Advanced Therapeutic Approaches for the Management of Uraemia— ‘The Met and Unmet Needs’

Chronic renal failure occurs from single or cumulative pathologic insults to the kidney and irreparable loss of renal parenchyma. The uraemic syndrome manifests when residual renal mass is insufficient to meet the excretory, metabolic and endocrine needs of the body. The management of renal insufficiency must be formulated to ameliorate all identifiable clinical, metabolic, endocrine and biochemical consequences induced by renal failure including: (1) azotaemia, (2) nutritional inadequacies/excesses, (3) hypoproliferative anaemia, (4) disordered mineral metabolism, (5) electrolyte disturbances, (6) metabolic acidosis (8) proteinuria, (9) disordered water metabolism, (10) systemic hypertension, and (11) the potential for progression of the renal injury. In the past 15 years there have been profound advances to facilitate the medical and non-medical control of uraemic symptomology in all species including cats. These medical advances have permitted veterinarians to ‘meet’ many of the therapeutic objectives for the control of uraemia in some animals while the same objectives remain ‘unmet’ in others.

It is important to keep in mind that renal insufficiency is spectrum from mild to severe, and a therapeutic objective that is easily met in an animal with mild uraemia may require specialized and advanced approaches in an animal with more extensive disease. For diagnostic, prognostic and therapeutic purposes, renal insufficiency can be categorized into three basic stages: mild, moderate and severe which can be loosely defined by serum creatinine as: mild, 140–195 μmol/l (1.6–2.2 mg/dl); moderate, 196–440 μmol/l (2.3–5.0 mg/dl); and severe, >440 μmol/l (>5.0 mg/dl). The therapeutic and dietary requirements of one stage will be different than those of the other stages.

Azotemia, uraemia toxins, and the dietary prescription

Many of overt and classical clinical manifestations of the uremic syndrome are a consequence of retained uraemia toxins. Uraemia toxins constitute a diverse array of solutes of varying molecular classifications and size. Small molecular weight toxins (<300 daltons) have been considered to be the most significant retained solutes because many, but not all, of the manifestations of uraemia can be corrected with their removal from the body by dialysis. However, the uremic syndrome is more complex than can be defined by retained small molecular weight solutes and involves the retention of larger solutes (middle molecules between 300 and 15 000 daltons) that are poorly removed by dialysis as well as derangements of hormonal balance and enzymatic processes.

Many uraemia toxins and clinical consequences of uraemia derive from dietary sources due to the inability of the patient to excrete the daily load of dietary constituents per se (ie, phosphate, potassium, hydrogen ion) or their metabolic derivatives (ie, urea). Dietary protein has played an historic and pivotal role in both the pathophysiology and management of the uraemic syndrome. Extremes of protein intensify the clinical expression of uraemia, while moderation of dietary protein is a cornerstone of its medical management. High protein intake exacerbates the azotaemia and morbidity of chronic renal failure, while protein malnutrition is strongly correlated with both morbidity and mortality in animals and human patients. Proteins are considered the most harmful dietary constituent because of their metabolism to nitrogenous waste products that can only be eliminated by renal excretion. The accumulated metabolic end-products of protein metabolism create a multitude of ‘uraemia toxins’ which underlie the overt signs of uraemia. Urea is the protein-derived toxin produced and retained to the greatest extent and is regarded as an index for all small molecular weight nitrogenous ‘uraemia toxins’ that accumulate with renal failure. As a result, therapies designed to reduce protein intake and the generation of urea are presumed to reduce other nitrogenous ‘uraemia toxins’ and usually correlate with clinical improvements similar to those seen following removal of these solutes from uraemic patients by dialysis.

Blood urea nitrogen (BUN) also has been designated as the marker of the dietary protein prescriptions, but there has been little recognition of the influence of other factors besides the intake of dietary protein on the validity of BUN as a marker of the protein prescription in uraemic animals. Uraemia is associated with variable dietary intake, intestinal malabsorption, metabolic acidosis, and comorbid conditions that independently influence nitrogen balance. Reliance on BUN as the sole predictor of protein metabolism may fail to adequately differentiate influences of protein-calorie malnutrition or those secondary to protein hypercatabolism. A low BUN concentration suggesting a favourable therapeutic outcome may be highly inappropriate for a given protein prescription and reflect protein-calorie malnutrition.

Guidelines for dietary protein restriction in cats—a generally ‘met need’

Issues of when in the course of progressive renal failure to modify dietary protein, and what constitutes appropriate dietary modification are unresolved. Despite genuine effort over the past 25 years to clarify these issues, there has been little consensus as to the role and efficacy of protein modification in uraemic animals. The proliferation of new dietary products for the management of chronic renal failure has made these issues more difficult to resolve, and the veterinary community has less foundation or direction for management decisions. Controversy notwithstanding, we should not lose sight of the fact that every patient symptomatic for chronic renal failure should benefit from a protein restricted diet.

