Management of Proteinuria in Dogs and Cats with Chronic Kidney Disease.

Abstract

Companion Notes

Review on proteinuria in dogs and cats with chronic kidney disease

Overview

- proteinuria is a negative prognostic indicator for chronic kidney disease (CKD)

- in 1 report of dogs with CKD with a initial UPC > 1.0

- found associated with 3 times higher risk of uremic crisis and death

- in 2 report of cats with CKD, proteinuria found related to shortened survival

- persistently elevated urine protein:creatinine ratio (UPC) should be investigated

(levels above those below should be investigated)

- urine protein:creatinine ratio should be less than 0.4 in dogs

- urine protein:creatinine ratio should be less than 0.2 in most cats

- normal female cats and neutered male cats should have a UPC under 0.2

- normal intact males can have a UPC up to 0.6 (most likely due to cauxin)

- standard of care for renal proteinuria in dogs and cats

- angiotensin-converting enzyme inhibitors

- and/or angiotensin receptor blockers

- blood pressure control

- nutritional modification

- in dogs with glomerular proteinuria that have not responded to standard therapy

- consider renal biopsy and immunosuppressive agents

- biopsy will elucidate if there’s a an active immunopathogenesis

- indicating whether immunosuppressants are indicated or not

Laboratory testing for urine protein

- urine dipstick (interpret positives in this and SSA in light of specific gravity)

- sensitivity and specificity in the dog reported as low as:

- sensitivity: 54%

- specificity: 69%

- low sensitivity and specificity in the cat reported as low as:

- sensitivity: 60%

- specificity: 31%

- primarily detects albumin but also measures globulins

- sulfosalicylic turbidimetric test (SSA, Bumin test)

- more reliable than urine dipstick for detection of proteinuria

- test requires appropriate reagents and standards

- urine protein:creatinine ratio (UPC) uses a quantitative test for total urine protein

- indications for using UPC

- dogs and cats with repeatable positive dipsticks or SSAs

- in urine samples that are free of the following:

- pyuria

- color change from hematuria

- test correlates well with 24-hour urine protein losses

- detection of persistent microalbuminuria (often the earliest, detectable proteinuria)

- urine albumin measured quantitatively by commercial reference laboratory

- using species-specific assay

Clinical assessment of proteinuria

- assessing proteinuria involves 3 key elements:

- persistence (persistent proteinuria)

- proteinuria detected on 3 or more occasions 2 or more weeks apart

- localization

- persistent proteinuria should be localized as follows

- prerenal

- increased delivery of low molecular weight plasma proteins

(to normal glomerulus)

- hemoglobinuria from intravascular hemolysis

- myoglobinuria from rhabdomyolysis

- immunoglobulin light chains

- from multiple myeloma or lymphoma

- renal (abnormal metabolism of normal plasma proteins by kidneys)

- functional (physiologic) proteinuria is poorly documented

- involves transient stressors altering renal physiology

- strenuous exercise

- fever

- seizure

- exposure to extreme heat or cold

- glomerular

- involves altered permselectivity of basement membrane

- membranoproliferative glomerulonephritis

- membranous nephropathy

- glomerulosclerosis

- amyloidosis

- tubular

- impaired tubular recovery of normal plasma proteins

- acute tubular necrosis

- Fanconi syndrome

- interstitial

- exudation of proteins from interstitium into urinary space

- interstitial nephritis

- tubular and interstitial can be difficult to differentiate clinically

- often referred to as tubulointerstitial

- postrenal

- protein entering urine via exudation of blood or serum

(into lower urinary or genital tracts)

- urinary tract infection

- urolithiasis

- transitional cell carcinoma

- vaginitis

- magnitude (assessed after prerenal and postrenal causes eliminated)

- assessed with a quantitative test for urine protein

- this generally is a UPC but could also be urine albumin

- International Renal Interest Society recommends staging of CKD

- based on animal’s UPC

- dogs with renal proteinuria and a UPC of 2.0 or higher

- these usually have glomerular disease

- dogs with UPC under 2.0

- these might have glomerular disease or tubulointerstitial disease

- in cats with UPC over 2.0 suspect glomerular diseases

(though they occur much less commonly in cats )

- concurrent hypoalbuminuria supports glomerular disease

Inhibition of renin–angiotensin–aldosterone system (RAAS) to manage proteinuria

- hemodynamic forces affect the transglomerular movement of proteins

- therefore, changing renal hemodynamics could reduce proteinuria

- influencing the RAAS has been the major method to achieve such changes

- agents that target RAAS include the following:

- angiotensin-converting enzyme inhibitors (ACEi)

