A 12-year-old, 20 kg, castrated male Cocker Spaniel presented for evaluation of a 48-hour history of anemia, icterus, and anorexia. Physical examination identified dull mentation, icterus, tachycardia (170 beats/min), tachypnea (60 breaths/min), dyspnea, profound weakness, and a grade IV/VI left apical systolic heart murmur. CBC including blood smear examination revealed an anemia (hematocrit 0.13 L/L, reference range, 0.39–0.56 L/L), neutrophilia (28.63 × 109/L, reference range, 2.9–10.6 × 109/L), spherocytosis, and auto-agglutination. Pertinent biochemical profile abnormalities included hypokalemia (2.94 mEq/L, reference range, 3.8–5.4 mEq/L), hyperchloremia (122 mEq/L, reference range, 104–119 mEq/L), hypoalbuminemia (2.4 g/dL, reference range, 2.9–4.3 g/dL), hyperbilirubinemia (8.13 mg/dL, reference range, 0–0.23 mg/dL), and increased alanine transferase (445 U/L, reference range, 10–107 U/L), and alkaline phosphatase (532 U/L, reference range, 22–143 U/L) activity. Results of coagulation testing were unremarkable. Urinalysis revealed a urine specific gravity of 1.042, bilirubinuria, hemoglobinuria, pH 8.5, struvite crystalluria, and a catheterized urine sample for culture yielded no bacterial growth. Left atrial enlargement was noted on thoracic radiographs and was consistent with mitral valve endocardiosis. Abdominal ultrasound examination was unremarkable. These changes were consistent with a diagnosis of primary immune-mediated hemolytic anemia (IMHA).
Treatment for IMHA was instituted with dexamethasone sodium phosphatea (0.25 mg/kg IV q24h), azathioprineb (2 mg/kg PO q24h), a packed red blood cell transfusion (13 mL/kg), a heparinc infusion (500 U/kg/d IV), and famotidined (0.5 mg/kg IV q12h). IV administration of a maintenance fluid solutione was commenced (75 mL/h IV), and potassium chloridef was administered as a constant rate infusion over 4 hours (0.5 mEq/kg/h, IV) to treat hypokalemia.
Results of venous blood gas analysis on hospital admission revealed a metabolic acidosis and a normal anion gap (Table 1). As diarrhea was not present to account for bicarbonate loss, the presumptive diagnosis was hyperchloremic metabolic acidosis because of renal tubular acidosis (RTA). Urine electrolyte and creatinine concentrations were sodium 154 mEq/L; potassium 84.4 mEq/L; chloride 61 mEq/L; calcium 1.8 mEq/L; phosphorus 55.11 mg/dL; creatinine 101.81 mg/dL; bicarbonate 14.6 mEq/L. The fractional excretion of bicarbonate ([urine bicarbonate × plasma creatinine]/[plasma bicarbonate × urine creatinine] × 100%) and the urine anion gap ([sodium+potassium]−[chloride+bicarbonate]) were consistent with a diagnosis of distal RTA (Table 1). One hundred milliequivalents per liter of sodium bicarbonateg in sterile water (supplemented with 20 mEq/L of potassium chloride) was administered IV at a maintenance fluid rate to correct the plasma bicarbonate concentration to 18 mEq/L over a 12-hour period; however, bicarbonate increased to only 15.1 mEq/L after 12 hours of infusion. Supplementation was continued (4 mEq/kg/d sodium bicarbonate IV) throughout hospitalization and plasma bicarbonate concentration increased and remained between 18.1 and 19.7 mEq/L and blood pH was maintained at 7.37.
