Slowing The Progression Of Chronic Renal Failure

Gregory F. Grauer, DVM, MS, Diplomate, ACVIM (Internal Medicine)
Department of Clinical Sciences,
Kansas State University, Manhattan, Kansas

 

Etiology and Pathogenesis:

The cause of chronic renal disease leading to chronic renal failure (CRF) is usually difficult to determine. Because of the interdependence of the vascular and tubular components of the nephron, the end-point of irreversible glomerular or tubular damage is the same. A morphologic heterogeneity among nephrons exists in the chronically diseased kidney, with the changes ranging from severe atrophy and fibrous scar tissue replacement to marked hypertrophy. The histopathologic changes however, are not process-specific; therefore the cause is usually unknown. Nevertheless, recent studies have shown that primary glomerular disorders are a major cause of CRF in the dog. Because glomerular filtration in toto is uniformly reduced, CRF in dogs and cats may be considered a single pathologic entity, although many diverse pathways can lead to this end-point. In progressive diseases that slowly destroy nephrons, intact nephrons undergo a compensatory hypertrophy. When renal failure finally occurs, the hypertrophied nephrons can then no longer maintain adequate renal function. Renal lesions associated with CRF are usually irreversible and often progressive; therefore treatment of the CRF rarely improves renal function.

The pathophysiology of CRF can be considered at both the organ and systemic level. At the level of the kidney, the fundamental pathologic change that occurs is a loss of nephrons and decreased GFR. Reduced GFR in turn results in increased plasma concentrations of substances that are normally eliminated from the body by renal excretion. The constellation of clinical signs known as the uremic syndrome is thought to occur, at least in part, as a result of increasing plasma concentrations of these substances. Components of the uremic syndrome include sodium and water imbalance, anemia, carbohydrate intolerance, neurologic disturbances, gastrointestinal tract disturbances, osteodystrophy, immunologic incompetence, and metabolic acidosis.

In addition to excreting metabolic wastes and maintaining fluid and electrolyte balance, the kidneys also function as endocrine organs and catabolize several peptide hormones. Therefore hormonal disturbances also play a role in the pathogenesis of CRF. For example, the decreased production of erythropoietin and calcitriol in animals with CRF contributes to the development of nonregenerative anemia and hyperparathyroidism, respectively. Conversely, decreased metabolism and increased concentrations of parathyroid hormone and gastrin contribute to the development of hyperparathyroidism and gastric hyperacidity, respectively.

Part of the pathophysiologic changes that occur in CRF are brought about by compensatory mechanisms. The osteodystrophy of CRF occurs secondary to hyperparathyroidism, which develops in an attempt to maintain normal plasma calcium and phosphorus concentrations. Similarly, the GFR of intact, hypertrophied nephrons increases in CRF in an attempt to maintain adequate renal function; however, intraglomerular hypertension, proteinuria and glomerulosclerosis in these individual nephrons leading to additional nephron damage and loss may be consequences of this hyperfiltration.

Clinical Features and Diagnosis:

Chronic renal failure develops over a period of weeks, months, or years and its clinical signs are often relatively mild for the magnitude of the azotemia. Unique historical, physical, and clinicopathologic findings in dogs and cats with CRF often include a history of weight loss, polydipsia-polyuria, poor body condition, nonregenerative anemia, and small and irregularly shaped kidneys. A diagnosis of CRF is usually based on a combination of compatible historical, physical examination, and clinicopathologic findings. Plain radiographs can confirm the presence of small kidneys. Renal ultrasonography will usually show diffusely hyperechoic renal cortices with loss of the normal corticomedullary boundary. The increased cortical echogenicity results from replacement of the irreversibly damaged nephrons with fibrous scar tissue. Radiographic studies and ultrasonography can also help identify or rule out potentially treatable causes of CRF, such as pyelonephritis and renal urolithiasis. Renal biopsy is not routinely performed in animals with CRF unless the diagnosis is in question. Renal histopathologic preparations will show some combination of a loss of tubules with replacement fibrosis and mineralization, glomerulosclerosis and glomerular atrophy, and foci of mononuclear cells (small lymphocytes, plasma cells, and macrophages) within the interstitium in association with fibrous scar tissue replacement.

