Abstract
Most clinical information on diagnosis and treatment of renal failure in reptiles has been reported in exotic pet medicine, primarily in the green iguana (Iguana iguana). Ante-mortem diagnosis of renal disease is difficult in reptiles. Blood work changes are not reliable, although increase of phosphorous, decrease in total calcium, and increase in uric acid are reported in the green iguana. Calcium: phosphorous ratio inversion may be the first change noted. Hyperuricemia is not always present, repeatable mild-moderate elevations in herbivores should prompt additional diagnostics. Management should focus on optimizing husbandry, administering fluids, providing appropriate nutritional support, and treating concurrent diseases. Allopurinol may be helpful in reducing hyperuricemia.
Introduction
Renal disease categories are poorly defined in reptile species and relationships between disease location (e.g., glomeruli, tubules), histological change, clinical signs, and laboratory values are not clearly established. Species variability in susceptibility to disease, clinical presentation, and diagnostic changes are being defined. Renal disease is routinely diagnosed in clinical practice and in pathology reviews. A review of reptile renal pathology for the clinician is available.35 Early disease diagnosis is difficult and a high index of suspicion may lead to more effective diagnosis and management. Renal failure etiology, diagnosis and treatment are best described in the green iguana (Iguana iguana) and some tortoise species. One renal failure syndrome in green iguanas with consistent blood work changes has been described; decreased to normal total calcium (TCa), significantly increased phosphorous (P), and increased uric acid (UA).3 Etiology of renal pathology in reptiles is likely multi-factorial and may include: inappropriate husbandry (too dry and/or cool), inappropriate nutrition (level or type of protein, low water consumption, incorrect vitamin levels), toxic injury (such as nephrotoxic drug administration), bacterial or parasitic infection, neoplasia, and possibly senescence.
Reptiles are an extremely diverse class. While snakes and crocodiles are carnivorous, dietary habits vary widely in chelonians and lizards. Knowledge of natural habitat and diet is important in developing husbandry standards.
Reptiles generally have paired kidneys. Glomeruli and nephrons are present, but nephrons lack the Loop of Henle and urine is not concentrated above plasma levels in the kidney. Ureters generally insert into the cloaca. Urine is stored in the distal colon or a separate urinary bladder. Snake and crocodilian species do not possess bladders, but other reptiles commonly do. Water can be absorbed from the bladder or colon and electrolytes are recovered from the bladder in some species.19 Glomerular filtration rate (GFR) is important for maintaining urine flow. GFR is decreased by low temperatures and dehydration. Dehydrated reptiles decrease GFR by decreasing the number of filtering glomeruli. The tubules are the primary site of uric acid (UA) excretion.17 The rate of tubule UA excretion does not appear related to GFR or hydration status, though low temperatures reduce tubule function. Chronic, mild dehydration and hypothermia in captive green iguanas is theorized to contribute to renal failure in this species and is likely an issue for other species. Theoretically, diseases limited to the glomeruli would not cause hyperuricemia; however, if filtrate flow is reduced and uric acid excretion continues, uric acid deposition in the kidney can occur.