Cats tolerate renal insufficiency better than dogs, have longer survival times, and are usually less symptomatic than dogs at equivalent degrees of azotaemia. Although therapeutic recommendations are poorly defined, the rationale for the management of uraemic cats is analogous to other species. It is generally accepted that overt signs of chronic uraemia do not manifest until the BUN exceeds 22 to 28 mmol/l (60 to 80 mg/dl). This range of azotaemia can be regarded as the maximum tolerable threshold to guide dietary recommendations. Restriction of dietary protein reduces the degree of azotaemia and ameliorates the clinical expression of renal insufficiency, however, the dietary requirement for protein in cats is considerably greater (approximately three to five times) than the requirement for dogs. Consequently, the ability to provide graded protein restriction proportional to the degree of renal insufficiency is less practical. The provision of an adequate caloric intake with a formulated or prescription diet is as essential as the requirement to limit other dietary constituents (protein, phosphorus, salt). Energy requirements are estimated at 70 to 80 kcal/kg/day for cats. These estimates serve only as baseline requirements and must be reassessed on an individual case basis. Infection, fever, growth, metabolic three disturbances, progressive weight loss, repair of renal injuries, or unusual physical activity require upward adjustment of the caloric intake.

For cats with documented azotaemia and consistent clinical signs, dietary protein should be reduced to approximately 3.8–4.4 gm/kg/day (28% to 32% protein, dry matter). At this level of protein reduction, the progressive anorexia of uraemic cats and the limited palatability of the diet usually results in reduced dietary consumption and predisposes the potential for protein-calorie malnutrition. As a defense against the reduced dietary intake, it is common practice to feed a diet with greater protein content and greater palatability. This dietary approach may achieve a transient improvement in appetite and food consumption but is contrary to the therapeutic needs of uraemic cats and on a long-term basis will exacerbate the clinical consequences of the azotaemia. The poor appetite of uraemic animals, the innate reluctance of cats to switch diets, and the reduced palatability of therapeutic diets make dietary therapy a problematic and ‘unmet’ clinical objective as the uraemia progresses.

Delivery of dietary therapy

Of equal importance to dietary prescription in the management of chronic uremia, is how to insure the delivery of adequate nutrition to anorectic patients and how to assess net protein balance (excess or deficiency) when feeding therapeutic diets. The anorexia and inappetence that characterize uraemia make it difficult to confirm if a dietary prescription has been provided or if adequate nutrition has been achieved. Consequently dietary therapy must be formulated to minimize simultaneously the signs and metabolic disorders of uraemia while maintaining adequate nutrition and insure compliance with the dietary prescription. To be effective, the dietary therapy (no matter how expertly formulated) must be delivered to the patient in sufficient quantity to meet the animal's nutrient requirements. When the serum creatinine exceeds 350 to 440 μmol/l (4 to 5 mg/dl), most animals fail to eat sufficient food voluntarily (regardless of its palatability or protein content) to achieve minimum protein and calorie requirements. Pet owners may claim that their pet is eating the prescribed food, but if asked to quantitate food intake, the measured amount will rarely match the required intake for extended periods of time. Most animals have obvious anorexia despite the dietary offering. Contrary to evidence of polydipsia/polyuria, these same animals frequently do not drink sufficient water to maintain adequate hydration. Consequently, cats with moderate/severe renal insufficiency usually develop protein-calorie malnutrition, weight loss, poor body composition, and dehydration that ultimately cause a rapid escalation to death.

To correct these conditions, it is necessary to circumvent the diminished appetite and deliver the diet directly into the stomach. Delivery of the diet, extra water, and most medications can be achieved on an indefinite basis through an esophagostomy or endoscopically or surgically placed or gastrostomy tube. The ability to provide both appropriate and adequate nutrition via gastric feeding is an important and useful aspect of therapy and should be instituted in all patients who are not in nutritional balance or refuse to eat prescribed diets. With tube feeding, nutritional requirements can be provided with diets that are most appropriate for the stage of renal insufficiency regardless of their palatability and thus ‘meet’ the therapeutic and nutritional requirements of the dietary prescription. Phosphate binding agents can be pre-mixed with the diet to achieve maximal efficacy for phosphate control, and the tube provides access for delivery of other oral medications and supplemental water. Esophageal or gastric tube feeding can reverse the progressive weight loss characteristic of CRF, promote weight gain and long-term nutritional sufficiency, and appropriate fluid balance without the need for parenteral (subcutaneous) fluid administration.

Monitoring the dietary prescription

Monitoring the therapeutic response is equally as important as the delivery of appropriate nutrition (and protein) to animals with CRF. Many parameters have been used to predict protein intake and nutritional adequacy, but each has limitations that may provide imprecise or incorrect assessments. Both short-term and long-term assessments of nutritional sufficiency should be monitored to direct the nutritional therapy. The dynamics and interrelationships of nitrogen metabolism in uraemic animals can be simplified into the following metabolically coupled components: (1) input of nitrogen to the body (dietary protein intake); (2) tissue protein pool (total inventory of body nitrogen); (3) catabolic removal from the tissue protein pool (protein catabolic rate); (4) metabolic conversion of nitrogen to urea (urea generation); and (5) urea removal from the body (renal excretion). Blood urea nitrogen (BUN) has been used as the de facto marker of global protein metabolism in uraemic animals with little recognition of the influences of dietary protein intake or the catabolic generation of urea on this marker. Uraemia is associated with variable dietary intake, intestinal malabsorption, metabolic acidosis, and co-morbid conditions which independently influence nitrogen balance. Reliance on BUN as the sentinel of protein metabolism may fail to differentiate adequately influences of protein-calorie malnutrition or those secondary to protein hyper-catabolism. A low BUN concentration suggesting favourable dietary therapy may be inappropriate for the dietary prescription and reflect protein-calorie malnutrition. Clearly, a more quantitative understanding of the interrelated components of protein metabolism is necessary to fully define recommendations for the clinical management and monitoring of protein balance in uraemic animals—an ‘unmet’ need.

