Abstract
Five cases of central diabetes insipidus (CDI) in domestic shorthair cats are described. All cats were under 3 years of age at the onset of clinical signs, and outdoor or outdoor/indoor cats, in which a prior trauma was either present or possible. The history included polydipsia and polyuria, and physical examination abnormalities included urinary bladder distention and dehydration. All cats had hyposthenuria with a urine specific gravity between 1.003 and 1.006. The diagnosis was confirmed by an observed inability to concentrate urine during a water deprivation test or compatible serum osmolality, followed by an increase in urine concentration after desmopressin administration. All cats in this report were treated successfully with oral desmopressin. The dose (25–50 μg q8–12h) and the response to therapy were variable. Oral desmopressin administration may serve as an effective alternative route for cat owners who find the conjunctival or nasal application of the solution an inconvenient mode of therapy.
Central diabetes insipidus (CDI) has been described in 10 single case reports in cats (Green and Farrow 1974, Rogers et al 1977, Burnie and Dunn 1982, Court and Watson 1983, Winterbotham and Mason 1983, Mason and Burren 1985, Kraus 1987, Brown et al 1993, Pittari 1996, Smith and Elwood 2004). CDI can be partial or complete, and both forms have been described in cats (Burnie and Dunn 1982, Pittari 1996, Feldman and Nelson 2004). Complete CDI results from complete absence of Arginine-Vasopressin (AVP), while in partial CDI some AVP is present.
Well-known aetiologies of CDI in cats include trauma, neoplasia and hypothalamic/pituitary malformations. Most cases of CDI are idiopathic, and may appear at any age, breed or gender (Feldman and Nelson 2004, Smith and Elwood 2004). An age range of 8 weeks to 6 years (mean 1.5 years) was reported in 11 cats with CDI, seven of which were domestic short- or longhair cats (Feldman and Nelson 2004). The history of cats with congenital, idiopathic or trauma-induced CDI typically includes polyuria/polydipsia (PU/PD), urinary incontinence, increased frequency of replacing cat-litter by the owners, consumption of other liquids, appetite loss and weight loss. Physical examination findings are usually unremarkable (Feldman and Nelson 2004).
In order to diagnose CDI, all other potential causes for PU/PD should be ruled out. The diagnosis of CDI is based on the inability to concentrate urine in response to a modified water deprivation test (MWDT), followed by a marked increase in urine specific gravity (USG) or urine osmolality with a consequent dramatic drop in the daily water consumption in response to desmopressin or to AVP administration (Court and Watson 1983, Brown et al 1993, Feldman and Nelson 2004). Plasma osmolality (Posm) measurements may aid in the differentiation between primary polydipsia (PP) and DI. The diagnosis of PP is likely when Posm is <280 mOsm/l. Alternatively, plasma AVP concentrations may be measured in response to osmotic stimulation by hypertonic saline infusion (Rijnberk 2000, Feldman and Nelson 2004).
The current drug of choice in complete CDI is desmopressin (DDAVP), a synthetic analogue of AVP, which has a longer half-life, higher antidiuretic potency and lower pressor activity than AVP (Nichols 2000, Feldman and Nelson 2004). Desmopressin is available as an injectable, intranasal spray and oral tablet forms. Cats with CDI were reported to be treated with the nasal spray or solution, applied either to the conjunctival sac or intranasally (1.5–16 μg q12–24h), or with the subcutaneous injection (0.5–2 μg q12–24h) (Mason and Burren 1985, Pittari 1996, Nichols 2000, Feldman and Nelson 2004). The recommended oral desmopressin dose in dogs and cats is 50–100 μg q8–12h (Rijnberk 2000), however, to the best of our knowledge, no reports of oral desmopressin therapy in cats or in dogs have been published.
This paper describes a series of five cats with complete CDI successfully treated with oral desmopressin.
