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This article explores the treatment of chronic kidney disease (CKD). CKD is relatively common in general practice and early identification and appropriate management may improve the outcome of patients with this condition.

Louise Bird BVM&S MRCVS, ACVIM and ECVIM resident in Small Animal Internal Medicine, Anderson Moores Veterinary Specialists, The Granary, Bunstead Barns, Poles Lane, Hursley, Winchester, Hampshire, SO21 2LL

David Walker BVetMed(Hons) DipACVIM DipECVIM MRCVS, RCVS, American and European Specialist in Small Animal Internal Medicine, Anderson Moores Veterinary Specialists, The Granary, Bunstead Barns, Poles Lane, Hursley, Winchester, Hampshire, SO21 2LL


Key points:

Chronic kidney disease (CKD) is irreversible and progressive; however, treatment can significantly improve quality of life and survival in many patients with CKD. By the time azotaemia has developed, at least 75% of functioning nephrons have been lost (Polzin, 2010) and identifying the inciting cause of CKD is often not possible. Therapy is aimed at managing the complicating factors that can arise as a result of CKD as well as slowing the progression of disease.

International Renal Interest Society staging of CKD

The severity of CKD is determined by the International Renal Interest Society (IRIS) staging system, which takes into account azotaemia, urine protein:creatinine ratio and systemic arterial blood pressure (see table 1-3) (Elliott and Watson, 2013). The IRIS staging system assists with establishing prognosis and targeting therapy in CKD. CKD is a dynamic disease and therapy will need to be adjusted as disease progresses. The IRIS staging system is used in combination with regular monitoring of patients with CKD and IRIS staging is typically performed every 3 months.

Table 1: Recommendations for IRIS staging CKD (based on blood creatinine concentration)

Stage

Blood creatinine

μmol/l

mg/dl

Comments

Dogs

Cats

At

risk

<125

<1.4

<140

<1.6

History suggests the animal is at increased

risk of developing CKD in the future because

of a number of factors (e.g., exposure to

nephrotoxic drugs, breed, high prevalence of

infectious disease in the area, or old age).

1

<125

<1.4

<140

<1.6

Nonazotemic. Some other renal abnormality

present (e.g. inadequate urinary concentrating

ability without identifiable nonrenal cause,

abnormal renal palpation or renal imaging

findings, proteinuria of renal origin, abnormal

renal biopsy results, increasing blood creatinine

concentrations in samples collected serially).

2

125 – 180

1.4 – 2.0

140 – 250

1.6 – 2.8

Mild renal azotemia (lower end of the range lies

within reference ranges for many laboratories,

but the insensitivity of creatinine concentration

as a screening test means that animals with

creatinine values close to the upper reference

limit often have excretory failure). Clinical signs

usually mild or absent.

3

181 – 440

2.1 – 5.0

251 – 440

2.9 – 5.0

Moderate renal azotemia. Many extrarenal

clinical signs may be present.

4

>440

>5.0

>440

>5.0

Increasing risk of systemic clinical signs

and uraemic crises

(IRIS = Internal Renal Interest Society)

(Adapted from Elliott and Watson, 2013)

Table 2: Recommendations for IRIS substaging CKD (based on proteinuria)

UP/C value

Substage

Dogs

Cats

<0.2

<0.2

Non-proteinuric

0.2 to 0.5

0.2 to 0.4

Borderline proteinuric (BP)

>0.5

>0.4

Proteinuric (P)

(IRIS = Internal Renal Interest Society)

(Adapted from Elliott and Watson, 2013)

Table 3: Recommendations for IRIS substaging CKD (based on proteinuria)

Systolic BP

mm Hg

Diastolic BP

mm Hg

Adaptation when

breed-specific reference

range is available*

Arterial Pressure

Substage (AP)

<150

<95

<10 mm Hg above

reference range

0

Minimal Risk

150 – 159

95 – 99

10 – 20 mm Hg above

reference range

1

Low Risk

160 – 179

100 – 119

20 – 40 mm Hg above

reference range

2

Moderate Risk

≥ 180

≥ 120

≥40 mm Hg above

reference range

3

High Risk

(IRIS = Internal Renal Interest Society)

(Adapted from Elliott and Watson, 2013)

General management of CKD

The following basic guidelines should be followed for any patient newly diagnosed with CKD:

  1. Discontinue potentially nephrotoxic drugs where possible
  2. Correct any pre- or post-renal abnormalities such as dehydration
  3. Identify and treat any extra-renal disease (such as urolithiasis, urinary tract infections, hyperthyroidism or hyperadrenocorticism) which may perpetuate renal damage

Renal diets

Renal diets are restricted in protein, phosphorus and sodium, and are supplemented with omega-3 fatty acids, B vitamins and anti-oxidants. In addition, feline renal diets contain supplemental potassium. Dietary modification has been shown to increase quality and quantity of life in dogs and cats with IRIS stage 2 or higher disease (Bartges, 2012). There are currently no studies evaluating dietary modification in patients with IRIS stage 1 disease.