The long-term aspects of protein metabolism are best predicted by changes in body protein stores. Body composition can be separated into lean body mass (composed of somatic and visceral proteins and intracellular water), extracellular water, fat mass, and bone mineral which in sum equal body weight. Changes in body weight may not accurately document depletion or gain of lean body mass (body protein stores) in the face of opposing changes in extracellular water or body fat. Serum albumin reflects visceral protein content of the body, and hypoalbuminemia has been shown to predict sustained malnutrition and correlate with the morbidity and mortality of chronic renal failure. Serum albumin is readily measured but is a late predictor of protein malnutrition. It may take many weeks or months of sustained malnutrition to deplete visceral protein stores sufficiently to change serum albumin. Lean body mass (LBM), on the other hand, reflects the status of somatic protein metabolism and provides a more responsive and sensitive predictor of long-term protein balance and subclinical protein malnutrition. Semi-quantitative predictions of lean body mass can be estimated by careful and serial body condition scoring. Body condition scoring is a useful and practical way to follow changes in body composition and should be incorporated into the management of animals with CRF. Multi-frequency bioimpedance spectroscopy (BIS) is a new and noninvasive technique to quantitate sequential changes in body composition including: extracellular fluid volume, intracellular fluid volume (lean body mass), total body water, fat free mass, and percentage of body fat. The technique assesses the specific resistance of each body fluid compartment to the passage of a small electrical current and converts these measurements into volume predictions. When taken serially in time, BIS permits accurate assessment of the changes in body composition in response to disease progression or therapy.

Anaemia of chronic progressive renal failure

Failure of the erythroid bone marrow and anaemia are universal consequences of progressive uraemia in all species. Anaemia is also one of the consistently ‘unmet’ clinical consequences of chronic uraemia in cats. There is a direct correlation between the severity of the renal insufficiency and the magnitude of anaemia. Anaemia clearly contributes to the debility of end-stage renal disease in animals and is responsible (in part) for the inappetence, weakness, fatigue, lethargy, cold intolerance, dehydration and ‘social apathy’ that characterize uraemia in cats. The pathogenesis of the anaemia is multifactorial; however, it is established that bone marrow failure from deficient production of erythropoietin by the diseased kidneys is the predominant cause. In the late 1980's recombinant human erythropoietin (r-HuEPO) became available for clinical application and has revolutionized the therapeutic management of anaemia in both dogs and cats. When adequately dosed, the erythron of most cats can be normalized within 2–4 weeks of therapy. The proliferative response is signalled by a marked reticulocytosis throughout the first month of treatment, and, cumulatively over this time, the haematocrit may increase by as much as 0.5% to 1.0% per day. The availability of recombinant erythropoietin has provided a solution to one of the most fundamental clinical problems associated with chronic uraemia in cats, but anaemia remains a consistently ‘unmet’ therapeutic goal primarily due to the reluctance of veterinarians to prescribe this essential drug and in part due to development of side-effects in a minority of cats in which it is prescribed.

Clinical improvement in appetite, energy, weight gain, and alertness is reported in almost every treated patient. The improvements in clinical well-being facilitate the concurrent dietary and medical therapy of renal failure in these animals and bolster owner satisfaction and commitment to therapy. The changes in clinical attributes also affirm the important contributions of anaemia to the signs of inappetence, weakness, fatigue, lethargy, cold intolerance and ‘behavioural apathy’ that characterize uraemia in dogs and cats. Clinical benefits are realized with correction of any degree of anaemia in uraemic animals, however, the adverse consequences of therapy (see below) restrict its use to those with moderate to severe anaemia. Overall, the short- and long-term efficacy of erythropoietin replacement to resolve the anaemia and improve well-being is unparalleled by any other modality of therapy and reinforces the necessity to treat the anaemia in all animals with chronic renal failure.

Recommendations for r-HuEPO administration in uraemic animals

Erythropoietin-replacement with r-HuEPO is indicated in animals symptomatic for the hypoproliferative anaemia of renal failure. The clinical consequences of anaemia become significant as the haematocrit falls below 25% and become more profound as the anaemia progresses. Correction of even mild degrees of anaemia can be dramatic and beneficial, but the clinical gains of r-HuEPO administration must justify the attendant risks. For animals with moderate anaemia and minimal disability, the use of r-HuEPO should be reserved. In animals with moderate to severe anaemia (haematocrit <25%) and clinical signs consistent with the anaemia, the risks of treatment usually are warranted and beneficial.