Treatment:

The regenerative and compensatory nephron changes have had time to occur in an animal with CRF, yet the fact that renal failure has occurred indicates the inadequacy of these compensatory processes. Even though CRF is usually irreversible, the severity of clinical signs can generally be reduced with proper treatment. In addition, treatment is directed at the amelioration of several disorders that may contribute to progression of renal failure (e.g., systemic hypertension and soft-tissue mineralization). In animals with CRF, polyuria and compensatory polydipsia occur as a result of a decrease in the urine concentrating ability. There is a decrease in the renal medullary sodium concentration gradient because of the decrease in the number of functional nephrons, and thus in the number of sodium pumps. Decreased medullary hypertonicity decreases the medullary osmotic pressure gradient that drives the passive resorption of water from the distal tubules and collecting ducts when ADH is present. Because of the compensatory polydipsia, it is important that the animal with CRF always have water available for ad libitum consumption. If anorexia, vomiting, or diarrhea results in dehydration, fluid deficits should be aggressively replaced parenterally. The volume of fluids required is determined by the extent of dehydration and the maintenance and continuing fluid loss requirements of the patient. Daily maintenance fluid requirements in animals with CRF are higher than those of normal animals because of polyuria. If the patient with CRF is not able to drink enough to keep up with its urine output, daily subcutaneous fluids may be indicated. 

Hypertension is common in dogs and cats with CRF, occurring in as many as 75% of the patients. Although the exact mechanism responsible for causing the hypertension is not known, a combination of glomerular capillary and arteriolar scarring, a decreased production of renal vasodilatory prostaglandins, an increased responsiveness to normal pressor mechanisms, and activation of the renin-angiotensin aldosterone system may be involved. A reduction in dietary salt intake is often recommended as the first line of treatment; however, in many cases angiotensin-converting enzyme inhibitors (ACEIs) or calcium channel blockers may also be necessary to control the hypertension. Hypertension may contribute to progressive nephron loss by causing further glomerular damage associated with intraglomerular hypertension.  Recently, benazepril treatment in cats with surgically induced CRF sustained single nephron glomerular filtration.  Benazepril also reduced systemic hypertension and increased whole kidney glomerular filtration in these cats.  Based on these results, ACEIs may be an effective treatment to slow the rate of progression of renal failure in cats and possibly dogs with CRF.

A reduction in dietary protein intake has long been the cornerstone of management in dogs and cats with CRF. The benefits of this include decreased serum urea nitrogen and phosphorus concentrations. There are, however, potential undesirable effects associated with dietary protein reduction. Specifically, if dietary protein is restricted in relation to the animal’s protein needs, reduced renal hemodynamics, protein depletion (decreased body weight, muscle mass, and serum albumin concentration), anemia, and acidosis can occur or be aggravated. Just as increased dietary protein intake results in increased glomerular filtration, restricted intake is often associated with a reduction in the GFR. The anemia of CRF is exacerbated because protein depletion further compromises erythrogenesis. Dietary protein restriction also decreases renal ammoniagenesis, and therefore renal acid excretion.

Ideally, when dietary protein intake is reduced, all essential amino acid requirements are met without excesses by feeding the animal a reduced amount of high biologic-value protein. Reduced intake also results in a decreased requirement for the renal clearance of phosphorus, urea, and other nitrogenous metabolites. In animals being fed protein-reduced diets, it must be kept in mind that the energy requirements of the body have a higher priority than protein anabolism does; therefore, if the available carbohydrates and fats are insufficient to meet caloric requirements, endogenous proteins are often broken down as a source of energy. The catabolism of endogenous proteins for this purpose increases the nitrogenous waste the kidney must then excrete and exacerbates the clinical signs of renal failure.

It is generally thought that the minimum protein requirements for dogs and cats with CRF are higher than those of normal animals. Ideally, dogs with CRF should receive a minimum of 2 to 2.2 g and cats a minimum of 3.3 to 3.5 g of protein per kilogram body weight per day. One relatively common recommendation is to feed the least reduced protein diet that will still result in a reduction of the serum urea nitrogen and phosphorus concentrations. At the same time, the patient’s serum creatinine and albumin concentrations as well as their body weight should be stable. As the renal failure progresses, additional dietary protein reduction will likely be necessary. Dietary protein reduction should be initiated when the animal’s blood urea nitrogen concentration is between 60 and 80 mg/dl. Examples of commercially available diets that contain reduced-quantity, high quality protein include Hill’s Prescription Diet k/d, Purina NF-formula diets, Iams early and advanced stage renal failure, and Waltham Veterinarium medium- and low-protein diets.

