This study was presented as an abstract at the ACVECC Post-Graduate Course Society of Critical Care Medicine San Diego, January 26th, 2002.
Evaluation of adding diltiazem therapy to standard treatment of acute renal failure caused by leptospirosis: 18 dogs (1998–2001)
Article first published online: 10 MAY 2007
Journal of Veterinary Emergency and Critical Care
Volume 17, Issue 2, pages 149–158, June 2007
How to Cite
Mathews, K. A. and Monteith, G. (2007), Evaluation of adding diltiazem therapy to standard treatment of acute renal failure caused by leptospirosis: 18 dogs (1998–2001). Journal of Veterinary Emergency and Critical Care, 17: 149–158. doi: 10.1111/j.1476-4431.2007.00232.x
- Issue published online: 10 MAY 2007
- Article first published online: 10 MAY 2007
- calcium channel blocker;
- Top of page
- Materials and Methods
Objective: To assess efficacy and safety of intravenous (IV) diltiazem as a treatment for acute renal failure (ARF) secondary to leptospirosis in dogs.
Design: Retrospective study
Animals: Eighteen dogs with ARF caused by Leptospira spp treated during the months of September to December (1998–2001).
Procedure: All dogs treated for ARF caused by Leptospira spp were enrolled in the study and were treated with standard care consisting of IV fluids, +/− furosemide, and antibiotics. With owner consent some dogs were treated with diltiazem at 0.1–0.5 mg/kg (0.045–0.22 mg/lb) IV slowly, followed by 1–5 μg/kg/minutes (0.45–2.2 mg/lb/minutes) constant rate infusion. Outcome measures were compared between the 2 groups (diltiazem versus standard). Diltiazem was administered within 60 hours of admission until serum creatinine fell into the normal range or stabilized. The primary outcome measurement of safety was systolic blood pressure (SBP). The primary measurement of efficacy outcome was the rate and magnitude of reduction of serum creatinine
Results: Eleven out of 18 dogs received diltiazem. The rate of reduction in creatinine in the diltiazem group was 1.76 times faster than the standard group (P=0.054). Recovery of renal function showed a trend towards significant association with treatment group (exact P=0.08, odds ratio=3.62). This effect may be clinically relevant. Diltiazem had no clinically relevant effect on SBP.
Conclusions and clinical relevance: Renal recovery in dogs with acute renal failure secondary to leptospirosis is improved with the administration of diltiazem in addition to ‘standard’ therapy.
- Top of page
- Materials and Methods
Acute renal failure (ARF) in dogs has many etiologies.1 In addition to treating the underlying cause, various treatment modalities have been recommended to enhance renal blood flow (RBF) and glomerular filtration rate (GFR). Commonly administered treatments include fluid therapy, mannitol, furosemide or dopamine, or combinations of these. In many instances, these treatments are not successful in reversing renal failure. Where oliguric or anuric renal failure exists, attempts to increase RBF and GFR, without producing fluid overload (ascites, pulmonary and subcutaneous edema), becomes a challenge. Peritoneal or hemodialysis is necessary to manage these patients until such time that RBF and GFR are re-established. This can be costly and does not guarantee return to function. Based on the pathophysiological events occurring in ARF2–4 the calcium channel blocker diltiazem may be suitable as a treatment. In humans, diltiazem has been used to treat or prevent ARF in the transplanted kidney5–8 and to prevent ARF during and following invasive cardiac surgery.9,10 The purported mechanism of action of diltiazem for improved GFR and enhanced urine production is reversal of renal vasoconstriction, by causing predominantly pre-glomerular dilation, and natriuresis independent of GFR,11,12 and effective inhibition of tubuloglomerular feedback induced pre-glomerular vasoconstriction.13 In the laboratory setting, an acute ischemic renal failure model was used to investigate the efficacy of diltiazem administration, 0.3 μg/kg/hr intravenous (IV) for 60 minutes, in improving GFR and RBF in the rat.11 When compared with controls, diltiazem administration significantly improved GFR, and improvement continued for a further 120 minutes beyond cessation of the infusion. In the human clinical setting, diltiazem has been used as a modulator of cyclosporin A (CsA)-induced renal vasoconstriction and renal hypoperfusion,6 and to protect the renal allograft from delayed function at the time of transplant.7 Graft function was more rapid, and the one-year graft survival was higher, in patients receiving diltiazem compared with the control group. The authors concluded that diltiazem may blunt the ischemic response of the transplant procedure, and vasoconstriction associated with CsA administration.7 Endothelin-1 (ET-1) has been proposed as a mediator of CsA induced hypoperfusion.6 Diltiazem administration abolished the effects of ET-1 by re-establishing pre-CsA GFR and RBF, but did not have an effect on the plasma concentration of ET-1, which remained elevated.6 Intrarenal vasoconstriction induced by thromboxane A2 is also reversed with the calcium channel blocker.14 Calcium channel blockers may also have a cytoprotective effect by preserving or improving mitochondrial respiration by preventing cytosolic and mitochondrial calcium accumulation, and inhibiting Ca-dependent and calmodulin-regulated enzymes, thus reducing the generation of reactive oxygen metabolites and other radicals.15,16
The purpose of this study was to establish whether diltiazem may be beneficial in treating dogs with ARF caused by leptospirosis.