Prescription diets should be introduced when patients are clinically stable, as attempting dietary modification in clinically unwell or hospitalised patients may result in food aversion. Although there is no evidence to support renal diets in IRIS stage 1 patients, introducing a renal diet in an asymptomatic patient may improve acceptance.

Treatment of hyperphosphataemia and renal secondary hyperparathyroidism

Approximately 60% of dogs and cats with CKD are hyperphosphataemic (Cortadellas et al. 2010; Korman and White, 2013). Methods for controlling hyperphosphataemia include initiating a phosphate-restricted renal diet, introducing phosphate binding agents and supplementing calcitriol. Blood samples to monitor serum phosphate concentrations should ideally be collected after a 12-hour fast to avoid post-prandial effects and sample haemolysis should be avoided as this will falsely elevate phosphate.

Phosphate binding agents (PBAs)

If serum hyperphosphataemia persists despite the initiation of a reduced phosphate diet, an enteric phosphate binding agent (PBA; such as aluminium hydroxide, aluminium carbonate, calcium acetate or lanthanum carbonate) should be introduced. The total recommended daily dosage should be given in divided doses through the day with food. Patients should be dosed to effect although side effects may limit dosing. Aluminium containing PBAs can occasionally cause microcytosis, generalised muscle weakness and constipation (more common in cats). Calcium containing PBAs should not be given to patients with hypercalcaemia and should be discontinued or given in combination with an aluminium-containing PBAs (to enable a dose reduction) should hypercalcaemia occur on treatment. Blood calcium concentrations should be monitored every 4-6 weeks initially after starting treatment with a calcium-containing PBA and then every 12 weeks.

Correcting dehydration

Patients with CKD will have reduced urine concentrating ability; concurrent disease or inappetence (and reduced water intake) often mean these patients are unable to adequately compensate for their polyuria. Depending on the clinical condition of patients at presentation, intravenous crystalloid fluid therapy (IVFT) may be necessary to correct hypovolaemia and/or dehydration. Water intake should be encouraged by improving water access, providing clean and fresh water, using water fountains, feeding canned food or adding water to food. Conditions predisposing to dehydration or hypovolaemia (such as those resulting in vomiting, dehydration or inappetence) should be corrected immediately and IVFT instituted early if necessary.

Treatment of proteinuria

As well as proteinuria being a consequence of CKD, it can also promote progression of kidney disease. Experimental studies have found that proteins within the tubular fluid promote the release of inflammatory cytokines which may promote further renal damage (Jepson, 2013). Interventions for proteinuria differ depending on the IRIS stage of CKD as the number of functioning nephrons across which protein can be lost declines as disease progresses. Therapy to manage proteinuria should be considered in the following patients:

All patients presenting with proteinuria and CKD should ideally be thoroughly assessed for concurrent disease. If concurrent disease is identified this should be appropriately managed. Most patients with CKD will be receiving a protein-restricted renal diet. If dietary therapy and the management of concurrent disease(s) fails to improve proteinuria, treatment with an angiotensin-converting enzyme inhibitor (ACEi) should be instituted. ACEi moderate proteinuria by inhibition of the renin-angiotensin-aldosterone system (RAAS) which decreases efferent glomerular arteriolar resistance leading to decreased glomerular transcapillary hydraulic pressure (Brown et al. 2013). The lower end of the ACEi dose range should be use initially. Typically, an ACEi is given once daily initially, but some patients will require incremental dose adjustments and more than half of the dogs will eventually need twice- daily administration (Brown et al, 2013). Patients receiving ACEi should be closely monitored (urinalysis (including UPCR), non-invasive blood pressure and serum urea and creatinine concentration as a baseline) every 2-4 weeks until stable and then at least every three months thereafter. In general, a reduction in the UPCR to <0.5 (or a reduction in the UPCR of 50% or more) should be considered as evidence of therapeutic success (Brown et al. 2013).

In patients with severe renal disease or concurrent hypovolaemia, glomerular hypertension is required to maintain GFR and ACEi may be detrimental to renal function. Hypovolaemic or dehydrated patients should not be started on ACEi until these abnormalities are corrected. Increases in the creatinine concentration > 30% from pre-treatment concentrations, or clinical signs of uraemia, warrant review of dosage and potentially cessation of the ACEi.

