Comorbidities in chronic kidney disease

Introduction

Chronic kidney disease (CKD) is the most common disease of the renal system in both dogs and cats (1), and is characterized by an irreversible decline in the structural or functional capacity of one or both kidneys that persists for more than three months (2). CKD is commonly seen in older cats (3), with 53% of affected animals being over seven years old (4), while in dogs the risk of CKD also significantly increases with age, being up to 5 times more common in those 12 years or older (5). The most frequent histologic finding in older pets with CKD is chronic tubulointerstitial nephritis, while younger animals have a higher incidence of glomerulopathy (6). CKD is a progressive disease, with 47% of cats showing signs of progression within one year of diagnosis (7). Common symptoms include polyuria and polydipsia, loss of appetite, dehydration, weight loss, lethargy and vomiting (Figure 1) (8). Diagnosis is based mainly on a detailed history, clinical examination, blood pressure measurement, bloodwork, urinalysis and abdominal ultrasound, and staging based on the International Renal Interest Society (IRIS) guidelines should always be performed (Table 1). Serum creatinine and serum symmetric dimethylarginine (SDMA) concentrations provide a reliable estimation of the glomerular filtration rate (GFR), which correlates with disease progression. Treatment is symptomatic and supportive, and will depend on disease severity and stage, but is based on discontinuation of nephrotoxic agents, management of dehydration, hypertension and proteinuria, as well as appropriate therapy for other frequent comorbidities.

The most common complications in CKD patients – beyond systemic hypertension and proteinuria – are anemia consequent to the renal disease, secondary renal hyperparathyroidism, cardiovascular disease, urinary tract infection (UTI), hyperthyroidism (in cats), uremic gastroenteropathy, and hypokalemia (more commonly in cats). Managing these comorbidities becomes more challenging with increasing CKD stage, and necessitates prompt diagnosis and treatment.

 

Table 1. IRIS^a CKD Staging for Dogs (D) and Cats (C) ^©.

Figure 1. Muscle atrophy, dehydration and poor coat condition in a cat with CKD. © Dr. Anja Strobl (Small Animal Internal Medicine, Veterinary Medicine University Vienna, Austria)

 

Systemic hypertension

Systemic hypertension is a common comorbidity of CKD and is driven by several interrelated mechanisms. The activation of the renin-angiotensin-aldosterone system (RAAS) plays a pivotal role, as decreased renal perfusion leads to increased renin secretion, angiotensin II production, and aldosterone release. This results in vasoconstriction and sodium and water retention, contributing to elevated blood pressure. Impairment of sodium excretion, causing fluid overload (2) and stimulation of the sympathetic nervous system (1), further increases vascular resistance. Endothelial dysfunction secondary to uremic toxins reduces nitric oxide availability, leading to inhibition of vasodilation (5). Additionally, dysregulation of calcium-phosphorus metabolism promotes vascular calcification, which decreases vascular flexibility, while CKD anemia contributes to hypertension through increased cardiac output to compensate for the hypoxia. Profound hypertension can lead to target organ damage (kidney, heart, brain, eyes) (Figure 2) and death (8). 

Figure 2. Bilateral retinal bleeding resulting from hypertensive retinopathy in a cat with CKD IRIS Stage 3 and systemic hypertension. © Dr. Juliana Giselbrecht (Ophthalmology Veterinary Medicine University Vienna, Austria)

 

Systolic blood pressure categorization is shown in Tables 1 and 2. Note that multiple measurements of blood pressure over a period of a month should be performed to confirm a diagnosis of systemic hypertension and begin treatment. This aims to reduce the systolic blood pressure to < 160 mmHg and diastolic blood pressure to < 100 mmHg, and involves using RAAS inhibitors like angiotensin converting enzyme inhibitors (ACEIs) or angiotensin receptor blockers (ARBs), calcium channel blockers, and dietary sodium restriction (Table 3) (9). In most cases treatment is lifelong, with adjustments to the choice of drugs or dosages being warranted as necessary to circumvent target organ damage and to avoid further reduction in GFR.

 

Table 2. Staging of systemic hypertension with systolic and diastolic blood pressure (BP).

 

Table 3. Drugs and dosages for treating systemic hypertension and/or proteinuria in CKD patients.

