Transient distal renal tubular acidosis in a dog with gastric-dilatation-volvulus

Abstract

A case of distal renal tubular acidosis occurring as a transient complication in a 13-year-old female greyhound dog with gastric-dilatation-volvulus was diagnosed. The acute renal ischemia and inflammatory condition associated with this syndrome could be considered the main underlying mechanisms responsible for the acute, severe, and complicating renal tubular dysfunction.

Renal tubular acidosis refers to an unusual group of kidney disorders characterized by the presence of normal anion gap hyperchloremic metabolic acidosis associated with reduced bicarbonate reabsorption in the renal proximal tubule or failure of the renal distal tubule to synthesize new bicarbonate in the absence of substantial renal insufficiency (1–4). Distal renal tubular acidosis (DRTA) can be a transient or permanent disorder and can occur either as a primary disease (congenital DRTA) or as a complication (acquired DRTA) of other diseases, both of renal and non-renal origin. Acquired DRTA has been described infrequently in the veterinary literature, mainly in association with some drugs and nephrotoxins, infectious diseases, autoimmune disorders, chronic hypocalcemic conditions, and neoplastic disorders (1,5–8).

The diagnostic criteria and clinical management of transient but severe DRTA in a geriatric dog presenting with a gastric-dilatation-volvulus syndrome (GDV) is described. The authors hypothesize about the underlying mechanisms responsible for this disorder.

Case description

A 13-year-old, spayed female, 23-kg greyhound dog was presented to the Fundació Hospital Clínic Veterinari-UAB for evaluation of acute abdominal distention and non-productive retching. The clinical history included a previous diagnosis of hypothyroidism under treatment with levothyroxine.

Physical examination revealed dull mentation, tachypnea (60 breaths/min) with increased respiratory effort, congested and dry mucous membranes, capillary refill time < 2 s, tachycardia (176 beats/min), left side apical systolic heart murmur (grade 3/6), synchronous and bounding pulses, body temperature of 39.2°C, painful abdomen, and tympanic abdominal distention. On admission, a mean arterial blood pressure (MAP) of 136 mmHg was obtained by oscillometric method (Vet20; B. Braun Medical S.A., Barcelona, Spain) and the electrocardiogram (ECG) showed ventricular tachycardia without hemodynamic consequences. Initial blood tests revealed a packed cell volume (PCV) of 65% [reference range (RR): 37% to 55%], total plasma protein concentration of 72 g/L (RR: 52 to 82 g/L), plasma glucose concentration of 8.32 mmol/L (RR: 3.89 to 7.94 mmol/L), and plasma lactate of 4.7 mmol/L (RR: < 2.0 mmol/L). Emergency treatment upon admission included flow-by oxygen at 4 to 5 L/min, percutaneous gastrocentesis, and intravenous fluid therapy with an isotonic crystalloid solution; a bolus of Lactated Ringer’s solution (B. Braun Medical S.A.), 20 mL/kg body weight (BW) was initially administered in 15 min, followed by a fluid rate of 10 mL/kg BW per hour. It should be noted that in spite of the moderate hyperlactatemia, use of this solution is not contraindicated in patients with type A hyperlactatemia (tissue hypoperfusion). At the normal dosages, use of this balanced replacement solution is not associated with an increase in blood lactate concentration if clearance mechanisms are not impaired (i.e., liver failure, lymphoma).

Pain control was achieved by administration of a bolus of fentanyl (Fentanest; Kern Pharma S.A., Madrid, Spain), 5 μg/kg BW, IV, and lidocaine (Lidocaina; B. Braun Medical S.A.), 2 mg/kg BW, IV, followed by a constant rate infusion (CRI) of both drugs (5 μg/kg BW per hour and 60 μg/kg BW per min, respectively). Treatment with cefazolin (Cefazolin; Laboratorios Normon SA, Madrid, Spain), 25 mg/kg BW, IV, was also initiated before surgery. Cefazolin was added to the pre-operative treatment plan following the surgical protocols of the FHCV-UAB for gastrointestinal surgery, in patients at risk for splanchnic hypoperfusion and gastrointestinal compromise.

