A 16-year-old 2.4-kg (5.28-lb) vasectomized male ring-tailed lemur (Lemur catta) was evaluated because of extreme lethargy, hyperpnea, and a draining abscess of the right pectoral scent gland. Two years prior to this evaluation, suspected chronic renal failure had been diagnosed on the basis of serum biochemical analysis, with results interpreted by comparison with values in the ISIS database for ring-tailed lemurs.1 Data for physiologic variables in this database are not reference intervals established by laboratory standardization but are frequently used as reference guidelines by veterinary practitioners working with uncommon or zoological species. The ISIS values (provided as mean ± SD) were used as a reference for CBC and serum biochemical evaluations for the lemur of this report. The primary findings included azotemia (BUN concentration, 120 mg/dL [ISIS value, 22 ± 8 mg/dL]; creatinine concentration, 1.4 mg/dL [ISIS value, 1.0 ± 0.3 mg/dL]), and high amylase activity (2,537 U/L; ISIS value, 1,779 ± 770 U/L) and lipase activity (491 U/L; ISIS value, 66 ± 106 U/L). A CBC at that time revealed mild, normocytic, normochromic anemia (Hct, 42.1%; ISIS value, 50.5 ± 6.2%).
The lemur was anesthetized to facilitate examination, which revealed an impacted right pectoral scent gland with serosanguineous exudate. During blood collection for diagnostic testing, the sample appeared grossly anemic. A CBC and serum biochemical analysis revealed severe, microcytic, hypochromic anemia (Hct, 7.1%); marked azotemia (BUN concentration, 220 mg/dL; creatinine concentration, 1.3 mg/dL); hyperphosphatemia (11.6 mg/dL; ISIS value, 5.4 ± 2.0 mg/dL); and hypocalcemia (5.7 mg/dL; 9.7 ± 0.9 mg/dL). The scent gland was cleaned, and silver sulfadiazine cream was applied topically. Supportive treatments included administration of an electrolyte-balanced solution (lactated Ringer's solution; 50 mL/kg [22.7 mL/lb], SC), meloxicam (0.1 mg/kg [0.05 mg/lb], SC), a combination of penicillin G procaine and penicillin G benzathine (31,000 U/kg [14,091 U/lb], SC), and darbepoetin alfa (0.52 μg/kg [0.24 μg/lb], SC).
The lemur was prescribed amoxicillin clavulanate (15.0 mg/kg [6.82 mg/lb], PO, q 12 h for 10 days), aluminum hydroxide (15.0 mg/kg, PO, q 12 h), and darbepoetin alfa (0.52 μg/kg, SC, q 7 d). However, weakness, lethargy, and social isolation from the troop continued, and the lemur was anesthetized 4 days after the initial examination to receive a blood transfusion. The lemur was premedicated with diphenhydramine hydrochloride (1.0 mg/kg [0.45 mg/lb], IM) and midazolam hydrochloride (0.1 mg/kg, IM) and anesthetized with isoflurane gas. Whole blood (12.0 mL) was collected aseptically from a healthy adult female ring-tailed lemur from the same troop, diluted with 2.6 mL of acid-citrate-dextrose solution, and then administered IV to the recipient through an 18-μm blood filtera over a 10-minute interval because the recipient was markedly hypoxemic (as determined via pulse oximetry) and a reduction in overall anesthetic time was desired. Although a larger transfusion volume was desired, this volume was all that could be safely and aseptically collected from the donor. No adverse reactions were detected following the transfusion. Electrolyte-balanced saline solution was administered for additional fluid support (62.5 mL/kg [28.4 mg/lb], SC).
Four days after the transfusion, the lemur developed dependent penile edema and continued to have intermittent periods of weakness. This raised concerns about a delayed transfusion reaction, and treatment with tapering dosages of prednisone (1.0 mg/kg, PO, q 24 h for 28 days, then 0.6 mg/kg [0.27 mg/lb], PO, q 12 h for 7 days, then 0.6 mg/kg q 72 h for 7 days) was initiated. Urinalysis of an opportunistic, free-catch sample on the same day revealed moderate proteinuria and severe hyposthenuria (specific gravity, 1.007).
