Identifying hydric, electrolyte and acid-base imbalances in dogs with Chronical Kidney Disease (CKD)

[Identificação de desequilíbrios hídricos, eletrolíticos e ácido-básicos em cães com doença renal crônica (DRC)]

ABSTRACT

This study aimed to characterize water, electrolyte and acid-base imbalances and evaluate traditional and quantitative approaches in dogs with renal azotemia. We evaluated 34 dogs with clinical and laboratory diagnosis of chronic kidney disease (CKD) and ten healthy dogs were evaluated. Venous blood gas analysis was performed during the patient's initial care before any therapeutic measure was instituted. The parameters measured were pH, pCO₂, HCO₃ ^-, BE (ecf), Na⁺, K⁺, Cl^-, iCa²⁺, glucose, lactate, phosphate, and albumin. The mean, median and standard deviation of all analyzed parameters were calculated for sick and healthy dogs. 52.9% (18/34) of animals did not show apparent dehydration. The most common electrolyte changes were hyperkalemia 76.4% (26/34), hypochloremia 58.8% (20/34) and hyponatremia (52.9%) (18/34). Metabolic acidosis was the most common acid-base disorder in both approaches. Using the traditional approach, 70.5% (24/34) presented metabolic acidosis due to reduced HCO₃ ^- concentration. When considering the AG value, 61.76% (21/34) of the dogs showed an increase in AG or acidosis due to an increase in unmeasured anions. While using the quantitative approach, metabolic acidosis was identified by evaluating the reduction in SIG in 82.3% (28/34) of dogs and 14.7% (5/34) with hyperchloremic acidosis by reducing SID. Only in this approach, metabolic alkalosis was detected due to a reduction in Atot 55.8% (19/34) and an increase in SID due to hypochloremic alkalosis in 35.3% (12/34). It is concluded that the most common imbalances found in these dogs with nephropathy were hyperkalemia, hypochloremia and metabolic acidosis due to an increase in unmeasurable anions and a greater number of acid-base disorders were identified by the quantitative approach.

Keywords:
metabolic acidosis; hypochloremia; hyperkalemia; blood gas analysis

RESUMO

Este estudo teve como objetivo caracterizar os desequilíbrios hídrico, eletrolítico e ácido-básico e avaliar as abordagens tradicional e quantitativa em cães com azotemia renal. Foram avaliados 34 cães com diagnóstico clínico e laboratorial de doença renal crônica (DRC) e 10 cães saudáveis. A gasometria venosa foi realizada no atendimento inicial ao paciente, antes da instituição de qualquer medida terapêutica. Os parâmetros mensurados foram pH, pCO₂, HCO₃ ^-, BE (ecf), Na⁺, K⁺, Cl^-, iCa²⁺, glicose, lactato, fosfato e albumina. Calculou-se média, mediana e desvio-padrão de todos os parâmetros analisados, dos cães doentes e dos saudáveis. A maioria dos animais, 52,9% (18/34), não apresentava desidratação aparente. As alterações eletrolíticas mais comuns foram hipercalemia, 76,4% (26/34); hipocloremia, 58,8% (20/34); e hiponatremia, 52,9% (18/34). A acidose metabólica foi o distúrbio ácido-básico mais comum em ambas as abordagens. Pela abordagem tradicional, 70,5% (24/34) apresentaram acidose metabólica por redução da concentração de HCO₃ ^-. Ao se considerar o valor da AG, 61,76% (21/34) dos cães apresentaram aumento do AG ou acidose por aumento de ânions não mensurados. Pela abordagem quantitativa, identificou-se acidose metabólica por redução da SIG em 82,3% (28/34) dos cães, e em 14,7% (5/34) acidose hiperclorêmica por redução da SID. Apenas nesta abordagem detectou-se alcalose metabólica por redução da Atot, 55,8% (19/34), e 35,3% (12/34) aumento da SID por alcalose hipoclorêmica. Conclui-se que os desequilíbrios mais comuns encontrados nesses cães com nefropatia foram hipercalemia, hipocloremia e acidose metabólica, devido ao aumento de ânions não mensuráveis, e um número maior de distúrbios ácidos-básicos foram identificados pela abordagem quantitativa.

Palavras-chave:
acidose metabólica; hipocloremia; hipercalemia; gasometria

INTRODUCTION

Among the various alterations that CKD causes are dehydration, electrolyte imbalances and acid-base alteration, such as metabolic acidosis, which affects the body's homeostasis due to loss of renal function. Anorexia, great water and electrolyte loss caused by episodes of vomiting and loss of urinary concentration capacity are the main causes of the alterations. Dehydration can aggravate uremia and, consequently, worsen kidney damage (Polzin, 2011; Nelson and Couto, 2019; Crivellenti and Giovaninni, 2021). The main laboratory alterations that can be found are azotemia, hyperphosphatemia, metabolic acidosis, non-regenerative anemia and isosthenuria (Polzin et al., 2005; Nelson and Couto, 2019).

Electrolyte changes can also be detected, depending on the course of the disease, due to reduced GFR, loss of renal excretory function, or reduced renal tubular reabsorption (Kogika et al., 2008; Crivellent and Giovaninni, 2021). Hypocalcemia is considered as relatively common, associated with hyperphosphatemia and reduced calcitriol concentration in CKD patients (Polzin et al. 2011; Chen et al., 2020). In addition, hyperkalemia, derived from the accumulation of non-organic acids, due to the cellular exchange of K⁺ ions for H⁺ to the circulation and mainly, due to the reduction of its renal excretion, due to the functional loss in CKD (Di Bartola and Morais, 2012; Kogika and Morais, 2016).

Metabolic acidosis leads to reduction in blood pH from reduction in serum bicarbonate or base excess (Hopper and Epstein, 2012). In the CKD patient, it occurs due to renal impairment in the excretion of hydrogen ions, tubular reabsorption of bicarbonate and by the process of renal ammoniagenesis (Kraut and Madias, 2017; Chen, Levy and Abramowitz, 2019; Kajimoto et al., 2021). According to the traditional Henderson-Hasselbalch approach, alkalosis is characterized by a primary increase in serum bicarbonate and blood pH, due to gastric or renal acid loss or net accumulation of bicarbonate ions in the extracellular fluid (ECF) (Khanna and Kurtzman, 2006). In small animals it can occur due to obstruction of the gastrointestinal tract, treatments with diuretics and bicarbonate and loss of gastric contents (Hopper and Epstein, 2013). In humans there is an association between metabolic acidosis and the progression in humans of CKD with increased mortality (Kraut and Madias 2017; Tangri et al., 2021; Kim et al., 2021).

The interpretation of imbalances can be performed using two approaches, both complementary and non-exclusive. The traditional approach determines that the blood pH is the dependent variable and the respiratory (pCO₂) and metabolic components (HCO₃ ^-) are the independent variables (Di Bartola, 2012). The strong ion model or quantitative approach determines that pH and HCO₃ ^- are the dependent variables, which varies because of the following independent variables: pCO₂, strong ion difference (SID) and total concentration of Non-Volatile Weak Acids (Atot) (Constable, 1999; Muir, 2017). This approach becomes important, as it considers how pH changes and integrates electrolyte and acid-base physiology thus establishing the best fluid therapy option (Kaplan et al., 2009; Seifter, 2014; Magder and Emami, 2015; Kwok et al., 2016). The strong ion model or quantitative approach provides greater accuracy in acid-base diagnosis, leading to an appropriate choice of fluid therapy, thus reducing the inappropriate plasma volume expansion in the patient (Kaplan et al., 2009).