Throughout the emergency stabilization period, monitoring was carried out by continuous ECG, pulse-oximetry, non-invasive oscillometric blood pressure measurements and body temperature measurements. Blood samples were obtained for complete blood (cell) count (CBC), serum biochemistry, and electrolyte and coagulation profiles. Results of the blood analysis revealed a leukogram showing slight neutrophilia (12.45 × 10⁹/L; RR: 2.95 to 11.64 × 10⁹/L), marginal eosinopenia (0.05 × 10⁹/L; RR: 0.06 to 1.23 × 10⁹/L) and mild lymphopenia (0.83 × 10⁹/L; RR: 1.05 to 5.1 × 10⁹/L). Serum biochemistry showed mild hyperglycemia (8.32 mmol/L; RR: 3.89 to 7.94 mmol/L) and elevated alanine-aminotransferase (287 U/L; RR: 10 to 125 U/L). After stabilization, abdominal X-rays were taken and confirmed the final diagnosis of gastric dilatation volvulus (GDV).

The dog was premedicated with methadone (Semfortan; Laboratorios Esteve, Barcelona, Spain), 0.4 mg/kg BW, IM, and midazolam (Midazolam; Normon EFG, Madrid, Spain), 0.25 mg/kg BW, IV. No induction agent was necessary, and the patient was endotracheally intubated and connected to an anesthetic circuit. Intermittent mandatory positive-pressure ventilation with 100% oxygen was provided. Anesthesia was maintained using a CRI of a combination of fentanyl and lidocaine (5 μg/kg BW per hour and 60 μg/kg BW per minute, respectively), plus isofluorane (IsoFlo, Laboratorios Esteve). Intravenous fluid therapy was continued, using the same crystalloid solution given on admission, at a rate of 10 to 20 mL/kg BW per hour depending on the patient’s blood pressure.

During anesthesia the patient was monitored by continuous ECG, invasive blood pressure, pulse-oximetry, end-tidal carbon dioxide (ETCO₂), and body temperature. All parameters were registered in the anesthesia flowsheet every 10 min throughout the anesthetic procedure. Exploratory laparotomy and gastropexy were performed routinely. After 20 min of the surgical procedure, a sudden episode of hypotension secondary to a sustained supraventricular tachycardia (190 to 220 beats/min) was detected. A single dose of esmolol (Brevibloc; Baxter SA, Lessines, Belgium), 0.05 mg/kg BW, IV, was administered with a positive response and normal sinus rhythm and arterial blood pressure were re-established during the rest of the procedure. The patient recovered uneventfully from anesthesia.

Postoperative therapy included intravenous balanced isotonic crystalloid solution (Lactated Ringer’s solution; B. Braun Medical S.A.) supplemented with potassium chloride (potassium chloride 2 M; B. Braun Medical S.A.), 30 mEq/L, to provide rehydration (5%) and maintenance needs. Dehydration percentage was estimated based on dry mucous membranes and slightly increased body temperature. Additionally, broad-spectrum antibiotics including cefazolin (Cefazolin; Laboratorios Normon SA), 25 mg/kg BW, IV, q8h, and enrofloxacin (Enrofloxacin; Bayer AG), 10 mg/kg BW, IV, q24h; oxygen therapy by nasal prongs; omeprazole (Omeprazol; Laboratorios Cinfa SA, Pamplona, Spain), 1 mg/kg BW, IV, q12h; maropitant (Cerenia; Zoetis-España, Madrid, Spain), 1 mg/kg BW, IV, q24h, and levothyroxine (Leventa; Merck Sharp & Dohme Animal Health SL, Salamanca, Spain), 20 μg/kg BW, PO, q12h, were also started. Fentanyl and lidocaine CRI were continued after surgery, plus methadone as needed (0.2 to 0.4 mg/kg BW, SQ, q6h) for pain control. Packed cell volume, plasma concentration of total proteins, and glucose and lactate concentrations were recorded every 4 to 6 h during the first 24 h after surgery; body weight, hydration status, perfusion and respiratory parameters were also monitored 1, 2, and 4 times per day, respectively. An indwelling urinary catheter connected to a closed collection system was also placed immediately after surgery to monitor urinary output. Assessment of urinary specific gravity and urinary sediment was performed every 48 h during hospitalization. Early enteral nutritional support was initiated by placing a nasogastric feeding tube.