Materials and Methods
- Top of page
- Materials and Methods
Only dogs in which leptospirosis was suspected to be the primary cause of ARF were enrolled. All dogs were referred from urban or suburban areas during the months of September, October, and November (1998–2001), when rainfall tends to be high in southern Ontario, Canada. Dogs, confirmed, or suspected of having leptospirosis, and with complete data (fluids received, urine measured, admission and discharge creatinine values) for at least 4 days and either receiving continuous diltiazema therapy, or not receiving diltiazem therapy, in addition to standard therapy, were included. During the months of the study, the attending clinician and owners were asked on a case by case basis for permission to include diltiazem in the ARF protocol (selected by the clinician), which included fluid therapy isotonic crystalloidb, ±furosemidec, ±dopamined and ampicillin. With permission, diltiazem was added to the regimen, preferably within 12 hours of admission, but dogs could be enrolled up to 60 hours when ‘standard’ therapy failed or showed minimal improvement. Diltiazem (0.3–0.5 mg/kg IV administered slowly, followed by 3–5 μg/kg/minutes constant rate infusion [CRI]) as recommended for supraventricular tachycardia17 was used as a guide for a potential dosing regimen. In the early stages of the study, for safety reasons, the proposed protocol was initiated at a lower dose (0.1 mg/kg slow IV push over 30 minutes) while assessing effect on blood pressure. As no clinically relevant reduction in systolic blood pressure (SBP) was noted, the initial dosages of diltiazem for dogs enrolled later in the study were increased to 0.3 mg/kg slow push for larger dogs (≥20 kg [44 lbs]), followed by a CRI of 1 μg/kg/minute, increasing to 2–5 μg/kg/minute; and in smaller dogs, an initial dose of 0.3 mg/kg, increasing to 0.5 mg/kg slow push, followed by a CRI of 3 μg/kg/minute, increasing to 5 μg/kg/minute if required. The objective of using the higher dosage was to potentially hasten renal recovery to normal. Treatment continued until normal creatinine values (150 μmol/L [1.87 mg/dL]) were obtained.
The primary measurement used to assess efficacy of treatment was serum creatinine, which was obtained upon admission, daily or on alternate days until normalized, and finally upon discharge from hospital. All samples were measured on a biochemical analyzer.e The degree of improvement (the difference between the creatinine upon admission and discharge) was calculated for the 2 groups. Efficacy was assessed by (i) the rate (μmol/L/hr) at which the serum creatinine concentration decreased during the initial 144 hours, and (ii) recovery of normal renal function (serum creatinine <150 μmol/L the upper reference interval for our laboratory); these were the 2 main criteria for determining the success of therapy.
Additional information included total urine production for each 12-hour period, and total balanced electrolyte solution (fluids) received for each 12-hour period. Urine production was recorded at 1–4 hours intervals (with longer intervals as the patient improved), and fluids administered were recorded hourly in the medical chart. Assessments were made for up to 144 hours (6 days) as beyond this time the number of dogs in each group was too small to continue with analysis. The volume of fluid administered was included to assess adequacy of this therapy with respect to urine output.
SBP was measured indirectly, using oscillometricf or Dopplerg techniques, as hypotension is a potential adverse effect of diltiazem administration. Clinical safety was assessed by measuring SBP during a 1–2 hour period after initiation of diltiazem, followed by measurements at a minimum of 12-hour intervals after initiation and during the diltiazem CRI, and again upon completion of therapy. For comparison, SBP measurements were also analyzed in a similar manner during a 12-hour treatment period in dogs not receiving diltiazem, and again upon completion of therapy. The frequency of measurement during the 12-hour period depended on the individual animal's condition and potential concerns for hypo- or hypertension.
SAS softwareh was used for the statistical tests and Log Xact-Turbo softwarei to obtain exact P-values for the logistic regression.18 Efficacy of the diltiazem treatment was assessed by the rate of reduction of creatinine up to 144 hours. Pre- and post-creatinine values were log transformed to put change in creatinine on a ratio scale giving a direct estimate of rate and improving the distribution of the data. The logged pre- minus post-differences in creatinine for each animal were analyzed with a paired t test to compare between the groups.
Efficacy was also assessed by the number of dogs that recovered to within normal range of creatinine at 144 hours. Exact conditional logistic regression was used to determine if the outcome variable ‘recovered’, or ‘not recovered’, was dependent on the group controlling for the initial creatinine value.