Four weeks after initial evaluation, the lemur was anesthetized and a blood sample was collected to assess response to treatment. A CBC revealed moderate lymphopenia (174 lymphocytes/μL; ISIS value, 3,748 ± 2,141 lymphocytes/μL) and severe microcytic, hypochromic, mildly regenerative anemia that had improved since the previous month (Hct, 19.5%; manual reticulocyte count, 212,550 reticulocytes/μL [6.5%; ISIS value, 0.2%]). Serum biochemical analysis indicated an improvement in the azotemia (BUN concentration, 138 mg/dL; creatinine concentration, 1.7 mg/dL), with normophosphatemia (3.7 mg/dL) and persistent hypocalcemia (6.6 mg/dL). The frequency of aluminum hydroxide administration was reduced (15.0 mg/kg, PO, q 24 h), and administration of calcitriol (1.7 ng/kg [0.77 ng/lb], PO, q 24 h) was initiated to manage renal secondary hyperparathyroidism.
A recheck examination was performed 4 weeks later, revealing a weight loss of 0.3 kg (0.66 lb) with no other important clinical findings. Results of hematologic analysis indicated persistent, severe, microcytic regenerative anemia (Hct, 15.6%; reticulocyte count, 249,480 reticulocytes/μL [8.4%]) with progressive azotemia (BUN concentration, 181 mg/dL; creatinine concentration, 2.1 mg/dL), persistent hypocalcemia (6.4 mg/dL), and normophosphatemia (7.4 mg/dL). A serum sample was also submitted for evaluation of TIBC and total iron and ferritin concentrations.b At that time, the calcitriol dosage was increased to 2.57 ng/kg (1.17 ng/lb), PO, every 24 hours.
Four weeks later, the lemur was again anesthetized for blood collection. Physical examination findings were unchanged with the exception of a 0.5-kg (1.1-lb) increase in weight. The CBC revealed persistent, severe, microcytic nonregenerative anemia (Hct, 14%; reticulocyte count, 50,400 reticulocytes/μL [1.8%]), and serum biochemical results continued to reflect azotemia (BUN concentration, 187 mg/dL; creatinine concentration, 2.0 mg/dL) and hypocalcemia (6.9 mg/dL). The darbepoetin dosage was increased to 3.22 μg/kg (1.46 μg/lb), IM, every 7 days.
One week later, zoological staff reported that the lemur was obtunded and not staying with the rest of the troop. Because of concerns about potential gastric ulceration and gastrointestinal hemorrhage secondary to uremia, famotidine (0.8 mg/kg [0.36 mg/lb], PO, q 24 h) was prescribed. Four days later, zoological staff reported that the lemur continued to appear lethargic and had what appeared to be a large oral ulcer at the base of the mandibular incisors. During the same time period, the results for the serum iron analysis were returned and, compared with mean ± SD values reported elsewhere for healthy lemur species,2,3 indicated a low degree of transferrin saturation (4.8% vs 40 ± 15%3), hypoferremia (iron concentration, 24 μg/dL vs 157 ± 62 μg/dL3), normal ferritin concentration (113 ng/dL vs 73 ± 57 ng/dL3), and high TIBC (499 μg/dL vs 392 ± 50 μg/dL3).
The lemur was anesthetized for a complete oral examination. Moderate to severe periodontal disease was present, with the mandibular incisor teeth most severely involved. An erosive gingival lesion associated with the lingual aspect of the mandibular incisors was also identified. The lesion was debrided, and dental prophylaxis was performed after a 3-mm punch biopsy sample of affected tissue was obtained. During the examination, the lemur received an electrolyte-balanced saline solution (50 mL/kg, SC) and iron dextran (25 mg/kg [11.4 mg/lb], IM). Amoxicillin clavulanate (13.4 mg/kg [6.10 mg/lb], PO, q 12 h for 10 days) and sucralfate (250 mg/kg [113.6 mg/lb], PO, q 12 h for 14 days) were prescribed. A CBC (estimated by slide differential cell count) revealed moderate leukocytosis (18,000 leukocytes/μL; ISIS value, 8,642 ± 3,751 leukocytes/μL) with marked neutrophilia (15,300 neutrophils/μL; ISIS value, 4,267 ± 2,938 neutrophils/μL). A PCV of 7% and serum total protein concentration of 8.0 g/dL (ISIS value, 7.3 ± 0.8 g/dL) determined in-house were consistent with slow, chronic hemorrhage or blood loss. Results of a fecal occult blood test were negative; serum biochemical analysis was not performed because of insufficient sample volume. Histologic results for the oral lesion were consistent with an inflammatory exudate with marked bacterial colonization. The oral lesion appeared to resolve with treatment, and the lemur was reported to be integrating back into the troop and appeared brighter overall.