Despite the initial positive recovery over the first 24 h, progressive mental depression, anorexia, non-ambulatory weakness, and polyuria/polydipsia were observed throughout the following 48 to 72 h. On the third day, blood samples were submitted for analysis, including a CBC, complete biochemical profile, and venous blood gas analysis. Urinalysis, thoracic radiographs and abdominal ultrasound were also performed. Laboratory abnormalities revealed a moderate hypernatremia, severe hyperchloremia, and metabolic acidosis (Table 1). Analysis of urine obtained by cystocentesis revealed isostenuria (USG: 1.010), a pH of 7.0, ketonuria (2+), bilirubinuria (2+) and proteinuria (2+), with an inactive urinary sediment and increased urine protein/creatinine (UPC) ratio (0.9; reference value: < 0.5). The urinary anion gap (UAG) was also abnormal (UAG 29.8; RR: −10 to +10 mEq/L). Thoracic radiographs and abdominal ultrasound did not show abnormalities.

Table 1.

Results of biochemistry and venous blood gas measurements during hospitalization in the ICU and subsequent follow-up.

Parameters	Reference	Units	T0	T1	T2	T3	T4	T5	T6	T7	T8
pH	7.28 to 7.40	—	7.12	7.20	7.31	7.35	7.31	7.36	7.41	7.38	7.33
pvCO2	32.7 to 44.7	mmHg	31.9	33.3	40.2	39.3	45	43.4	39.2	36	38
pvO2	32 to 74	mmHg	—	44	38	39	45	33	34	45	43
SBE	−4 to 4	mmol/L	−19	−15	−6	−4	−3	−1	1	−2	−1
AGAP	12 to 25	mmol/L	22	—	—	18	20.2	16.9	—	14	18
HCO3−	17 to 24	mmol/L	10.5	13.1	20.5	21.4	27.8	24.7	25.2	23	22
Na+	144 to 163	mmol/L	169	168	167	166	163	162	154	156	150
K+	3.5 to 5.8	mmol/L	5.1	4.5	3.6	3.4	3.5	3.6	4	4.1	3.8
Cl−	109 to 122	mmol/L	142	—	—	130	118	124	—	111	110
Ca2+	1.25 to 1.5	mmol/L	1.54	1.5	1.44	1.48	1.5	1.43	1.35	1.34	1.26
Glucose	3.89 to 7.94	mmol/L	7.66	7.38	7.71	6.49	7.22	6.83	6.22	4.56	6.2
Lactate	< 2.5	mmol/L	1.4	0.9	1.6	2.6	—	1.3	1.3	1.4	1.1
Creatinine	44.2 to 132.6	μmol/L	100.78	—	—	68.95	—	63.65	—	61	61.9

pvCO₂ — partial venous pressure of CO₂; pvO₂ — partial venous pressure of O₂; SBE — standardized base excess.

T0 — 72 h post-admission; T1 — post-administration of 1/3 total dose of NaHCO₃; T2 — post-administration of a total dose of NaHCO₃; T3 — 24 h post-T0; T4 — 36 h post-T0; T5 — 48 h post-T0; T6 — 72 h post-T0; T7 — 120 h post-T0; T8 — 1 month later.

