Research Article

Metabolomics of Periparturient Holstein-Friesian Cows Associated with Feeding a Negative Dietary Cation-Anion Difference (DCAD)

Asaad A. Fares1*, Mohamed M. Ghanem2, Yasein M. Abd El-Raof2, Hossam M. El-Attar2, Ameer A. Megahed2, Heba M. El-Khaiat2

1Department of Veterinary Services, Egyptian Armed Forces, Nasr City, Cairo, 11765, Egypt; 2Animal Medicine Department, Internal Medicine, Faculty of Veterinary Medicine, Benha University, Moshtohor, Toukh, Kalyobiya, 13736, Egypt.

Received | February 26, 2022; Accepted | April 27, 2022; Published | June 20, 2022

*Correspondence | Asaad A. Fares, Department of Veterinary Services, Egyptian Armed Forces, Nasr City, Cairo, 11765, Egypt; Email: [email protected]

Citation | Fares AA, Ghanem MM, El-Raof YMA, El-Attar HM, Megahed AA, El-Khaiat HM (2022). Metabolomics of periparturient Holstein-Friesian cows associated with feeding a negative dietary cation-anion difference (DCAD). Adv. Anim. Vet. Sci. 10(7):1504-1512.

DOI | https://dx.doi.org/10.17582/journal.aavs/2022/10.7.1504.1512

ISSN (Online) | 2307-8316

Copyright: 2022 by the authors. Licensee ResearchersLinks Ltd, England, UK.

This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).

INTRODUCTION

The percentage of metabolic diseases and health complications increases in the transition period. Reduction of Ca occurs due to an increased calcium excretion in the colostrum, delay within the absorption of Ca from GIT and bone mobilization at parturition (Diehl et al., 2018). Acute and severe hypocalcemia happens once Ca loses 1.9 to 2.8 g/kg of colostrum (Bojkovski et al., 2005; Abd El-Fattah et al., 2012) and 1.1 g/kg of milk (Tsioulpas et al., 2007). Preserving Ca level depends on the rate of gastrointestinal Ca absorption (Martin-Tereso and Verstegen, variations are constrained by parathyroid hormone (PTH) and calcitriol (1, 25 dihydroxy vitamin D3), which are viewed as the principal Ca regulatory hormones in mammals. Calcium homeostasis in periparturient dairy cattle is driven principally by the balance between, iCa admission (a function of the calcium content of the diet and feed intake), Ca absorption from the gastrointestinal tract, Ca mobilization from accessible stores and Ca lost to the fetus, colostrum, bone accretion, and urinary excretion (Martin-Tereso and Verstegen, 2011). Feeding negative DCAD ration prepartum stimulated Ca absorption and mobilization, thus preventing hypocalcemia, and maintained DMI and increased milk production after parturition (DeGroot et al., 2010). Accordingly, several studies were conducted to characterize the change in serum [Ca] in periparturient multiparous Holstein- Friesian cows fed a negative DCAD ration in the close-up period reposing beneficial effects for lactating dairy cows immediately after calving (El-Sheikh et al., 2002; Chan et al., 2005; Hu et al., 2007b). Therefore, the objectives of this study were to determine the effect of feeding a diet with different levels of negative DCAD on the concentration of mineral elements, acid-base balance, calcium homeostasis, milk production, and health status in dairy cows.

MATERIALS AND METHODS

Experimental design

On day 21 before the estimated parturition date, cows were assigned to 1 of 2 treatment groups: Group 1 had 24 cattle were fed an acidogenic TMR with negative-DCAD (dietary cation-anion difference) = −50 mEq/100 g of DM mEq/100g of matter, where DCAD = ([Na+] + [K+]) – ([Cl–] + [S2–]) based on formulations recommended by the National Research Council for close-up cows (Table 1). Group 2 included 24 control cows that fed the ration without DACD(CONT). Multiparous Cattle were fed an acidogenic close-up ration starting 3 wk before parturition. The ration was fed three times daily (every 8h). Cows in both\groups were switched to a lactating cow TMR immediately after parturition based on the formulation recommended by NRC for fresh cows. The time of calving was recorded to the nearest hour, and the calf and dam separated within a few hours of parturition. Calf birth weight was determined as described previously (Hiew et al., 2016). Cows were kept in temperature-controlled individual box stalls for 3 d after parturition or until they had recovered from any postpartum health disorders before being moved to a free-stall barn for lactating cows. After parturition, cows were milked three times daily every 8 h, in a milking parlor. Daily milk production was recorded.

