Treatment

6. Treatment

Tailored supportive medical therapy has been the mainstay of management for chronic renal failure for decades. The goals of medical management are to:

1. Reduce the renal work load
2. Alleviate the clinical signs and biological consequences of the uremic intoxications
3. Minimize disturbances in fluid, electrolyte, vitamin, mineral and acid base balance
4. Slow progression of the disease.

Therapy should not necessarily be expected to reverse or eliminate the renal lesions responsible for the CRF. However, when CRF progresses due to an evolving disease (pyelonephritis, chronic urinary obstruction, nephrolithiasis, renal lymphoma, some immune-mediated diseases), rapid identification and appropriate treatment of the disorder may halt or slow progression of the renal disease.

Chronic renal failure is progressive and dynamic, hence, serial clinical and laboratory assessment of the patient and modification of the therapy in response to changes in the patient's condition is integral to successful therapy. Select therapeutic agents used in the management of chronic renal failure are listed in Table 5.

Many renal failure patients are exquisitely sensitive to the gastrointestinal side-effects of prescribed drugs. The clinician also needs to consider the potential adverse effects of "poly pharmacy" and drug interactions. Furthermore, many medications undergo renal excretion and the dosages will need to be modified to account for delayed clearance and the longer half life the drug. Ideally dosage adjustments should be made according to changes in drug clearance which may be estimated by measuring creatinine clearance. The drug dose is then adjusted according to the percent reduction in creatinine clearance (i.e. the ratio of the patients' creatinine clearance to normal creatinine clearance). For example if the normal dose is 10 mg/kg q 8 hrs and the creatinine clearance is 25% of normal, the dose should be altered to 2.5 mg/kg q 8 hrs or 10 mg/kg q 32 hours. For the owner's compliance, decreasing the dose is often better accepted than stretching the administration interval (although it might be necessary for specific drugs, i.e. concentration-dependent antibiotics).

The dosage regimen should be adjusted for drugs mainly excreted (>80%) unchanged by the kidney, and for drugs which are not totally excreted by the kidney and have a low therapeutic index. e.g.:

• Gentamicin: renal excretion and low therapeutic index; prescription not recommended but sometimes necessary in case of multiresistant infections
• Carboplatin: antineoplastic agent with a very low therapeutic index and renal excretion.

Although the relationship between serum creatinine concentration and creatinine clearance is not linear, creatinine clearance evolution can be estimated by the modifications of the serum creatinine concentration measured in standardized conditions for stages I and II of CRF.

Anemia

Treatment of anemia encompasses administration of androgens, blood transfusions or erythropoietin replacement therapy with recombinant human erythropoietin. In addition, every attempt should be made to minimize blood loss by venipuncture, gastrointestinal ulcerations, gastrointestinal parasites and uremic bleeding. Androgen therapy is not particularly effective in increasing the hematocrit, although improvements in lean body mass and attitude have been reported (Cowan et al., 1997). Blood transfusions will temporarily correct the anemia and are useful when rapid correction of the anemia is required prior to anesthesia or surgery. Repeated transfusions have been used to support the anemia of chronic renal failure but they are not recommended due to the increased risk of transfusion reaction.

Effective erythropoiesis is readily obtained by the administration of recombinant human erythropoietin (Cowgill et al., 1995; 1998). A dose dependent response in hematocrit can be seen within the first week of therapy, however 2 to 8 weeks of therapy is generally required to normalize the hematocrit. Erythropoietin therapy is initiated at 100 U/kg subcutaneously three times weekly with weekly monitoring of the hematocrit. Once the hematocrit is 35 - 40%, the dosing interval is decreased to twice weekly therapy. The lowest dose/frequency that maintains the hematocrit in the normal range should be identified by monitoring the hematocrit. Side effects of erythropoietin therapy include polycythemia, vomiting, seizures, pain at the injection site, fever and hypertension.