Materials and methods
All five cats in this study were referred to, and initially treated, at the Hebrew University Veterinary Teaching Hospital. Some of the follow-up data were obtained through the referring veterinarians. Basal urine samples were collected by cystocentesis. During the MWDT, samples were obtained by urinary bladder catheterisation. The urinalysis included urine dipstick chemistry (Multistix; Bayer, Germany) and microscopic examination of urine sediment. USG was measured using a standard refractometer. Complete blood counts were performed using an analyser calibrated for feline blood (Abacus, Diatron, Austria). Serum biochemistry analyses were performed using an autoanalyser (at 32°C, Kone Progress Selective Chemistry Analyser, Kone Corporation Instrument Group, Finland). Electrolyte measurements were preformed using the Nova 8 electrolyte analyser (Nova Biomedical, MA, USA). Posm was calculated using the following formula: 2[sodium (mEq/l)+potassium (mEq/l)]+0.05glucose (mg/dl)+0.33blood urea nitrogen (mg/dl). Modified water deprivation tests were preformed as previously described (Feldman and Nelson 2004). Prior to the test, the cats were weighed, blood was sampled for urea and creatinine concentrations, the urinary bladder was catheterised and emptied, and USG was measured. Water and food were withheld, and every 30–60 min the cats were weighed, the urinary bladder was emptied, and USG was determined from that sample. The test was terminated when the cats lost 5% of their body weight. The diagnosis of CDI was based on a negative response to the MWDT, followed by a positive response (ie, a rise of USG to 1.015 and above) to desmopressin injection (Minirin; Ferring, 2 U/cat SC); or by a combination of a normal to high calculated Posm, followed by a positive response to desmopressin injection as above or a therapeutic trial with an oral desmopressin formulation.
Case reports
Table 1 summarises the data from all the five cats, including the history, physical examination, haematological, biochemical and ultrasonographic findings, daily water consumption, and USG at the time of presentation after desmopressin injection and in response to oral desmopressin therapy, as well as the final oral desmopressin dose. Table 1 also includes the diagnostic procedures for CDI, and the response to therapy (ie, daily water consumption and USG). Additional data regarding individual cases are provided in the following sections.
Summary of the history, physical examination, clinicopathological and ultrasonographical findings, method of diagnosis, desmopressin dose and response to therapy in five cats with CDI
PU/PD=polyuria/polydipsia; USG=urine specific gravity; RSO=random serum osmolality; UBD=urinary bladder distention; CDI=central diabetes insipidus; DDAVP=desmopressin; MWDT=modified water deprivation test.
Reference range − 308–335 mOsm/kg.
Case 1
Case 1 was a 3-year-old female spayed domestic shorthair (DSH). At the time of presentation all haematological and serum biochemical parameters were within the reference ranges with the exception of a mild azotaemia (creatinine 209.5 μmol/l (2.4 mg/dl), reference interval (RI) 44.2–132.6 μmol/l (0.5–1.5 mg/dl); blood urea nitrogen (BUN) 10.67 mmol/l (29.9 mg/dl), RI 3.33–10.1 μmol/l (9.3–28.2 mg/dl)). These abnormalities were interpreted as prerenal azotaemia secondary to dehydration. Abdominal ultrasonography revealed urinary bladder distention and mild bilateral hydronephrosis, with no other abnormalities in the kidneys and urinary tract. The cat was initially treated with desmopressin nasal solution (Minirin solution; Ferring AB, Sweden) applied into the conjunctival sac, 1 drop (1.5–4 μg, Nichols 2000) to each eye q12h, but owner compliance was poor due to difficulties in medicating the cat. During a 3-week treatment period, the USG did not change, and PU/PD persisted. Oral desmopressin therapy was initiated (Minirin; Ferring, 12.5 μg q12h), and the USG measured on several occasions during a following 7-month period was 1.010–1.015. As the cat still had marked PD (daily water consumption 100–200 ml/kg/d), desmopressin dosage was increased (25 μg PO q12h). On several occasions over the following 8-month period, the USG measured between 1.015 and 1.018, and although the cat still had some PD (daily water consumption of 90–100 ml/kg/d), the owners found the situation acceptable. Financial considerations made the owners decline further increase of the desmopressin dose. The cat was followed for 3 years with no other complications except for mild to moderate PU/PD.