The objectives of this study were to characterize water, electrolyte and acid-base imbalances, comparing traditional and quantitative approaches in dogs with chronic kidney disease.

MATERIALS AND METHODS

This study was approved by the Committee on Ethics in the Use of Animals- State University of Londrina-UEL (CEUA-UEL) under protocol number 14630.2017.98.

The sick group consisted of 34 dogs of different breed, sex, and age, who had chronic kidney disease. Animals had a history of vomiting, anorexia, weight loss or polyuria and polydipsia. The inclusion criterion was the presence of any of the clinical signs, as well as the presence of azotemia and hyperphosphatemia during the period from March to August 2018. After laboratory results, the dogs were staged into 14 IRIS III and 20 IRIS IV, based on serum creatinine values, according to IRIS 2023.

The tutors signed a consent form for the inclusion of the animal in the study. Exclusion criteria were animals that had pulmonary disease, dogs with live weight below seven kilograms and/or with anemia in which the hematocrit was below 25%. In this group, the characterization of water, electrolyte and acid-base imbalances was carried out.

The control group consisted of 10 healthy dogs, five males and five females, with varying weights and an average age of four years. The dogs were submitted to a clinical, hematological, and biochemical evaluation to confirm their healthy state.

From both groups, four mL of venous blood were collected and distributed half in a commercial tube containing the anticoagulant ethylenediamine tetracetic acid (EDTA), to perform a complete blood count in an automatic analyzer poCH-100 iV Diff®-Sysmex, and the other half in a commercial tube containing heparin to the processing of biochemical tests (creatinine, urea, albumin, total proteins, calcium, and phosphorus) in the Dimension X Pand® Plus-Siemens analyzer. The sample for venous blood gas analysis was collected in a heparinized syringe and immediately sent to the RAPIDPoint® 500 analyzer, System Siemens, for analysis of blood pH, pCO₂, HCO₃ ^-, base excess (BE ecf), Na⁺, K⁺, Cl^-, glucose, lactate, ionic calcium. The variables calculated were strong ion difference (SID) and Anion Gap (AG) and equations were performed to calculate SIG and Atot. The following formulas were used: AG=(Na⁺+K⁺)-(Cl⁻+HCO₃ ⁻) (Di Bartola, 2006a), SID=(Na⁺+K⁺)-(Cl⁻) (Constable, 1999), Atot = albumin contribution + phosphorus contribution (Hopper et al., 2014) and SIG=[albumin (g/L)]x0.49-AG (Constable and Stampfli, 2005).

For purposes of comparison with the sick group, plasma concentrations of phosphorus, albumin and total proteins were determined, in addition to blood gas analysis for analysis of blood pH, pCO₂, HCO₃ ^-, base excess (BE ecf), Na⁺, K⁺, Cl^-, glucose, lactate.

The degree of dehydration in small animals is analyzed through physical examination (skin turgor, mucosal evaluation, increased capillary refill time (CPT), tachycardia and cold extremities) together with laboratory tests (elevated hematocrit and hyperproteinemia). Water imbalance was classified as unapparent (<5%), when there is no change in skin elasticity; mild/mild dehydration (5-6%) slight loss of skin elasticity; moderate (7-9%), loss of skin elasticity, slight prolongation of CPT, enophthalmos, dry mucous membranes and severe (10-12%), prolonged wrinkling of the skin, prolongation of CPT, enophthalmos, dry mucous membranes, signs of shock (tachycardia, rapid and weak pulse, cold extremities) (Benesi and Kogika, 2017).

Values obtained from control group were applied to the classification of electrolyte and acid-base imbalances in sick dogs. Cl^- was corrected using the formula Cl^- measured x (normal Na⁺ concentration/ measured Na⁺ concentration) (Hopper et al., 2014).

To classify the acid-base imbalance, the variable AG (Anion Gap) was considered according to the traditional approach, and by the acid-basic approach (quantitative/Stewart) the variables SID (Strong Ion Difference), Aᴛᴏᴛ (total concentration of weak acids non-volatile) and SIG (Strong Ion Gap) (Table 2).

Mean, median, standard deviation, 25th and 75th percentiles were calculated from both groups, healthy and sick dogs. The reference interval was considered as mean ( standard deviation from healthy dogs, considering an error probability of 0.05.

RESULTS

The results of laboratory tests in the control group are shown in Table 1 as for the electrolyte evaluation, values above and below those presented by the control group were considered imbalances, obtained after venous gasometry.

Table 1
Mean and standard deviation values and reference interval (RI) considered based on the values, obtained by blood gas analysis, from dogs in the control group from the Londrina -PR region

Parameter	RI	Mean	Standard deviation
pH	7,299 - 7,451	7,375	0,038
pCO2 (mmHg)	30,08 - 45,54	37,81	3,87
HCO3-st (mmol/L)	17,73 - 24,91	21,32	1,8
BE ecf (mmol/L)	(-8,14) - 1,58	-3,28	2,43
Na+ (mmol/L)	146,29 - 154,59	150,44	2,07
K+ (mmol/L)	2,96 - 4,11	3,54	0,29
Cl- (mmol/L)	110,64 - 117,56	114,10	1,73
iCa (mmol/L)	1,95 - 4,86	3,4	0,73
SID (mmol/L)	36,96 - 42,79	39,88	1,46
AG (mmol/L)	13,75 - 23,37	18,56	2,41
Lactate (mmol/L)	0,53 - 3,36	1,94	0,71
TP (g/dL)	5,08 - 8,12	6,60	0,76
Albumin (g/dL)	2,47 - 3,26	2,86	0,20
Fosfate (mg/dL)	2,75 - 5,05	3,90	0,57
Atot (mmol/L)	11,37 - 14,98	13,17	0,90
SIG (mmol/L)	(-9,80) - 0,75	-4,52	2,64

• Abbreviations: Hydrogen potential (pH); partial pressure of carbon dioxide (pCO2); bicarbonate (HCO3-st); Excess base (BE ecf); sodium ion (Na+); potassium ion- (K+); chloride ion (Cl-); ionic calcium (iCa); Strong Ion Difference (SID); Anion gap (AG); total protein (TP); Non-Volatile Weak Acids (Atot) and Strong Ion Gap (SIG).

According to the identified acid-base imbalance and its classification, the values ​​are presented in Table 2 for both approaches. Mean, standard deviation, median, 25th and 75th percentile values of the blood gas, biochemical and electrolyte variables of the 34 dogs with chronic kidney disease before SRL fluid therapy are shown in Table 3. The metabolic acid-base imbalances identified in the 34 azotemic dogs are shown in Figure 1.

Table 2
Values of variables used to identify acid-base disorders using traditional and quantitative approaches

VARIABLES	ALKALOSIS	ACIDOSIS
HCO3 - mmol/L	> 24,9	< 17,7
pCO2 mmHg	< 30,1	> 45,5
AG mmol/L	< 13,8	> 23,4
SID mmol/L	> 42,8	< 37,0
Atot mmol/L	< 11,4	> 15,0
SIG mmol/L		< -9,80

• Abbreviations: HCO₃-: bicarbonate; pCO₂: partial pressure of carbon dioxide; SID: Strong Ion Difference; Atot: Non-Volatile Weak Acids; SIG: strong ion gap. Reference range considered based on values obtained from dogs in the control group from the Londrina -PR region.