Administration of r-HuEPO is divided into an initiation phase to activate erythropoiesis and a maintenance phase to perpetuate the response. The target haematocrit is 30–40% for cats. An initial dose of 100 units/kg body weight administered subcutaneously three times weekly is maintained until the bottom of the target range is reached. Thereafter the dosage interval is decreased to twice weekly to prevent overshooting the target range. As the haematocrit approaches the upper target value, the dosage interval is reduced further to once weekly to prevent polycythaemia. The dosage schedule is further modified as required between once and three times weekly to maintain the haematocrit within the target range.

A lower initial dose (50–100 units/kg three times weekly) may be used if a slower response is acceptable or appropriate for the patient. If the target haematocrit is not achieved within 8–12 weeks, the initial dose can be incremented progressively by 25–50 unit/kg every 3 to 4 weeks while maintaining the dosage interval at three times weekly. Treatment should be withheld temporarily if the haematocrit exceeds reference ranges. Once the haematocrit is reestablished at the upper limit of the target range, treatment should be re-instituted at a lower dosage schedule. Due to the finite lag between dosage modifications and responses in haematocrit, adjustments to either the dosage or interval of administration should not be performed more frequently than every three weeks. More frequent dosage adjustments may result in large fluctuations of haematocrit, the tendency to ‘chase’ the volatile excursions with further dosage adjustments, and failure to achieve a smooth transition to the maintenance dosage. Rapid decreases in haematocrit following usual dosage reductions may indicate anti-r-HuEPO antibody formation and should prompt further evaluation of the patient (see below).

The maintenance dosage to sustain the haematocrit within the target range must be established according to the responses of individual patients by frequent monitoring of the haematocrit and judicious adjustment of the dosage and/or interval of administration. Generally, a dose of 75–100 units/kg subcutaneously once or twice weekly is sufficient. r-HuEPO therapy is required for the life of the patient and should not be discontinued when the anaemia is corrected. Maintenance treatments should not exceed thrice weekly or be less than once weekly.

Failing an adequate initial response or if the patient becomes unresponsive to r-HuEPO, a thorough evaluation for iron deficiency, external blood loss, concurrent haemolytic, infectious, inflammatory or neoplastic diseases, or the development of anti-r-HuEPO antibodies that could diminish or prevent erythropoiesis should be performed.

Iron supplementation

All patients treated with r-HuEPO should be supplemented with iron to prevent iron depletion and to foster the therapeutic response. Serum iron concentration, total iron binding capacity (TIBC), and percent transferrin saturation [(serum iron/TIBC)x100] should be normalized prior to initiating r-HuEPO therapy by administration of ferrous sulfate orally at 50 to 100 mg/day for cats. Maintenance iron therapy should be provided with oral ferrous sulfate or multivitamin preparations that contain ferrous sulfate at similar daily doses. Many cats do not tolerate oral iron supplementation and are better treated with parenteral injections of iron dextran at 50 mg IM every 3 to 4 weeks.

Monitoring the therapeutic response

The potency of r-HuEPO and the requirement for lifelong therapy necessitate regular evaluation of the patient to insure therapeutic efficacy and to identify untoward effects of treatment. Hematocrit should be monitored weekly until it is established within the target range for at least 4 weeks. Thereafter, a complete blood count including an absolute reticulocyte count should be performed at monthly or bimonthly intervals to insure adequacy of the erythropoietic response and to monitor for adverse hematologic reactions. A sudden decrease in haematocrit, absolute reticulocyte count, or development of anaemia in the face of adequate doses of r-HuEPO and normal iron metabolism may signal development of iron deficiency, external blood loss, haemolytic disease, concurrent infectious, inflammatory or neoplastic diseases or the development of anti-r-HuEPO antibodies that could diminish erythropoiesis. The development of these disorders should be investigated before the dosage is increased. The absence of circulating reticulocytes or a bone marrow aspirate demonstrating severe erythroid hypoplasia (M:E ratio >10) is consistent with development of anti-r-HuEPO antibodies and contraindicates further r-HuEPO administration. Antibody formation is unpredictable but commonly manifests after 4 to 16 weeks of therapy.

Serum iron, TIBC and erythrocyte indices (MCV, MCH, MCHC) should be monitored 3 to 4 weeks after starting r-HuEPO therapy and then monthly or bimonthly for the duration of treatment to assess disorders of iron metabolism and the adequacy of iron supplementation. Systemic blood pressure should be measured at least monthly during the initiation phase of therapy and monthly or bimonthly thereafter to monitor the development or exacerbation of hypertension. Complications including pain, inflammation or discoloration at injection sites should be evaluated regularly to ascertain if the patient is allergic or sensitive to the drug.

Cessation of therapy

r-HuEPO therapy should be discontinued if any of the following adverse events are recognized: polycythaemia, fever, anorexia, joint pain, cellulitis or cutaneous or mucosal ulceration which might indicate systemic or local sensitivity to r-HuEPO. Treatment should be started cautiously (or withheld) from patients with moderate to severe hypertension or iron deficiency until these conditions have been controlled. Treatment should be withheld temporarily if the haematocrit exceeds normal limits until it is re-established within the target range.