Case 2
Case 2 was a 2-year-old male castrated DSH. It disappeared for 14 days prior to the initial manifestation of PU/PD. When he returned, left hindlimb lameness was noticed, and was found to be due to a femoral fracture, and the cat had marked PU/PD. The fracture was surgically repaired, and the cat was discharged. Signs of PU/PD persisted for 7 days and transitionally subsided. However, 10–14 days later the PU/PD recurred and persisted for an additional 7 months, at which time the cat was presented again and the diagnosis of CDI was made. Urine culture at this time was negative. The MWDT was performed for 3 h, and USG was 1.004, 1.006, 1.004 and 1.004 at times 0, 30, 60 and 180 min, respectively. The cat received desmopressin (2 μg SC) and USG was 1.010, 1.016 and 1.020 at times 2, 4 and 9 h after injection, respectively. This cat was followed for 3 months, and the owners reported adequate control of PU/PD. The USG could not be obtained.
Case 3
This 7-month-old, female spayed DSH presented after recovery from blunt trauma, probably a result of being hit by a car 2 months before presentation. The MWDT was completed in 4 h, and USG was 1.006, 1.006, 1.006, 1.008 and 1.007 at times 0, 60, 120, 180 and 240 min, respectively. The cat received desmopressin (2 μg SC) and USG was 1.012 and 1.018 after 2 and 3 h, respectively. The MWDT was repeated 7 days later to comply with the owner's request, with similar results. Desmopressin was injected again (2 μg IM), and USG was 1.030 at 4 h post-injection. This cat was followed for 18 months after the diagnosis of CDI. The owners reported adequate control of PU/PD. USG was 1.018 on several occasions during that period, and the daily water consumption has been 30–65 ml/kg/d. Due to financial considerations, the owners tried to reduce the dose of desmopressin from 50 μg q12h to 25 μg q12h for 2 days. However, PU/PD recurred, and the dose was readjusted to the prior dose.
Case 4
This 13-month-old, male DSH was initially treated with oral desmopressin (25 μg PO q12h for 5 days). Water consumption varied between 55 and 330 ml/kg/d and USG was 1.010–1.014. This response was unacceptable, and desmopressin dose was increased to 50 μg q12h. The USG was 1.015 then, and water consumption was 202 ml/kg/d. Increased water consumption was most severe 8–12 h after medication; therefore, the dosing interval was decreased. During the next 3 days, desmopressin was administered at 25 μg q8h, USG was 1.014–1.022, and water consumption was 130–255 ml/kg/d. As water consumption was considered still high, desmopressin dose was further increased to 50 μg q8h for 3 days. This led the water consumption to drop to 92–147 ml/kg/d, with a USG of 1.010–1.032. Modification of the desmopressin regimen to 75 μg q12h led to a drop in USG (1.006–1.020) and an increase in water consumption (105–242 ml/kg/d). The cat was discharged with desmopressin at 50 μg q8h, and was followed for 3 months and the owners reported an adequate control of PU/PD.
Case 5
This was a 12-month-old male DSH. Oral desmopressin (50 μg q8h for 3 days) led to a marked decrease in water consumption (34–135 ml/kg/d) and an increase in urine concentration (USG 1.026–1.031). An increase in the desmopressin dosing interval (50 μg q12h) led to an increase in water consumption (92–150 ml/kg/d) and to some loss in urine concentration (USG 1.008–1.013). The cat was discharged with desmopressin administered at a dose of 50 μg q8h, was followed for 2 months. The owners reported an adequate control of PU/PD.
Discussion
There are certain similarities between the cats in the present study. All were either outdoor or indoor/outdoor DSHs, and in all cases the onset of PU/PD occurred at a relatively young age (at 28, 17, 7, 13 and 2 months of age for cases 1–5, respectively). A wide age range for feline CDI has been previously reported. However, the condition has also been diagnosed in very young cats (Winterbotham and Mason 1983, Feldman and Nelson 2004, Smith and Elwood 2004).