Table 3
Mean values, standard deviation, median, 25th and 75th percentiles of the blood gas, biochemical and electrolyte variables of the 34 dogs with chronic kidney disease, before fluid therapy with lactated Ringer

Parameters	Mean	Median	Standard deviation	Percentile 25	Percentile 75	IR
pH	7.2	7.3	0.09	7.21	7.36	7.299 - 7.451
pCO2(mHg)	31.2	30.9	6.05	27.9	34.9	30.08 - 45.54
HCO3st (mmol/L)	14.7	15.4	4.52	11.8	18.8	17.73 - 24.91
BEecf (mmol/L)	-11.9	-11.6	5.79	-15.6	-6.4	(-8.14) - 1.58
Na+ (mmol/L)	142.8	146	10.0	142	148	146.29 - 154.59
K+ (mmol/L)	4.9	4.85	1.10	4.1	5.5	2.96 - 4.11
Cl- (mmol/L)	105.9	108	12.8	99.2	114.2	110.64 - 117.56
iCa (mmol/L)	3.1	3.3	1.18	2.25	4.25	1.95 - 4.86
SID (mmol/L)	42.6	42.3	7.54	38.1	47.6	36.96 - 42.79
AG (mmol/L)	28	26.5	8.37	22	34	13.75 - 23.37
Lactate (mmol/L)	3.4	1.2	0.92	1.0	1.8	0.53 - 3.36
PT(g/dL)	7.8	7.5	1.89	6.6	8.6	5.08 - 8.12
Albumin (g/dL)	2.1	2.2	0.58	1.8	2.5	2.47 - 3.26
Fosfate (mg/dL)	17.8	16.8	8.7	10.5	25.7	2.75 - 5.05
Atot (mmol/L)	15.1	14.5	5.34	10.8	18.6	11.37 - 14.98
SIG (mmol/L)	-17.5	-15.3	9.00	-24.9	-11.4

• Abbreviations: pH, Partial carbon gas pressure (pCO2 mmHg), bicarbonate (HCO3-st mmol/L), Excess base (BE ecf mmol/L), sodium ion (Na+ (mmol/L), potassium ion (K+ (mmol/L), chloride ion (Cl- (mmol/L), ionic calcium (iCa (mmol/L), Strong Ion Difference (SID (mmol/L), anion gap (AG (mmol/L), total proteins (PT(g/dL), Nonvolatile weak acids (Atot) and Strong Ion Gap (SIG mmol/L).

Figure 1
Flowchart of metabolic acid-base imbalances in the 34 azotemic dogs.

DISCUSSION

The main findings were hyperkalemia, hypochloremia, hyponatremia, metabolic acidosis was the most common acid-base imbalance in both approaches found, and regarding water imbalance, the majority presented inapparent dehydration. These findings are common in patients with CKD, due to the reduction in the glomerular filtration rate (GFR) due to reduced renal function.

Assessment using quantitative approach is an effective way to understand how electrolyte changes can cause acid-base imbalances, such as the presence of increased SID due to hypochloremic alkalosis. Chloride levels are reduced, and to compensate, there is increased reabsorption of the HCO₃ ^- ion, leading to an increase in blood pH, or metabolic alkalosis due to a reduction in Atot, due to hypoproteinemia caused by the reduction in acid load.

Hyperkalemia, the most frequent electrolyte imbalance in this study. The hyperkalemia is a hydro-electrolytic alteration that frequently occurs in patients with chronic kidney disease (CKD) (Nicola et al., 2018), mainly due to reduced renal potassium excretion. Physiologically, 90-95% of this ion is eliminated in the urine (Di Bartola and Morais, 2012; Kogika and Morais, 2017) and being associated with an unfavorable prognosis in humans by promoting cardiotoxicity (Collins et al., 2017).

The impairment of renal function in CKD leads to a reduced ability to excrete H⁺ ions and tubular reabsorption of HCO₃ ^-, which leads to an increase in serum K⁺ (Soleimani and Rastegar, 2016), as in oliguria or anuria, due to the abrupt reduction in GFR in acute and accentuated phase in the final stages of CKD (Di Bartola and Morais, 2012).

According to Segev et al. (2010) hyperkalemia is expected in CKD patients and was observed at a relatively early stage in dogs. Segev et al., (2010) observed that 47% of CKD dogs had at least one episode of hyperkalemia and 25%≥3 episodes when potassium intake (diet) exceeded excretory capacity. Although it can also be associated with non-renal causes, it frequently occurs in metabolic acidosis, due to the extracellular deviation of K⁺, in order to maintain electroneutrality, as the H⁺ ions are captured by the cell, the cations K⁺ must leave it (Adrogue and Madias, 1981; Weiner, 2017; Criveletti and Giovaninni, 2021) which characterizes hyperkalemia by redistribution. In this study, as the dogs were in advanced stages of CKD, hyperkalemia occurred due to impairment of renal function in CKD and due to metabolic acidosis, as occurred in the study of Harris et al. (2018).

The second most common electrolyte disturbance was hypochloremia in 20/34 (58.8%) of these dogs. Chloride is the main anion of the extracellular fluid, and its imbalance influences acid-base metabolism, acting in an inversely proportional manner to bicarbonate. In metabolic alkalosis, with an increase in HCO₃ ^- the tendency is for a reduction in chloride to maintain electroneutrality (Morais, 1992; Di Bartola, 2012). Like sodium and water, chloride is also reabsorbed in the proximal tubule (50-60%), which is linked to sodium reabsorption. Its increase together with sodium, leads to hyperchloremic acidosis, consuming bicarbonate. To compensate for the lack of negative charge, there is increased absorption of chloride, which leads to hyperchloremic acidosis. Its decrease with constant sodium concentration, however, leads to metabolic alkalosis, which will lead to an increase in bicarbonate to maintain electroneutrality (Di Bartola, 2012; Crivellenti and Giovaninni, 2021). The loss of fluids through vomiting can cause hypochloremia, (Tello and Perez-Freytes, 2017) and consequent hyponatremia (Langston, 2008; Lyons Waddell., 2018), as observed in this study.

Results of hypochloremia observed in this study may have been caused by vomiting, common in CKD due to uremia, which is one of the factors that lead to an increase in SID due to a relative increase in sodium, to maintain electroneutrality, which leads to hypochloremic metabolic alkalosis. Other factors involve renal adaptation in the control of metabolic acidosis, in which there is excretion of Cl^- ions and conservation of bicarbonate ions (Di Bartola, 2012; Benesi and Kogika, 2017).

Plasma osmolality is determined according to the plasma concentration of Na⁺, glucose and urea, mainly. Hyponatremia is usually reflected in plasma hyposmolality. Generally, hyponatremia results from an increase in total body water rather than a loss of sodium from the body (Di Bartola, 2006b; Rondon and Badireddy, 2023). Natremia does not reflect the total concentration of this ion, but the amount of sodium in relation to the patient's circulating blood volume (Di Bartola, 2006b; Morais and Di Bartola, 2008).

Therefore, the interpretation of hyponatremia should be considered with the hydration status, which in this study 52.9% (18/34) were normovolemic, against 11/34 (32.5%) with moderate dehydration and hyponatremia being the third electrolyte alteration most found, in 18/34 (52.9%) of the dogs. Thus, having a close relationship with the fluid status of the patient, in addition to the frequency and intensity of vomiting in renal patients (Morais and Di Bartola, 2008). Ueda et al. (2015) observed hyponatremia in 55.8% of the dogs that presented loss due to vomiting, which is common in renal patients due to uremia. As the loss of renal function is irreversible and progressive, the compensatory response of the remaining nephrons becomes increasingly ineffective throughout CKD, resulting in increasingly lower GFR levels.