Comparisons between the 2 groups for urine output at 12 hours after beginning treatment, and at peak excretion time; the volume of fluids administered during the first 12 hours; SBP measurements, and the age of dogs were made using pooled paired or pooled Student t tests. Significance for all tests was set at P<0.05.
- Top of page
- Materials and Methods
Eighteen dogs fulfilled the criteria for study inclusion. Leptospirosis was suspected based on acute history and clinical signs (±polyuria, ±polydipsia) and serum creatinine measurements >150 μmol/L (above upper reference interval for our laboratory). A diagnosis of leptospirosis was based on acute or convalescent serum titres >1:320 in 16 dogs. In one dog the diagnosis was confirmed on renal biopsy. In another dog, the diagnosis was not confirmed but suspected based on an acute titre of 1:80; however this dog was euthanized at day 4 without a convalescent titre obtained. A more in-depth discussion of these cases is presented elsewhere.19
Of the 18 dogs enrolled, 11 received diltiazem treatment within 60 hours of admission, 7 did not (Table 1). There was no significant difference (P=0.55) in age between the 2 groups (mean 6.39 years, range 3.5 months–11 years for the diltiazem group and 5.52 years range 1–10 years in the non-diltiazem group) (Table 1). There were 5 males and 6 females in the diltiazem group and 6 males and 1 female in the non-diltiazem group (Table 1). Various breeds were represented with no breed predilection noted (Table 1).
|3||Shih Tzu||7.3||6 years||FS||Yes|
|4||Alaskan Malamute||61.2||7 years||MC||Yes|
|5||Lhasa Apso||10.9||11 years||MC||Yes|
|7||Siberian Husky||20.4||8 years||MC||Yes|
|8||Yorkshire Terrier||4.1||5 years||FI||Yes|
|9||Border Collie||28||7 years||FI||Yes|
|11||Siberian Husky||29.4||8 years||FS||Yes|
|12||English Cocker Spaniel||17||9 years||MI||No|
|14||German Shepherd||37.0||2 years||MI||No|
|15||Labrador Retriever||39.2||2 years||MC||No|
|16||Mini Schnauzer||11.7||6 years||MC||No|
|17||Labrador Retriever||42.6||1.5 years||MC||No|
|18||Bichon Frise||6.7||8 years||FS||No|
Upon admission the mean±SE serum creatinine values for the diltiazem group was 649±86 μmol/L with a range of 287–1225 μmol/L, and for the non-diltiazem group 544±83 μmol/L with a range of 227–810 μmol/L (Figure 1). There was no significant difference (P=0.42) between the 2 groups upon entry. Individual results are presented in Table 2. Two dogs in the diltiazem group were anuric (dogs 2 and 5). Two dogs in the non-diltiazem group (dogs 5 and 20) and 1 in the diltiazem group (dog 6) had urine production assessed at <1 mL/kg/hr during the first 2–20 hours after fluid administration. The remaining dogs produced a urine volume assessed at >1 mL/kg/hr.
|Dog||Initial creatinine||Final creatinine||Days hospitalized||Diltiazem|
IV fluidsb were administered to all dogs upon admission with adjustments to rate based on urine production primarily (Figure 2) but losses due to vomiting were also considered. One anuric dog in the diltiazem group was edematous with ascites and received only enough fluid to administer the CRI drugs.
Diltiazem was administered to 11 dogs, which was commenced within 6 hours in 8 dogs, at 20 hours in 1 dog, 28 hours in 1 dog, and at 60 hours in 1 dog (Table 3). Dosages and duration of diltiazem therapy differed among the dogs (Table 3).
|Dog||Dose||Time after admission (hours) commenced||Duration|
|1||0.2 mg/kg IV slow push||20|
|3 μg/kg/minute CRI||6 hours|
|5 μg/kg/minute CRI||5.5 days|
|2||0.2 mg/kg IV slow push||2|
|5 μg/kg/minute CRI||7 days|
|3||0.5 mg/kg IV slow push||60|
|5 μg/kg/minute IV CRI||3.5 days|
|4||2 μg/kg/minute CRI||2||2 days|
|5||0.15 mg/kg IV slow push||28|
|2 μg/kg/minute||8 hours|
|5 μg/kg/minute||1.5 days|
|6||0.10 mg/kg IV slow push||4|
|2 μg/kg/minute||5 days|
|1 μg/kg/minute||2 days|
|0.5 μg/kg/minute||1.5 days|
|7||5 μg/kg/minute||4||2 days|
|8||5 μg/kg/minute||6||3 days|
|9||0.3 mg/kg IV slow push||4|
|5 μg/kg/minute||2.5 days|
|10||0.2 mg/kg IV slow push||6|
|2 μg/kg/minute||1.25 days|
|5 μg/kg/minute||1 day|
|2 μg/kg/minute||1 day|
|11||0.3 mg/kg IV slow push||6|
|5 μg/kg/minute||4.5 days|
|3 μg/kg/minute||1 day|
Furosemide was administered continuously in 10/11 dogs in the diltiazem group and 4/7 in the non-diltiazem group. The dosages and duration of administration are listed in Table 4. In dogs receiving diltiazem, furosemide was discontinued when urine production was >2 mL/kg/hr usually 12–48 hours after administration of diltiazem. The one dog that did not receive furosemide beyond admission in the diltiazem group had been anuric for 36 hours before referral, having already received several 2–4 mg/kg boluses of furosemide. The clinicians' decision when, or whether, to administer furosemide was based on their assessment of patient volume status and adequate urine production.
