Chronic kidney disease (CKD) - Bibliovet The Encyclopaedia of Veterinary Medicine

Details: Category: Schede; Published: 13 September 2017; Hits: 12

Disciplina: Urologia
Specie: Cane e Gatto

The term chronic kidney disease (CKD) indicates functional or structural renal damage present for at least 3 months, with or without a reduction in the glomerular filtration rate (GFR), or with a greater than 50% reduction in the GFR for more than 3 months._¹ The renal damage, or rather, the presence of pathological abnormalities, can be shown by changes in blood and/or urine tests and/or imaging studies. This definition of CKD resumes that used in human medicine, reported by the National Kidney Foundation in its guidelines (K/DOQI)._²

CKD is often considered to be the state of chronic renal failure characterized by abnormally high levels of urea and creatinine in the serum, which are found when 75% of the nephrons are no longer functioning. However, in the early stages of CKD subjects have normal levels of urea and the disease has not yet resulted in failure of the kidneys. Although not correlated with age, CKD is more frequent in elderly subjects. The prevalence of CKD in cats is 1% among animals less than 1 year old, 10% in those over 8 years old and 15% in animals that are 15 years of age.

STAGING

The International Renal Interest Society (IRIS) proposed a staging system for CKD in the context of veterinary medicine._³ Four stages of CKD have been identified in the dog and cat on the basis of serum creatinine (SCr) values.

	Stage 1	Stage 2	Stage 3	Stage 4
Dog	SCr < 1.4	1.4< SCr< 2.0	2.1< SCr< 5.0	>5.0
Cat	SCr < 1.6	1.6< SCr< 2.8	2.9< SCr< 5.0	>5.0

Table 1– IRIS classification of CKD.

Stage 1: subjects have normal levels of azotaemia but have other signs of kidney disease: a decrease in the specific gravity of the urine without evidence of non-renal causes, persistent proteinuria of renal origin, a significant number of casts in the urine, a progressive increase in the values of SCr within the normal range, kidneys abnormal at palpation, changes in renal ultrasound structure and histopathological alterations seen in a renal biopsy.
Stage 2: subjects have a slight increase in azotaemia; the clinical signs are mild or may be absent.
Stage 3: moderate azotaemia in the presence of systemic clinical signs.
Stage 4: severe azotaemia with obvious clinical signs and concomitant alterations in electrolyte and acid-base homeostasis.

The IRIS classification also includes a substaging based on proteinuria and hypertension.

Proteinuria is evaluated quantitatively through the ratio of urinary protein to urinary creatinine (UP/C), having excluded pre-renal and post-renal causes of proteinuria. Colorimetric methods (Coomassie brilliant blue or pyrogallol red) are used for the quantification.

Patients are defined as:

Non-proteinuric: when the UP/C is < 0.2 in both the dog and cat;
Borderline proteinuric: when the UP/C is between 0.2 and 0.5 in the dog and between 0.2 and 0.4 in the cat;
Proteinuric: when the UP/C is > 0.5 in the dog and > 0.4 in the cat.

The role of proteinuria in the progression of kidney disease has been extensively described in human medicine, in which tubulo-interstitial lesions secondary to primary glomerular disorders have been found. The proteinuria amplifies the interstitial damage through a mechanism of lysosomal flooding. Furthermore, albumin, transferrin and IgG dose-dependently stimulate the synthesis of endothelin-1 by the epithelial cells of the proximal renal tubules and small proteins with a molecular weight of less than 28 kDa are able to stimulate the production of monocyte chemoattractant protein-1 (MCP-1)._⁴

Persistent proteinuria is associated with higher rates of morbidity and mortality from renal causes and increased mortality from non-renal causes; mortality increases as the severity of the proteinuria increases._^5,6

The analytic variability of parameters_⁷ and the demonstration of variations in the UP/C ratio (on a single sample) in bitches with stable glomerular proteinuria_⁸ suggest that this ratio should be calculated on serial samples to obtain an average value and that this value should, in any case, be considered cautiously.