 

Table 1: Ingredients of the ration for close-up, fresh cows, and control diet.

Ingredients	Kg/day	Kg/day	%
	(DM)	(As-Fed)	(DM)
Close-up
Corn grain, cracked	2.39	2.75	19.46
Soybean meal, solv. 44% CP	1.81	2.00	14.72
Wheat bran	0.89	1.00	7.24
Vitamin premix 1	0.04	0.05	0.36
Sod. bicarbonate	0.00	0.00	0.00
Calcium phosphate	0.06	0.06	0.49
Magnesium oxide	0.00	0.00	0.00
Salt	0.02	0.02	1.16
Alfalfa meal, 17% CP	1.35	1.50	10.98
Beet Pulp	0.46	0.50	3.74
Vegetable oil	0.05	0.05	0.40
Calcium chloride	0.11	0.11	0.89
Limestone	0.16	0.16	1.27
Zinc	0.00	0.00	0.00
Silage	4.95	16.50	40.26
Fresh
Corn grain, cracked	5.44	6.25	23.38
Soybean, meal, solv.44% CP	4.16	4.60	17.90
Wheat bran	1.29	1.45	5.55
Vitamin premix 1	0.07	0.07	0.28
Sodium bicarbonate	0.20	0.20	0.85
Calcium phosphate (mono-)	0.05	0.05	0.21
Magnesium oxide	0.05	0.05	0.21
Salt	0.09	0.09	0.38
Alfalfa meal, 17% CP	4.05	4.50	17.41
Beet pulp	0.00	0.00	0.00
Vegetable oil	0.51	0.52	2.19
Calcium chloride	0.00	0.00	0.00
Limestone	0.00	0.00	0.00
Zinc	0.01	0.01	0.03
Silage	7.35	24.50	31.60
Control
Corn grain, cracked	1.2375	1.375	16.86
Soybean meal, solv. 44% CP	0.225	0.25	3.07
Wheat bran	0.2975	0.35	4.05
Vitamin premix 1	0.04	0.05	0.54
Sod. bicarbonate	0.00	0.00	0.00
Calcium phosphate	0.06	0.06	0.82
Magnesium oxide	0.00	0.00	0.00
Salt	0.02	0.02	0.27
Alfalfa meal, 17% CP	1.35	1.50	18.39
Beet pulp	0.46	0.50	6.27
Vegetable oil	0.05	0.05	0.68
Calcium chloride	0.00	0.00	0.00
Limestone	0.00	0.00	0.00
Zinc	0.00	0.00	0.00
Silage	3.6	12	49.05

 

Animals, housing, and feeding

Fourty-Eight multiparous periparturient Holstein-Friesian cows (4-7y old) from private dairy farm in Sharqia (out of a total of 150 dairy cows) were fed on DCAD ration. The study was conducted between January 2020 and May 2020. All cows were kept in free-stall barns and under similar environmental conditions. Enrolled cows were moved from the outdoor to temperature-controlled individual box stalls (3.1 ×3.1 m) 21 days before the estimated parturition date. All enrolled cows underwent a daily routine health check including a California mastitis test for subclinical mastitis detection and all animals were deemed healthy. Access to clean water was maintained at all times at libitum.

Experimental study and sampling

Urine and blood sampling were performed daily between 09:00 and 11:00 h with the animal gently restrained in a headlock. Mid-stream urine samples were collected by perineal stimulation into a 20-mL plastic collection cup on d −1, 0, +1, and +2 relative to calving (d 0). The vials were completely filled with urine and immediately closed to minimize exposure to air. Urine samples were then placed in a water bath at 38°C and urine pH was measured within 15 min of collection using a pH meter (Orion 20A, Thermo Electron Corp., Beverly, MA). Urine samples were stored at −20°C for further analysis. Blood samples were obtained daily at approximately 08:00 h from the jugular vein on d −1, 0, 1 and 2 relatives to calving using 20-gauge Vacutainer needles, Vacutainer holders, and 10-mL plan blood collection tubes (BD Diagnostics, Franklin Lakes, NJ). The proposed puncture site at the side of the neck was cleared of debris by swabbing the site with gauze containing 70% isopropyl alcohol. Blood samples were centrifuged for 5 min at 1,300 × g within 30 min of collection.