|Dog||Dose (IV)||Treatment after admission (hours) commenced||Duration|
|1||0.25 mg/kg q 8 h||3||2.5 days|
|2||4 mg/kg||1||1 dose|
|3||4 mg/kg||10||1 dose|
|0.5 mg/kg/hr CRI||1 day|
|0.25 mg/kg/hr CRI||2 days|
|4||3 mg/kg||1 dose|
|0.15 mg/kg/hr CRI||2 days|
|5||0.75 mg/kg/hr CRI||24||8 hours|
|1.0 mg/kg/hr CRI||1.5 days|
|6||4 mg/kg q 1 h||2||3 doses|
|then 4 mg/kg q 2 h||3 doses|
|0.15 mg/kg/hr CRI||5.5 days|
|0.08 mg/kg/hr CRI||1 day|
|0.04 mg/kg/hr CRI||12 hours|
|7||0.2 mg/kg/hr CRI||2||2 days|
|8||2 mg/kg bolus||1||1 dose|
|0.3 mg/kg/hr||2.5 days|
|9||0.3 mg/kg/hr||2||2.5 days|
|10||0.05 mg/kg||2||1 dose|
|0.15 mg/kg/hr||8 hours|
|0.5 mg/kg/hr||1 day|
|0.75 mg/kg/hr||3 days|
|0.15 mg/kg/hr||1 day|
|11||4 mg/kg q 1 hr||4||8 doses|
|0.3 mg/kg/hr||3 days|
|0.15 mg/kg/hr||2 days|
|0.25 mg/kg/hr||1 day|
|0.19 mg/kg/hr||0.5 days|
|0.13 mg/kg/hr||0.5 days|
|0.25 mg/kg/hr||2 days|
|13||3.5 mg/kg||4||1 dose|
|1.8 mg/kg q 4 h||1 day|
|14||2 mg/kg IV q 1 h||3||2 doses|
|0.25 mg/kg/hr||1 day|
|0.13 mg/kg/hr||2 days|
|0.09 mg/kg/hr||1.5 days|
|0.06 mg/kg/hr||1 day|
|15||1 mg/kg||16||1 dose|
|0.3 mg/kg/hr||12 hours|
|0.6 mg/kg/hr||1 day|
Dopamine was administered at 2 μg/kg/minute in one dog in each group within 2 hours of admission. A CRI was established for 12 hours in 1 dog in the diltiazem group (dog 2), as this dog's initial SBP was 90 mmHg. The SBP increased to 132 mmHg but decreased to 97 mmHg once the dopamine infusion was discontinued. As it was not known whether diltiazem would lower the SBP further, this dog was monitored every 15 minutes for 2 hours; as no further decrease was noted subsequent monitoring was every 60–120 minutes. The SBP remained unchanged for 12 hours when it normalized. Dopamine was administered for 72 hours in the dog (dog 15) in the non-diltiazem group. The SBP was not measured before the infusion, however, during the infusion the SBP ranged between 154 and 121 mmHg.
Peritoneal dialysis was performed in 1 dog in the diltiazem group (dog 2) for 7 hours beginning 7 hours after admission. The catheter was removed at this point due to technical problems and was not re-established as urine production had increased to 6 mL/kg/hr.
Anuria was identified in 2 dogs in the diltiazem group. Within 4 hours of diltiazem and dopamine administration a consistent 0.5 mL/kg/hr of urine was produced by dog 2, which increased to 6 mL/kg/hr by 14 hours. The second dog (dog 5) received furosemide at 24 hours followed by diltiazem at 28 hours post-admission, as no urine had been produced during this time. Urine volume during the following 4 hours was 8 mL (approximately 1 mL/kg/hr).