Five weeks later, a recheck examination revealed mild persistent gingivitis and complete healing of the oral lesion. The lemur received an electrolyte-balanced saline solution (50 mL/kg, SC) for fluid support and a second injection of iron dextran (16.0 mg/kg [7.27 mg/lb], IM). A CBC and serum biochemical analysis revealed progressive azotemia (BUN concentration, 213 mg/dL; creatinine concentration, 2.3 mg/dL), mild hypocalcemia (7.6 mg/dL), and mild hyperphosphatemia (8.4 mg/dL), with marked decrease in the severity of the anemia (Hct, 21.6%). No changes in medications were made at this time. A serum sample was submitted for quantification of TIBC, total iron and ferritin concentrations, and transferrin saturation.b These results revealed an improvement in the patient's total serum iron concentration (66 μg/dL),3 increased TIBC (771 g/dL), and low ferritin concentration (65 ng/dL) with increased transferrin saturation (11.8%).
A blood sample was collected as part of regular monitoring 6 weeks later, and CBC results indicated an improved Hct (27.2%), with no reticulocytes identified. Serum biochemical analysis revealed persistent azotemia (BUN concentration, 215 mg/dL; creatinine concentration, 1.8 mg/dL), normocalcemia (9.2 mg/dL), hyperphosphatemia (10.0 mg/dL), and high serum activities of GGT (55 U/L; ISIS value, 28 ± 18 U/L), ALT (654 U/L; 94 ± 59 U/L), and AST (309 U/L; 48 ± 37 U/L). No additional abnormalities were identified during examination. Electrolyte-balanced saline solution (50 mL/kg, SC) was administered, the frequency of aluminum hydroxide administration was increased to twice daily (15.0 mg/kg [6.82 mg/lb], PO, q 12 h), and a milk thistle supplement (72.0 mg/kg [32.7 mg/lb], PO, q 24 h) was added to the treatment regimen. Owing to concerns that hepatic injury may have developed secondary to administration of iron dextran, a third injection was not administered, with the intention of allowing the liver to recover.
Four weeks later, the lemur was reevaluated because of a 48-hour history of ptyalism and obtunded behavior. Physical examination of the anesthetized patient revealed a focal abscess in the rostral aspect of the oropharynx just caudal to the maxillary right third molar tooth. The abscess was debrided and probed; the lesion extended down to, but did not involve, the right mandibular ramus. Compared with its body weight during the previous examination, the lemur had lost 0.6 kg (1.32 lb). Administration of electrolyte-balanced saline solution (50 mL/kg, SC) was again repeated, and meloxicam (0.05 mg/kg [0.023 mg/lb], SC) and penicillin G procaine (30,000 U/kg [13,636 U/lb], SC) were administered. Amoxicillin clavulanate was prescribed (15.0 mg/kg, PO, q 12 h for 10 days).
A CBC (via slide differential cell count) revealed marked leukocytosis (53,700 leukocytes/μL), with predominant neutrophilia (49,940 neutrophils/μL) and monocytosis (2,690 monocytes/μL; ISIS value, 375 ± 466 monocytes/μL) and a PCV of 18.5%. Serum biochemical analysis revealed severe azotemia (BUN concentration, 236 mg/dL; creatinine concentration, 5.0 mg/dL), severe hyperphosphatemia (31.2 mg/dL), and hypocalcemia (6.9 mg/dL); compared with the previous evaluation, activities of GGT (13 U/L) and ALT (238 U/L) were decreased, and AST activity was slightly increased (330 U/L). Calcitriol administration was discontinued because of severe hyperphosphatemia. Because this condition was attributed primarily to underlying presumptive osteomyelitis associated with the oral lesion, the aluminum hydroxide dose was not adjusted.
The TIBC and serum iron concentration at that time (transferrin analysis was not available due to laboratory shortage of species-specific conjugate) were reportedb 1 month later and reflected a low total iron concentration (23 μg/dL)2,3; TIBC had decreased from the previous measurement, but remained high at 500 μg/dL. When these laboratory results were received, the lemur was anesthetized for collection of another blood sample.
A CBC revealed a low Hct (10%) and moderate leukocytosis (19,200 leukocytes/μL) with neutrophilia (16,890 neutrophils/μL) and monocytosis (1,730 monocytes/μL). Results of serum biochemical analyses indicated an improvement in the patient's azotemia (BUN concentration, 184 mg/dL; creatinine concentration, 2.4 mg/dL), compared with results of the previous evaluation, and mild hyperphosphatemia (8.4 mg/dL) with mild hypocalcemia (7.9 mg/dL) and mild hypoproteinemia (total protein, 5.6 g/dL). Hepatic enzyme activities had also decreased from the previous values and were considered normal (GGT activity, 8 U/L; ALT activity, 17 U/L; AST activity, 12 U/L). Because of continued concern about iron deficiency anemia, ferrous sulfate treatment was instituted (2.36 mg/kg [1.07 mg/kg], PO, q 24 h). This treatment was chosen instead of resuming injectable iron dextran administration in an attempt to reduce adverse effects on the liver. The aluminum hydroxide dose was also increased (24.76 mg/kg [11.25 mg/lb], PO, q 12 h). All other medications were continued as prescribed.