Systemic hypertension is included among both the “initiation factors” and the “progression factors” of CKD._² In veterinary medicine the prevalence of arterial hypertension in patients with CKD is estimated to be about 20%. Hypertension has various effects on target organs: heart (left ventricular hypertrophy), eyes (retinal haemorrhages, hyphaema, retinal detachment, glaucoma), central nervous system (seizures, behavioural changes, dementia) and kidneys (glomerulosclerosis, proliferative glomerulitis, hyalinisation and occlusion of the glomerular capillaries, fibrinoid necrosis). These last phenomena cause glomerulosclerosis and ischaemia, with consequent worsening of the parenchymal damage._⁹

The subclassification of CKD into risk classes according to blood pressure values is as follows:

	Substage 1 *Minimal risk*	Substage 2 *Low risk*	Substage 3 *Moderate risk*	Substage 4 *High risk*
Systolic blood pressure (mmHg)	<150	150-159	160-179	≥180
Diastolic blood pressure (mmHg)	< 95	95-99	100-119	≥120

Table 2. Systemic hypertension: substaging and risk classes for target organs.

Blood pressure should be monitored every 2 months in animals at moderate risk and every week in those at high risk._¹⁰

CLINICAL AND LABORATORY SIGNS

Depending on the stage of their disease, patients can show weight loss, dehydration, loss of appetite, polyuria and polydipsia. Besides the azotaemia, proteinuria and hypertension already mentioned, other possible findings in animals with CKD are:

Anaemia. The characteristic pattern is that of a non-regenerative normochromic, normocytic anaemia due to decreased synthesis of erythropoietin as a result of loss of functioning renal tissue. The disease leads to uraemic gastritis, high levels of gastrin in the blood and ulcerative gastroduodenitis which can cause other patterns of anaemia (e.g., microcytosis and hypochromia).

Hyperphosphataemia and secondary hyperparathyroidism. Hypophosphataemia is an effect of CKD, but also one of the factors that is recognized as a cause of its progression. A reduction in GFR and the consequent hyperphosphataemia lead to inhibition of the activity of 1a-hydroxylase, the enzyme responsible for converting 25-hydroxycholecalciferol into the more active form 1,25 hydroxycholecalciferol (calcitriol) in the kidney. The result is less absorption of calcium in the intestine and inhibition of the negative feedback of parathyroid hormone (PTH), mobilisation of calcium and phosphorus from the bones and bone demineralisation. Furthermore, when the plasma concentrations of calcium and phosphate exceed the solubility product of the salts, ectopic mineralisation can occur in the vessels and soft tissues._^11,12

Persistent hyperphosphataemia causes hypertrophy and hyperplasia of the parathyroid cells. Since each cell has an “autonomous” percentage of secretion, the hyperplasia results in more secretion of not-suppressible PTH. During anaemia the number of calcitriol-sensitive receptors in the parathyroid glands decreases, thus reducing their inhibitory effects on PTH._¹³

There are numerous effects of hyperparathyroidism in subjects with kidney disease: myelofibrosis, in vitro inhibition of the proliferation of bone marrow cell lines, increased osmotic fragility of red blood cells, dysfunction of platelets and leucocytes. These are the effects of high levels of PTH on the haematopoietic system; the role of PTH as a neurotoxin and its involvement in blood lipoprotein abnormalities and insulin-resistance are still under debate._¹⁴

Hypokalaemia – Potassium levels are low in 20-30% of cats with CKD. This is often caused by the increase in the amount of potassium excreted in the urine. The clinical signs of hypokalaemic polymyopathy are asthenia, muscle weakness, reluctance to move, ventroflexion of the neck, shallow, rapid breathing and faecal impaction (Fig. 1).

Metabolic acidosis - Metabolic acidosis is the most frequent acid-base imbalance in advanced stages of CKD. It may give rise to signs/symptoms such as anorexia, vomiting, lethargy, weight loss, weakness. If the pH falls below 7.20, there may be serious repercussions on the cardiovascular system.