Other medications administered to the dogs included antiemetics, gastric protectants and analgesics. Butorphanolj or oxymorphonek was administered to 15 dogs for management of mild to severe abdominal pain (Table 5). Excluding dogs 8, 11, and 14, all dogs received ranitidine (1.0 mg/kg IV q 12 h), ompeprazolel (0.7 mg/kg PO q 24 h) or pantoprazolm (1 mg/kg, max 30 mg IV q 24 h) combined with sucralfate.n (0.5–1 g/dog PO q 8 h) Metoclopromideo (1–2 mg/kg/day as a CRI or divided SQ q 8 h) was administered to 9 dogs (1, 3, 4, 5, 6, 13, 16, 17, 18) due to nausea or vomiting. Ondansatronp (0.5–1.0 mg/kg IV slowly q 12 h) was administred to dog 2 as vomiting was refractory to metoclopromide. Dog 5 received a regular insulinq (0.25 U/kg) plus dextrose (1.5 g/U insulin as a slow push, followed by 2.5% dextrose) infusion due to markedly increased potassium. Dog 6 received partial parenteral nutrition due to prolonged inappetance. All dogs received ampicillinr (20 mg/kg IV q 6 h).
|1||0.2 mg/kg q 4 h||1 day|
|3||0.2 mg/kg q 12 h||1 day|
|0.1 mg/kg||1 dose|
|5||0.2 mg/kg q 4 h||2 days|
|6||0.2 mg/kg q 4 h||2 days|
|8||0.2 mg/kg||1 dose|
|9||0.2 mg/kg q 4–8 h||2 days|
|10||0.2 mg/kg||1 dose|
|11||0.2 mg/kg||2 doses|
|12||0.2 mg/kg||1 day|
|13||0.4 mg/kg q 4 h||3 doses|
|15||0.2 mg/kg||1 dose|
|16||0.2 mg/kg q 4–6 h||2 days|
|17||0.2 mg/kg||1 dose|
|18||0.2 mg/kg q 4–6 h||2 days|
|2||0.025 mg/kg q 6 h||1 day|
|0.013 mg/kg q 4 h||2 days|
|0.013 mg/kg q 24 h||2 days|
|11||0.025 mg/kg q 8 h||1 day|
|13||0.05 mg/kg q 12 h||2 days|
|14||0.05 mg/kg||1 dose|
The final serum creatinine value (mean±SE) for the diltiazem group was 166±38.3 μmol/L with a range of 54–537 μmol/L (Figure 1), and for the non-diltiazem group 275±88 μmol/L with a range of 82–727 μmol/L (Figure 1). Recovery of renal function (final serum creatinine measurement <150 μmol/L) occurred in 8/11 dogs in the diltiazem group compared with 2/7 in the non-diltiazem group. Efficacy was assessed by the number of animals recovering to within normal range for creatinine at 144 hours. Exact conditional logistic regression was used to determine if the outcome variable, recovered or not recovered, was dependent on group controlling for the initial creatinine value. Recovery of renal function showed a trend towards significant association with treatment group (exact P=0.08, odds ratio=3.62). Two of the 3 diltiazem failures (creatinine >150 μmol/L, and one non-diltiazem failure, were discharged with a creatinine of 166, 166 and 167 μmol/L, respectively. Worthy of note is the final creatinine of the 2 dogs in anuric renal failure; 54 μmol/L (from 435 μmol/L) for dog 2, where diltiazem was commenced within 6 hours, and 126 μmol/L (from 717 μmol/L) in dog 5, commenced at 20 hours. Efficacy was also assessed by the rate of reduction of creatinine. The mean log difference between the groups was 0.561 (95% CI, 0.008–1.129). The inverse log of this value is 1.76, indicating the rate of recovery being 1.76 times faster in the diltiazem group P=0.054.
Urine production during the first 12 hours of hospitalization was similar (P=0.58) in both groups; 1.92±0.52 mL/kg/hr for dogs receiving diltiazem and 1.46±0.65 mL/kg/hr for dogs not receiving diltiazem. Urine production increased in both groups during the first 24 hours with a mean peak production of 11.75±2.39 mL/kg/hr at 84 hours in the diltiazem group, and of 3.98±2.56 mL/kg/hr at 72 hours in the non-diltiazem group; the difference approached significance (P=0.06) (Figure 3). The IV fluid volume administered to dogs in both groups was similar (P=0.67) during the first 12 hours; 3.71±0.60 mL/kg/hr for dogs not receiving diltiazem, and 4.04±0.45 mL/kg/hr for dogs receiving diltiazem. Fluid administration was increased in dogs in both groups following this time period and determined predominantly by urine production (Figure 2).
Two of the dogs in the non-diltiazem group were in declining health after 4 days, which was discouraging to the clinicians and owners and resulted in euthanasia. No adverse effects were encountered with the use of diltiazem. All dogs in this group were discharged from the hospital.