Recommendations regarding dietary therapy and other components of conservative medical management need to be individualized to patient needs based on clinical and laboratory findings. (© Lenfant).

Some dogs will develop erythropoietin antibodies that effectively neutralize endogenous and exogenous erythropoietin. These patients are identified by either refractory anemia or the development of anemia weeks to months following institution of therapy. Diagnosis requires elimination of other causes of anemia and bone marrow assessment of myeloid to erythroid ratios (M:E ratio > 10). Treatment requires cessation of recombinant erythropoietin therapy. After therapy is stopped, the antibody concentrations will decline and the pretreatment levels of endogenous erythropoietin and hematocrit will be obtained. Blood transfusions may be required until the hematocrit stabilizes. The future availability of canine recombinant erythropoietin will eliminate the development of antibodies to human recombinant erythropoietin (Randolph et al., 2004).

A risk-benefit assessment is necessary prior to institution of human recombinant erythropoietin. Erythropoietin therapy is generally recommended when the packed cell volume is less than 25%. At this stage, the benefits of improved clinical status with increases in appetite, body weight, energy level and sociability appear to out weigh the risks of antibody formation. Iron deficiency secondary to gastrointestinal blood loss generally accompanies CRF. Iron status can be assessed by serum iron, transferrin, ferritin, or total iron binding capacity (TIBC). Oral supplementation with iron sulfate (100 to 300 mg/day) is recommended, particularly in patients starting erythropoietin replacement therapy. Intramuscular iron dextrans can be used, however, the risk of iron overload is increased. Side effects of iron therapy include gastrointestinal disturbances (diarrhea).

Two to eight weeks are generally needed to normalize the hematocrit during erythropoietin replacement therapy.

Acidosis

Alkalinizing agents (potassium citrate, sodium bicarbonate, calcium carbonate) should be initiated when the TCO2 or bicarbonate concentration is less than 18 mmol/L. Alkalinization therapy will improve the clinical signs of anorexia, lethargy, nausea, vomiting, muscle weakness and weight loss in addition to preventing the catabolic effects of metabolic acidosis on protein metabolism.

Sodium bicarbonate is the most commonly utilized alkalinizing agent but it will contribute to the sodium load of the patient and may need to be avoided in patients with hypertension or cardiac insufficiency. Calcium carbonate should be used with caution in hyperphosphatemic patients as the increased dietary calcium may precipitate soft tissue mineralization. Potassium citrate provides the additional advantage of supplying potassium and may be attractive for patients with both hypokalemia and metabolic acidosis. The dose of alkalinizing agent needs to be individualized for each patient and requires routine monitoring of acid base status.

Fluid Balance

Compensatory polydipsia balances excessive fluid loss associated with polyuria, however, some patients will fail to consume sufficient water to prevent volume depletion. In these cases, cautious fluid supplementation should be used to prevent dehydration and attendant vascular depletion. Maintenance fluids (e.g., plasmalyte 56, plasmalyte M, Normosol M) can be administered subcutaneously. Chronic administration of lactated ringers solution or sodium chloride will cause hypernatremia due to failure to provide sufficient free water. Conversely, 5% dextrose in water is hypotonic and should not be administered subcutaneously.

Hypokalemia

Potassium supplementation is indicated when the serum potassium concentration is less than 4 mmol/L and may be achieved by oral potassium gluconate or potassium citrate supplementation. Muscle weakness typically resolves within five days of institution of therapy. Side effects include gastrointestinal irritation, ulceration, nausea and vomiting. Potassium dosage should be adjusted by monitoring the serum potassium concentration and response to supplementation.

Antihypertensive Therapy

Antihypertensive therapy is indicated upon the repeatable demonstration of systemic hypertension. The clinical diagnosis of hypertension should never be made on the basis of a single blood pressure measurement.