Ethical approval

This longitudinal observational study used a convenience sample of per parturient multiparous dairy cattle. The study design and protocols were performed under the owner’s consent, approval of the Internal Ethics Review Committee of Faculty of Veterinary Medicine, Benha University, Benha city, Egypt (No: BUFVTM 11-02-22).

Urine and serum biochemical analysis

Stored urine samples were thawed at room temperature and vortexed for 10 s immediately before biochemical analysis. Urine concentrations of Ca (cresolphthalein), and creatinine (picric acid) concentrations were determined spectrophotometrically (BioTek Instruments Inc., Winooski, VT, USA) at the Veterinary Diagnostic Laboratory, Faculty of Veterinary Medicine Benha University, Egypt. Urine Ca excretion (g/d) for each 24-h period was calculated from two days prepartum to two days postpartum using the measured urine Ca concentration (urine Ca expressed in mg/dL), measured urine creatinine concentration (urine creatinine, expressed in mg/dL).

Serum biochemical analysis

All continuous data were evaluated for normal distribution or homogeneous variances. Log-transformation was used for data that deviated from normality. Data are expressed as mean ± stadard deviation and P < 0.05 was assigned as statistically significant. To test the effects of treatment (2 levels) and time (3 levels), and the interaction between treatment and time, with cow nested within treatment, repeated-measures ANOVA was used using the MIXED procedure of SAS version 9.4 (SAS Institute Inc., Cary, NC, USA). Whenever the F-test was significant, Bonferroni-adjusted P-values were used to assess differences between two treatment groups at a specific time and between times within a treatment group.

RESULTS

Effect of DCAD ration on urine pH, urine Creatinine, and urine Ca

The data in the Table 2 showed that: Cows fed DCAD ration showed a significant decrease (P<0.001) in urine pH at –1 day compared to non-DCAD group at the same time period (Table 2, Figure 1). Urine creatinine showed non-significant changes before parturition (-1 day), and after parturition (+1 day) in cows fed DCAD ration, While urine creatinine in NON DCAD group showed a significant decrease (P<0.001) before parturition (-1 day) compared to zero day but a significant increase (P<0.0001) after parturition (+1 day) and (+2 day) compared to DCAD group (Table 2, Figure 2).Urine Ca execration showed a significant increase before parturition (-1 day) at group fed DCAD ration, compared to the NON-DCAD group (Table 2, Figure 3).

 

Table 2: Changes in urine pH, urine Ca, urine creatinine during -1,0,1,2 peripartum day in multiparous dairy cattle fed acidogenic and non-acidogenic diets.

Group	Dayspp	Urine pH	urine Ca	Urine creatinine
DCAD	-1	6.6±0.17b	36.59±0.78a*	30.61±0.63a
DCAD	0	7.30±0.51a	20.74±0.67b	33.71±1.44a
DCAD	1	7.36±0.20a	15.87±3.05b	31.54±4.12a
DCAD	2	7.7±0.26a*	13.21±2.23b	16.46±0.76b
Non-DCAD	-1	7.9±0.00a*	12.82±0.16b	37.06±1.29b
Non-DCAD	0	7.66±0.05a	22.23±0.38a	45.08±4.02a*
Non-DCAD	1	7.73±0.64a	16.15±0.59b	53.36±2.49b*
Non-DCAD	2	7.56±0.40a	14.93±0.27b	48.40±0.96b*

 

a-b Values with different letters within a column are significantly different between zero and other time points for each type of diet (P<0.05). significant increase of Ca in urine occurs at -1 day before parturition. * Values within a column are significantly different between same time points at different diets (P<0.05).