 

Proteinuria

Proteinuria is a hallmark of CKD, as it correlates with disease severity and significantly contributes to CKD progression (10). It primarily arises from damage to the glomerulus, but tubular damage also influences protein loss. With impaired glomerular filtration, proteins (particularly albumin) pass into the urine, while tubular damage reduces the ability of cells to reabsorb filtered proteins, leading to additional proteinuria (11). The presence of excessive protein in the renal tubules triggers inflammation, oxidative stress and the release of profibrotic factors, promoting tubulointerstitial fibrosis and further impairment of renal function. Proteinuria also activates the RAAS, which increases intraglomerular pressure and exacerbates protein leakage (12). 

Detection of protein in the urine can be easily achieved with a dipstick, although the urine protein creatinine (UPC) ratio is a more reliable and sensitive method; this quantifies the severity of proteinuria and is to be preferred. An UPC < 0.2 is considered normal, between 0.2-0.5 in dogs and 0.2-0.4 in cats is considered borderline proteinuria, while dogs with a UPC > 0.5 and cats with a UPC > 0.4 are considered proteinuric (Table 1). Treatment of proteinuria should be given whatever the CKD stage, and can include either ACEIs or ARBs (Table 3), with a study suggesting superiority of telmisartan (ARB, 1.0 mg/kg PO q24h) versus enalapril (ACEI, 0.5 mg/kg PO q12h) for controlling proteinuria in dogs (13). A renal diet with low to moderate amount of protein and restricted phosphorus content should be prescribed in patients with CKD in addition to medical treatment.

Anemia 

Anemia secondary to CKD in both dogs and cats is an important comorbidity that correlates linearly with disease severity and can increase morbidity (14). The main mechanism is reduced erythropoietin (EPO) production, a hormone essential for stimulating red blood cell (RBC) production in the bone marrow. As renal function declines, the capacity to produce EPO diminishes, resulting in decreased RBC formation and a non-regenerative anemia. The accumulation of uremic toxins also suppresses the ability of the bone marrow to produce RBCs. These toxins not only cause uremic gastroenteropathy and gastrointestinal (GI) bleeding, they also directly affect the structural integrity of RBC membranes, making them more fragile and reducing their lifespan. In addition, hepcidin levels (a peptide hormone) rise due to inflammation, which inhibits dietary iron absorption and mobilization of stored iron from the liver and macrophages. This results in a functional iron deficiency, such that it is unavailable for erythropoiesis, despite normal or elevated levels of total body iron (15). 

Blood transfusions are needed for patients with hemodynamically decompensating anemia, whilst animals with a slowly progressive anemia can be treated with erythropoiesis-stimulating agents such as recombinant human erythropoietin (rHuEPO) or darbepoetin to stimulate RBC production. Darbepoetin (1-1.5 μg/kg SC q1 week), with its longer half-life and lower immunogenicity, is often preferred, and treatment should be continued until normal hematocrit levels (25-35% in cats and 37-42% in dogs) are achieved, at which point the dosage can be reduced to every 2-4 weeks. However, up to 25% of cats and 50% of dogs treated with EPO develop antibodies against both the administered and endogenic EPO. Renal diets, enriched with essential nutrients and anti-inflammatory components like omega-3 fatty acids, as well as cobalamin and folic acid, can help manage anemia by reducing inflammation and improving nutrient availability.

Uremic gastroenteropathy

Uremic gastroenteropathy is a common GI complication of CKD. The pathophysiology involves several interconnected processes including accumulation of uremic toxins, hypergastrinemia, mucosal ischemia, reduced motility, impaired mucosal defense, gut microbiota disruption and coagulopathy (16), which in combination lead to GI erosions and ulcers in dogs (Figure 3) and gastric fibrosis in cats. Common signs include vomiting, diarrhea, GI bleeding, anorexia and nausea (8). 

Figure 3. Diffuse erosive lesions in the stomach of a dog with CKD and uremic gastroenteropathy. © Dr. Pavlos Doulidis (Small Animal Internal Medicine, Veterinary Medicine University Vienna, Austria)

 

Treatment is based on dietary management and protein restriction to minimize nitrogenous waste production, and on symptomatic medication with antiemetics (e.g., maropitant (1-2 mg/kg q24h) or ondansetron (0.1-0.5 mg/kg q8-12h), gastroprotective agents (e.g., sucralfate (20-40 mg/kg q8-12h)), proton pump inhibitors (e.g., omeprazole (1 mg/kg q12-24h)), or H2-blockers (e.g., ranitidine (2.5 mg/kg q12-24h) or famotidine (0.5-1 mg/kg q24h)). The serotonin 5-HT3 receptor antagonist ondansetron has been shown to be more effective than metoclopramide in controlling uremic vomiting in humans, and is an excellent choice for both dogs and cats (12). In case of anorexia, mirtazapine (1.87 mg/cat q8h and 3.75-30 mg/dog q24h) can be considered, while feeding via esophageal or gastric tube remains an alternative for patients with chronic anorexia.

