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Chronic Renal Failure Therapies Lori A. Wise, DVM, MS, DACVIM
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Chronic kidney disease (formerly known as chronic renal failure) Definition of CKD: Presence of structural or functional abnormalities of one or both kidneys for 3 months or longer
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Evidence based approach to treatment of CKD in dogs and cats Associated problems: • Hyporexia • Systemic arterial hypertension • Proteinuria • Anemia
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CKD therapy • Diet • Fluids • Calcitriol • Phosphate binders, Epakitan ® • ACEi • Antihypertensives • Appetite stimulants • Darbepoetin • Azodyl ® •
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Other therapies not discussed today • Acid blockers • Potassium supplementation • Omega 3 PUFA • Antioxidants • Assisted feeding • Hemodialysis/CRRT • Renal transplantation • Stem cell therapy •
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Evidence based medicine
Evidence-based medicine is the conscientious, explicit and judicious use of current best evidence in making decisions about the care of individual patients. The practice of evidence-based medicine means integrating individual clinical expertise with the best available external clinical evidence from systematic research. • 9
Grades of Evidence Grade I - one or more properly designed, randomized, controlled clinical studies performed in clinical patients of the target species. Grade II - properly designed randomized controlled studies using animals of target species with spontaneous disease in lab or research animal colony setting.
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Grade III- controlled non-randomized studies, cohort or case-control studies, studies using acceptable models of disease; dramatic results from uncontrolled studies or case series. Grade IV - studies conducted in other species, descriptive studies, case reports, pathophysiological justification, expert consensus or opinions of experts based on their clinical experience. 10
Rating evidence A Meta-analysis of randomized controlled trials A- At least one randomized controlled trial B Well-designed controlled study without randomization B- Other type of well-designed study C Non-experimental study, e.g., comparative, correlational, or case C- Opinion of experienced expert D Unbiased testimonial F Manufacturer-provided testimonials, 'back-of-the-magazine' ads
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IRIS staging Dog Modified 2013 • Creatinine 5 Stage 4 • UPC 0.2- 0.5 borderline >0.5 proteinuric • Systolic BP >150 mmHg abnormal www.iris-kidney.com
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IRIS staging Cat Modified 2013 • Creatinine < 1.6 mg/dl normal • 1.6-2.8 Stage 2 • 2.9-5 Stage 3 • >5 Stage 4 • UPC 0.2-0.4 borderline >0.4 proteinuric • Systolic BP >150 mmHg abnormal
studies
and TV infomercials
www.iris-kidney.com • 13
General management • Discontinue nephrotoxic drugs • Treat pre- and post-renal abnormalities • Rule out treatable conditions- urolithiasis, infection • Treat extrarenal disease-hyperthyroidism, hyperadrenocorticism, etc
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Dietary management
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Renal diets • Limited dietary phosphorus • Restricted sodium content • Increased potassium (feline) • Restricted protein • N-3 PUFA supplementation
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Alkalinizing Calcium, sodium, vit B & C
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Renal diets-dogs • Randomized controlled clinical trials with spontaneous CKD • Creatinine > 2 mg/dl (stages 3 & 4) • Jacob, et al JAVMA 2002, Polzin, et al 2005, Ross et al 2006 • Reduced uremic crises by 72% • Reduced death by 69% • Median survival 594 days compared to 188 days on maintenance diet
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Renal diets- cats • Clinical evaluation of dietary modification for treatment of spontaneous chronic kidney disease in cats JAVMA 2006 September; 229(6):949-57. Sheri J Ross, Carl A Osborne, Claudia A Kirk et al • Prospective, double-masked, randomized, controlled clinical trial • 45 pet cats, creatinine 2.1- 4.5 mg/dl (stages 2,3) • Renal diet vs adult diet, 24 months
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Renal diets- cats • Body weight, HCT, UPC, creat, K+, Ca++, PTH not significantly different • More uremic episodes in cats on adult diets • Significant reduction in renal related deaths in cats on renal diets • Median survival increases from 266633 days with diet therapy only
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Renal diets conclusion • Grade 1 evidence – dogs stages 3, 4 • Grade 1 evidence- cats stages 2, 3
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Evaluation of recipes for home-prepared diets for dogs and cats with CKD Larsen, et al JAVMA 2012; 240 (5)532-8 • 67 home prepared diet recipes • 39 for dogs, 28 for cats • Computer software analysis • Nutritional adequacy- many problems • Most would not meet nutritional and clinical needs of patients • Use caution for long term feeding •
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Fluid Therapy
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Less is more- fluid therapy for kidney disease “No evidence that aggressive IVF promotes the rate of excretion of uremic solutes beyond that which can be achieved by restoration of normal physiologic perfusion parameters.” Langston, J Fel Med Surg 2012
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SQ fluid therapy proposed benefits • Prevent dehydration • Maintain renal blood flow, GFR • Increase urine output
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Correct pre-renal azotemia Balanced electrolyte solution (e.g., LRS) SC every 1 to 3 days - 75-100 ml per dose
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Problems Dr. Audrey Cook, TAMU • Intrinsic renal function will not be improved • Sodium content of fluids too high • Hard for diseased kidney to excrete • Patient must drink more water to excrete sodium • Intermittent fluid admin may be worse • Kidneys can’t adjust quickly • Dehydration results • • •
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SQ fluids Does patient feel better? Or do we?