The history of two cats (cases 2 and 3) included trauma before the appearance of PU/PD. Thus, it is reasonable to assume that the aetiology of CDI was traumatic. In the other three cats, the history could not exclude trauma, as all three were outdoor or outdoor/indoor cats. CDI has been previously associated with prior head trauma in cats that presented neurological abnormalities and/or hypernatraemia (Smith and Elwood 2004, Temo et al 2004a, 2004b). The diagnosis of a lesion, traumatic or neoplastic, in the hypothalamus/neurohypophysis requires advanced diagnostic brain imaging techniques (computerised tomography and/or magnetic resonance imaging). Due to financial constraints and the low probability of neoplasia in these young cats, this procedure was not performed. The fact that all three cats were young, and remained neurologically normal over periods of 2–36 months makes the possibility of brain neoplasia unlikely. Therefore, these cases should probably be classified as idiopathic CDI. All cats were brought for examination due to signs of PD, and in most, the owners also noticed PU. All cats were normal upon physical examination, with the exceptions of a moderately to markedly distended urinary bladder and mild dehydration in four of the five cats.
In case 2, the owners had reported signs of PU/PD for 7 days immediately following trauma, which subsided, but recurred 10–14 days later, and persisted from then on. This pattern might have been consistent with the triphasic response observed after surgical trauma to the hypothalamus/neurohypophysis (Feldman and Nelson 2004). Immediately after surgical trauma to the feline hypothalamus sufficient to cause DI, signs of PU/PD begin, and last 4–5 days, followed by a 6-day period of antidiuresis, which later on is followed by permanent CDI. The first phase is thought to result from the acute damage to the hypothalamus and consequential disruption in the ability to release AVP, while the second phase is believed to follow degeneration of hormone-laden axons and release of excessive AVP, leading to antidiuresis and disappearance of PU/PD (Feldman and Nelson 2004). A cat with head trauma has been recently reported to initially present with hypernatraemia and dehydration, and later on presented PU/PD and was subsequently diagnosed with CDI (Smith and Elwood 2004).
Urinalysis performed at presentation revealed USG of 1.003–1.006 in all cats, with no other abnormalities. There were no haematological abnormalities at the time of presentation. These results are consistent with previous findings in dogs and cats with CDI (Harb et al 1996, Feldman and Nelson 2004). Serum biochemistry abnormalities were observed in only one cat. In this cat (case 1), azotaemia was present, and was presumed to be prerenal and secondary to dehydration. The presence of renal disease and other causes of PU/PD cannot be ruled out in this cat. However, as it did not show any clinical or clinicopathological sign compatible with primary renal disease, and because it survived for 3 years after presentation with no deterioration of renal function, the diagnosis of concurrent renal failure seems to be highly unlikely. Other causes of PU/PD in case 1 were ruled out based on the signalment, history, clinical and clinicopathological signs.
Ultrasound examination in one cat (case 1) revealed mild bilateral hydronephrosis. This might have been a result of high pressure in the ureters and renal pelvis because of the persistently distended urinary bladder. Hydronephrosis was previously described in human patients with DI (Uribarri and Kaskas 1993, Ichiyanagi et al 1995). To the best of our knowledge, it has not been described in feline DI. As other ultrasonographic renal abnormalities were not observed in this case, and primary renal disease was considered unlikely (as discussed above), we believe that the hydronephrosis was caused by chronic urinary bladder distention due to DI.
The confirmation of CDI in three cats (cases 2, 3 and 5) was accomplished using an MWDT with subsequent failure to concentrate urine, followed by desmopressin injections that led to a rise in urine concentrating ability, and a decrease in daily water consumption, as has been previously reported (Burnie and Dunn 1982, Court and Watson 1983, Kraus 1987, Brown et al 1993, Harb et al 1996, Pittari 1996, Feldman and Nelson 2004, Smith and Elwood 2004). The complete inability to increase urine concentration during an MWDT ruled out the presence of PP and partial CDI. In the other two cats (cases 1 and 4), an MWDT was not performed due to owners' objections. However, in both cats the diagnosis of PP was rendered unlikely based on the normal to increased Posm, and the positive response to desmopressin administration, as judged by an improvement in USG and daily water consumption. This method was previously described as a simpler diagnostic alternative to the water deprivation test (Kraus 1987, Nichols 2000, Feldman and Nelson 2004). Furthermore, PP has never been reported in cats up to date (Feldman and Nelson 2004). In cases 2–5, an increase in USG was observed after SC desmopressin administration, although it did not reach the 1.025–1.035 range, and there was a subsequent increase in USG (1.032 and 1.028 in cases 4 and 5, respectively) following a longer oral desmopressin treatment period.