In dogs receiving diltiazem, there was no significant difference (P=0.91) in SBP from baseline (152.8±4.4 mmHg) to that measured after the slow-push administration of the loading dose of diltiazem (151.7±9.4 mmHg) in 6/11 dogs where this information was recorded. When assessing the effects on SBP after a 12-hour infusion of diltiazem, the mean±SE drop in systolic blood pressure (subtracting the pretreatment SBP from that obtained at the end of the 12-hour infusion for each dog) was 15.1±6.8 mmHg which approached significance (P=0.058). A drop of 6.2±16.3 mmHg (P=0.72) was noted for a similar 12-hour period in the dogs with non-diltiazem treatment. The difference between the 2 groups was not significant (P=0.56). There was no significant difference (P=0.68) in the mean±SE 12-hour SBP measurements (diltiazem, 136.7±9.2 mmHg and non-diltiazem, 143.4±16.1 mmHg) between the groups, or between the SBP measurements before discharge from the hospital (diltiazem, 151.9±9.6 mmHg and non-diltiazem, 141.8±14.4 mmHg, P=0.56) or at admission (diltiazem, 148.4 ±6.4 mmHg and non-diltiazem, 149.6±10.2 mmHg, P=0.91).
- Top of page
- Materials and Methods
One limitation of this study is that it was not randomized or blinded. The sample size was also small, which may have contributed to several of the nonsignificant statistical findings in this study. Severity of disease was not a deciding factor as can be seen by the admission values of creatinine. While there was no statistically significant difference in admission creatinine values or age, the clinically worst and older (9/11 in the diltiazem group versus 4/7 in the non-diltiazem group were ≥5 years of age and 1/11 in the diltiazem group versus 3/7 in the non-diltiazem group were <2 years of age) cases were entered into the diltiazem treatment arm of the study (Tables 1 and 2). The dogs in this study experienced significant renal injury based on the history, degree of illness and azotemia, and confirmed leptospirosis.
Infection with Leptospira spp produces a generalized inflammatory state during the period of tissue invasion. Leptospiremia produces direct injury to the endothelium and capillaries causing vascular damage, thrombocytopenia and hemorrhage. The extent of damage to internal organs is variable depending on the virulence of the organism and host susceptibility; however renal colonization occurs in most infected animals because the organism replicates and persists in renal tubular epithelial cells.20 These lesions are potent stimulators of ET-1 and thromboxane A2 production, both potent vasoconstrictors14,21 with the vasoconstrictive peptide ET-1 being the most potent vasoconstrictor currently known, and the kidney being the most sensitive organ to ET-1.22 Vasoconstriction of the afferent renal arteriole results in a reduced renal blood flow and GFR.23,14 In addition, focal, mild to severe, interstitial nephritis due to the presence of the spirochete, and the inflammatory response, produces moderate to severe renal tubular injury.20,4 Intracellular calcium accumulation, and cell death follows such injuries resulting in sloughing of cells and tubular debris into the tubular lumen.23,4 Eventually obstruction of tubular flow, increased intratubular pressure and back-leak of glomerular filtrate into the interstitium occurs. Physical congestion of medullary capillaries by red blood cells, platelets and leukocytes also occur in ARF.3 It is expected that all these lesions would be present in dogs with inflammation-induced ARF. This injury also stimulates release of cytokines, leukocytes and adhesion molecules, as well as expression of their ligands on endothelial cells.3 These events result in further release of vasoconstrictors and direct endothelial cell injury. A vicious cycle ensues where ET-1 production is able to perpetuate its own production, even after the initiating injury has resolved.24 Diltiazem's effect as an ET-1 and thromboxane A2 antagonist may be one of the most useful effects in treating the dogs with ARF in our study. Endothelin measurements in dogs with various illnesses, including chronic renal failure, have been reported and ET-1 was the predominant endothelin in sick dogs when compared with controls, regardless of the pathophysiological condition.25
A direct action of calcium channel blockers is blockade of slow calcium channels and reduction of intracellular calcium content.11 This results in afferent arteriolar dilation within the kidney with improved blood flow into the glomerulus.26 Interestingly, these effects are much less pronounced in the efferent arteriole; preservation of efferent arteriolar tone26 also contributes to improved GFR.11 Another proposed mechanism for diltiazem's improved GFR is an increase in glomerular ultrafiltration coefficient (Kf) due to inhibition of mesangial cell contractility.11 With acute administration, calcium channel blockers generally produce a parallel rise in RBF and GFR.27
The cytoprotective effects of the calcium channel blockers offer another theoretical benefit in the treatment ARF. In ARF renal tubular cell injury may be sublethal or lethal. Sublethal injury results in cellular dysfunction due to loss of polarity, loss of tight junction gate function and loss of cell-substrate adhesion.3 These cells may be described as ‘stunned’. Diltiazem may be beneficial in the ‘healing’ process of these cells. As cell necrosis is preceded by reduced activity of membrane transport pumps and an increase in intracellular free calcium, the calcium-channel blocking effects of diltiazem may prevent the influx of calcium and subsequent cell death. The so-called cytoprotective effect of these drugs15,16 may also have contributed to renal recovery of dogs in the diltiazem group.