|Parameter||Reference Range||Dog 1||Dog 2||Dog 3|
|Pco2 (mmHg)||23–42 mmHg||18.4||27.6||24.4|
|Po2 (mmHg)||40–54 mmHg||37.6||31.1||56|
|Hco3 (mEq/L)||18.5–22.7 mEq/L||9.8||11.6||11.3|
|Serum potassium (mEq/L)||3.8–5.4 mEq/L||2.94||3.1||3.1|
|Anion gap (mEq/L)||12–25 mEq/L||13||23||14|
|Fractional excretion of bicarbonate (%)||1.3||2.4||0.5|
|Urine anion gap (mEq/L)||−10 to +10 mEq/L||162.8||16.5||70.5|
Increased respiratory effort persisted that was not responsive to oxygen supplementation. Arterial blood gas analysis (day 3) on nasal oxygen supplementation was suggestive of pulmonary thromboembolism (Paco2 20 mmHg, reference range, 23–40 mmHg; Pao2 68.3 mmHg, reference range, 80–112 mmHg). Despite improvement in the PCV, the dog continued to deteriorate and euthanasia was elected and postmortem examination declined.
A 6.5-year-old, 40 kg, castrated male Coonhound presented for evaluation after a 72-hour history of inappetence, lethargy, vomiting, anemia, and hemoglobinuria. Physical examination revealed generalized weakness, dull mentation, tachycardia (160 beats/mim), profuse salivation, and icteric mucous membranes. A neurological evaluation revealed right-sided central vestibular signs with lesion localization to the right rostral medulla. CBC and blood smear examination revealed a regenerative (reticulocyte count 125.7 × 109/L) anemia (hematocrit 0.20 L/L), neutrophilia (15.77 × 10^9/L) with a left shift (band neutrophil count 0.57 × 109/L, reference range, 0.0–0.3 × 109/L), spherocytosis, and red blood cell agglutination consistent with IMHA. Pertinent biochemical profile abnormalities included hypokalemia (3.1 mEq/L), hyperbilirubinemia (11.35 mg/dL), azotemia (urea 48.46 mg/dL, reference range, 9.8–25.21 mmol/L; creatinine 3.85 mg/dL, reference range, 0.23–1.7 mg/dL), and increased alkaline phosphatase (2165 U/L), alanine transferase (7540 U/L), amylase (2260 U/L, reference range, 299–947 U/L), and lipase (10,940 U/L, reference range, 60–848 U/L). Urinalysis collected via free catch revealed a urine specific gravity of 1.013, pH 7.0, proteinuria (SSA protein >1.0 g/L), 3+ amorphous crystals and bilirubinuria. Coagulation profile revealed an increased prothrombin time (23.4 seconds, reference range, 5.5–9.8 seconds), increased activated partial thromboplastin time (29.1 seconds, reference range, 9.8–19.6 seconds) and a normal platelet count. A Coomb's test was positive at a titer of 1 : 64 (reference range <1 : 16). An ELISA test for Heartworm antigen, Lyme disease antibody, Ehrlichia canis and Anaplasma phagocytophila was negative. Thoracic radiographs were unremarkable; however, an abdominal ultrasound revealed turbulent echogenic blood flow in the caudal vena cava suggestive of early thrombus formation. These findings were consistent with a diagnosis of primary IMHA and possible concurrent disseminated intravascular coagulation (DIC).
Treatment for IMHA was instituted with dexamethasone (0.25 mg/kg IV q24h), azathioprine (1.8 mg/kg PO q24h), a packed red blood cell transfusion (6 mL/kg), famotidine (0.5 mg/kg IV q12h), and aspirinh (0.5 mg/kg PO q 24h) for thromboprophylaxis. The posttransfusion PCV increased to 24% and improvements in heart rate (84 beats/min) and respiratory rate were noted. IV fluid therapy consisted of Plasmalyte-Ai at 100 mL/h supplemented with 20 mEq/L of potassium chloride.