 

 

 

 

 

Effect of DCAD ration on blood minerals, bicarbonate, urea and creatinine

The data in Table 3 showed that serum Ca concentration (Figure 4) showed a significant increase (P<0.05) before and after parturition at the DCAD group, compare to NON-DCAD group. Serum P concentration (Figure 5) showed a significant increase (P<0.05) before and after parturition at group fed DCAD ration, compared to the NON-DCAD group. Serum Mg concentration showed a significant increase (P<0.05) before and after parturition at group fed DCAD ration, compared to the NON-DCAD group. Serum Na concentration (Figure 6) showed a significant increase (P<0.05) before and after parturition at group fed DCAD ration, compared to the NON-DCAD group. Serum K concentration (Figure 7) showed a significant increase (P<0.05) before and after parturition at group fed DCAD ration, compared to the NON-DCAD group. Serum Cl concentration (Figure 8) showed a significant increase (P<0.05) before and after parturition at group fed DCAD ration, compared to the NON-DCAD group. Serum Bicarb concentration (Figure 9) showed significant decrease (P<0.05) at group fed DCAD ration before and after parturition, compared to NON-DCAD group. Serum urea concentration (Figure 9) showed a significant increase (P<0.05) before parturition (-1 day), compared to the NON-DCAD group. Serum creatinine (Figure 10) concentration increased significantly before parturition (-1 day) and decreased after parturition (+1 day) at group fed DCAD ration compared to NON-DCAD group (Table 3).

Effect of DCAD ration on milk production and calf weight

The data in Table 4 showed non-significant change in the weight of the calf between the two groups (Figure 12). The Milk production (Figure 13) showed a significant increase at group fed DCAD ration compared to the NON-DCAD group.

 

Table 3: Changes in blood minerals, bicarbonate, urea and creat during -1,0,1,2 peripartum day in multiparous dairy cattle fed acidogenic and non-acidogenic diets.

Parameters	DCAD group				Non-DCAD group
	-1day	0 day	1 day	2 day	-1 day	0 day	1 day	2 day
Ca (mg/dl)	10.33± 0.19b*	9.06± 0.09b*	10.46± 0.45b*	11.05± 0.50a*	7.47± 0.42a	6.6± 01.10a	7.8± 0.06a	7.8± 0.06a
P (mg/dl)	5.58± 0.56b*	4.85± 0.06b*	6.43± 0.21a*	6.9± 0.13a*	3.61± 0.03a	3.06± 0.10b	4.05± 0.05a	4.55± 0.05a
Mg (mg/dl)	3.79± 0.09b*	2.81± 0.13b*	3.5± 0.07a*	3.77± 0.10a*	1.36± 0.37a	1.03± 0.27a	2.05± 0.27a	2.75± 0.27a
Na (mEq/l)	144.01 ±4.74a*	133.61± 3.54a*	141.90± 3.87a*	154.49 ±2.25a*	127.95± 0.66b	124.90± 1.17b	131.25± 0.72a	131.1± 1.83a
K (mEq/l)	5.02± 0.62a*	4.56± 0.12b	5.24± 0.09a	5.54± 0.30a	4.06± 0.07a	3.53± 0.04a	3.85± 0.05a	3.93± 0.04a
Cl (mEq/l)	120.84± 1.67a*	100.19± 1.75a*	124.28± 1.66a*	126.77± 1.56a*	100.08± 0.08a	92.16± 1.28b	98.01± 0.23a	99.76± 0.49a
Bicarb(mg/dl)	27.38± 3.61b	30.88± 0.69b	33.53± 2.15a	34.64± 1.90a	30.60± 0.53b*	32.77± 1.27b*	35.95± 0.43a*	36.94± 0.55a
Urea (mg/dl)	51.69± 6.84b*	62.45± 0.59a	41.72± 0.45b*	31.76± 0.46b	47.15± 1.55b	72.04± 1.56a*	37.01± 0.06b	32.46± 2.45b
Creat (mg/dl)	2.47± 0.45a*	2.71± 0.07a	1.46± 0.17b*	0.94± 0.05b	1.85± 0.04b	2.90± 0.05a	0.86± 0.03b	0.81± 0.15b

 

a-b Values with different letters within a column are significantly different between zero and other time points for each type of diet (P<0.05). * Values within a column are significantly different between same time points at different diets (P<0.05).

 

Table 4: Calf weight, Milk weight during 0, 1, 2, -1 peripartum day in multiparous dairy cattle fed acidogenic and non-acidogenic diets.