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SQ fluids- evidence • No studies yet examining risks or benefits • Pathophysiologic justification and expert opinion • Grade IV evidence
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Calcitriol
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Calcium metabolism • Kidneys convert 25-OH cholecalciferol to calcitriol • Calcitriol modulates PTH activity • Low calcitriol renal secondary hyperPT • Elevated PTH • Phos retention from CKD further elevates PTH • • •
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Elevated PTH levels • Elevates intracellular calcium-destroys cell membranes, proteins, nucleic acids, decreases ATP levels • Appetite suppression • Has not been conclusively shown to be a uremic toxin in vet medicine
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Calcitriol Proposed benefits • Indirect- suppressing hyperparathyroidism • Direct- effect on systemic calcitriol receptors • Improved survival in human CKD patients • May activate Vit D receptor directly • May prolong survival independent of calcium, - Vit D receptor - Paracalcitol •
phosphorus and calcitriol
Renal secondary hyperparathyroidism • iCa++ is active component • Phosphorus is absorbed from intestine and excreted by kidney • CKD: - reduced GFR phos retention elevated PTH - renal production of calcitriol decreases -hypo or hypercalcemia
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Calcitriol in dogs Polzin, et al JVIM 2005 • 37 dogs stage 3&4 CKD • RCCT • Enhanced survival (365 days vs 250 days placebo) • Improved activity, appetite, alertness- grade IV evidence
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Calcitriol in cats • Grade IV evidence for other clinical benefits- pathophysiologic justification, clinical observations • 1 year RCCT in cats failed to confirm any clinical benefits in stages 2,3,4 CKD (Polzin, 2005)
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Dosing calcitriol • Baseline Ca++, phos, PTH • Lower phosphorus 2 • Azotemic, UPC >0.5 dog >0.4 cat • Goal is to reduce UPC < 1 • If not, then reduce UPC by ½
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ACEi in dogs • Strong evidence from RCCT that proteinuria is reduced (Grauer, 2000) • Renoprotective effects not proven in Grauer study • Samoyeds with hereditary nephritis- survival 1.36 X longer in treated dogs
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Tolerability and efficacy of benazepril in cats with CKD King et al, JVIM 2006 • Prospective, db blind, multicenter, placebo controlled, randomized, 192 pet cats • Creatinine >2 mg/ml • Benazepril 0.5-1 mg/kg Q24 h up to 3 yrs • Renal diet given in 184 cats •
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Tolerability and efficacy of benazepril in cats with CKD
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King et al, JVIM 2006 • Well tolerated • Proteinuria significantly reduced in benazepril group • QOL not significantly different • Mean survival time unaffected by treatment • Number of adverse events not significantly different 56
Evidence for ACEi use Dogs • Grade I evidence for reducing proteinuria • Grade II -delay loss of renal function, prolong survival Cats • Grade I evidence does not support its use
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Antihypertensives
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Hypertension • Common sequela • 19% cats 61% dogs • Eye, heart, brain, kidney end organs • Increased mortality in dogs CKD stage 3, 4 • Elevated BP reduces renal function, increases proteinuria
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Blood pressure measurement • Doppler, oscillometric • Cuff size, technique, acclimation, reproducible • Defined as greater than 150/95 mmHg • Goal is to reduce systemic BP to