Thus, hyponatremia may be associated with excessive sodium loss or even reduced tubular reabsorption of sodium by the kidneys and, therefore, sodium concentration may vary according to the evolution of CKD (Chew and Di Bartola, 1992). It was observed in an experimental study that metabolic acidosis was associated with progressive decline in GFR in rats with reduced mass of functional nephrons (Wesson and Simoni, 2010).

Martinez and Carvalho (2010) reported that CKD dogs had greater excretion of electrolytes, such as sodium, to compensate for the reduction in GFR. As well as in dogs with moderate to severe progression of renal function, in the study by Buranakarl et al. (2007). Mandai et al. (2017) and Mezones-Holguin et al. (2019) reported an association between changes in sodium and chloride concentrations as possible predictive indicators of mortality in chronic kidney disease in human patients.

In the present study, hyponatremia was the third most frequently observed electrolyte disorder, which may be related to the progression of CKD. These dogs were IRIS-III and IRIS-IV. Additionally, factors such as dehydration and disturbances in water balance, such as vomiting, can contribute to this condition. Changes in these ions may be associated with the severity and outcome of some of these dogs, as many died, corroborating data from humans with CKD.

According to Crivellenti and Giovaninni (2021) the fraction of calcium not bound to proteins is filtered by the glomeruli and largely reabsorbed by the tubules, in addition to the ionic fraction representing metabolic activity, being of greater diagnostic value. Ionized hypocalcemia is common in CKD patients due to metabolic acidosis and may occur due to lower tubular reabsorption, due to interference from hyperphosphatemia, parathyroid hormone (PTH) and low synthesis of calcitriol (active form of vitamin D) (Galvão et al., 2017). Corroborating the high percentage of metabolic acidosis present in these dogs, in advanced stages of CKD, due to hyperphosphatemia due to the reduction in GFR in CKD.

CKD causes hyperphosphatemia by decreasing renal excretion of phosphorus and reduces tubular reabsorption of calcium, which leads to an increase in PTH as a compensatory mechanism in the Ca:P balance (increasing the serum level of calcium and decreasing that of phosphorus) (Polzin, 2011). As CKD progresses, the difficulty in maintaining the calcium level increases, which will lead to greater PTH release. Consequently, bone demineralization and soft tissue mineralization will occur due to hyperplasia of the parathyroid gland, known as secondary renal hyperparathyroidism.

Hypocalcemia was detected in 20.5% (7/34) of the dogs. Hypocalcemia usually precedes secondary renal hyperparathyroidism, which occurs mainly in more advanced stages of CKD, reflecting the imbalance in bone and mineral metabolism, caused by decreased renal function. The inability of the kidneys to excrete phosphate and adequately activate vitamin D leads to a reduction in calcium levels, which stimulates excessive secretion of PTH (Rossi et al., 2023). Furthermore, calcium deposition in other organs and decreased absorption in the gastrointestinal tract, due to low calcitriol synthesis, also contribute to low levels of ionizable calcium in these patients (Harjes et al., 2017). The dogs in the present study, in stages IRIS III and IRIS IV, corroborate this information. Therefore, hypocalcemia may be associated with reduced phosphorus excretion due to the progression of GFR reduction.

The respiratory system plays a fundamental role in acid-base balance. Its action is to control the concentration of carbonic acid through pulmonary ventilation (Furoni et al., 2010). During metabolic acidosis, respiratory alkalosis, caused by hyperventilation, appears as a compensatory effect to increase pH, due to acidemia, which stimulates respiratory chemoreceptors to increase CO₂ excretion and, consequently, reduces [H⁺] concentration (Hopper and Epstein, 2012). Sixteen of the thirty-four dogs presented with acidemia and reduced HCO₃ ^-, classified as metabolic acidosis using the traditional approach. In this approach, 41.1% (14/34) presented a compensatory response (respiratory alkalosis) to metabolic acidosis, through hyperventilation. Such compensation was effective in six dogs, with the restoration of the pH to the physiological range by respiratory buffering tamponade, however, it was not effective in the other eight dogs. The absence of compensatory response was also observed in eight dogs. Pulmonary inefficiency may be based on secondary complications from the initial disease or pre-existing respiratory changes (Andrei, 2014), which contributed to the worsening of the primary condition of acid-base imbalance. Dogs with concomitant pulmonary involvement were excluded from the study before it began, therefore, animals with metabolic acidosis that present reduced lung function and consequent respiratory acidosis, because of hypoventilation and CO₂ accumulation (Kraut and Madias, 2017), were not observed, also because the clinical condition of those included in the study did not represent severe cases of the disease.

Both by the traditional approach and by the quantitative approach, the most common acid-base imbalance found was metabolic acidosis. Metabolic acidosis in CKD occurs as there is a reduction in the ability to excrete acidic substances, resulting in the retention of acids in the body (Raphael, 2019). In patients with CKD, reduced renal function compromises the capacity for tubular regeneration of bicarbonate (HCO₃⁻), while increasing chloride (Cl⁻) reabsorption (Kim, 2021). This imbalance is one of the main factors contributing to the development of metabolic acidosis in CKD. Metabolic acidosis is associated with the progression of CKD and mortality in these patients (Kraut and Madias, 2017; Raphael, 2019).

Metabolic alkalosis was only blocked by the traditional approach due to the increase in SID, 12/34 (35.2%) dogs had hypochloremic metabolic alkalosis, and in the Atot analysis, 19/34 (55.8%) were identified with metabolic alkalosis. While the quantitative approach failed to detect % (6/34) changes, the traditional approach was unable to identify imbalances in % (10/34) dogs

Using the traditional approach, metabolic acidosis can be assessed by reducing bicarbonate, leading to acidemia or increased AG. By the traditional approach, only metabolic acidosis was detected. In this approach, acidemia is assessed by reducing the concentration of bicarbonate 24/34 (70.5%) and 21/34 (61.76%) dogs presented metabolic acidosis evaluating the AG values observed by the increase in AG. Which is attributed to the increase in non-measured anions (NMA) such as endogenous acids (lactate, sulfates, phosphates and ketoacids) (Hopper et al., 2014). The loss of renal capacity to secrete acids, in kidney disease, due to the reduction in GFR, alters the acid-base balance, retaining organic acids, phosphates and sulfates, accumulation of anions, which leads to an increase in AG, which is characterized by due to metabolic acidosis (Palmer and Sterns, 2009; Di Bartola, 2011; Chen, Levy and Abramowitz, 2019). As these dogs had CKD-III and CKD-IV, there was already an intense reduction in renal function, leading to an increase in fatty acids, such as sulfates and phosphates, which explains the metabolic acidosis.

One of the consequences of CKD is metabolic acidosis, with a reduction in the GFR being one of the causes (Kraut and Madias, 2017). Metabolic acidosis, when not treated, worsens the reduction in GFR, due to the chronic compensatory response of hormones, such as aldosterone and angiotensin II, which increase the urinary excretion of accumulated acids in the DRC. This chronic regulation will cause kidney cell damage, inflammation, and fibrosis, thus compromising its function (Wesson and Simoni, 2010; Kraut and Madias, 2018). It can consider that acidosis is interconnected with the progression of CKD (Kraut and Madias, 2018; Goraya and Wesson, 2019).