Results of the laboratory tests confirmed a severe hyperchloremic metabolic acidosis with normal anion gap (absence of unmeasured organic anions) and inappropriately alkaline urine and concomitant increased UAG and DRTA was strongly suspected. Because the patient’s blood pH was less than 7.2 (Table 1), acidosis was considered severe and at risk to cause life-threatening cardiovascular complications. Therefore, infusion of an alkalizing HCO₃ solution (sodium bicarbonate 1/6 M; B. Braun Medical S.A.) was started according to the calculated patient’s base deficit. The total amount of HCO₃ to be infused was estimated based on formulas described in the veterinary literature (9). A third (43 mmol of NaHCO₃) of the total dose was administered over 30 min and venous blood gas was re-evaluated. The rest of the dose (86 mmol of NaHCO₃) was administered over 6 h at a rate of 0.6 mmol/kg BW per hour. Immediately after infusion, the plasma HCO₃ concentration was within normal limits and the metabolic acidosis was almost corrected (Table 1). The urine fractional excretion (FE) of HCO₃ (0.34%; RR: 0.04% to 0.13%) was measured once the infusion of NaHCO₃ was completed and the results were consistent with a diagnosis of DRTA (7).

After alkalinizing therapy, acid-base and electrolyte disturbances were corrected progressively showing normalization of the anomalies on day 4 after admission. The dog remained in the ICU for 5 more days and during that period fluid therapy was adjusted according to the daily fluid balance assessment and blood analysis (Table 1). During those days, the dog remained bright and alert, her appetite was normal, and she showed no abnormal clinical signs.

The patient was discharged 13 d after admission. Three days later, the dog was re-evaluated, and the owner reported good attitude, appetite, and normal water intake. The patient was scheduled for follow-up 1 mo later. The dog continued to have a good attitude, normal appetite, and absence of clinical signs. Re-check blood analysis did not show abnormalities (Table 1) and urinalysis performed following cystocentesis revealed persistent isosthenuria (USG: 1.018; RR: 1.015 to 1.045) and increased UPC ratio (1; reference value: < 0.5). At that time a renal diet was prescribed.

The dog was scheduled for re-evaluation monthly, but the owner decided to continue follow-up with his own veterinarian and additional information was, therefore, unavailable. However, 6 mo after discharge telephone contact was resumed, and the owner reported a good condition with no changes in attitude, appetite, body weight, or daily water consumption. Recheck blood analysis and urinalysis were offered but the owner declined.

Discussion

Distal renal tubular acidosis refers to a group of disorders characterized by normal anion gap hyperchloremic metabolic acidosis that occurs as a result of failure of the distal tubules to synthesize bicarbonate or acidify the urine by H⁺ excretion, despite normal or only mildly reduced glomerular filtration rate (GFR) (1,2). Patients with DRTA show a decreased FE of HCO₃ and an impaired capacity to excrete H⁺ at the distal tubule. As a result, the patient’s urine pH was > 5.5 in the presence of acidemia, characterized by a severe decrease in HCO₃ plasma concentration (< 10 to 12 mmol/L) (1,2,10,11). Human patients with DRTA typically show a urine FE-HCO₃ less than 3% after plasma HCO₃ has been restored with an alkalizing solution. In this dog, urine FE-HCO₃ was above the reference range but below the percentage previously described for this tubular disorder in dogs (7). In any case, the dog in this report met the main diagnostic criteria previously described for humans but also accepted for canine species.

Other tests have been described to confirm the diagnosis of DRTA, such as the ammonium chloride loading test (1) which is considered the gold standard in human medicine. This test consists of repeated measurements of urine pH and UAG (before and hourly), during 6 h after oral administration of NH₄Cl, 0.1 g/kg BW. In clinically normal dogs, the kidneys excrete excess H⁺ in the urine, and pH should decrease to a minimum value of 5.5 at 4 h post-administration. Failure to acidify urine 6 to 8 h after NH₄Cl administration confirms the diagnosis of DRTA. The UAG represents an indirect index of urinary NH₄⁺ that under normal circumstances is positive and ranges from 20 to 90 mEq/L. Patients with normal urinary acidification capacity should be expected to produce a negative UAG following NH₄Cl administration. An inappropriately positive UAG suggests the possibility of DRTA resulting in lower amounts of NH₄⁺ and chloride in the urine. That test was not performed in our patient for several reasons: i) it is commonly associated with dysrhythmia and gastrointestinal side effects such as nausea and vomiting associated with the NH₄Cl administration; ii) the test is considered unnecessary in patients with obvious hyperchloremic metabolic acidosis with inappropriately high urine pH; and iii) the test could be unsafe in patients which are already acidemic, as in the dog in the present report. In these cases, a single positive UAG measurement may be sufficient to verify the diagnosis of DRTA, such as the case described in this report (3,10–12).