The amount of urine produced in dogs receiving diltiazem was extremely high and started within the first 24 hours of the diltiazem infusion. The high rate of urine production continued beyond normalization of the creatinine requiring a longer period of IV fluids, and therefore hospitalization, than the control group. The diuretic activity of calcium channel blockers may be associated with redistribution of renal blood flow from juxtamedullary nephrons to cortical nephrons28–30; an effective inhibition of the tubuloglomerular feedback mechanism with improved afferent blood flow; and a reduction in cytosolic calcium in tubular epithelial cells.28–30 However, it may also be associated with the natriuresis produced by calcium-channel blockers due to reduced reabsorption of sodium.5 This cannot be confirmed in our study as urine sodium concentration and the fractional excretion of sodium was not measured. The natriuresis may preserve cellular integrity by decreasing active transport (metabolic work) and therefore, energy requirements in the tubular epithelial cells. This reduction in metabolic ‘work’ in the ‘stunned’ tubular epithelial cells would potentially allow for a reparative period. Furosemide would also have contributed to this diuresis by a similar mechanism,23 however, furosemide was discontinued as urine production increased in most dogs. Four of the dogs in the non-diltiazem group received furosemide but urine production was not as voluminous as with the dogs receiving diltiazem. The volume of urine produced and fluids administered was assessed to rule out deficiencies in maintaining intravascular volume in either group, which may have biased the results. Initially, dogs in both groups received a similar hourly volume of fluid. However, as urine production increased, the replacement fluid volume was also increased to meet that lost in the urine in both groups. This study emphasizes the importance of continual monitoring of urine production. Dogs in the diltiazem group would have developed a prerenal component to the existing renal azotemia had we empirically selected a volume for infusion rather than increase the hourly fluid rate to meet the rate of urine produced. A similar approach is required when urine production is negligible, such as that occurring in dog 2 before presentation, as continual empirical fluid administration results in edema and ascites.
While the rate of reduction of serum creatinine in this study was faster in dogs receiving diltiazem than those not, a clinically relevant drop was not observed for approximately 48–72 hours; however beyond this time, a dramatic decrease was noted. The delay in reduction in serum creatinine, or GFR, even with brisk urine flow, noted in our study, may be as a result of reduced glomerular permeability due to endothelial cell swelling, an increase in intratubular hydrostatic pressure due to inflammation and edema of the interstititum, and obstruction within renal tubules by obstructing casts and cellular debris.31 Brisk and voluminous urine flow would ‘flush’ out the debris and casts within the tubules, potentially enhancing recovery of GFR. It is apparent that a reparative process must take place after renal perfusion is established before function is improved. In addition to the direct effects of infection and inflammation on renal tissue, one must consider that potential injury due to reperfusion also occurs, which would require time for repair.
The inciting cause of renal failure in the current study (Leptospira spp) would be expected to resolve with appropriate antibiotic treatment and rehydration; however, the rate of creatinine decline was more rapid, with more dogs achieving renal recovery in the diltiazem group suggesting that in the non-diltiazem group, the residual pathological effects continue for several days. Potentially, the purported beneficial effects of diltiazem may have improved renal perfusion in dogs in our study.
A major concern with administration of calcium channel blockers is the potential for hypotension. In the experience of the author (K.M.), and others,32 ARF tends to be accompanied by hypertension, therefore, a reduction in systemic blood pressure may be advantageous; however the degree of reduction may be excessive and vigilance is warranted. Not all calcium channel blockers produce the same degree of cardiovascular effects,10 with some differences existing among those available for potential use in ARF. Diltiazem is reported to have minimal effects on cardiac conduction and contraction as well as on systemic vascular resistance.10 In our study we found no significant difference in SBP following initial slow push or with prolonged infusion when compared with the non-diltiazem group. Our dose of diltiazem in larger dogs is similar to that reported in humans.10 As diltiazem has not been used to treat ARF in the setting proposed in our study, the diltiazem regimen selected was empirical using a protocol we currently use for treatment of supraventricular cardiac arrhythmias in dogs17 as a guideline. Initially, a titration approach was used due to concern for hypotension. Continual electrocardiogram monitoring or hourly blood pressure and heart rate assessment is advised and the dose reduced or discontinued should these parameters drop below normal. The doses of diltiazem used in our study were similar to those used in humans for renoprotection. Diltiazem was administered to human patients at 0.28 mg/kg bolus followed by a 2 μg/kg/minute CRI for 2 days after renal transplant.7 Another study assessing the potential protective effects of diltiazem also used a 0.28 mg/kg bolus followed by CRI of 1 μg/kg/minute before undergoing cardiac surgery, a reduction in systemic blood pressure was not detected and heart rate was minimally reduced.10 In another study of humans undergoing cardiac bypass surgery, a bolus dose of diltiazem was not administered but a CRI of 1 or 2 μg/kg/minute was established; an improved GFR and urine production with the higher diltiazem dose was noted, and the SBP was also higher in this group when compared with the lower dose group.9 However, when diltiazem was discontinued in the postoperative period, a decrease in mean arterial pressure was noted, but was of no clinical significance.9 The results of our study concur with those in humans and indicate that a clinically significant drop in SBP does not occur with diltiazem administration, at least in this study where SBP is higher than normal.