AG can be maintained normal or elevated depending on the nature of the acid-base disorder. When unmeasured anions (lactate, ketoacids, phosphates and sulfates) are high, to maintain electroneutrality, the bicarbonate concentration tends to decrease. If there is a concomitant increase in chloride, the AG does not change and this acidosis is classified as hyperchloremic or normal AG acidosis, suggesting that the acidosis is secondary to hyperchloremia. When there is a primary reduction in bicarbonate associated with the accumulation of organic acids, the increase in AG is due to normochloremic acidosis (Di Bartola, 1999). In this study, 7/34 (20.5%) presented hyperchloremic acidosis, due to renal tubular acidosis and loss of bicarbonate, or in renal failure, due to impaired acid excretion (Kraut and Madias, 2007; Berend, 2017), leading to an increase in AG in these dogs. While 13/34 (38.2%) dogs presented normochloremic acidosis due to increased unmeasured anions. In metabolic acidosis with increased AG, the presence of weak acids, which are not compensated by chloride, causes an increase in AG.

By traditional approach, the increase in AG with reduced pH was found in 47% (16/34) of these dogs, or within the reference range. This change may be caused by the presence of organic (endogenous) acidosis, considered the main cause, hyperproteinemia, and hyperphosphatemia (Morais, 1992). In this study, 11/34 (32,3%) dogs presented hyperproteinemia and 22/34 (64,7%) hyperphosphatemia, which may have contributed also, with the increase in AG. Therefore, hyperphosphatemia due to CKD progression was the biggest contributor to the increase in AG in the present study.

Hyperphosphatemia is considered common in dogs with reduced GFR, observed in more advanced stages of CKD because the renal route is the main excretory route for phosphorus (Polzin, 2011). Kojika et al. (2006) observed that 92% of CKD dogs presented hyperphosphatemia. Almeida et al. (2011) observed this electrolyte disorder in all IRIS III and IV dogs, as in the present study.

The quantitative approach is based on the strong ion model, such as Na⁺, K⁺, cl^-, lactate, sulfate and ketoacid ions. The variation of the independent variables (PCO₂, SID and Atot) interferes with the concentration of H⁺ and HCO₃ ^-, dependent variables to maintain the law of electroneutrality, dissociation equilibrium for incompletely dissociated solutes and conservation of mass (Stewart, 1983). Using the traditional approach, the increase in the Anion Gap (AG) is due to unmeasured anions, which are identified using the quantitative approach by SIG and Atot, for example (Hopper et al., 2014).

SID is important in CKD patients, as it helps classify metabolic acidosis in relation to chloremia (Di Bartola, 1999). In this study, an increase in SID was observed in 11/34 (32.3%) dogs, which generally occurs due to a reduction in chloride (excessive loss in relation to sodium) or an increase in sodium (dehydration), leading to metabolic alkalosis, of strong ions (Constable et al., 1997). According to quantitative approach, 12/34 (35.2%) dogs presented hypochloremic alkalosis, often caused by digestive disorders (vomiting), common in CKD, with excessive loss of Cl^- in relation to Na⁺ (Morais and Di Bartola, 2008), as in CKD. In this study, metabolic alkalosis could be explained by the quantitative approach due to the reduction of chloride due to the reduction in renal function of CKD, by hypochloremic alkalosis detected by the increase in SID.

As hyponatremia was one of the most common electrolyte changes and few were dehydrated. In this case, the increase in SID is correlated with the reduction of strong anions, such as hypochloremia, the second most common electrolyte change observed in these dogs, leading to hypochloremic alkalosis. Six of the thirty-four dogs presented with metabolic acidosis, due to the reduction in SID. The increase in unmeasured strong anions, such as hyperphosphatemia in CKD, is one of the causes for the reduction in SID leading to organic metabolic acidosis (Morais, 2008). Probably, the hyperphosphatemia in these dogs may be associated with metabolic acidosis due to the reduction in SID in these 6/34 dogs.

Atot represents non-volatile weak acids (albumin, globulins and inorganic phosphate) in plasma, not completely dissociated at physiological pH (Stewart, 1983). Changes in their concentrations directly affect the acid-base balance (Di Bartola, 2012; Adrogué and Madias, 2016). In our study, the Atot analysis, 19/34 (55.8%) presented metabolic alkalosis due to the reduction of Atot, caused by hypoproteinemia and 09/34 (26.4%) had metabolic acidosis, from excess phosphate. Hypoalbuminemia (Table 3) is considered the main cause of metabolic alkalosis because it leads to a secondary increase in serum bicarbonate (Constable, 2014). The quantitative approach can explain changes in pH due to protein levels alterations (Constable et al., 1997), as occurred in the present study.

Using the unmeasurable strong ion quantitative approach, 28/34 (82.3%) dogs in this study presented metabolic acidosis due to an increase in SIG, which is due to an increase in unmeasured strong anions, such lactic or uremic acidosis (Torrente, 2014). SIG reflects the difference between strong unmeasurable ions (calcium, ketoacids, sulfate, citrate, acetate and lactate) and is part of the quantitative approach (Di Bartola, 2012), which may have occurred in the dogs in the present study. It is considered more specific than AG, as it considers the contribution of albumin, phosphate and strong ions not included in the AG formula (Morais and Di Bartola, 2006; Hopper et al., 2014).

Both AG and SIG are affected by the hyperphosphatemia (Kaae and Morais, 2008) observed in these dogs, leading to an increase in these parameters. The increase in anion concentrations may not be detected using the traditional approach, by AG when there is hypoalbuminemia, due to its interference reducing its values, making it difficult to detect the increase in unmeasured anions (Morais, and Leisewitz, 2006; Di Bartola, 2012), as observed in 64.70% (22/34) with hypoalbuminemia in this study. Therefore, the traditional approach would not indicate acid-base imbalance (Constable, 2000; De Morais and Leisewitz, 2006).

Using the quantitative approach, it is considered that the SIG is more accurate in identifying unmeasurable strong ions than the AG (Constable et al., 1998; Ho et al., 2016), from the traditional approach and therefore should be calculated when there is hypoalbuminemia, as this does not interfere with SIG, as in AG. Therefore, the use of AG is considered a simplistic assessment of the situation, only taking into consideration changes in Na⁺, K⁺, Cl^-, HCO₃ ^-, in addition to being interfered with by albumin (Morais, 2006; Di Bartola, 2012; Muir, 2017).

Regarding acid-base imbalances, comparing the two approaches: with the traditional approach, 10/34 (29,4%) did not show imbalances, 24/34 (70.5%) had metabolic acidosis with decreased HCO₃ ^- concentration and 21/34 (61.7%) due to the increase in AG using the traditional approach. In the quantitative approach, six dogs (17,6%) presented no abnormalities. Metabolic acidosis was detected in 5/34 (14.7%) due to the reduction in SID, in 7/34 (20.5%) due to the increase in Atot and in 28/34 (82.3%) due to the increase in SIG. Metabolic alkalosis was observed only in quantitative approach, present in 12/34 due to the increase in SID classified as hypochloremic, 19/34 (55.8%) due to the reduction in Atot due to hypoproteinemia in Figure 1.

Metabolic acidosis was the most common acid-base disorder found in both approaches. With 24/34 dogs using the traditional approach, by reducing HCO₃ ^-, against 40 identified disorders, such as metabolic acidosis, analyzing the values ​​of SID, SIG and Atot, in these 34 dogs, using the quantitative approach in Figure 1. The quantitative approaches are more sensitive than the traditional approach in identification of the imbalances, as this does not consider the concentrations of total proteins and electrolytes to determine the acid-base status in dogs. (Hopper et al., 2014).