Venous blood gas analysis on hospital admission revealed a moderate metabolic acidosis and a normal anion gap (Table 1). Hyperlactatemia (6.9 mmol/L reference range, <2.0 mmol/L) was also present but resolved with initiation of treatment. A hyperchloremic metabolic acidosis persisted throughout hospitalization despite correction of the lactic acidosis. In the absence of diarrhea, the metabolic acidosis and alkaline urine pH were attributed to RTA. Urine electrolytes and creatinine were measured on day 4 of hospitalization (sodium 81 mEq/L; potassium 23.5 mEq/L; chloride 86 mEq/L; creatinine 22.62 mg/dL; bicarbonate 2.0 mEq/L). The fractional excretion of bicarbonate and the urine anion gap were consistent with distal RTA (Table 1). Neurologic signs progressively worsened on day 4 and further diagnostics and treatment were declined. Euthanasia was elected and the owners declined postmortem examination.
An 8-year-old, 29 kg, spayed female English Setter presented for a 24-hour history of anemia, pyrexia, red-brown discolored urine, lethargy, and anorexia. Physical examination revealed dull mentation, generalized icterus, tachycardia (140 beats/min), tachypnea (48 breaths/min), pyrexia (104.4°F), cranial organomegaly, and profound weakness. CBC and blood smear examination revealed a nonregenerative (reticulocyte count 58.8 × 109/L), anemia (hematocrit 0.17 L/L), neutrophilia (19.47 × 109/L) with a left shift (band neutrophils 1.37 × 109/L), thrombocytopenia (68 × 109/L; reference interval 117–418 × 109/L), spherocytosis, and a positive slide agglutination test supportive of IMHA. Pertinent biochemical profile abnormalities included increased urea (37.82 mg/dL), hypokalemia (3.1 mEq/L), hyperchloremia (125 mEq/L), marked hyperbilirubinemia (58.07 mg/dL), and increased alkaline phosphatase (219 U/L) and creatine kinase (2282 U/L; reference interval, 40–255 U/L). Coagulation testing revealed a mildly increased prothrombin time (13.7 seconds) and a fibrinogen concentration decreased beyond the level of detection (reference interval, 80–300 mg/dL). The prolonged prothrombin time, thrombocytopenia, and hypofibrinogenemia were suggestive of concurrent DIC. Urinalysis revealed a urine specific gravity of 1.019, pH 7.0, bilirubinuria, and hemoglobinuria, and a urine culture was negative for bacterial growth. Thoracic radiographs were unremarkable and an abdominal ultrasound revealed moderate splenomegaly with diffuse hypoechoic nodules suggestive of extramedullary hematopoiesis. Based on these findings, a diagnosis of primary IMHA with concurrent DIC was made.
Treatment for IMHA was instituted with dexamethasone (0.25 mg/kg IV q24h), azathioprine (2 mg/kg PO q24h), a packed red blood cell transfusion (10 mL/kg), aspirin (0.5 mg/kg PO q24h), and famotidine (0.5 mg/kg IV q12h). IV fluid therapy with a maintenance solutione supplemented with 40 mEq/L of potassium chloride was commenced (90 mL/h). The posttransfusion PCV was 26% and remained stable for the remainder of hospitalization.
Venous blood gas analysis on hospital admission revealed a metabolic acidosis and a normal anion gap (Table 1). On day 2 of hospitalization, the metabolic acidosis persisted and the bicarbonate concentration had decreased to 9 mEq/L. Urine electrolyte and creatinine concentrations were measured (sodium 136 mEq/L; potassium 113 mEq/L; chloride 171 mEq/L; calcium 7.0 mEq/L; creatinine 56.56 mg/dL; bicarbonate 7.5 mEq/L). The fractional excretion of bicarbonate and the urine anion gap were calculated to be consistent with distal RTA (Table 1). Treatment with sodium bicarbonate at 0.35 mEq/kg/h was instituted for 4 hours to correct a 3rd of the bicarbonate deficit. After treatment, the dog developed a marked increase in respiratory effort. Given the progression of her clinical condition, euthanasia was elected and postmortem examination declined.
