine concentration (15, 27 and 36).A systematic review and meta-analysis of observational studies found that higher DAL could signi cantly increase the risk of CKD (37). Some cohort studies with follow-up periods of more than 10 years have shown the correlation of a high DAL with increased risk of progressing CKD (11,20). Of course, some other cohort studies (38,39) found no association between DAL and CKD disease. In one interventional study (40), effect of fruits and vegetables or bicarbonate in attenuation of kidney injury was concluded. The mechanisms of the effect of dietary acid load on the development of renal dysfunction can include: First, acidosis caused by high dietary acid load can increase amount of ammonium ions in kidney tissue without reducing bicarbonate levels, but can lead to toxic effects and damage to the tissue of the renal tubules, which in the long term reduces the function of the nephrons. This type of metabolic acidosis can also lead to increased production of endothelin, which reduces GFR and exacerbates renal tubular tissue damage. The second possible mechanism is increased production of oxygen free radicals and oxidative stress, which can lead to nephrotoxicity (41)(42)(43)(44).
This is one of the limitations of studies such as our study that PRAL and NEAP estimating formulas is used to calculate the acidity, because these formulas do not account the biological availability of nutrients and sulfur content of different protein foods (46).

Conclusion
Finally, it can be said that indexes of dietary acid load include the PRAL,NEAP and NAE are related to renal function indices, but to understand the cause-and-effect relationships; Because, while the validity ofdietary acidi load values calculated by PRAL formula versus it's measured vale from urine has been con rmed (47,48), due to the limited interpretation of the results obtained from the formulas for estimating the dietary acid load in different situations of urinary pH and blood bicarbonate concentration (28), long-term study with more and more population and taking into account blood bicarbonate concentration and urinary pH is proposed. Availability of data and materials The analysis dataset for the current study is available from the corresponding author on reasonable request.