Using the quantitative approach, 71 metabolic disorders were detected in the 34 CKD dogs with an additional diagnosis of metabolic alkalosis in 31 of them, observed only in this approach, considering the increase in SID and reduction in Atot in Figure 1. Like Hopper et al. (2014), in this study Stewart's approach was more sensitive and identified more disorders than the traditional Henderson-Hasselbach approach in dogs in critical health and in the study of dogs with hemorrhagic gastroenteritis of the Hasuda et al. (2020) and in the study with cats with CKD (Chun and Yu, 2021).

The traditional approach only considers the HCO₃ ^- and PCO₂ variables, not detecting interference from electrolytes and plasma proteins, therefore, not identifying the cause of the imbalance. While in the quantitative approach, these values are used, classifying the metabolic acidosis or alkalosis present, in which PCO₂, SID and Atot are independent and cause changes in blood pH (Stewart, 1983; Constable, 2000). Electrolyte changes are very common in CKD patients, with the quantitative approach being the most appropriate alternative for more accurate identification of the imbalances present and their consequences for animals’ metabolism.

The loss of renal mass in CKD leads to water imbalance, due to the decrease in the renal ability to concentrate urine (Bartges, 2012; Di Bartola, 2012; Martorelli et al., 2017). Dehydration worsens due to the association of emesis in chronic kidney disease (Quimby, 2016). Of the dehydrated, most had a moderate degree 32.3% (11/34). In CKD, dehydration occurs due to polyuria, when water loss exceeds its intake, in addition to nausea, emesis, failure of the kidney's ability to concentrate urine (Bartgez, 2012; McGrotty and Randell, 2019). In addition, nitrogenous compounds that would normally be eliminated in the urine are retained due to the decrease in GFR. This retention is associated with triggering some clinical signs, such as emesis, causing more fluid loss (Bartgez, 2012; Galvão et al., 2020).

It is important to evaluate the concentration of total proteins in relation to the fluid status of the patient. Hyperproteinemia may not be considered real, as it occurs due to water reduction in the dehydrated body (Morais and Constable, 2012). In this study, 32.35% (11/34) dogs had hyperproteinemia, the same amount had moderate dehydration 32.35% (11/34), while the rest of the animals 67.65% (23/34) had protein values ​​within the reference range. Rehydration with SRL can lead to hypoproteinemia, previously masked by dehydration, probably due to urinary protein loss caused by renal damage in CKD (Harley and Langston, 2012).

This study had some limitations. For example, it was not possible to control the experimental group, which would be interesting in future research to exclude the interference of other factors. The animals under study were not classified according to the different stages of CKD and degrees of impairment. New studies must be carried out to provide additional information on the control of CKD, facilitating clinical management and reducing the length of hospital stay for animals.

CONCLUSION

Most of the chronic kidney patients studied did not present apparent dehydration, while the most observed electrolyte imbalances were hyperkalemia and hypochloremia. Metabolic acidosis was the most common acid-base imbalance, due to an increase in unmeasurable anions. The quantitative approach detected more acid-base disorders than the traditional one.