Secondary renal hyperparathyroidism

Secondary renal hyperparathyroidism (SRHP) is another common complication of CKD in dogs and cats. It plays a significant role in disease progression and contributes to various clinical signs and laboratory abnormalities that complicate management of CKD. It is driven by disturbances in phosphorus excretion, calcitriol production and calcium homeostasis (1). Due to the inability of the kidneys to excrete phosphorus effectively, hyperphosphatemia develops, leading to a reduction in serum calcium levels through calcium-phosphate precipitation and further parathormone (PTH) stimulation. Additionally, the decrease in calcitriol production (the active form of vitamin D) leads to further reduction of calcium concentration and impairment of the inhibitory effect of calcitriol on PTH synthesis (17). The combined effects of hyperphosphatemia and reduced calcitriol levels lead to chronic stimulation of the parathyroid glands, resulting in parathyroid gland hyperplasia and persistently elevated PTH secretion, even when calcium levels are within normal or near-normal ranges. Elevated PTH levels have significant skeletal and systemic consequences and can lead to bone demineralization, a condition known as renal osteodystrophy (Figure 4) (18). Additionally, chronic hyperparathyroidism contributes to vascular and soft tissue calcification, which exacerbates CKD progression and increases the risk of cardiovascular complications. Fibroblast growth factor 23 (FGF23) is a phosphatonin involved in phosphorus metabolism; it has been shown to progressively rise with loss of GFR and before any increase in total phosphorus in humans and in cats (19) and may be a useful biomarker to identify at-risk cases.

Figure 4. A radiograph from a dog with CKD and secondary renal hyperparathyroidism showing bone demineralization due to renal osteodystrophy. © Dr. Nicole Luckschander-Zeller (Small Animal Internal Medicine, Veterinary Medicine University Vienna, Austria)

 

Reducing dietary phosphorus intake is essential in animal with hyperphosphatemia or increased FGF23 concentration. Renal diets are specifically formulated with restricted phosphorus and adequate calorie intake to help control hyperphosphatemia and minimize PTH stimulation. When dietary restriction alone is insufficient, especially in more advanced stages of CKD, phosphate binders (Table 4) should be administered to reduce phosphorus absorption from the GI tract. Calcitriol administration in patients with CKD Stage 3 or 4 can help restore serum calcium levels, suppress PTH secretion, and slow parathyroid gland hyperplasia (1). Careful monitoring of calcium and phosphorus levels, based on the IRIS staging, is essential to avoid hypercalcemia or further soft tissue calcification (17).

 

Table 4. Options for treating animals with hyperphosphatemia.

 

Feline hyperthyroidism

Feline hyperthyroidism (FHT) and CKD are frequent comorbidities in older cats, often presenting concurrently (20). The interaction between these two conditions complicates their diagnosis and management, as each can influence the progression and treatment of the other. FHT increases cardiac output, heart rate and systemic blood pressure; these hemodynamic changes can enhance renal perfusion and GFR, potentially masking an underlying CKD. On the other hand, uncontrolled hypertension (due to a combination of both conditions) can exacerbate CKD progression and increases the risk of cardiovascular events. Treatment of FHT may cause GFR to decline, revealing or exacerbating pre-existing CKD (20). Diagnosis of FHT is based on the history, clinical examination with thyroid palpation, and blood work with measurement of T4 levels, with further diagnostics performed as necessary. A cat with FHT may show GI signs, polyphagia, weight loss, dehydration, an enlarged thyroid on palpation, aggressiveness, tachycardia and other abnormalities. High T4 levels in the blood are indicative of FHT, especially in a patient with chronic disease, but if necessary thyroid ultrasound or scintigraphy can confirm the diagnosis (Figure 5). FHT leads to increased protein catabolism and muscle wasting, resulting in reduced muscle mass and a drop in serum creatinine levels, leading potentially to underestimation of CKD severity and erroneous staging (20), so in affected cats, especially those suffering from severe muscle wasting, SDMA measurement can be a more reliable marker for early CKD detection, as it is less influenced by muscle mass than creatinine. 