Three weeks later, the lemur developed acute right-sided maxillofacial swelling and became lethargic. The animal was anesthetized, and physical examination revealed a severe soft tissue abscess overlying the ventral aspect of the ramus and body of the right mandible. Radiography of the skull revealed no evidence of osteomyelitis. The abscess was drained and debrided. An electrolyte-balanced saline solution (30 mL/kg [13.6 mL/lb]), meloxicam (0.1 mg/kg), penicillin G procaine (30,000 U/kg), and cefovecin sodium (8.0 mg/kg [3.64 mg/lb]) were administered SC. The lemur had a prolonged anesthetic recovery but was able to be returned to the troop.
The following day, zoological facility staff reported that the lemur was severely obtunded, weak, and isolated from the troop. Maxillofacial swelling present the previous day had spread to include the periorbital tissues. When disturbed, the lemur assumed a prone position; moderate dyspnea was observed, and the mucous membranes appeared white. Analysis of blood collected at time of examination revealed progressive anemia (Hct 7.1%), lymphopenia (492 lymphocytes/μL), marked azotemia (BUN concentration, 268 mg/dL; creatinine concentration, 3.2 mg/dL), acidosis with a total CO2 concentration of 7 mEq/L (ISIS value, 17.3 ± 5.3 mEq/L), hypocalcemia (6.3 mg/dL), moderate hyperphosphatemia (17.5 mg/dL), and persistent hypoproteinemia (5.3 g/dL). Hepatic serum enzymatic activities were considered normal.
Owing to the patient's rapidly declining condition and severe hematologic abnormalities, euthanasia was elected. Gross necropsy findings revealed pallor of most internal organs, a mass on the spleen, small cystic kidneys bilaterally, and destruction of the right mandibular ramus with bony lysis. Histopathologic findings included severe necrosuppurative sialoadenitis and facial cellulitis, severe necrosuppurative inflammation within and adjacent to alveolar bone of the mandible with marked bacterial colonization and bone necrosis, an infarcted lymph node, mild neutrophilic endocarditis, severe bilateral nephrosclerosis, mild chronic gastroenterocolitis with edema, hematomas in the spleen and mesentery, mild chronic cholecystitis, and mild portal lymphocytic hepatitis. Liver total iron concentration was low at 15 μg/g, compared with values previously reported for healthy lemurs (349 ± 140 μg/g).4
Discussion
Age-related renal degeneration is a common cause of illness and death in prosimians.5–7 Reduction of glomerular filtration rate leads to increased serum concentrations of toxic by-products, including urea and ammonia. As kidney mass is lost, production of erythropoietin and calcitriol is decreased, leading to nonregenerative anemia and, in some cases, renal secondary hyperparathyroidism. Management of veterinary patients with this condition involves fluid therapy to reduce concentrations of toxic by-products, dietary management to reduce protein and phosphorus intake, administration of histamine type 2 (H2)-receptor antagonists to ameliorate the effects of gastritis, and treatment with phosphate binders if hyperphosphatemia develops.8 In patients with moderate to severe anemia, synthetic erythropoietin can be administered to stimulate RBC production. The administration of calcitriol is gaining support for management of secondary renal hyperparathyroidism and to improve overall patient well-being.9
The lemur of this report had severe, microcytic nonregenerative to poorly regenerative anemia that was refractory to treatment with darbepoetin alfa. Darbepoetin alfa is a recombinant DNA protein with similar action to erythropoietin and has been used to bolster the Hct of anemic human and veterinary patients.10–12 Although darbepoetin is commonly used in canine, feline, and human patients, to our knowledge, its use in prosimian species has not been previously reported. No adverse effects associated with darbepoetin administration were detected in the lemur of this report.
Hypochromic, microcytic nonregenerative anemia is most often secondary to iron deficiency. Other causes of nonregenerative anemia include chronic disease, bone marrow disorders, renal disease, endocrine disorders (eg, hypothyroidism or hypoadrenocorticism), and acute blood loss.13 In this lemur, clinical signs and clinicopathologic findings were most consistent with iron deficiency anemia coupled with anemia of chronic renal disease. Iron deficiency was confirmed by identification of low hepatic iron concentrations (15 μg/g) at necropsy. These findings support that comparison with previously published values2,3 for serum total iron concentration, TIBC, and ferritin concentration was diagnostic for iron deficiency in this patient.