Adverse effects of r-HuEPO in animals

Progressive decreases in haematocrit, red blood cell count, and haemoglobin concentration secondary to development of anti-r-HuEPO antibodies are the most problematic consequence of r-HuEPO administration in animals. Development and onset of antibody formation is variable in individual animals, but current experience predicts the incidence may be on the order of 25% to 30% of treated animals. The binding of antibody to r-HuEPO and native erythropoietin nullifies their physiologic actions on erythroid progenitor cells to cause bone marrow failure and refractory anaemia. Antibodies dissipate with a variable time course after discontinuation of r-HuEPO, but the anaemia can resolve only to pretreatment haematocrit values. Assays to document the production of anti-r-HuEPO antibodies are not available for routine clinical assessment, but their presence can be predicted by M:E ratios greater then 10 in bone marrow aspirates or absence of circulating reticulocytes in animals receiving r-HuEPO. The adverse consequences of r-HuEPO administration temper the benefits associated with resolution of the anaemia and make therapy with r-HuEPO a serious clinical responsibility. Other adverse effects associated with r-HuEPO therapy in animals result from pathophysiologic adaptations to the increased red cell volume in animals acclimated to the anemic state or secondary to the stimulation of erythropoiesis per se. These effects include seizures, systemic hypertension, and iron depletion. For those unfortunate cats who develop anti-r-HuEPO antibodies the availability of species specific recombinant erythropoietin or erythropoietin gene therapy remain on the foreseeable horizon and should resolve this ‘unmet’ need for those animals.

Systemic hypertension

Systemic hypertension is a consistent clinical feature of chronic renal failure in cats although the prevalence varies regionally and with differences in the definition of abnormal blood pressures. Acute blindness, retinal detachment, hyphaema, and retinal haemorrhage are its major external features but occur uncommonly and only at systolic pressures exceeding 180 mmHg. The most consistent manifestations are subclinical resulting from sustained increases in perfusion pressure to peripheral organs. The arterial vasculature and secondarily the kidneys, heart, eyes and brain are affected most profoundly. Left ventricular hypertrophy, coronary artery occlusion, arteriosclerosis and myocardial ischaemia may be recognized in animals with hypertension. The cerebrovascular effects include hypertensive-induced encephalopathy (manifested by intermittent confusion, depression and collapse), dementia and cerebrovascular haemorrhage causing coma and death. Ophthalmic lesions include, haemorrhage in the anterior chamber, vitreous, and retina, papilledema, constriction of the retinal vasculature, retinal edema, perivasculitis and retinal atrophy. The renal effects of hypertension are most significant because of their insidious and life-threatening consequenses. Necrosis, focal and segmental proliferation and sclerosis, fibrinoid lesions, hyalinization, and capillary occlusion develop in glomeruli in direct response to elevated pressures. Tubulointerstitial lesions include ischaemia, necrosis and atrophy, interstitial fibrosis, nonsuppurative interstitial nephritis, and nephrosclerosis. Proteinuria and hyposthenuria are also consistent features.

Despite the long-standing recognition of the consequences of hypertension in cats with chronic uraemia, it remains one of the most consistently ignored and ‘unmet’ clinical consequences of uraemic animals. This circumstance is not due to a lack of specific therapeutic options but rather the generalized lack of professional awareness of systemic hypertension in animals and the failure of veterinarians to measure blood pressure in their routine assessment of animal disease. The diagnosis and management of hypertension requires accurate measurements of arterial blood pressure and an understanding of normal blood pressure regulation. Many variables including the measuring technique and conditioning of the animal cause inconsistencies in blood pressure assessment and may lead to erroneous diagnoses. The accuracy of indirect Doppler techniques and oscillometry in cats make these non-invasive and non-painful techniques well suited for routine clinical evaluations in cats. The clinical definition of hypertension is poorly defined in cats and has changed over recent years with increased reliance on indirect measurement techniques. By historical convention systolic pressures between 160–165 mmHg and diastolic pressures between 90–95 mmHg have been considered upper thresholds of normotension in cats. Although these ranges may be redefined in the future they serve as useful clinical guidelines.

In veterinary practice the diagnosis of hypertension generally is established with spot pressure measurements obtained in the clinic or hospital. In the clinical setting, blood pressure measurements have been shown to increase variably compared to pressure measurements obtained in more neutral areas. Screening blood pressure measurements are sufficient for the majority of animals who are normotensive. Animals with elevated screening blood pressures require subsequent testing at a time when the animal is acclimated to the testing environment to discriminate between those with clinical hypertension and those with a predisposition to hypertension or a ‘white-coat’ influence. A diagnosis of hypertension should be established on the basis of a series of blood pressure measurements that span at least 30 min. The clinical diagnosis of hypertension should never be established on the basis of a single blood pressure measurement.