- initially given once daily but over ½ of dogs will need bid use eventually

- “and perhaps additional dosage escalations”

- benazapril, enalapril or lisinopril, 0.25-0.5 mg/kg PO q24h dog or cat

- employ lower starting doses in animals with stage 3 or 4 CKD

- or if concurrent problems might lead to dehydration or anorexia

- escalating dose strategy

- increase by 0.25–0.5 mg/kg to maximum daily dose of 2 mg/kg

- can be given q12h

- ramipril, 0.125 mg/kg PO q24h dog

- escalating dose strategy

- increase by 0.125 mg/kg q24h to a maximum of 0.5 mg/kg q24h

- usually given q24h

- imidapril, 0.25 mg/kg PO q24h dog

- escalating dose strategy

- increase by 0.25 mg/kg q24 h to a maximum of 2 mg/kg q24h

- usually given q24h

- ACEis associated with positive outcomes in dogs and cats with CKD

- concerning ACEi use in a dog or cat that’s already azotemic

- seems uncommon there’s a severe worsening of azotemia from ACEi

(> 30% increase from baseline)

- that is if the animal is clinically stable before starting the ACEi

- dehydrated dogs may be at highest risk for worse azotemia

- correct dehydration before initiating ACEi therapy

- there’s no scientific data establishing that one ACEi is superior

- angiotensin receptor blockers (telmisartan and losartan)

- use of these in pets with proteinuric CKD still being developed

- aldosterone receptor antagonists

- “aldosterone breakthrough”

- seen in some humans getting RAAS inhibitors at maximal dosages

- despite maximal dosages, serum aldosterone increases over time

- preliminary studies show it may occur in up to 1/3 of dogs

(dogs with proteinuric renal diseases)

- little data to show spironolactone effective for glomerular disease in dogs

- should only work if serum or urine aldosterone levels are increased

(indicative of aldosterone breakthrough)

- trial and error with different drugs or combinations of drugs may be necessary

- targets of inhibition therapy in dogs with renal proteinuria

- acceptable results of therapy

- serum potassium < 6.0 mEq/L

- systolic blood pressure “>120 mm Hg”

- staging of blood pressure by risk of future target organ damage

(in dogs and cats)

- < 150 mm Hg: normotensive, little or no risk

- 150-159 mm Hg: borderline hypertensive, little risk

- 160-179 mm Hg: hypertensive, moderate risk

- ≥ 180 mm Hg: severe hypertension, high risk

- serum creatinine is stable or minimally increased

- < 30% increase above baseline when stage 1 or 2 CKD

- < 10% when stage 3 CKD

- no increase when stage 4 CKD

- target reduction in proteinuria

- “UPC <1 (primary) or >50% reduction from baseline (secondary)”

- if target UPC reduction is not achieved with a maximal dosage an ACEi

- add an ARB

or

- ARB monotherapy in dogs apparently intolerant of an ACEi

- monitoring therapy in animals being treated for proteinuric renal disease

- the following should be monitored at least quarterly in fasting samples

- UPC varies day-to-day in most dogs with glomerular proteinuria

- consider assessing trends in UPC over time

- average 2 to 3 serial UPCs

- measure UPC in urine pooled from 2-3 collections

- urinalysis

- systemic blood pressure

- serum albumin, creatinine and potassium levels

- assess the below 1-2 weeks after an ACEi or ARB is added or changed

- UPC

- systemic blood pressure (SBP)

- serum creatinine and potassium

- severe worsening of renal function: >30% increase in creatinine

- managing hyperkalemia

- seems a common side effect of RAAS inhibition in dogs with renal disease

- true hyperkalemia can be managed by 1 of the following:

- reduce ACEi or ARB drug dosage

- discontinue spironolactone

- reduced potassium diets

- renal diets may be supplemented with potassium

- managing hypertension (kidneys are target organs for hypertensive damage)

- RAAS inhibitors generally reduce blood pressure by about 10-15%

- in dogs and cats with sustained SPB ≥ 160 mm Hg while on inhibitors

- first increase dose of RAAS inhibitor

- if maximum dosage used

(and there’s moderate to high risk of target organ damage)

- add calcium channel blocker (amlodipine usually recommended)

- amlodipine, starting at 0.2-0.4 mg/kg every 24 hours

- can be incrementally increased

- to total daily dose of 0.75 mg/kg

- “can be divided to every 12 hours”

- in cats, amlodipine monotherapy may be more appropriate

- may lower UPC to under 0.2 in hypertensive cats

- avoid high salt intake

- diet

- generally held that renal diets reduce magnitude of proteinuria

(diets modified in protein content)