Group	Dayspp	Calf weight (Kg)	Milk weight (Kg)
DCAD	-1	-	-
DCAD	0	40±5a	30.33±0.57a*
DCAD	1	40±5b	32.66±0.57a*
DCAD	2	40±5a	34.66±0.57b*
Non-DCAD	-1	-	-
Non-DCAD	0	41.66±1.52a	21.66±1.52a
Non-DCAD	1	41.66±1.52a	23.33±1.15a
Non-DCAD	2	41.66±1.52a	25.0±5.55a

 

a-b Values with different letters within a column are significantly different between zero and other time points for each type of diet (P<0.05). * Values within a column are significantly different between same time points at different diets (P<0.05).

 

 

DISCUSSION

One of the recurring problems in dairy farms, especially those with high production Holstein-Friesian cows, is the emergence of Ca deficiency cases, in late gestation. One of the ways that dairy farms help reduce cases of hypocalcemia

 

 

 

 

 

 

 

 

in multiparous cattle is to use Negative DCAD diets, which increase blood calcium concentrations postpartum. That leads to enhance health outcomes, improved production, and reproduction. The discovery of improved turnover can stimulate systemic acidsis. In addition, (Goff et al., 2014) state that dietary metabolic acidosis activates the PTH vitamin D axis, increasing intestinal Ca absorption and renal Ca reabsorption. This study found that prepartum feeding of the DCAD diet on dairy farms reduced urinary pH and increased urinary Ca excretion. Moore et al. (2000); Charbonneau et al. (2006) reported that increased acidity in the diet leads to mild compensatory metabolic acidosis that lowers urinary pH. Aciduria is caused by an excessively acidic diet that causes excessive proton excretion in the urine. The decrease in urine pH at peripartum intervals observed in this study is consistent with previous findings that urinary pH in cows fed an acidogenic diet in the late dry season did not change until 12- 24 hours after parturition (DeGaris and Lean, 2008; Grünberg et al., 2011). Elevated H + levels in the distal tubules block the ability of Ca receptors to reabsorb Ca, causing hypercalcemia (Zahed and Chehrazi, 2017). This study found that feeding a DCAD diet reduced levels of HCO3. (Oberleithner et al., 1982) stated that there was less iCa complex with bicarbonate, resulting in more iCa available in the blood (Roche et al., 2003), with changes in urinary pH. By changing changes in blood pH, the kidneys play an important role in minimizing this change by making urine pH alkaline, excreting more HCO3-, and conserving H +. The feeding of the DCAD diet before parturition in dairy cows helps to reduce cases of hypocalcemia in periparturient Holstein-Friesian cows. Charbonneau et al. (2006) said that feeding an acidogenic diet lowers the decrease in serum calcium 24 hours after parturition and reduces the incidence of prepartum and postpartum hypocalcemia from 16.4% to 3.2%. As a result, the serum calcium concentration before and after parturition was significantly increased in the DCAD distribution group compared to the NON-DCAD group. El-Sheikh et al. (2002) and Couto-Serrenho et al. (2021) found that a negative prepartum DCAD diet increased postpartum serum Ca levels and reduced the incidence of mastitis, abomasum dislocation, and clinical mastitis (Reinhardt et al., 2011; Miltenburg et al., 2016). Negative relationship between serum Ca before and after confinement, (Espino et al., 2003) maintains the ability of bovine Ca homeostasis obtained by acidification promoting the mobilization by removing calcium from bone (Goff, 2000; Espino et al., 2003) by promoting the action of PTH on bone and kidney or by the role of bone in buffering. This study found that prepartum feeding an acidogenic diet increased serum P levels before and after parturition (Ramos-Nieves et al., 2009). Agree with some previous studies (Ramos-Nieves et al., 2009; Vieira-Neto et al., 2021). Recently, it was reported that serum P concentration was negatively correlated with urinary pH (Vieira-Neto et al., 2021). However, these results reports are in contrast to previous studies that reported a direct association between DCAD reduction and P concentration (Castro et al., 2004). As mentioned earlier, metabolic acidosis and cystinuria promote renal Pi loss, so take an acidogenic diet before parturition (Grünberg et al., 2011). This study found that feeding a prepartum acidogenic diet increased serum Mg levels around calves (Goff, 2008). Similarly, in this study, high serum Mg levels in cattle fed an acidogenic diet were observed in previous studies (Goff and Horst, 2003; Farnia et al., 2018; Megahed et al., 2018; Rodney et al., 2003, 2018). Transient hypermagnesemia is most often due to increased renal Mg reabsorption in response to decreased blood Ca levels that stimulate PTH release (Rodney et al., 2018). Interestingly, cows fed an acidogenic diet showed increased serum Na and K levels around the calf compared to NON-DCAD cows. Metabolic acidosis has a dual effect on electrolyte balance, and increased electrolyte levels around calves are likely to be of renal origin (Stacy and Wilson, 1970). High serum levels in DCAD cattle are likely due to high Cl content in low DCAD diet (El-Sheikh et al., 2002; Grünberg et al., 2011). Renal function indices which includes serum urea and creatinine used to evaluate the functional integrity of the kidney, with expanded values being a demonstration of defective functional state (Yakuba et al., 2003). Linearly multiplied serum urea and the tendency to linearly increase creatinine concentrations found on this study also additionally mean some degree of renal toxicity imposed by negative DCAD. The urinary pH to as little as 5.5. By decreasing the pH from ordinary values 8.5 to values near 5.5 (3 Ph units), an immoderate load is imposed at the kidneys, as they need to excrete 1,000 instances the extra H+ produced by the body (Goff, 2018). The most negative DCAD also caused some indications of liver and kidney damage. This study found that feeding a prepartum acidogenic diet increased postpartum milk yield in calves (DeGroot et al., 2010). Postpartum (Puntenney, 2006) stated that acidifying the diet before parturition reduces the incidence of clinical and asymptomatic hypocalcemia and increases postpartum DMI and milk yield.