REFERENCES

• ADROGUÉ, H.J.; MADIAS N.E. Assessing acid-base status: physiologic versus physicochemical approach. Am. J. Kidney Dis., v.68, p.793-802, 2016.
• ADROGUÉ, H.J.; MADIAS, N.E. Changes in plasma potassium concentration during acute acid-base disturbances. Am. J. Med., v.71, p.456-467, 1981.
• ALMEIDA, A.L.; BELONI, S.N.E.; BALARIN, M.R.S.; PRETI, M.C.P. Avaliação dos níveis de fósforo em animais azotêmicos no período de setembro de 2008 a setembro de 2010. In: CONGRESSO BRASILEIRO DE MEDICINA VETERINÁRIA, 38, 2011, Florianópolis. Anais… Florianópolis: Conbravet, 2011.
• ANDREI, G.B. Avaliação clínica da acidose metabólica: estudo de casos em animais de companhia. 2014. 97f. Dissertação (Mestrado Integrado em Medicina Veterinária) - Universidade de Lisboa, Lisboa, POR.
• BARTGEZ, J.W. Chronic kidney disease in dogs and cats. Vet. Clin. North Am. Small Anim. Pract., v.42, p.669-692, 2012.
• BENESI, F.J.; KOGIKA, M.M. Fluidoterapia. In: SPINOSA, H.D.S; GÓRNIAK, S.L; BERNARDI, M.M. Farmacologia: aplicada a medicina veterinária. 6.ed. Rio de Janeiro: Guanabara Koogan, 2017. p.1273-1301.
• BEREND, K. Review of the diagnostic evaluation of normal anion gap metabolic acidosis. Kidney Dis., v.3, p.149-159, 2017.
• BURANAKARL, C.; ANKANAPORN, K.; THAMMACHAROEN, S. et al. Relationships between degree of azotaemia and blood pressure, urinary protein:creatinine ratio and fractional excretion of electrolytes in dogs with renal azotaemia. Vet. Res. Commun., v.31, p.245-257, 2007.
• CHEN, H.; DUNAEVICH, A.; APFELBAUM, N. et al. Acute on chronic kidney disease in cats: Etiology, clinical and clinicopathologic findings, prognostic markers, and outcome. J. Vet. Intern. Med., v.34, p.1496-1506, 2020.
• CHEN, W.; LEVY, D.S.; ABRAMOWITZ, M.K. Acid base balance and progression of kidney disease. Semin. Nephrol., v.39, p.406-417, 2019.
• CHEW, D.J.; DI BARTOLA, S.P. Diagnóstico e fisiopatologia da molestia renal. In: ETTINGER S.J. (Ed.). Tratado de medicina interna veterinária: moléstias do cão e gato. 3.ed. São Paulo: Manole, 1992. p.1975-2046.
• CHUN, D.; YU, D. A comparison of traditional and quantitative analysis of acid-base and electrolyte imbalance in 87 cats. Korean J. Vet. Res., v.61, p.e40, 2021.
• COLLINS, A.J.; PITT, B.; REAVEN, N. et al. Association of serum potassium with all-cause mortality in patients with and without heart failure, chronic kidney disease, and/or diabetes. Am. J. Nephrol., v.46, p.213-221, 2017.
• CONSTABLE, P.D. Acid-base assessment: when and how to apply the henderson-hasselbalch equation and strong ion difference theory. Vet. Clin. North Am. Food Anim. Pract., v.30, p.295-316, 2014.
• CONSTABLE, P.D. Clinical assessment of acid-base status. Vet. Clin. North Am. Food Anim. Pract., v.15, p.447-471, 1999.
• CONSTABLE, P.D. Fluid and electrolyte therapy in ruminants. Vet. Clin. Food Anim., v.19, p.557-597, 2003.
• CONSTABLE, P.D. Review article clinical assessment of acid-base status: comparison of the henderson-hasselbalch and strong ion approaches. Vet. Clin. Pathol., v.29, p.115-128, 2000.
• CONSTABLE, P.D.; HINCHCLIFF, K.W.; MUIR, W.W. Comparison of anion gap and strong ion gap as predictors of unmeasured strong ion concentration in plasma and serum from horses. Am. J. Vet. Res., v.59, p.881-887, 1998.
• CONSTABLE, P.D.; STAMPFLI, H.R. Experimental determination of net protein charge and A. J. Vet. Intern. Med., v.19, p.507-514, 2005.
• CONSTABLE, P.D.; STREETER, R.N.; KOENIG, G.J. et al. Determinants and utility of the anion gap in predicting hyperlactatemia in cattle. J. Vet. Intern. Med., p.1171-1179, 1997.
• CRIVELLENTI, L.Z.; GIOVANINNI, L.H. Tratado de nefrologia e urologia em cães e gatos. In: ______. Doença renal crônica. São Paulo: MedVep, 2021. p.325-352.
• DI BARTOLA, S.P. Disorders of sodium and water: Hypernatremia and hyponatremia. In DI BARTOLA, S.P. (Ed.). Fluid, electrolyte and acid-base disorders in small animal practice. St Louis: Saunders, 2006b. p.47-79.
• DI BARTOLA, S.P. Electrolyte and Acid-Base Disorder. In: WILLARD, M.D.; TVEDTEN, H. (Eds.). Small animal clinical diagnosis by laboratory methods. 5.ed. St. Louis, Missouri: Saunders Elsevier, 2012. p.112-125.
• DI BARTOLA, S.P. Fluid, electrolyte, and acid-base disorders in small animal practice. St Louis: Elsevier Health Sciences, 2011.
• DI BARTOLA, S.P. Metabolic acid-base disorders. In: ______. Fluid therapy in small animal practice. 2.ed. Philadelphia, W.B: Saunders, 1999. p.211-239.
• DI BARTOLA, S.P. Metabolic acid-base disorders. In: ______.(Ed). Fluid, electrolyte, and acid-base disorders in small animal practice. 3.ed. St Louis: Saunders Elsevier, 2006a. p.251-283.
• DI BARTOLA, S.P.; MORAIS, H.A. Disorders of potassium: hypokalemia and hyperkalemia, In: DI BARTOLA, S.P. (Ed.). Fluid, electrolyte, and acid-base disorders. 4.ed. St Louis: Elsevier, 2012. p.92-119.
• FURONI, R.M.; PINTO NETO, S.M.; GIORGI, R.B.; GUERRA, E.M.M. Distúrbios do equilíbrio ácido-básico. Rev. Fac. Ciênc. Méd. Sorocaba, v.12, p.5-12, 2010.
• GALVÃO, A.L.B.; MOSTACHIO, G.Q.; BRESCIANI, K.D.S. O Plantonista. São Paulo: MedVet, 2020. p.279.
• GALVÃO, B.J.F.; PARKER, V.J.; SCHENCK P.A.; CHEW, D.J. Update on Feline Ionized Hypercalcemia. Vet. Clin. North Am. Small Anim. Pract., v.47, p.273-292, 2017.
• GORAYA, N.; WESSON, D.E. Clinical evidence that treatment of metabolic acidosis slows the progression of chronic kidney disease. Curr. Opin. Nephrol. Hypertens, v.28, p.267-277, 2019.
• HARJES, L.M.; PARKER, V.J.; DEMBEK, K. et al. Fibroblast growth factor-23 concentration in dogs with chronic kidney disease. J. Vet. Internal. Med., v.31, p.784-790, 2017.
• HARLEY, L.; LANGSTON, C. Proteinuria in dogs and cats. Can. Vet. J., v.53, p.631-638, 2012.
• HARRIS, A.N.; GRIMM, P.R.; LEE, H.W. et al. Mechanism of hyperkalemia-induced metabolic acidosis. J. Am. Soc. Nephrol., v.29, p.1411-1425, 2018.
• HASUDA, A.L.; FLAIBAN, K.K.M.C.; LISBÔA, J.A.N. et al. Identifying hydric, electrolytic and acid-base imbalances through traditional and quantitative approaches in dogs with hemorrhagic gastroenteritis. Arq. Bras. Med. Vet. Zootec., v.72, p.93-101, 2020.
• HO, K.M.; LAN, N.S.; WILLIAMS, T.A. et al. A comparison of prognostic significance of strong ion gap (SIG) with other acid-base markers in the critically ill: a cohort study. J. Intens. Care, v.4, p.43, 2016.
• HOPPER, K.; EPSTEIN, S. E. Incidence, nature, and etiology of metabolic acidosis in dogs and cats. J. Vet. Intern. Med., v.26, p.1107-1114, 2012.
• HOPPER, K.; EPSTEIN, S.E. Incidence, nature, and etiology of metabolic alkalosis in dogs and cats. J. Vet. Intern. Med., v.27, p.847-853, 2013.
• HOPPER, K.; EPSTEIN, S.E.; KASS, P.H.; MELLEMA, M.S. Evaluation of acid-base disorders in dogs and cats presenting to an emergency room. Part 1: Comparison of three methods of acid-base analysis. J. Vet. Emerg. Crit. Care, v.24, p.5493-5501, 2014.
• KAAE, J.; MORAIS, H.A. Anion gap and strong ion gap: a quick reference. Vet. Clin. North Am. Small Anim. Pract., v.38, p.443-447, 2008.
• KAJIMOTO, S.; SAKAGUCHI, Y.; ASAHINA, Y.; KAIMORI, J.Y.; ISAKA, Y. Modulation of the association of hypobicarbonatemia and incident kidney failure with replacement therapy by venous pH: a cohort study. Am. J. Kidney Dis., v.77, p.35-43, 2021.
• KAPLAN, L.J.; CHEUNG, N.; HAM-TING, M.L. et al. A Physicochemical approach to acid-base balance in critically 3 trauma patients minimizes errors and reduces inappropriate plasma volume expansion. J. Trauma Injury, Infect. Critic. Care, v.66, p.1045-1051, 2009.