Figure 5. Scintigraphy images from of a cat with eutopic and intrathoracic thyroid tissue and hyperthyroidism prior to radioactive iodine therapy. © Scintigraphy Archive – Dr. Florian Zeugswetter – (Small Animal Internal Medicine, Veterinary Medicine University Vienna, Austria)

 

Medical treatment is preferred for cats with both CKD and FHT. Methimazole (Felimazole^®) can be administered orally (as a tablet or oral solution) or transdermally (gel) and allows for reversible control of thyroid hormone levels. Radioactive iodine therapy can offer a definitive treatment by destroying hyperactive thyroid tissue, and is therefore often recommended for cases where there is minimal to no evidence of CKD, but is not recommended in cats with evident CKD as it can rapidly reduce GFR and exacerbate progression of the renal disease. Surgical removal of the thyroid gland is an option, but is less common due to the risk of complications such as hypoparathyroidism and worsening of the CKD. Clinical revaluation, bloodwork, blood pressure measurement and urinalysis should be regularly performed in cats with FHT and CKD to ensure good control of both thyroid hormone levels and kidney function.

Hypokalemia

Hypokalemia is a common electrolyte disturbance in cats with CKD (20-30%) (4,21) but is rarer in dogs. It can contribute to the progression of CKD and cause characteristic clinical signs, necessitating prompt recognition and management. CKD results in impaired renal tubular function, particularly affecting the distal tubules, leading to increased potassium excretion. High aldosterone concentration due to RAAS activation further promotes potassium loss. Possible GI losses (vomiting, diarrhea) of potassium and reduced potassium dietary uptake due to anorexia are also frequent. Furthermore, acid-base imbalances, particularly metabolic alkalosis, can shift potassium from the extracellular to the intracellular space, further lowering serum potassium levels. Metabolic alkalosis may occur as a compensatory mechanism for CKD-associated GI losses of hydrogen ions or as a consequence of diuretic treatment. Hypokalemia in cats often leads to generalized muscle weakness, with characteristic cervical ventroflexion, lethargy and anorexia (Figure 6) (22). 

Figure 6. Cat with CKD and severe hypokalemia (2.8 mmol/L), demonstrating signs of hypokalemic myopathy with characteristic ventroflexion of the neck. © Dr. Nicole Luckschander-Zeller (Small Animal Internal Medicine, Veterinary Medicine University Vienna, Austria)

 

In patients with moderate or severe hypokalemia (< 3 mmol/L) and clinical signs, parenteral potassium supplementation via constant rate infusion (CRI) is warranted (23). The infusion rate should not exceed 0.5 mEq/kg/h to prevent cardiac arrhythmias. For long-term management of hypokalemia, oral potassium supplements are recommended; potassium citrate or potassium gluconate can be used in either liquid or powder form, and are effective in increasing or maintaining a stable potassium concentration, and at the same time help with acid-base management. Most commercial renal diets are formulated with adequate potassium levels to ensure adequate oral supplementation. 

Urinary tract infections (UTIs)

Patients with CKD are predisposed to developing UTIs due to impaired renal function and changes in urine concentration and pH. Decreased urine concentrating ability, and decreased concentrations of bacteriostatic substances like urea, can combine with a defective local immune response to create an environment conducive to bacterial growth. In some cases, infection of the lower urinary tract can remain subclinical for a long time, and can then ascend to the kidneys to cause pyelonephritis, which can aggravate CKD. Signs are unspecific and can be mistaken for progression of the CKD. Presence of fever, detection of active sediment on routine urinalysis, or an acute worsening of the clinical signs or laboratory changes may indicate a UTI with or without pyelonephritis, and a bacterial culture with susceptibility testing (using urine collected by cystocentesis) should be performed. Antibiotic selection and duration of treatment should always be appropriate to the individual, whilst following guidelines on good antimicrobial stewardship (24,25). Antibiotics which achieve high urine concentrations and are not nephrotoxic should be preferred, always in alignment with the susceptibility testing (Table 5). Dosage reduction is recommended in patients with reduced GFR.

 

Table 5. Classification of UTIs and treatment recommendations (from (24)). 

 

Conclusion

CKD is a progressive and irreversible condition frequently complicated by various comorbidities, including systemic hypertension, proteinuria, anemia, hyperparathyroidism, and UTIs. Each of these can contribute to the progression of CKD and can worsen the clinical outcome. Early detection and comprehensive management of these comorbidities, alongside CKD staging based on IRIS guidelines, are crucial. Effective interventions, such as blood pressure monitoring and proteinuria control, dietary modifications and the use of appropriate medication, can slow disease progression and improve the patient’s quality of life. 

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