Elevation in UA may reflect renal disease (especially tubule disease), although not all increases are pathologic. Uric acid is produced in the liver from the breakdown of purine bases, primarily derived from dietary protein. Meat protein has a higher purine content than plant protein. Uric acid normally increases after a meal. This is reported in snakes and would be expected in other carnivorous reptiles.32 Inappropriately high levels or types of dietary protein (e.g., herbivorous reptiles fed high protein diets) can increase UA production and exceed renal excretion capability causing hyperuricemia.32,14 Hyperuricemia causes gout, the deposition of crystals and associated inflammation in tissue (including the kidney).24 The UA level at which gout deposition develops is not known for all species, but values over 24.7 mg/dl (1469.16 µmol/L) are commonly cited.7 If UA values are elevated, the animal should be assessed for gout and renal disease.24
Reviews of reptile calcium and phosphorous regulation and relation to metabolic diseases and renal failure are available.5,9,16,22,23
Clinical Signs and Physical Exam
Animals with early stages of renal disease may have no obvious clinical signs. A thorough review of husbandry and history may indicate predisposing factors (e.g., chronic low humidity and/ or temperature, elevated dietary protein levels, possibility of metabolic bone disease).31
Chronic renal failure (CRF) has been more commonly identified than acute renal failure (ARF) in the green iguana.6,34 Animals with CRF often have a history of inadequate housing (past or present) and appear unthrifty. Animals with ARF generally have better husbandry and body condition. There may be history of known toxin exposure, including drug administration. Anorexia or declining appetite and weakness are commonly reported. Polyuria and polydipsia are rarely reported.34 Dehydration is generally appreciated, digit tremors or muscle fasciculation may be present, and enlarged kidneys may be palpable in some cases. Pain or reluctance to move may be appreciated if gout deposits are present. Chronic renal failure can present as acute collapse if a gradual decline in condition was not appreciated.
Diagnostics
Blood Work
Renal disease may be present without obvious hematological changes, particularly in the early stages of disease. In advanced cases, blood changes are often present. Blood values may vary with season, species and sex and normal ranges are poorly defined for many species. Establishing "normal ranges" for individual animals through routine sampling during wellness exams can be an invaluable tool for identifying concerning trends prior to severe clinical changes.
The white blood cell count may be elevated.1–3,7, 31 Mild leukocytosis with monocytosis or heterophilia is most frequently described; however, more severe increases are expected if infection or severe inflammation is present.3,7 The hematocrit (Hct) may be increased due to dehydration but nonregenerative anemia has been reported with CRF.7,31
Total calcium levels are variable in renal disease and impacted by multiple factors (e.g., protein levels, ovulation).31 In green iguanas, normal or decreased levels are described more commonly than increased values.7,34 A mean value of 7.8 mg/dl (1.95 mmol/L) was reported in a case series of 12 green iguanas.3 Total calcium is not always decreased and renal failure should still be considered if calcium levels are normal or high.21 Ionized calcium (iCa) levels may be helpful in evaluating animals. In mammals, CRF animals with normal or high TCa may have low iCa.30 Regular monitoring of iCa in normal and ill reptiles will allow for better definition of the utility of this value.
Phosphorous is frequently elevated, generally significantly in advanced disease. In the case series noted above, average P levels were 23.8 mg/dl (7.69 mmol/L) though not all animals have hyperphosphatemia.3,22 Hemolysis in the green iguana is associated with artificially increased phosphorous levels, so it is important to assess sample quality.16 TCa:P ratio inversion may be the first sign of renal disease in green iguanas.7 Significant increases in P may be more consistent with renal failure than "metabolic bone disease" and elevations should prompt addition diagnostics.22
Metastatic mineralization may occur from excessively high Ca and/or P levels. In mammals, the solubility index (the product of TCa (mg/dl) and P (mg/dl)) is utilized to evaluate deposition risk. An index > 70 mg/dl (12 mmol/L) is associated with deposits in healthy tissue, an index between 55 – 70 mg/dl (9 – 12 mmol/L) is associated with deposits in abnormal tissue, and an index < 55 mg/dl (9 mmol/L) is not associated with deposits.9,31 The solubility index may have relevance in reptiles, though it is not validated.
Uric acid values typically increase with end-stage renal disease, but in earlier stages of renal disease may be normal. In addition, uric acid levels may increase normally (e.g., post-prandial carnivores). Uric acid is secreted by the tubules and this rate appears unrelated to glomerular filtration rate.17,22 A single elevated value is not diagnostic for renal failure. Some authors propose that relatively minor elevations in herbivorous reptiles increase concern for renal disease. Values over 7 mg/dl (413.36 µmmol/L) may be concerning in green iguanas.1 Reported ranges for wild and captive herbivorous species show uric acid values commonly under 10 mg/dl (594.8 µmol/dl).5,22,26,28,29 Obtaining blood samples on fasted samples will limit post-prandial increases.32 The UA level at which gout deposition develops is not known for all species, but values over 24.7 mg/dl (1496.16 µmol/L) are commonly cited in herbivorous reptiles.6
Blood urea nitrogen (BUN) does not reflect renal function in reptiles; however, it may increase with dehydration or catabolism.4,5,29 BUN is expected to be relatively high in normally hydrated carnivorous chelonians [up to 75 mg/dl (26.78 mmol/L)] compared to normally hydrated herbivorous reptiles.29 Elevations of BUN should prompt evaluation for improper husbandry and causes of dehydration, including renal failure.