CONCLUSION

Feeding diets-induced mild metabolic acidosis during the close-up period enhances minerals homeostasis around calving, particularly calcium level, DCAD diet also enhanced milk production in dairy cattle fed acidogenic diet in late gestation. However, mild adverse effect on kidney function was detected. Further investigation on required adjust the doses of DCAD for dairy cows to overcome this effect.

ACKNOWLEDGMENT

The authors thank all the staff and owner dairy farm in Sharqia governorates for their help in collecting samples.

Novelty Statement

The authors declared that the results of this study are novel specially the effect of DCAD on the liver and kidney function and its addition to lactating cows should be under caution.

Author’s Contribution

AF design and perform the study. MG revised the study design and write the draft with graphing. YA revised the manuscript, HE review the study design and statistics, AM revised the manuscript and help in practical part. HE review the results and interpretation.

Conflict of interest

The authors have declared no conflict of interest.

REFERENCES

Abd El-Fattah AM, Abd-Rabo FHR, El-Dieb SM, El-Kashef HA (2012). Changes in the composition of colostrum of Egyptian buffaloes and Holstein cows. BMC Vet. Res., 8: 19. https://doi.org/10.1186/1746-6148-8-19

Bojkovski J, Borozan S, Jozef I, Samanc H (2005). Colostrum composition before and after calving in Holstein-Friesian cows. Vet. Rec., 156: 744–745. https://doi.org/10.1136/vr.156.23.744

Castro SIBI, Phillip LE, Girard V, Tremblay TA (2004). Altering dietary cation-anion difference in lactating dairy cows to reduce phosphorus excretion to the environment. J. Dairy Sci., 87: 1751-1757. https://doi.org/10.3168/jds.S0022-0302(04)73330-5

Chan PS, West JK, Bernard JK, Fernandes JM (2005). Effects of dietary cation-anion difference on intake, milk yield, and blood components of the early lactation cow. J. Dairy Sci., 88: 4384-4392. https://doi.org/10.3168/jds.S0022-0302(05)73125-8

Charbonneau E, Pellerin D, Oetzel GR (2006). Impact of lowering dietary cation-anion difference in nonlactating dairy cows: A meta-analysis. J. Dairy Sci., 89: 537–548. https://doi.org/10.3168/jds.S0022-0302(06)72116-6

Couto-Serrenho R, Bruinjé TC, Morrison EI, DeVries TJ, Duffield TF, LeBlanc SJ (2021). Controlled trial of the effect of negative dietary cation-anion difference on postpartum health of dairy cows. J. Dairy Sci., 104: XXXX–XXXX. https://doi.org/10.3168/jds.2020-19389