Management of systemic hypertension

It is not possible to accurately diagnose nor is it rational to manage systemic hypertension without accurate and reproducible measurements of blood pressure. The risks for acute complications of hypertension appears as systolic pressures exceed 180 mmHg and diastolic pressures exceed 110 mmHg. For patients with overt signs of retinal haemorrhage or detachment, blindness, seizures, epistaxis, encephalopathy or accelerated renal failure the decision to treat hypertension is incontrovertible. For milder forms of hypertension (systolic pressure 160–179 mmHg; diastolic pressure 90–109 mmHg), the indications to treat are more controversial, but a judicious therapeutic approach seems appropriate in light of the pathologic effects of sustained hypertension. The treatment for hypertension remains anecdotal but generally consists of dietary salt restriction and antihypertensive drugs to counteract the disordered pressor control systems.

Non-drug therapy. Dietary sodium restriction provides a foundation for other antihypertensive measures but alone corrects only mild hypertension. Sodium intake should be reduced moderately to approximately 0.3% of the diet (dry matter). Commercial diets may provide greater than 0.6% sodium. To limit dietary sodium, it is usually necessary to prescribe specialty dietary products or commercial ‘senior’ diets. In patients with moderate or advanced renal insufficiency, the transition from a high- to a lower-sodium diet should be made gradually. Salt restriction provides only modest decreases in blood pressure but serves as adjunctive therapy for antihypertensive drugs and is pivotal to the treatment plan.

Drug Therapy. Antihypertensive therapy is intended to counteract derangements of cardiac output or peripheral vascular resistance, the major determinants of blood pressure. Many traditional antihypertensive drugs have been replaced by newer agents with specific actions and improved patient tolerance. Therapy should achieve the desired pressor control with the least amount and least number of drugs, the lowest toxicity, and the least client involvement and expense. Antihypertensive therapy should be initiated only if the capability to monitor blood pressure exists. Otherwise, it is impossible to document efficacy and avoid hypotension. For mild or moderate degrees of hypertension with no overt ocular, CNS or cardiovascular complications, therapy should be initiated with a single antihypertensive drug.

Angiotensin converting enzyme (ACE) inhibitors are often reserved for refractory hypertension or combination drug therapy but may be prescribed as a first-choice drug in moderate or severe hypertension. Enalapril, benazepril, or lisinopril block the conversion of angiotensin I to angiotensin II, reverse vasoconstriction, and decreased peripheral vascular resistance and aldosterone secretion. Caution should be used when ACE inhibitors are given to patients with renal insufficiency as they can initiate acute decompensation of renal function and progressive azotaemia in some patients. ACE inhibitors are gaining increased attention for their capacity to reduce glomerular protein loss and their potential to slow the progression of renal insufficiency. As these therapeutic effects are confirmed, ACE inhibitors may become the predominant therapy for renal parenchymal hypertension.

Calcium entry blockers inhibit the entry of calcium into cardiac and smooth muscle and interfere with calcium-dependent contraction of the heart and vascular smooth muscle. These actions promote potent negative inotropic and chronotropic effects and decreases in vascular resistance. This class of drugs (includes diltiazem and amlodipine) is useful in resistant forms of hypertension. Amlodipine has been used most consistently for hypertension in cats. Potential side effects include hypotension, edema, conduction disturbances, heart failure and bradycardia. Calcium entry blockers should be used cautiously with other negative inotropic drugs like propranolol.

Vasodilators act directly on the vascular smooth muscle via incompletely understood mechanisms to promote vasodilation and reduce peripheral vascular resistance. Because of these actions, they are effective antihypertensive agents but stimulate sodium retention and reflex sympathetic tone requiring combination with diuretics or adrenergic inhibitors for prolonged efficacy. Hydralazine is a direct acting vasodilator that has been used safely and effectively in dogs and cats for the management of both hypertension and congestive heart failure. Because of its renal excretion, the dosage should be modified in animals with renal insufficiency.

If the response to dietary salt restriction and initial drug therapy is inadequate after two weeks of treatment, the following actions should be considered: (1) Increase the dose of the current drug to a higher but nontoxic level. (2) Change to another class of antihyperrtensive drug and prescribe as monotherapy. (3) Add a second drug to the treatment regimen. Long-term antihypertensive management requires ongoing control of predisposing diseases and frequent surveillance of blood pressure. The response to initial therapy in individual patients is highly variable. Similarly, many patients become refractory to initial therapy and require dosage adjustments or drug modifications to maintain pressor control.

Mineral disorders of chronic renal insufficiency

Disorders of mineral metabolism have been well characterized and represent classic disturbances of renal homeostasis and the adaptation to progressive nephron loss. The biochemical and clinical manifestations of these disorders affect virtually every organ in the body. The biochemical abnormalities include hyperphosphatemia, hypo- or hypercalcaemia, increased [calcium] x [phosphate] product, increased fractional phosphate excretion, hypermagnesemia and sometimes increased serum alkaline phosphatase. Hyperparathyroidism is an important feature of renal insufficiency, and parathyroid hormone has been regarded as a significant ‘uraemia toxins’. The final conversion of vitamin D to its metabolically active form, 1,25-dihydroxyvitamin D₃, occurs exclusively in the kidney. With progressive destruction of renal parenchyma 1,25-dihydroxyvitamin D₃ synthesis is impaired and a deficiency state proportional the severity of renal failure results. In addition to its effects to promote intestinal calcium absorption and its permissive role in osseous calcium mobilization, 1,25- dihydroxyvitamin D₃ is an integral component in the feedback regulatory control of parathyroid gland proliferation and PTH synthesis.