Management of the hyperphosphatemia that occurs in CRF is closely related to dietary protein reduction, inasmuch as protein-reduced diets are also usually reduced in phosphorus concentrations. Hyperphosphatemia in animals with CRF occurs as a result of decreased renal excretion of phosphate. Concurrently, a decrease in the concentration of the active form of vitamin D decreases the intestinal absorption of calcium, which, in conjunction with the impaired tubular resorption of calcium, decreases the plasma concentrations of ionized calcium. Parathyroid hormone (PTH) production and release are stimulated by decreased plasma calcium and vitamin D3 concentrations. Increasing PTH concentrations facilitate the renal excretion of phosphorus and increase serum calcium concentrations by increasing renal calcium resorption and calcium absorption from bones and the gastrointestinal tract. The consequences of this hyperparathyroidism, however, can be severe and include osteodystrophy and soft-tissue mineralization. Soft-tissue mineralization occurs predominantly in damaged tissue. If it occurs in renal tissue irreversibly damaging nephrons, renal function will progressively decline. If the product of the serum calcium and phosphorus concentrations exceeds 50 to 70 mg/dl, the animal is at risk for soft-tissue mineralization. Studies in cats with CRF have shown that normal dietary phosphorus intake is associated with the occurrence of microscopic renal mineralization and fibrosis, and that decreasing the dietary phosphorus intake prevents these changes. Similar studies in dogs with CRF have shown that normal dietary phosphorus intake, as opposed to a reduced intake, is associated with a higher mortality rate. In addition to feeding the animal a phosphorus-restricted diet, enteric phosphate binders such as aluminum carbonate or aluminum hydroxide can be administered to help combat hyperphosphatemia. Enteric phosphate binders do not directly lower the plasma phosphorus concentration but bind phosphates in the intestinal tract and prevent their absorption. These agents are generally ineffective, however, if the dietary phosphorus intake is not already reduced.

A reduction in dietary phosphorus intake and the use of enteric phosphate binders usually lower but do not normalize serum PTH concentrations. The addition of ultra–low-dose (physiologic dose replacement) calcitriol treatment will generally further decrease serum PTH concentrations. Although the benefits of this treatment remain controversial, many investigators believe that PTH is a major uremic toxin that contributes to the progressive nature of CRF. Studies in dogs have shown that PTH concentrations are significantly increased in the setting of mild azotemia (serum creatinine concentrations as low as 1.5 to 2.5 mg/dl).  Calcitriol treatment should only be used, after hyperparathyroidism has been documented and the animal is well hydrated and is eating a phosphorus-restricted diet in conjunction with enteric phosphate binders. Serum phosphorus concentrations should be less than 6.0 mg/dl before and during calcitriol treatment, and the calcium X phosphorus product should be less than 70 mg/dl. Calcitriol may be given to animals with CRF that are hypercalcemic; however, their serum calcium concentration and their calcium X phosphorus product must be evaluated frequently to make sure it improves in response to treatment.  In addition, calcium-containing enteric phosphate binders should be avoided if calcitriol is administered.

Calcitriol doses of 1.5 to 3.5 ng/kg and 1.5 ng/kg PO once daily have been recommended for dogs and cats with CRF, respectively. The human formulation of calcitriol (Rocaltrol; Hoffmann-La Roche, Nutley, N.J.) comes in pharmacologic dose capsules and therefore is not suitable for dogs and cats. The proper calcitriol dose for dogs and cats should be formulated by compounding pharmacies.  For follow-up, a serum chemistry profile should be obtained at 1 week, 1 month, and then monthly to ensure that hypercalcemia and hyperphosphatemia do not occur. Hypercalcemia caused by ultra–low-dose calcitriol is rare and should resolve within 4 days of the discontinuation of treatment. If hypercalcemia does not resolve after discontinuation, other potential causes (e.g., hypercalcemia of malignancy) should be investigated. If hyperphosphatemia develops during calcitriol treatment, further dietary phosphorus restriction or an increase in the dosage of enteric phosphate binders, or both, are necessary. Ideally, serum PTH concentrations should be measured before and at 1, 3, and 6 months after the start of calcitriol treatment to ensure that they have decreased and remain in the normal range. Intact-PTH assays should be used for measuring serum PTH concentrations, and specific instructions for sample handling should be obtained in advance from the laboratory (e.g., Animal Health Diagnostic Laboratory, Endocrine Diagnostic Section, B629 West Fee Hall, Michigan State University, East Lansing, Mich. 48824-1316).