Other lab work changes may include increased aspartate aminotransferase, alanine aminotransferase, lactate dehydrogenase, and creatine phosphokinase but are non-specific.1,3,31,34 Aspartate aminotransferase is present in proximal tubules. Levels may be markedly elevated if proximal tubules are damaged.31 Total protein and electrolytes may increase with dehydration.27 Glomerular disease may cause protein loss. Hyperkalemia was reported in hyperuricemic tortoises with severe post-hibernation dehydration, but is not regularly described with renal failure in the green iguana.25
Urinalysis
Urinalysis can provide helpful information about overall hydration and urinary tract health.10,13 Bladder urine does not reflect renal function as it does in mammals and urine specific gravity (USG) in particular should be interpreted differently.7,10,18,21,27 A low USG is consistent with normal hydration, whereas elevated USG is abnormal. Urine specific gravity (USG) over 1.005 and 1.014 were considered abnormal in two chelonian studies.10,18 Renal disease in tortoises was associated with urine acidification and glucosuria on dipstick and renal casts and increased cell and bacterial counts on sedimentation.18 Uric acid crystals can be seen with gout and warrant closer evaluation of the animal. Bladder urine is contaminated due to passage through the cloaca, but a pure growth of one organism on culture should be considered significant.6,21 Techniques for cystocentesis have been described.13
Diagnostic Imaging
Radiographs may demonstrate increased renal size in some cases and mineralization of soft tissues (especially great vessels) which may be associated with renal failure.3,6 Intravenous contrast studies have been described and can help better define renal size and function.6,13,20 Ultrasound may be utilized to more fully assess renal parenchyma and allow evaluation of size, structural abnormalities, and deposits in species where imaging is achievable.1,27 Magnetic resonance imaging (MRI) may be useful to assess size and structure of the renal parenchyma.
Biopsy
Kidney biopsy allows for definitive diagnosis.12 Various techniques are described in the green iguana; transcutaneous, major celiotomy, endoscopy and caudal keyhole.1,6,8,12,15,34 Surgical approach will vary with operator experience, kidney changes, species anatomy, and stability of the patient. Biopsy may not lead to a change of treatment plan, but allows confirmation of disease and may influence prognosis. Multiple biopsies should be submitted. Renal biopsy with appropriate culture is particularly relevant if infectious etiologies are suspected.
Other Techniques
Glomerular filtration rate estimation with iohexol clearance has been reported in the green iguana and may prove useful in other species.15 A suggested protocol for clinicians in private practice is available.13
Research into nuclear scintigraphy to assess functional kidney mass in normal green iguanas indicated that uptake can be measured utilizing technetium Tc 99m dimercaptosuccinic acid and future results in abnormal animals may show utility.11 The authors also explored assessing bone density with dual energy x-ray absorptiometry (DEXA) and expanded blood profiles to assess for renal secondary hyperparathyroidism.11 In a preliminary study in corn snakes (Elaphe guttata guttata) 99m Tc-mercaptoacetyltriglycine provided high quality renal imaging.33 These techniques are not well established or widely available.