Furosemide was administered to most patients in this study as it is a recommended therapy in ARF. Furosemide is a loop diuretic and a vasodilator initially.31 In some patients with ARF furosemide may convert oliguric ARF to non-oliguric ARF; however, this has been shown not to alter the natural progression of ARF in humans.33,34 The benefits of conversion to non-oliguric renal failure are: easier management with fluid therapy, less risk of edema, ability to administer parenteral nutrition, and potentially better prognosis.2 Ototoxicity can occur with high dosages of furosemide in humans and may occur in dogs. Therefore, if there is no response to a trial of furosemide, then continued administration is not advised. Furosemide's action is predominantly within the renal tubules, and its efficacy is reduced if there is a substantial decline or absence of RBF or GFR as may occur in marked oliguric or anuric states. The administration of furosemide in this study was predominantly as a CRI, with occasional bolus therapy. Furosemide by constant infusion has been shown to produce a greater increase in urinary volume, 24-hour urinary sodium, potassium and chloride excretion compared with bolus injection in human patients with heart failure.35 More recently, a study in healthy dogs concluded that continuous furosemide infusion resulted in a greater diuresis, natriuresis and calciuresis, and less kaliuresis than intermittent bolus treatment.36
It is not known what influence the use of furosemide combined with diltiazem may have on the outcome of dogs in our study. It has been our experience, and is also reported in human patients, that furosemide alone is not consistent in improving renal function. Due to the small number of dogs in our study, further studies designed to look at combination drug therapy, and each drug alone, enrolling a large number of dogs with a single etiology ARF in a prospective, blinded, randomized manner would be required to answer this question.
A potential benefit of dopamine administration may be observed with an increase in blood pressure associated with improved cardiac output. Dopamine has been recommended as a treatment for ARF; however, this drug's potential benefits have been debated for years with earlier studies indicating that routine use should be discouraged.37 Investigations of dopamine's use as a standard treatment in ARF in human patients have shown no benefit.
The list of etiologies resulting in ARF in dogs is extensive.1 Assessing efficacy of a new therapy may be difficult to interpret if a heterogeneous population of dogs is included, as the treatment of the underlying disease may or may not be possible and would influence outcome. The opportunity for study with a homogenous population, such as the dogs with leptospirosis in this study, reduced the confounding influence of etiology with respect to treatment and recovery. The results of this study are encouraging and suggest that diltiazem, with or without administration of furosemide, is beneficial in recovery of renal function in dogs with leptospirosis. As ARF secondary to Leptospirosa spp in dogs may be associated with significant mortality and morbidity requiring prolonged and expensive treatment, a simple therapeutic modality that can improve outcome is of important clinical value. Acknowledging the limitations of this small, unblinded, retrospective study wherein individual clinicians primarily influenced the course of therapy initially, the results of this study are encouraging and justify a larger scale trial to determine if diltiazem, with or without administration of furosemide, is beneficial in recovery of renal function in dogs with leptospirosis.
Note added in proof: Caution is especially advised when administering diltiazem to Miniature Schnauzers as a marked reduction in heart rate occurred during initial administration in one dog since final reporting of this study.
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- Materials and Methods
The authors are very grateful to Dr. Judy Brown for retrieving and tabulating patient data from the medical records.
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- Materials and Methods
aCardizem injectable, Biovail Pharmaceuticals, Mississauga, ON, Canada.
bPlasma-lyte A, Baxter Corporation, Mississauga, ON, Canada.
cLasix, Aventis Pharma, Laval, QC, Canada.
dIntropin, Dupont Pharma, Mississauga, ON, Canada.
eHitachi 911, Roche Diagnostics, Laval, QC, Canada.
fDinamap™, Benson Medical, Markham, ON, Canada.
gDoppler, Ultrasonic Doppler Model 811-BTS, Parks Medical Electronics Inc., Aloha, OR.
hSAS OnlineDoc 9.1.3. SAS Institute Inc., Cary, NC.
iLogXact 5, Cytel Software Corporation, Cambridge, MA.
jTorbugesic, Wyeth Ayerst, Guelph, ON, Canada.
kNumorphan, Dupont Pharma, Mississauga, ON, Canada.
lLosec, AstraZeneca Canada Inc., Mississauga, ON, Canada.
mPanto IV, Byk Canada Inc., Oakville, ON, Canada.
nZofran, GlaxoSmithKline, Mississauga, ON, Canada.
oSulcrate Suspension Plus, Axcan Pharma Inc., Mont-Saint-Hilaire, QC, Canada.
pApo-Metoclop, Apotex, Weston, ON, Canada.
qHumulin R, Eli Lilly Canada Inc., Toronto, ON, Canada.
rApo-Amp, Apotex, Weston, ON, Canada.
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- Materials and Methods
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