• KHANNA, A.; KURTZMAN, N.A. Metabolic alkalosis. J. Nephrol., v.19, p.86-96, 2006.
• KIM, H.J. Metabolic acidosis in chronic kidney disease: pathogenesis, clinical consequences, and treatment. Electrol. Blood Press, v.19, p.29-37, 2021.
• KIM, H.J.; RYU, H.; KANG, E. et al. Metabolic acidosis is an independent risk factor of renal progression in korean chronic kidney disease patients: the know-CKD study results. Front. Med., v.8, p.707588, 2021.
• KOJIKA, M.M.; LUSTOZA, M.D.; NOTOMI, M.K.; WIRTHL, V.B.L.; MIRANDOLA, R.S.; HAGIWARA, M.K. Serum ionized calcium in dogs with chronic renal failure and metabolic acidosis. J. Vet. Clin. Pathol., v.35, p.441-444, 2006.
• KOGIKA, M.M.; MORAIS, H.A. Hypokalemia: a quick reference.Vet. Clin. North Am. Small Anim. Pract., v.38, p.481-484, 2008.
• KOGIKA, M.M.; MORAIS, H.A. A Quick Reference on Hypokalemia. The Veterinary clinics of North America. Small animal practice, v.47, n.. 2, p. 229-234, 2017.
• KRAUT, J.A.; MADIAS, N.E. Adverse effects of the metabolic acidosis of chronic kidney disease. Adv. Chronic Kidney Dis., v.24, p.289-297, 2017.
• KRAUT, J.A.; MADIAS, N.E. Serum anion gap: its uses and limitations in clinical medicine. Clin. J. Am. Soc. Nephrol., v.2, p.162-74, 2007.
• KRAUT, J.A.; MADIAS, N.E. Sodium bicarbonate for severe metabolic acidemia. Lancet, v.392, p.3-4, 2018.
• KWOK, M.H.; LAN, N.S.H.; WILLIAMS, A. et al. A comparison of prognostic significance of strong ion gap (SIG) with other acid‐base markers in the critically ill. A cohort study. J. Intens. Care, v.4, n.43, 2016.
• LANGSTON, C. Managing fluid and electrolyte disorders in renal failure. Vet. Clin. North Am. Small Anim. Pract., v.38, p.677-697, 2008.
• LYONS, B.M.; WADDELL, L.S. Fluid therapy in hospitalized patients: electrolyte abnormalities and fluid balance. Today's Vet. Prat., v.8, p.48-57, 2018.
• MAGDER, S.; EMAMI, A. Practical approach to physical-chemical acid-base management. Stewart at the bedside. Ann. Am. Thoracic. Soc., v.12, p.111-117, 2015.
• MANDAI, S.; KANDA, E.; IIMORI S. et al. Association of serum chloride level with mortality and cardiovascular events in chronic kidney disease: the CKD-ROUTE study. Clin. Exp. Nephrol., v.21, p.104-111, 2017.
• MARTÍNEZ, P.P.; CARVALHO, M.B. Participação da excreção renal de cálcio, fósforo, sódio e potássio na homeostase em cães sadios e cães com doença renal crônica. Pesqui. Vet. Bras., v.30, p.868-876, 2010.
• MARTORELLI, C.; KOGIKA, M.M.; CHACAR, F.C. et al. Urinary fractional excretion of phosphorus in dogs with spontaneous chronic kidney disease. Vet. Sci., v.4, p.67, 2017.
• MCGROTTY, Y. Diagnosis and management of chronic kidney disease in dogs and cats. Comp. Anim. Pract., v.30, p.502-507, 2008.
• MCGROTTY, Y.; RANDELL, S. Diagnostic approach to polyuria and polydipsia in dogs. In Practice, 41, p. 249-258, 2019.
• MEZONES-HOLGUIN, E.; NIÑO-GARCIA, R.; HERRERA-AÑAZCO, P. et al. Possible association between dysnatremias and mortality during hospitalization in patients undergoing acute hemodialysis: analysis from a Peruvian retrospective cohort. J. Bras. Nefrol., v.41, p.501-508, 2019.
• MORAIS, H.A. Metabolic acidosis: a quick reference. Vet. Clin. North Am. Small Anim. Pract., v.38, p.439-442, 2008.
• MORAIS, H.A., DI BARTOLA, S.P. Hyponatremia: a quick reference. Vet. Clin. North Am. Small Anim. Pract., v.38, p.491-495, 2008.
• MORAIS, H.A.; CONSTABLE, P.D. Strong ion approach to acid-base disorders in fluid, electrolyte, and acid-base disorders in small animal practice. St. Louis, Mo: Saunders/Elsevier, 2012.
• MORAIS, H.A.; DI BARTOLA, S.P. Strong ion approach to acid-base disorders. In: DI BARTOLA, S.P. (Ed.). Fluid, electrolyte, and acid-base disorders in small animal practice. 3.ed. St. Louis, Missouri: Saunders Elsevier, 2006. p.310-324.
• MORAIS, H.A.; LEISEWITZ, A.L. Mixed acid-base disorders. in: DI BARTOLA, S. (Ed.). Fluid, electrolyte, and acid-base disorders in small animal practice. 3.ed. St. Louis, Missouri: Saunders Elsevier, 2006. p.296-309.
• MORAIS, H.S.A. Chloride ion in small animal practice: the forgotten ion. J. Vet. Emerg. Crit. Care, v.2, p.11-24, 1992.
• MUIR, W. Effect of intravenously administered crystalloid solutions on acid-base balance in domestic animals. J. Vet. Intern. Med., v.31, p.1371-1381, 2017.
• NELSON, R.W.; COUTO, C.G. Acute kidney injury and chronic kidney disease. In: DI BARTOLA, S.P.; WESTROPP, J.L. (Eds.). Small animal internal medicine. 6.ed. St. Louis, MO: Elsevier Health Sciences, 2019. p.686-703.
• NICOLA, L.; DI LULLO, L.; PAOLETTI, E.; CUPISTI, A.; BIANCHI, S. Chronic hyperkalemia in non-dialysis CKD: controversial issues in nephrology practice. J. Nephrol., v.31, p.653-664, 2018.
• PALMER, B.F.; STERNS, R.H. Fluid, electrolytes, and acid-base disturbances. NephSAP, v.8, p.61-167, 2009.
• POLZIN, D.J. Chronic kidney disease in small animals. Vet. Clin. North Am. Small Anim. Pract., v.41, p.15-30, 2011.
• POLZIN, D.J. Chronic kidney disease. In: ETTINGER, S.J., FELDMAN, E.C. Textbook of veterinary internal medicine. St. Louis: Elsevier Saunders, 2005, p.1756-1785.
• QUIMBY, J. Update on medical management of clinical manifestations of chronic kidney disease. Vet. Clin. North Am. Small Anim. Pract., v.46, p.1163-1181, 2016.
• RAPHAEL, K.L. Metabolic acidosis in CKD: core curriculum 2019. Am. J. Kidney Dis., v.74, p.263-275, 2019.
• RONDON, H.; BADIREDDY, M. Hyponatremia. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2023 Jan-. PMID: 29262111.
• ROSSI, Y.A.; SOUSA, D.C.; ROCHA, J.R.; RODRIGUES, V.; DIAS, F.G.G. Fibrous osteodystrophy due to secondary renal hyperparathyroidism in a senile dog. Arq. Bras. Med. Vet. Zootec., v.74, p.1089-1095, 2023.
• SEGEV, G.; FASCETTI, A.J.; WEETH, L.P.; COWGILL, L.D. Correction of hyperkalemia in dogs with chronic kidney disease consuming commercial renal therapeutic diets by a potassium-reduced home-prepared diet. J. Vet. Intern. Med., v.24, p.546-550, 2010.
• SEIFTER, J.L. Integration of acid‐base and electrolyte disorders. N. Engl. J. Med., v.371, p.1821-1831, 2014.
• SOLEIMANI, M.; RASTEGAR, A. Pathophysiology of renal tubular acidosis: core curriculum. Am. J. Kidney Dis., v.68, p.488-498, 2016.
• STEWART, P.A. Modern quantitative acid-base chemistry. Can. J. Physiol Pharmacol., v.61, p.1444-1461, 1983.
• TANGRI, N.; REAVEN, N.L.; FUNK, S.E. et al. Metabolic acidosis is associated with increased risk of adverse kidney outcomes and mortality in patients with non-dialysis dependent chronic kidney disease: an observational cohort study. BMC Nephrol., v.22, p.185, 2021.
• TELLO, L.; PEREZ-FREYTES, R. Fluid and electrolyte therapy during vomiting and diarrhea. Vet. Clin. North Am. Small Anim. Pract., v.47, p.505-519, 2017.
• TORRENTE, C.; MANZANILLA, E.G.; GOPEGUI, R.R. A comparison of traditional and quantitative analysis of acid-base imbalances in hypoalbuminemic dogs. J. Vet. Emerg. Crit. Care, v.24, p.509-518, 2014.
• UEDA, Y.; HOPPER, K.; EPSTEIN, S.E. Incidence, severity and prognosis associated with hyponatremia in dogs and cats. J. Vet. Intern. Med., v.29, p.801-807, 2015.
• WEINER, I.D. Roles of renal ammonia metabolism other than in acid-base homeostasis. Pediatr. Nephrol., v.32, p.933-942, 2017.
• WESSON, D.E.; SIMONI, J. Acid retention during kidney failure induces endothelin and aldosterone production which lead to progressive GFR decline, a situation ameliorated by alkali diet. Kidney Int., v.78, p.1128-1135, 2010.

Publication Dates

• Publication in this collection
  27 Oct 2025
• Date of issue
  Sep-Oct 2025

History

• Received
  08 July 2024
• Accepted
  29 Jan 2025