DeGaris PJ, Lean IJ (2008). Milk fever in dairy cows: A review of pathophysiology and control principles. Vet. J., 176: 58–69. https://doi.org/10.1016/j.tvjl.2007.12.029

DeGroot MA, Block E, French PD (2010). Effect of prepartum anionicsupplementation on periparturient feed intake, health, and milk production. J. Dairy Sci., 93: 5268–5279. https://doi.org/10.3168/jds.2010-3092

Diehl AL, Bernard JK, Tao S, Smith TN, Kirk DJ, McLean DJ, Chapman JD (2018). Effect of varying prepartum dietary cation-anion difference and calcium concentration on postpartum mineral and metabolite status and milk production of multiparous cows. J. Dairy Sci., 1: 1–11. https://doi.org/10.3168/jds.2018-14828

El-Sheikh A, Hayam MS, Badr A (2002). Effect of diet, dietary cation anion difference, body condition score, milk yield, parities and season on the incidence of milk fever in dairy cows. XX11 World Buiatrics Congress, Hannover, Germany, 18-23.

Espino L, Guerrero F, Suarez ML, Santamarina G, Goicoa A, Fidalgo LE (2003). Long-term effects of dietary anion–cation balance on acid-base status and bone morphology in reproducing ewes. J. Vet. Med. A, 50: 488–495. https://doi.org/10.1111/j.1439-0442.2004.00590.x

Farnia SA, Rasooli A, Nouri M, Shahryari A, Khosravi Bakhtiary M, Constable PD (2018). Effect of postparturient oral calcium administration on serum total calcium concentration in Holstein cows fed diets of different dietary cation-anion difference in late gestation. Res. Vet. Sci., 117: 118-124. https://doi.org/10.1016/j.rvsc.2017.11.017

Goff JP, Horst RL (2003). Role of acid-base physiology on the pathogenesis of parturient milk fever: The DCAD Theory in principal and practice. Acta Vet. Scand. Suppl., 97: 51-56.

Goff JP, Liesegang A, Horst RL (2014). Diet-induced pseudo-hypoparathyroidism: A hypocalcemia and milk fever risk factor. J. Dairy Sci., 97: 1520-1528. https://doi.org/10.3168/jds.2013-7467

Goff JP (2008). The monitoring, prevention, and treatment of milk fever and subclinical hypocalcemia in dairy cows. Vet. J., 176: 50–57. https://doi.org/10.1016/j.tvjl.2007.12.020

Goff JP (2018). Invited review: Mineral absorption mechanisms, mineral interactions that affect acid-base and antioxidant status, and diet considerations to improve mineral status. J. Diary Sci., 101: 2763- 2813. https://doi.org/10.3168/jds.2017-13112

Goff JP (2000). Pathophysiology of calcium and phosphorus disorders. Vet. Clin. North Am. Food Anim. Pract., 16: 319–337. https://doi.org/10.1016/S0749-0720(15)30108-0

Grünberg W, Donkin SS, Constable PD (2011). Periparturient effects of feeding a low dietary cation-anion difference diet on acid-base, calcium, and phosphorus homeostasis and intravenous glucose tolerance test in high-producing dairy cows. J. Dairy Sci., 94: 727–297, 745. https://doi.org/10.3168/jds.2010-3230

Hiew MW, Megahed AA, Townsend JR, Singleton WL, Constable PD (2016). Clinical utility of calf front hoof circumference and maternal intrapelvic area in predicting dystocia in late gestation Holstein-Friesian heifers and cows. Theriogenology, 85: 384–395. https://doi.org/10.1016/j.theriogenology.2015.08.017

Hu W, Murphy MR, Constable PD, Block E (2007b). Dietary cation-anion difference effects on performance and acid-base status of dairy cows postpartum. J. Dairy Sci., 90: 3367-3375. https://doi.org/10.3168/jds.2006-515

Martín-Tereso J, Verstegen MW (2011). A novel model to explain dietary factors affecting hypocalcemia in dairy cattle. Nutr. Res. Rev., 24: 228–243. https://doi.org/10.1017/S0954422411000126