TREATMENT

Diet – Renal diets are characterized by modest protein restriction, a low phosphate content and supplementation with ω3-polyunsaturated fatty acids (PUFA). The efficacy of these diets has been demonstrated by the increased duration of survival of animals fed such a diet compared to animals in control groups not receiving a renal diet._¹⁵

The protein level is related to increases in the values of plasma urea and nitrogen-containing catabolites and, therefore, to the clinical signs of uraemia. It is not, however, completely clear yet whether protein restriction influences the mechanisms of hypertension, hypertrophy and glomerular hyperfiltration that cause progression of the kidney disease in the dog and cat. Certainly, excessive restriction increases the risk of malnutrition. The protein restriction necessary to decrease proteinuria in carriers of X-linked hereditary nephropathy causes malnutrition and hypoalbuminaemia._¹⁶

Phosphate restriction counteracts the secondary hyperparathyroidism and, consequently, slows the progression of the kidney disease. In one study, cats fed with a low phosphate diet had lower serum levels of creatinine, phosphate and PTH compared to those of a control group of animals._¹⁷ The administration of phosphate chelators is advised when dietary restriction is not sufficient to maintain the serum phosphate levels within the recommended range.

Serial measurements of serum phosphate and the Ca x P product (normal value = 40-70) are essential for monitoring the effects of dietary phosphate restriction and chelators. Phosphate chelaters marketed for veterinary use are aluminium hydroxide,_¹⁸ calcium carbonate and lanathum carbonate.

Supplementation with ω3-PUFA tends to reduce hypercholesterolaemia, mitigate inflammation and coagulation and positively influence hypertension. PUFA supplementation has given significant results in dogs with stage III or IV induced CKD._¹⁹

Proteinuria – Angiotensin II-induced vasoconstriction of the afferent arterioles, but above all of the efferent vessels causes, respectively, a reduction of glomerular perfusion and glomerular hypertension with a consequent increase in the hydrostatic pressure and greater convective glomerular transport of macromolecules (proteins). Furthermore, by promoting the production of local growth factors (platelet-derived growth factor and transforming growth factor-beta), it is able to induce fibrosis and sclerosis. This is the rationale for using ACE-inhibitors such as enalapril, benazepril_²⁰ and ramipril. Should the proteinuria persist, angiotensin II receptor antagonists (sartans) could be indicated.

Hypertension – Treatment of hypertension (after verification and monitoring) is indicated in the presence of lesions of target organs or when systolic blood pressure values are above 150-160 mmHg. The antihypertensive drugs that have been investigated in efficacy studies are ACE-inhibitors (dogs) and calcium antagonists such as amlodipine (cats).

Anaemia -The treatment must be tailored to the pattern of anaemia found and, therefore, its aetiopathogenesis. Recombinant human erythropoietin is used in non-regenerative, normochromic, normocytic anaemias. In cases of microcytosis, anti-H2 antihistamines may be considered. It is essential to monitor iron metabolism and, if necessary, to provide supplemental iron.

Hypokalaemia – Potassium gluconate or citrate 2-6 mEq/cat/day per os.

Metabolic acidosis – If the serum bicarbonate is <12-14 mEq/L, an alkylating agent must be given. The following alkalis may be used: potassium gluconate, potassium citrate and, above all, sodium bicarbonate, which has the advantage of being able to be given intravenously. The amount that needs to be administered is calculated using the following formula:

0.3 x Kg x NaHCO_3.normal - NaHCO_3.sample = mEq/L

References

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[ii]http://www.kidney.org/professionals/KDOQI/guidelines_ckd/p4_class_g2.htm
[iii]http://www.iris-kidney.com/
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[v]Lees GE, Brown SA, Elliott J et al.:Assessment and management of proteinuria in dogs and cats: 2004 ACVIM Forum Consensus Statement (Small animal), J Vet Intern Med, 19: 377-385, 2005.

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[xiii]Brown AJ, Dusso A, Lopez-Hilker S, et al.: 1,25-(OH)₂D receptors are decreased in parathyroid glands from chronically uremics dogs. Kidney Int, 35: 19-23, 1989.
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[xvii]Barber PJ, Rawlings JM, Markwell PG et al.:Effect of dietary phosphate restriction on renal secondary hyperparathyroidism in the cat. JSAP, 40, 62-70, 1999.
[xviii]Segev G, Bandt C, Francey T et al.: Aluminium toxicity following administration of alluminium-based phosphate binders in 2 dogs with renal failure, J Vet Intern Med, 22: 1432-1435, 2008.
[xix]. Roudebush P, Polzin DJ, AdamsLGet al.:An evidence-based review of therapies for canine chronic kidney disease. JSAP, 51, 244-252, 2010.
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