Renal tubular function is critical for the regulation of plasma bicarbonate and acid-base homeostasis. The proximal tubule indirectly reabsorbs approximately 80% of filtered bicarbonate ions.1 Because the amount of bicarbonate required to buffer the daily acid load exceeds that reabsorbed by the proximal tubule, the distal tubule must produce the remaining bicarbonate ions from the dissociation of water into hydrogen and hydroxide ions. Hydrogen ions are secreted into the tubular lumen and the hydroxide ion combines with intracellularly derived carbon dioxide to produce bicarbonate. RTA results from dysfunction of the proximal or distal tubules and is characterized by hyperchloremic metabolic acidosis with a normal anion gap and variable urine pH depending on the site of tubular dysfunction.1,2
In proximal RTA, tubular cells are unable to maximally reabsorb filtered bicarbonate ions, leading to urinary bicarbonate loss, and production of alkaline urine in the face of a metabolic acidosis.1,2 Over time, the plasma bicarbonate concentration equals the absorptive capacity of the tubule. In this “steady state,” hydrogen ions are excreted into the urine, all bicarbonate is reabsorbed, and an appropriately acidic urine is produced (pH < 6.0).1 In the veterinary literature, the etiology of proximal RTA in dogs has been well documented as idiopathic, hereditary (Fanconi syndrome in Basenjis and other breeds),3–5 or acquired secondary to various diseases (multiple myeloma, hypoparathyroidism),2,6 toxins, or drugs (gentamicin, streptozotocin, amoxicillin).7–13
Distal RTA results from the failure to secrete hydrogen ions into the filtrate to produce new bicarbonate ions.1,2,14 This leads to a progressive decrease in plasma bicarbonate concentration, severe metabolic acidosis, and failure to produce acidic urine (urine pH > 6.0).2 Three proposed mechanisms exist to explain the pathogenesis of distal tubular dysfunction in RTA. The classic form is characterized by either a congenital or acquired defect of the H+-ATPase pump. Concurrent hypokalemia arises because of the loss of potassium into the filtrate to neutralize the electronegative charge created by the inability to secrete hydrogen ions.1,2 Voltage-dependent distal RTA arises from the inability of the distal tubule to reabsorb sodium. This disrupts the creation of an electronegative tubular filtrate that would normally support excretion of both hydrogen and potassium, resulting in metabolic acidosis and hyperkalemia.1,2,15 Lastly, an increase in membrane permeability results in hydrogen movement into the tubular cell where it combines with the hydroxide ions intended for bicarbonate production. The increased membrane permeability also results in increased potassium secretion and hypokalemia.1,2
This report describes 3 dogs with IMHA and concurrent distal RTA. Distal RTA is a rarely reported condition in cats with 2 reports outlining the development of distal RTA secondary to pyelonephritis,16,17 and 1 report describing the presence of distal RTA in a cat with hepatic lipidosis.18 In a review of distal RTA, the authors discuss 2 dogs in which distal RTA was diagnosed.14 The presenting complaints in these 2 dogs were dysuria and hematuria secondary to struvite cystic calculi and anorexia.