The family Lemuridae has historically been considered to be prone to iron storage disease, although ring-tailed lemurs are thought to be less susceptible.3,6,7,14–17 Dietary modifications have been made to reduce overall iron availability in prosimian diets in response to evidence that diet plays a role in the development of iron storage disease.17,18 Recent reports19,20 suggest that hemosiderosis and hemochromatosis may not be as prevalent as historically suggested and that there may be species-specific and institution-specific susceptibility to this condition.
On the basis of historic veterinary knowledge regarding Lemuridae, iron deficiency anemia was unexpected, and this delayed the diagnosis for the ring-tailed lemur of this report. Total serum iron concentration, transferrin saturation, and TIBC were consistent with iron deficiency, and Hct improved markedly after the administration of iron dextran. In our opinion, the lemur's poor response to darbepoetin was likely attributable to the underlying iron deficiency and not a failure of this species to respond to the medication.
Iron deficiency anemia has been identified as a sequelae in humans affected by chronic renal failure and is the most common cause of a poor response to erythropoietin treatment.21,22 Causes of iron deficiency anemia in patients affected with chronic kidney disease include reduced uptake and impaired intestinal absorption of dietary iron, chronic inflammation, ongoing blood loss (often gastrointestinal), and iron consumption owing to increased requirements during erythropoietin treatment.23 Iron deficiency secondary to chronic renal failure has been poorly described in veterinary patientsc and may be more prevalent than previously thought. In human patients, management of iron deficiency anemia secondary to chronic kidney disease often involves the IV administration of iron because of impaired gastrointestinal absorption.24–26 In 1 study,27 IV administration of iron was sufficient to cause improvement in Hct in two-thirds of human patients without administration of erythropoietin, suggesting that anemia in many patients with chronic renal failure may primarily be attributable to underlying iron deficiency and not erythropoietin deficiency.
After a second injection of iron dextran, the lemur of this report developed signs of hepatic injury as determined by serum biochemical analysis. The pharmacokinetics of iron dextran in other species show an initial absorption of 60% of the drug 72 hours after administration, with most of the drug being absorbed over the following 1 to 3 weeks.12 After the absorption phase, iron is processed by reticuloendothelial cells of the liver, spleen, and bone marrow.12 Up to 40% of total body iron can be stored in hepatocytes, and in states of iron overload, storage of iron can move from ferritin to hemosiderin.28 High concentrations of iron or hemosiderin can be toxic to cells, with damage most frequently reflected by increased serum liver enzyme activities. In species prone to hemosiderosis or hemochromatosis, increased serum activity of hepatic enzymes is one of the findings.19 Hepatic serum enzymatic activities in our patient returned to normal values within 8 weeks after iron dextran treatment was discontinued; however, the lemur's Hct decreased markedly during this interval. Because of concerns about hepatic injury, attempts at oral administration of iron were made, first through dietary intervention (feeding cooked meat). When the lemur refused cooked meat, ferrous sulfate was administered PO. This medication was well tolerated by the lemur but failed to stimulate a regenerative response in the bone marrow. Such findings are similar to those described for humans with anemia of chronic kidney disease, in which oral iron administration is insufficient to maintain erythropoiesis.24–26 Lemur species are suspected to be prone to absorption of high amounts of iron from the gastrointestinal tract, so the lack of response to oral supplementation was unexpected; however, inhibition of iron absorption likely resulted from gastroenterocolitis, which was identified on postmortem examination. For similar patients, IV iron administration or continued IM iron injections should be considered with careful monitoring of hepatic enzyme activities and possible addition of concurrent hepatoprotectants. Despite serum biochemical evidence of hepatic injury in this patient, there was no histopathologic evidence of long-term hepatic injury at necropsy.
ABBREVIATIONS
| ALT | Alanine aminotransferase |
| AST | Aspartate aminotransferase |
| GGT | γ-Glutamyltransferase |
| ISIS | International Species Information System |
| TIBC | Total iron binding capacity |
Hemo-Nate, Utah Medical Products Inc, Midvale, Utah.
Kansas State Veterinary Diagnostic Laboratory, Manhattan, Kan.
Dondi F, Lukacs RM, Agnoli C, et al. Iron profile evaluation in chronic kidney disease: a retrospective study of 46 dogs (abstr). J Vet Intern Med 2010;1547.
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