Since the discontinuation of pituitary extracts production, most cats with complete CDI are treated with desmopressin. The most common route of administration is topical, via the conjunctival sac using the nasal spray or solution applied once or twice daily. This has been applied mostly in dogs, but also in cats (Mason and Burren 1985, Kraus 1987, Pittari 1996, Feldman and Nelson 2004). Alternatively, the drug can be introduced parenterally (SC), either as commercial sterile injectable solution, or as nasal spray or solution, passed through a bacteriostatic filter, which is a much more cost-effective preparation compared to the commercial injectable preparation, and its use was not associated with adverse effects (Nichols 2000). Application of desmopressin into the conjunctival sac may cause local irritation, as the solution is acidic, and may in fact fail in certain cases due to struggling of the cat, as was reported previously (Pittari 1996), and in case 1 of this report. The intranasal route is commonly used in human patients, and was applied in a cat with CDI (Pittari 1996), but has not been recommended for use in dogs and cats by others (Feldman and Nelson 2004).
An oral desmopressin preparation is used in human patients, and a dose for dogs and cats has been recommended (Rijnberk 2000); however, to the best of our knowledge its use has never been reported in cats and dogs with CDI. The tablet form of desmopressin is a more cost-prohibitive alternative compared to the nasal solution. Each 100 μg tablet is comparable to 5 μg (1 large drop) of the nasal spray solution (Nichols 2000). For some cat owners, the use of a tablet form may prove to be a more convenient, or the only possible route of administration, as was the case in all five cats in the present study. All cat owners in the present study preferred the oral route. The current monthly cost of the different desmopressin treatment modalities of cats are 39–81 US$, 21–165 US$, 9–23 US$, and 40–180 US$ for oral (75–150 μg/cat/d PO), commercial sterile injectable (0.5–4 μg/cat/d SC), parenteral nasal solution (2–5 μg/cat/d SC, Nichols 2000) and topical (intranasal or conjunctival) (1–8 drops/cat/d) treatments, respectively. Although oral desmopressin therapy may not always be the most cost-effective choice for treatment of cats with CDI, some owners may find it more convenient compared to daily SC injections or conjunctival instillation. Thus, use of the oral route may lead to better owner compliance in the life-long treatment of this chronic disorder.
Due to individual differences in absorption and metabolism, the dose required to achieve complete control of CDI varies from patient to patient (Nichols 2000). The effects of desmopressin therapy in the two cats that were closely monitored during the initiation of oral therapy (cases 4 and 5) were variable, and both USG and daily water consumption were inconsistent. However, many owners may be satisfied with partial control of PU/PD, due to financial constraints. From our experience with the cats in this study, an oral dose of 25–50 μg (0.25–0.5 tablet) q12h led to an adequate and acceptable, albeit incomplete control of PU/PD. In some cats (case 4), the effect of desmopressin did not last long enough, so in certain cases, the same dose applied q8h may yield better results. In our experience, a dose of 12.5 μg q12h did not achieve an acceptable control of clinical signs.
In conclusion, this paper describes five cases of complete CDI in young DSH cats. Two cats had a history of prior trauma, whereas the other three cats were classified as idiopathic CDI, although prior trauma could not be completely excluded. The chief complaints were PD and PU, and physical examination abnormalities included urinary bladder distention and dehydration. All cats had hyposthenuria with a USG between 1.003 and 1.006. The diagnosis of CDI was confirmed by an observed inability to concentrate urine during a water deprivation test. Further diagnostic support was obtained by an increase in urine concentrating ability following desmopressin administration and ruling out other causes of PU/PD. All cats in this report were successfully treated with oral desmopressin; however, the dose and the response to therapy were variable.