Distal renal tubular acidosis involves failure of the renal distal tubule to synthesize new bicarbonate and to acidify the urine due to impaired secretion of the H⁺ load in the collecting ducts. However, bicarbonate production failure may be due to: i) disabled voltage-dependent sodium reabsorption mechanism, with H⁺ and K⁺ retained inside the tubular cell causing metabolic acidosis and hyperkalemia; ii) a dysfunctional H⁺-ATPase pump mechanism, which impairs active secretion of H⁺ out of the cell but enhances losses of K⁺ into the tubular lumen because of increased electronegativity, triggering metabolic acidosis and hypokalemia; and iii) abnormal increased membrane permeability of distal tubular cells, which facilitates the exchange of H⁺ into the cell and potassium into the tubular lumen, also causing metabolic acidosis and concurrent hypokalemia in the affected patient (1,2,4,6). In the absence of abnormalities in plasma levels of potassium, to better characterize distal tubular dysfunction as either a defect in the H⁺-ATPase or voltage-dependent mechanism in patients with metabolic acidosis, a furosemide response test could be performed (5,7). This test assumes that furosemide increases distal tubular sodium delivery and enhances urine acidification by stimulation of Na⁺/H⁺ exchangers. In the present case, that test was not performed due to the dog’s clinical condition and the risks associated with furosemide administration in a dehydrated, polyuric, and polydipsic patient.

Although the present case fulfilled the main diagnostic criteria, other differential diagnoses such as urinary tract infection with urease-producing microorganisms or severe diarrhea had to be excluded before confirmation of a DRTA diagnosis. Based on the clinical history, symptoms, results of urinary sediment and culture, both diseases were ruled out. Underlying advanced chronic kidney disease was also excluded because of the absence of azotemia, hypertension, or evidence of chronic renal changes on abdominal ultrasound. Although patients with advanced stages of kidney disease frequently show acid-base disturbances and those metabolic disorders are commonly associated with normal anion gap metabolic acidosis too, this is not a common clinical finding in early stages of kidney disease in which capability of excretion of the H⁺ load is often preserved (1,5,10,13).

Isosthenuria was detected in our patient, 72 h after surgery. It should be noted that isosthenuria may be difficult to interpret in patients receiving intravenous fluid support. Therefore, it could be difficult to link that finding to an acute kidney injury instead of a previous asymptomatic chronic kidney disorder. Considering the patient’s age and other analytical findings, such as persistently increased UPC ratio during the first month of follow-up, an early stage of chronic kidney disease was strongly suspected. Although urinalysis on admission could have detected such abnormality, in the authors’ opinion information from that analysis would not have prevented the sudden and unexpected kidney injury and/or modified clinical management over the clinical course. Similarly, analytical determination of plasma or urinary biomarkers in early chronic kidney disease, such as symmetric dimethylarginine (SDMA) or neutrophil gelatinase-associated lipocalin (NGAL) could be considered. However, taking into consideration availability of these tests on an emergency basis and clinical findings obtained by the diagnostic work-up performed on the patient, additional information offered by these tests would not have modified the clinical management during the ICU stay nor the initial follow-up.

In humans, common causes of acquired DRTA are autoimmune disorders (i.e., systemic lupus erythematosus), nephrotoxins, pyelonephritis, chronic kidney disease from any cause, disorder in calcium metabolism (i.e., primary hyperparathyroidism), and marked volume depletion (3,10,11). Similarly, in animals, acquired DRTA has been associated with drugs and nephrotoxins (i.e., amphotericin B, tetracycline, heavy metal toxicity, zonisamide), pyelonephritis, immune-mediated hemolytic anemia, leptospirosis, multiple myeloma, and chronic hypocalcemic conditions (1,5,7,8). However, in the present case, no specific cause of DRTA could be found despite a complete analytical, acid-base, imaging, and relevant diagnostic work-up.