Management
Prognosis is grave but treatment and management of disease is rewarding in some cases. One author reports one-year survival rates of 64% (n = 11) with acute renal failure and 22% (n = 23) with chronic renal failure in lizards.6
Appropriate humidity and temperature are needed during hospitalization and long term management. Regular monitoring of weight and blood values (Hct, TS, Ca, P, UA) is helpful for monitoring progress.6,25 A description of therapeutic planning and monitoring in treating dehydrated post-hibernation tortoises is available and the same principles apply to treating other renal failure patients.25
Fluid support is the mainstay of therapy. A practical review of fluid therapy options is available.13 Appropriate initial rates as high as 40 ml/kg/day have been advocated,6 though lower rates (25 ml/kg/day) may be equally beneficial.27 Fluids can be given via many routes: oral (PO), intraosseous (IO), intravenous (IV), intracoelomic (ICe), subcutaneous (SC), and intracystic (bladder) (ICb). Intravenous or IO routes are advocated in severe cases.6,25,27,34 The ICb route was described for dehydrated post-hibernation tortoises to good effect.25 The ideal fluid for treating renal failure is unresearched in the veterinary literature and treatment has been reported with LRS, 0.18% saline + 4% dextrose, and ½ LRS + 2.5% dextrose among other fluids.6,13,27,31
Monitor for overhydration (e.g., edema, respiratory difficulty) especially at higher rates of administration. A gradual decrease in fluid administration should be initiated as the animal responds to treatment as judged by resumed urine production, improved blood work, and clinical improvement.6 As in small animal medicine, treatment of anuric animals may be attempted.6,31 Intracoelomic dialysis has been described but is less effective than in mammals.6
Allopurinol is used to manage hyperuricemia. Allopurinol is a xanthine inhibitor that decreases uric acid production by stopping the full breakdown of purine. It appeared to be effective in reducing hyperuricemia and gout deposition in tortoises when dosed at 50mg/kg every 72 hours.19 A dose of 20mg/kg daily for 3 months was used for post-hibernation hyperuricemia.25 A dose of 20mg/kg daily was reported to be beneficial in lizards with hyperuricemia secondary to renal failure.6 In green iguanas with experimentally induced hyperuricemia, allopurinol administration reduced blood uric acid levels and histological renal changes compared to non-treated animals.14 A dose of 25mg/kg daily was recommended.14
While phosphate binders may be utilized to help decrease phosphorus levels, diuresis is the primary management tool. Binders must be given with each meal to be effective, and patient acceptance may be problematic. There is concern that aluminum binders may lead to aluminum toxicity. Calcium carbonate acts as a phosphate binder and may be more appropriate for maintenance therapy.
Calcium supplementation may be needed either acutely or more chronically. Animals with twitching may have hypocalcaemia and benefit from IV or IO use of calcium gluconate. Ideally, this would be assessed via iCa levels. Treating animals with mild decreases and no clinical signs of hypocalcaemia may not be needed.6 Some authors monitor the solubility index and don't supplement until phosphorus levels are decreased.6 Oral supplement (such as with calcium glubionate) may be used for maintenance. Ultraviolet lights and sunlight can increase activated vitamin D3 naturally without direct supplementation which will help maintain calcium levels.6
Pain medications may also be useful, particularly if gout is present. Use of analgesics and anti-inflammatories is not well described in reptiles generally or in reptiles with renal failure specifically. There is a growing trend in reptile medicine to treat for pain, however, and if clinicians appreciate that pain is present their use may be warranted.
Dietary support is important in managing animals in the initial phases of treatment and appropriate water intake and foods are clearly important for long term care. Dehydration should be corrected prior to loading the gastrointestinal tract.25 Syringe feeding, orogastric tube feeding and pharyngostomy or esophagostomy tubes may be utilized in anorexic animals. There are no well-defined foods or feeding rates for reptiles with renal failure. Based on treatment support in dogs and cats, caloric intake is likely important. It is currently unknown if there are specific alterations that can be made to high quality base diets to optimize support of animals with renal failure. The best option currently available is to place the animal on an appropriate diet as far as it has been defined and provide high levels of hydration. Herbivorous animals should obviously not have insect or animal protein. Carnivorous lizards may benefit by changing to alternate meat sources (whole minced chicken, white fish, Hill's u/d).6 A discussion regarding diets in renal failure reptiles and the role of diet in causing renal failure is available.34
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