Vomiting and anorexia are common in dogs and cats with CRF and can often result in decreased caloric intake and dehydration. Causes of the vomiting and anorexia include (1) stimulation of the chemoreceptor trigger zone by uremic toxins; (2) decreased excretion of gastrin, resulting in increased gastric acid secretion (serum gastrin concentrations in dogs and cats with renal failure may be as high as five and 20 times the normal concentrations, respectively); and (3) gastrointestinal tract irritation secondary to uremic vasculitis. Vomiting may be treated with trimethobenzamide or metoclopramide, which blocks the chemoreceptor trigger zone, or with chlorpromazine, which blocks the emetic center. Metoclopramide also increases gastric motility and emptying without increasing gastric acid secretion and is the drug of choice for the management of vomiting associated with renal failure. Chlorpromazine ("-adrenergic blocker) may cause hypotension and decreased renal blood flow, and therefore should only be used if other antiemetics are ineffective. H2-receptor blockers (e.g., ranitidine) have been shown to effectively decrease gastric acid secretion, which may attenuate vomiting in dogs and cats with CRF. Oral ulcers, stomatitis, and glossitis may occur as a result of gastritis and vomiting or as a result of the effect of uremic toxins on mucous membranes. If vomiting can be controlled but the animal still will not eat enough to meet its daily calorie requirements, a feeding tube may be indicated.  Cats tend to tolerate gastrostomy tubes especially well and they can remain in place for months.  Esophagostomy and gastrostomy tubes not only facilitate provision of potentially unpalatable but appropriate calories but also provide a relatively stress-free route for fluid therapy.

The nonregenerative anemia observed in dogs and cats with CRF is the result of a combination of decreased erythropoietin production, shortened red blood cell survival, gastrointestinal tract blood loss, and the effects of uremic toxins such as PTH on erythropoiesis. Anabolic steroids may be of benefit to dogs and cats with CRF, because they promote red blood cell production and a positive nitrogen balance. These agents stimulate the differentiation of red blood cell precursors in the bone marrow, augment the renal activation of erythropoietin, and promote protein anabolism if caloric intake is adequate. In addition, increases in the red blood cell 2,3-diphosphoglycerate concentration stimulated by anabolic steroids facilitate the release of oxygen from hemoglobin to the tissues. However, several months of treatment with anabolic steroids is usually required before a response is observed, and the benefits are usually minimal. Short-term studies performed in uremic dogs treated with anabolic steroids have failed to show that they have any benefit in terms of increasing body weight, increasing the serum albumin concentration, and maintaining nitrogen balance and muscle mass. In contrast, studies assessing the effects of recombinant human erythropoietin (r-HuEPO) treatment on anemia in dogs and cats with CRF have generally shown it to be successful. However, the cost of treatment for medium-sized and large dogs is high. Although not approved for use in dogs and cats, 100 units of r-HuEPO (Epogen, Amgen, Thousand Oaks, Calif.) per kilogram of body weight given subcutaneously three times weekly has been used successfully. The dose interval is lengthened once a target packed-cell volume (PCV) is achieved (PCV of 30% to 35% in cats and 35% to 40% in dogs). This treatment, in addition to increasing the PCV, often results in increased appetite, weight gain, increased strength, and an improved sense of well-being. It should be noted, however, that there is a potential for antibodies to form in dogs and cats treated with r-HuEPO. Most studies show that anti-r-HuEPO antibodies will develop in approximately 30% to 40% of dogs and cats treated with r-HuEPO. If antibodies are produced against r-HuEPO, they may also react with endogenous erythropoietin, making the animal transfusion-dependent. In addition, oral iron supplementation may be necessary during r-HuEPO treatment because of the rapid initiation of erythropoiesis and marginal depletion of iron stores that occur in animals with CRF.  If canine and feline recombinant erythropoietins become available, our ability to treat the anemia of CRF will improve significantly.

Stressful situations should be avoided if at all possible in dogs and cats with CRF, because stress is associated with the release of endogenous corticosteroids, which may result in endogenous protein catabolism. In addition, many dogs and cats with CRF are geriatric animals that respond better to outpatient treatment than to hospitalization. Follow-up examinations of these animals should be performed at least every 2 to 4 months. Body weight; a complete blood count; the serum urea nitrogen, creatinine, calcium, phosphorus, and total protein concentrations; and urinalysis should be assessed at each follow-up visit. The keeping of data flow charts facilitates monitoring the progress of these patients. Plots of the reciprocal of the serum creatinine concentration versus age or time may help demonstrate a progressive decline in renal function, as well as a positive response to therapy.