Gastric-dilatation-volvulus syndrome is a common condition, associated with high morbidity and potential mortality in emergency patients, that may result in a systemic inflammatory response and potentially multiple organ dysfunction syndrome (MODS). Organ dysfunction documented as part of MODS in canine species may include the heart, lung, gastrointestinal tract, hemostatic system, and kidney (14). Acute kidney injury (AKI) has been reported in dogs as a common (8%) complication associated with GDV. Predisposing factors include: sustained poor perfusion, exposure to endotoxins, thromboembolic events, and ischemic-reperfusion injury (IRI) itself (15). In human medicine, several reports document that despite the causal event, AKI is characterized by a lower capacity to decrease urinary pH in the presence of systemic acidosis, which is intensified by the acute decrease in functioning nephrons. In veterinary medicine, there is only 1 experimental study in dogs that evaluated the impaired renal acidification capacity of the kidney following an acute ischemic event. This study demonstrated that acute renal ischemia in dogs could be associated with a tubular defect in H⁺ ion secretion, predominantly in the distal tubules (16). Considering these arguments and the fact that during the recovery phase, the re-establishment of the urine acid excretion capacity can be prolonged much more than the normalization of the GFR, both mechanisms could explain the clinical and laboratory findings in the reported case. Finally, according to the exclusion of other potential causes of DRTA and because of the well-known pathogenesis of GDV, the authors hypothesize that the associated intravascular volume depletion, distributive shock and the IRI syndrome could have generated an acute and reversible kidney injury affecting the renal tubules resulting in the development of a transient but severe DRTA.

In canines, DRTA can be asymptomatic or symptomatic. In symptomatic patients, most clinical signs are associated with the acidemic state itself and include lethargy, anorexia, nausea, vomiting, weight loss, muscle weakness, and neurologic signs such as paralysis (1). In humans, polyuria and polydipsia are mainly associated with enhanced kaliuresis and calciuresis. Although urinary FE of these electrolytes was not measured, and the dog did not show hypokalemia, both mechanisms in addition to the increased natriuresis associated with the disease could explain findings such as polyuria/polydipsia in the dog herein. In the authors’ opinion, the early supplementation of intravenous fluids with potassium chloride could have masked the hypokalemic nephropathy frequently associated with this tubular disorder.

In humans, chronic or prolonged DRTA may induce persistent metabolic acidosis that can lead to osteomalacia, urolithiasis, bone demineralization, and nephrocalcinosis, which may evolve into chronic renal failure (11). According to the acute onset, short period of disease process, and limited follow-up those signs could not be identified in the present case.

Treatment for DRTA is directed at identifying the underlying disease process and providing adequate alkali base to balance H⁺ production (2,13). In veterinary medicine, the recommended initial dose is 1.0 to 1.5 mEq/kg BW per day of sodium bicarbonate in divided doses, but higher doses (up to 4 mEq/kg BW per day) may be required to maintain normal pH (1,2). In this patient, an initial dose of 1.8 mEq/kg was administered. Due to the persistence of metabolic acidosis, a dose of 3.7 mEq/kg BW was administered to correct acid/base balance. The total dose of 5.5 mEq/kg BW per day is still considered moderate and compatible with a diagnosis of DRTA (1). Repeated evaluations after bicarbonate administration revealed resolution of the acidosis and alkali administration was discontinued.

Prognostic information about DRTA in canine species has not been reported in the veterinary literature. Human medicine reports describe a worse prognosis for DRTA compared to proximal RTA. This is due to the risk of complications such as urolithiasis and bone demineralization (1). In our patient, the tubular disorder appeared to have been transient in nature, a phenomenon that is rarely seen in human or veterinary medicine (17,18).

In the authors’ opinion, although DRTA is an uncommon disorder in veterinary patients, its incidence may be underestimated in the critical care setting. Despite a potential transient nature, this disorder might be associated with increased morbidity and mortality in affected individuals. Rapid detection of biochemical and electrolyte changes associated with DRTA in patients at risk of acute kidney injury and a careful correction of the associated acid-base and electrolyte disturbances should improve significantly the management of these critically ill patients. CVJ