Extraosseous, soft-tissue mineralization develops as the [calcium] x [phosphate] product increases and the excess insoluble mineral is deposited in soft tissues including: gastric mucosa, bronchial walls, myocardium, endocardium, renal interstitium, glomeruli, lungs, intercostal muscle, and the posterior capsule of the eye. There is compelling evidence in both dogs and cats that the mineral disorders promote interstitial inflammation, fibrosis, and progression of renal insufficiency.

Management of mineral disorders and hyperparathyroidism

Mild/Moderate Renal Insufficiency. The early stages of phosphate retention and hyperparathyroidism can be prevented by reductions in dietary phosphate proportional to the decrement in renal function. Therefore in mild/moderate renal insufficiency, phosphate should be reduced to 30% to 50% of normal intake, respectively (0.5–0.3%, dry matter). Prescription diets may be warranted in selected cases. In the early stages of renal insufficiency there will be no convenient means to document the efficacy of therapy since serum phosphate and calcium concentrations are generally well regulated at this stage of disease. At a minimum, however, therapy should maintain these solutes and parathyroid hormone concentration with reference ranges.

Moderate/Severe Renal Insufficiency. As renal function worsens, moderate restriction of dietary phosphate is usually insufficient to prevent phosphate retention, hyperphosphatemia, and hyperparathyroidism. Dietary phosphate should be reduced further by providing a therapeutic diet that is moderate to maximally restricted in protein and phosphate. When dietary measures alone (at the appropriate level of protein intake) fail to reduce serum phosphate to the reference range, dietary phosphate binding drugs should be added to the therapeutic regimen. Phosphate binding agents combine with soluble phosphates derived from the diet and digestive secretions to form insoluble complexes that escape intestinal absorption and augments fecal phosphate excretion. Aluminium-based antacid compounds (aluminium hydroxide, aluminium carbonate, aluminium oxide) have been used in both human and veterinary medicine. Each product has slightly different phosphate binding abilities but an empirical starting dosage of 30 to 90 mg/kg body weight/day divided with each feeding is recommended with phosphate-restricted diets. To be effective the binding agent must be administered simultaneously with the ingested meal. For animals with sporadic appetites, fixed dosing 2 to 3 times daily is generally ineffective. It is more effective to combine the phosphate-binding drug with the meal so it is always timed with the consumed diet. The dosage of phosphate binders must be adjusted at 2 to 3 week intervals until serum phosphate stabilizes in the reference range.

Aluminium-based phosphate binding agents are moderately efficacious but predispose patients to aluminium toxicity at high dosages or after long-term usage. The consequences of aluminium toxicity include encephalopathies, muscle weakness and osteomalacia. Microcytosis is an additional manifestation of aluminium ingestion identified in cats treated with large doses of aluminium carbonate. Aluminium antacids may also produce constipation in some animals. To obviate the concerns about aluminium, calcium-containing phosphate binding agents have been advocated. Calcium carbonate, calcium citrate and calcium acetate complex dietary phosphate as effectively as aluminium and are comparable substitutes. Calcium acetate has the most effective binding properties and is provided at initial dose of 60 to 90 mg/kg body weight/ day divided among each meal. This dosage must be monitored and adjusted to establish a normal serum phosphate concentration. Calcium-containing phosphate binders are contraindicated in patients with preexisting hypercalcaemia or markedly elevated serum phosphate concentration. In these circumstances, aluminium-containing phosphate binding agents should be used initially to lower serum phosphate closer to the reference range before substitution or combination of calcium-based binders to lower serum phosphate further into the reference range. Calcium citrate, however, should not be used in combination with aluminium-based agents because it enhances the intestinal absorption of aluminium. A non-mineral synthetic phosphate binding polymer is now available and may provide a better tolerated alternative to calcium or aluminium based drugs.

Investigations have demonstrated a pivotal role for 1,25-dihydroxyvitamin D₃ (Calcitriol) in the pathophysiology and management of the hyperparathyroidism of chronic renal failure. In subcalcemic doses, 1,25-dihydroxyvitamin D₃ inhibits parathyroid hormone secretion, parathyroid gland hyperplasia and alleviates the hyperparathyroidism of chronic renal failure in some (but not all) cats. When given at 1–5 ng/kg body weight/day it can resolve secondary hyperparathyroidism with inconsistent effects on intestinal calcium absorption and risk of hypercalcaemia. The current formulation of Calcitriol requires recapsulation of the product into dosage units suitable for cats. Because of its potential to cause hypercalcaemia, serum calcium should be closely monitored along with serum PTH during therapy to document its safety and efficacy.

Subtotal parathyroidectomy is an additional approach to the management of severe hyperparathyroidism. A newly described and clinically attractive approach involves percutaneous, ultrasound-guided thermal-ablation of hypertrophied parathyroid glands in dogs. This modality obviates the risks of surgery and the benefits of staged and graded degrees of ablation. This approach should be equally efficacious in cats with hyperparathyroidism of chronic uraemia.