Megahed AA, Hiew MWH, El-Badawy SA, Constable PD (2018). Plasma calcium concentrations are decreased at least 9 hours before parturition in multiparous Holstein-Friesian cattle in a herd fed an acidogenic diet during late gestation. J. Dairy Sci., 101: 1365-1378. https://doi.org/10.3168/jds.2017-13376

Miltenburg CL, Duffield TF, Bienzle D, Scholtz EL, LeBlanc SJ (2016). A randomized clinical trial of a calcium supplement for the improvement of health in dairy cows in early lactation. J. Dairy Sci., 99: 6550–6562. https://doi.org/10.3168/jds.2016-10961

Moore SJ, Vande-Haar MJ, Sharma BK, Pilbeam TE, Beede DK, Busholtz HF, Liesman JS, Horst RL, Goff JP (2000). Effects of altering dietary cation-anion difference on calcium and energy metabolism in peripartum cows. J. Dairy Sci., 83: 2095–2104. https://doi.org/10.3168/jds.S0022-0302(00)75091-0

Oberleithner H, Greger R, Lang F (1982). The effect of respiratory and metabolic acid- base changes on ionized calcium concentration in vivo and in vitro experiments in man and rat. Eur. J. Clin. Invest., 12: 451-455. https://doi.org/10.1111/j.1365-2362.1982.tb02223.x

Puntenney S (2006). The effect of prepartum anionic diets on cortisol, diponectin, and tumor necrosis factor-α expression at varying levels of body mass index in periparturient dairy Cows: Implications for insulin resistance. Ph.D. Dissertation. Oregon State University, Corvallis.

Ramos-Nieves JM, Thering BJ, Waldron MR, Jardon PW, Overton TR (2009). Effects of anion supplementation to low-potassium prepartum diets on macromineral status and performance of periparturient dairy cows. J. Dairy Sci., 92: 5677-5691. https://doi.org/10.3168/jds.2009-2378

Reinhardt TA, Lippolis JD, McCluskey BJ, Goff JP, Horst RL (2011). Prevalence of subclinical hypocalcemia in dairy herds. Vet. J., 188: 122–124. https://doi.org/10.1016/j.tvjl.2010.03.025

Roche JR, Dally D, Moate P, Grainger C, Rath M, Mara FO (2003). Dietary cation-anion difference and the health and production of pastured-fed dairy cows 2. Nonlactating periparturient cows. J. Dairy Sci., 86: 979-987. https://doi.org/10.3168/jds.S0022-0302(03)73681-9

Rodney RM, Martinez N, Block E, Hernandez LL, Nelson CD, Lean IJ, Santos JEP (2018). Effects of prepartum dietary cation-anion difference and source of vitamin D in dairy cows: Vitamin D, mineral, and bone metabolism. J. Dairy Sci., 101: 2519-2543. https://doi.org/10.3168/jds.2017-13737

Stacy BD, Wilson BW (1970). Acidosis and hypercalciuria: Renal mechanisms affecting calcium, magnesium, and sodium excretion in the sheep. J. Physiol., 210: 549-564. https://doi.org/10.1113/jphysiol.1970.sp009226

Tsioulpas A, Grandison AS, Lewis MJ (2007). Changes in physical properties of bovine milk from the colostrum period to early lactation. J. Dairy Sci., 90: 5012–5017. https://doi.org/10.3168/jds.2007-0192

Vieira-Neto A, Leão MR, Prim JG, Silva ACM, Nehme Marinho M, Zimpel R, Etheve S, Nelson CD, Santos JEP (2021). Effect of duration of exposure to diets differing in dietary cation-anion difference on Ca metabolism after a parathyroid hormone challenge in dairy cows. J. Dairy Sci., 104: 1018-1038. https://doi.org/10.3168/jds.2020-19127

Yakuba MT, Bilbis LS, Lawal M, Akanji MA (2003). Evaluation of selected parameters of rat liver and kidney function following repeated administration of yohimbine. Biokemistri, 15: 50-56.

Zahid NS, Chehrazi S (2017). The evaluation of the relationship between serum levels of Interleukin-6 and Interleukin-10 and metabolic acidosis in hemodialysis patients. Saudi J. Kidney Dis. Transpl., 28: 23-29. https://doi.org/10.4103/1319-2442.198106