IRIS (http://www.iris-kidney.com/) considers that an animal with CRF is hypertensive when its systolic blood pressure exceeds 180 mm Hg. If the systolic blood pressure is between 150 and 179 mm Hg, and if there is some extrarenal evidence of hypertension (e.g., retinopathy, left ventricular hypertrophy), the animal is also considered hypertensive. Otherwise, the case is borderline and re-evaluation of blood pressure is recommended within 2 months.

The goal of antihypertensive therapy is to lower the blood pressure to the normal range. The initial selection of antihypertensive agent will be guided by the presence or absence of clinical signs of hypertension, i.e. signs of retinal detachment and hemorrhage dictate a more aggressive therapeutic approach to lower systemic blood pressure and restore vision in a timely fashion. Repeated blood pressure determinations will be required to modify and guide a step wide selection of antihypertensive drugs.

Antihypertensive drugs include diuretics, adrenergic antagonists (propanolol), ACE-inhibitors, calcium channel blockers (amlodipine), and vasodilators. Selection of the appropriate therapeutic agent should be made on the basis of appropriate hypertensive control, expense, and side-effects. The most commonly recommanded treatment relies on the association between ACE-inhibitors and amlodipine. With ACE-inhibitors alone, blood pressure can be decreased by 30 mm Hg.

The blood pressure should be rechecked within 2 weeks following institution of therapy. If there has been no response consider:

1. Increasing the dose of the current drug
2. Change to a different class of drug
3. Adding an additional drug to the therapeutic regime.

Long term monitoring of blood pressure is required as frequent dosage adjustments may be required and some patients will become refractory to the initial therapy necessitating therapeutic modification.

ACE inhibitors have been used in normotensive dogs with glomerular disease. Enalapril has been shown to significantly reduce proteinuria and improve the clinical signs in dogs with naturally occurring glomerulonephritis (Figure 10) (Grauer & al, 2000). Proteinuria is not only a biological sign of renal injury, but also an aggravation factor of CRF. Reducing proteinuria is hence a therapeutic goal. Only the ACE inhibitors have a demonstrable antiproteinuria effect in dogs. Ace inhibitors can also slow down the progression of CRF (Lefebre & Toutain, 2004).

Figure 10. Mean value of urine protein to creatinine ratio in dogs treated with placebo or enalapril (Grauer et al., 2000).

Hyperphosphatemia

Minimizing hyperphosphatemia will limit renal secondary hyperparathyroidism, renal osteodystrophy, soft tissue calcification and the progression of renal failure. The restriction of dietary intake and oral administration of intestinal phosphorus binding agents (Table 6) normalizes serum phosphate concentrations. Intestinal phosphate binding agents combine with phosphate contained in dietary and digestive secretions to form insoluble complexes that are excreted in the feces. They should be mixed with the food prior to feeding to ensure maximal phosphate binding effectiveness.

Calcitriol Replacement Therapy

Calcitriol replacement therapy can limit renal secondary hyperparathyroidism. However supplementation is required for life (Nagode et al., 1996). Therapy mandates serial measurement of serum calcium and phosphorus levels to avoid hypercalcemia and soft tissue mineralization. The risk of hypercalcemia is heightened by the concurrent administration of calcium based intestinal phosphate binding agents. Calcitriol should not be given with meals because it enhances intestinal calcium and phosphate absorption. In addition, the serum phosphorus concentration must be within the normal range prior to initiating therapy to minimize the risk of soft tissue calcification. The serum PTH concentration should return to normal or almost normal within 1 to 2 weeks of initiating therapy.

A recent study (Gerber et al., 2003) indicated that calcitriol concentration was within reference range for most dogs with renal failure. These results suggest that calcitriol replacement would not be required in such patients.

Gastrointestinal Disorders

Antiemetics such as metoclopramide or phenothiazine derivatives can be used to suppress central vomiting centers. Histamine receptor blocking drugs (cimetidine, ranitidine, famotidine) or proton pump blockers (omeprazole) in combination with gastrointestinal protectorant agents such as sucralfate or misoprostol may be used to prevent gastrointestinal ulceration.