Renal replacement therapy—haemodialysis, renal transplantation, and specific sorbent therapy

Ultimately, renal insufficiency progresses to an end-stage. The efficacy of medical approaches for the treatment of chronic uraemia become limited as the serum creatinine exceeds 600 μmol/l (7 mg/dl), and the clinical manifestations of uraemia become overt as the BUN exceeds 3236 mmol/l (90 to 100 mg/dl). At this stage of disease, it becomes increasingly difficult to ‘meet’ the therapeutic goals of uraemic cats with conventional medical approaches, and some form of renal replacement therapy is necessary to ameliorate the azotaemia, electrolyte, mineral and acid base disorders, nutritional deficiencies, and systemic hypertension complicating chronic renal failure. Renal replacement therapy with dialysis or transplantation becomes the only available means to manage the uraemia. Improved haemodialysis equipment and techniques, the increased sophistication of veterinary practice and pet owners, and the development of medical adjuncts for the management of chronic renal failure have made intermittent haemodialysis feasible for the management of chronic uraemia and for the preoperative conditioning of animals prior to renal transplantation. Haemodialysis provides an ‘excretory boost’ that lessens the azotaemia and urea exposure and provides the therapeutic difference for an animal that can be treated and one that cannot be managed effectively or survive. The use of haemodialysis in animals with CRF is considerably less than its use in acute uraemia, despite its extensive use to manage human patients with chronic renal failure. Intermittent haemodialysis is required indefinitely for animals with end-stage renal disease; however, many pet owners desire only short periods of dialytic support to adjust to the inevitable outcome of the animal's disease. How much haemodialysis is necessary to adequately control chronic uraemia is unknown and awaits future definition. An intensive haemodialysis prescription provided every 2 to 4 days can amply supplement the residual renal function of these animals. Three treatments per week is a traditional dialysis schedule for human patients and is used for animal patients with serum creatinine concentrations greater than 700 μmol/l (8 mg/dl). Twice weekly dialysis is the minimum effective schedule but will still benefit animals with serum creatinine concentrations between 440 and 700 umol/l (5 mg/dl and 8 mg/dl). The justification to initiate chronic dialysis therapy in animals whose serum creatinine concentrations are less than 5 mg/dl is generally outweighed by the effectiveness of conventional management and cost of indefinite dialysis. Animals supported with maintenance haemodialysis still require comprehensive medical therapy to manage the nutritional deficiencies, anaemia, mineral disturbances, acidosis, and hypertension associated with severe renal failure.

A Bridge to (and from) renal transplantation

Finite periods of haemodialysis may be indicated for the preoperative management of animals awaiting renal transplantation. Many candidates for renal transplantation with end-stage renal disease have overt nutritional deficiencies, anaemia, and metabolic disorders that would preclude successful transplantation. Haemodialysis facilitates the conditioning of these animals otherwise unsuitable or at attendant risk for the surgery. Following transplantation, haemodialysis is used as required to support the recipient during periods of delayed graft function, revision of technical or surgical complications, acute rejection, or pyelonephritis until the graft is functioning adequately and complicating conditions have been resolved. Haemodialysis is a complimentary and essential adjunct to renal transplantation.

The high cost, intermittence, technical complications, inconvenience, ethical concerns, and very limited availability of dialysis and renal transplantation are overwhelming limitations for the generalized application of these forms of renal replacement in the management of chronic uraemia in cats. For this ‘unmet’ therapeutic goal, adjunctive therapy with therapeutic materials with the potential to selectively or nonselectively eliminate uraemia toxins and excessive solutes from the body could provide an alternative for these traditional forms of renal replacement. Oral sorbents have been evaluated as potential solutions to these therapeutic desires but historically have lacked efficacy or had too narrow a solute specificity to be of value. However, recent developments in polymer technology have generated materials with both uremia specific solute and fluid adsorptive properties which portend renewed opportunities for the clinical use of oral sorbents to ameliorate azotaemia, fluid overload, and dialysis dependency of uraemic animals. These advances will provide medical approaches for renal replacement with the potential to extend the efficacy of traditional therapeutic approaches to cats with severe chronic uraemia.

Summary

Existing advanced therapeutic approaches are able to ‘meet’ many of the contemporary ‘unmet’ clinical challenges of chronic uraemia in cats, but the effective management of uraemia requires a multifaceted approach proportional to the degree of renal insufficiency and the appearance of clinical signs. As therapeutic goals, we should resist over treatment of uraemic patients, but just as responsibly, veterinarians should be committed to an aggressive approach that is appropriate and adequate to manage all the signs and functional disorders associated with the loss of renal mass. Today, as never before, the management of renal failure is founded on a greater understanding of the causation and manifestations of uraemia and validation of contemporary therapeutics. Treatment options are facilitated by new and uniquely designed dietetic and pharmacologic modalities that both alleviate the expression and progression of chronic renal failure as well as cure some of its most devastating and deeply cloaked manifestations. The future radiates new optimism with the emergence of non-traditional and nonconventional therapeutic opportunities like species specific erythropoietin replacement, intermittent chronic haemodialysis, renal transplantation, and oral sorbents.