Although distal RTA is not specifically associated with IMHA in humans, it is a well-described component of other immune-mediated diseases such as Sjögren's syndrome, rheumatoid arthritis, and systemic lupus erythematosus (SLE).2,19,20 In a retrospective review of 58 people with distal RTA, 14% were classified as hereditary, 31% as acquired, and 55% as idiopathic distal RTA.21 Of the patients classified as having acquired distal RTA, 61% were secondary to an immune-mediated etiology. Immune-related distal RTA in humans occurs most commonly in postpubertal women and manifests with systemic features of immune-mediated disease including nephritis.22 Immune-mediated distal RTA in humans, similar to the dogs presented in this report, is likely to manifest with renal potassium wasting.22 The chronic autoimmune disorder, Sjögren's syndrome, primarily involves the salivary and lacrimal glands; however, extraglandular manifestation has also been demonstrated involving the kidneys, lung, pancreas, liver, skin, and central nervous system.19 Renal involvement has been well documented and is characterized as an interstitial nephrititis with subsequent, proximal, distal or diffuse tubulopathy. Distal RTA has also been reported as the initial clinical manifestation of patients developing SLE before development of other more classical symptoms.23,24 Distal RTA also occurs as a hereditary disorder in children,25 as a complication of renal transplantation,26 or secondary to disorders such as primary hyperparathyroidism, urinary tract obstruction20,26 and exposure to drugs or toxins such as amphotericin B, toluene, lithium or heavy metals.2,20
Distal RTA should be suspected in patients with hyperchloremic metabolic acidosis and urine pH > 6.0.1,2 Plasma bicarbonate concentrations are often < 10–12 mmol/L compared with 15–18 mmol/L in patients with proximal RTA.1,2 Other differential diagnoses for these laboratory findings include urinary tract infection with a urease-producing organism or hypokalemia resulting in increased urinary ammonia production.2 A urine culture should be performed to exclude bacterial cystitis. If the findings are because of hypokalemia, the urine anion gap will be negative, as ammonia production and secretion with chloride are unaffected when tubular acidification mechanisms are intact.2,27 The dogs in this report demonstrated a hyperchloremic metabolic acidosis, hypokalemia, markedly decreased plasma bicarbonate concentration, and alkaline urine consistent with RTA. Additionally, dogs with RTA will have positive urine anion gaps indicating impaired tubular acidification ability in the setting of a hyperchloremic metabolic acidosis, as demonstrated in the 3 dogs of this report.27,28
Once a diagnosis of RTA has been established, localization of tubular dysfunction should be pursued. Differentiation of proximal and distal RTA can be determined through calculation of the fractional excretion of bicarbonate.2 In humans with distal RTA, fractional excretion of bicarbonate is <3%, whereas this value can exceed 15–20% in proximal RTA.2 Urine fractional excretion of bicarbonate was calculated for all 3 of the dogs and results were consistent with a diagnosis of distal RTA. In cases where distal RTA is suspected but the urine pH is normal, a bicarbonate challenge or ammonium loading test can be performed.1,2 In patients with distal RTA, urine acidification is impaired and persistently alkaline urine is documented. To characterize distal tubular dysfunction as either a defect in the H+-ATPase or voltage-dependent distal RTA, a furosemide response test can be performed.2,27 Furosemide increases luminal electronegativity by increasing cortical distal tubular sodium delivery and reabsorption. Patients with a cortical H+-ATPase defect will have persistently alkaline urine with an increase in potassium secretion. Conversely, a defect within the medullary collecting tubule will produce an appropriate increase in hydrogen (urine pH < 5.5) and potassium secretion as the cortical tubule responds appropriately to the increased luminal electronegativity.2,27 With voltage-dependent distal RTA, hydrogen and potassium secretion will be unchanged.2,27 This diagnostic test was not performed in the dogs in this report.
Clinical signs of distal RTA are secondary to the acidosis and hypokalemia; however, some patients are asymptomatic aside from signs attributed to the underlying disease.1,2,14 Rickets, osteomalacia, and urolithiasis are consequences of distal RTA because acidosis results in the liberation of calcium phosphate from bone and inhibition of tubular calcium and phosphorus reabsorption, and alkaline urine promotes precipitation of calcium phosphate and decreases citrate excretion.2 Treatment for distal RTA is required if the acidosis is severe. Supportive therapy will be life long if the underlying condition cannot be resolved or if the tubular damage is permanent. Sodium bicarbonate supplementation (1–3 mEq/kg/d) is considerably lower than that required for proximal RTA (≥10 mEq/kg/d).1,2,14 Treatment with potassium citrate might be required for patients with concurrent hypokalemia.1
In summary, this report documents distal RTA in 3 dogs with IMHA. Given the frequent association of distal RTA with immune-mediated disorders in humans, the identification of these 3 dogs with immune-mediated disease and concurrent distal RTA emphasizes the importance for awareness of this condition when assessing and treating animals with immune-mediated conditions. Future studies are required to assess the incidence and significance of distal RTA in dogs with immune-mediated disease.