Angiotensin ll type 1 receptor blockers (ARBs) are another class of drug which act to reduce glomerular capillary bed hydrostatic pressure via inhibition of RAAS. Although ARBs are used commonly in people with glomerular disease, there are limited data on the use of ARBs in dogs. Losartan is the most commonly used ARB in veterinary medicine. Even though dogs do not appear to produce one of the major active metabolites of losartan, there is good evidence that losartan exerts pharmacodynamic effects in dogs and anecdotally that losartan has an antiproteinuric effect, particularly in combination with ACEi (Brown et al, 2013). The dose range for losartan in dogs is 0.125-0.25 mg/kg po once daily in azotaemic dogs and 0.5-1.0mg/kg po once daily in non-azotaemic dogs; concurrent administration of an ACEi is generally recommended (Brown et al, 2013).

Managing hypertension

Hypertension has been reported to occur in 65-75% of dogs with CKD (Bartges, 2012) and 20-60% of cats with CKD (Korman and White, 2013). Severe hypertension results in end-organ damage and potentially contributes to CKD progression. Therapy should be instituted if systolic blood pressure is persistently 160mmHg or above or if there is evidence of end-organ damage (on ophthalmic examination, clinical signs of end-organ damage within the eye include hyphema, retinal haemorrhage, retinal detachment and/or optic nerve oedema). The goal of treatment is to reduce systolic blood pressure ≤150mmHg.

If the initiation of a sodium-restricted renal diet is insufficient to manage hypertension, the use of calcium channel blockers (amlodipine: dose range 0.25-0.5mg/kg po q12-24hrs in dogs and 0.625-1.25mg/cat po q12-24hrs) should be considered (initially start at the lower end of the dose range). ACEi provide only modest reductions in blood pressure and are normally unsuitable as monotherapy; however, ACEi can be used in combination with calcium channel blockers if necessary,

Any patient on anti-hypertensive therapy should be monitored regularly. Once blood pressure is stabilised, monitoring should be performed at least every three months.

Therapy for uraemic gastroenteritis, nausea and inappetence

Gastrointestinal signs in CKD (inappetence, nausea, gastrointestinal ulceration, vomiting) can significantly affect quality of life and potentially worsen CKD by predisposing to dehydration or hypovolaemia. H2-receptor blockers (ranitidine, cimetidine etc); can be used to manage gastric hyperacidity. Altered gastrointestinal motility can occur secondary to gastroenteritis and ranitidine may be the drug of choice as it has some prokinetic action. If there is suspicion of mucosal erosion or ulceration, the proton-pump inhibitor omeprazole can be used instead.

Uraemic toxins directly affect the vomiting center and result in nausea. There are few studies investigating the efficacy of anti-emetics in patients with CKD, but maropitant or metoclopramide are suitable options.

Mirtazapine is often effective at stimulating appetite in veterinary patients and may have some anti-nausea effects via 5-HT3 receptor antagonism. Cats with stage 2-4 CKD may have prolonged renal clearance of mirtazapine and using the lower end of the dose range is recommended (Korman and White, 2013). See table 5 for all doses.

Table 5: Commonly administered agents for uraemic gastroenteritis, nausea and inappetence in dogs and cats

Drug

Dose in dogs

Dose in cats

Ranitidine

2mg/kg po q8-12hrs

3.5mg/kg po q12hrs

Cimetidine

5-10mg/kg po q8hrs

2.5-5mg/kg po q12hrs

Omeprazole

0.5-1.5mg/kg po q24hrs (typically for a maximum of 8 weeks)

0.75-1mg/kg po q24hrs (typically for a maximum of 8 weeks)

Sucralfate

500mg/dog po q6-8hrs (dogs up to 20kg); 1-2g/dog po q6-8hrs (dogs >20kg)

250mg/cat po q8-12hrs

Maropitant

2mg/kg po q24hrs (for a maximum of 5 days; if used chronically, a rest period of 2 days after every 5 doses if suggested)

2mg/kg po q24hrs (for a maximum of 5 days; if used chronically, a rest period of 2 days after every 5 doses if suggested)

Metoclopramide

0.25-0.5mg/kg po q12hrs or 0.17-0.33mg/kg po q8hrs

0.25-0.5mg/kg po q12hrs or 0.17-0.33mg/kg po q8hrs

Mirtazepine

1.1-1.3mg/kg po q24hrs

1.88mg/cat po q48hrs

(Ramsey, 2014)

Conclusion

CKD is unfortunately irreversible and progressive. The IRIS staging system assists with establishing prognosis and targeting therapy, which is aimed at managing the complicating factors that can arise as a result of CKD as well as slowing the progression of disease and improving patients’ quality of life. Hypertension and proteinuria are risk factors for progression of CKD and should be identified and treated early.

References

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Bartges JW (2012) Chronic kidney disease in dogs and cats. Vet Clin North Am Small Anim Pract 42: 669–692

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Published: 07-10-2015

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