Chronic renal failure is defined as primary kidney disease that has persisted for months to years and is characterized by a progressive destruction of nephrons. It is hypothesized that regardless of the inciting cause, after a critical level of renal dysfunction has been reached, that renal damage will be self perpetuating.

There are several similar terms used to describe this state including chronic renal disease, chronic renal failure, chronic renal insufficiency and others.

In the normal animal, not all nephrons are being fully perfused at any one time. The "resting, non-working nephrons" are the renal reserve and are called upon when the kidneys must perform "extra work" or are "called into the work force" as nephrons are lost to disease.

As CRD progresses, more and more nephrons are lost to disease and the renal reserve diminishes until all remaining nephrons are working, all of the time. The remaining nephrons hypertrophy and increase their workload in attempt to maintain homeostasis for the animal and the patient is asymptomatic. The workload per individual nephron is called the "single nephron GFR" (SNGFR). The SNGFR in disease is greater than in health but collectively the overall GFR of all the nephrons of both kidneys is reduced simply because fewer nephrons exist. The increase in SNGFR is also called hyperfiltration.

The adaptive mechanism of increased workload per nephron (hyperfiltration) is initially beneficial and initially prevents development of clinical signs but with time, the adaptive mechanisms may contribute to clinical signs and to progression of renal damage.

As renal disease progresses, the remaining nephrons show a narrower range of response to changes in the environment. The nephrons attempt to respond appropriately to changes in the environment but cannot abruptly respond as they were able to do in a state of health. For example, if the animal has a sudden increase in the intake of sodium in the diet, the nephrons will attempt to eliminate more sodium in the urine in order to keep body levels of sodium constant. The nephrons may not be able to respond completely to the change in sodium intake and sodium retension may occur. Conversely if the sodium intake in the diet is gradually increased, over days to weeks, then the remaining nephrons have time to adapt and will excrete excess sodium to maintain constant blood levels.

Eventually the increased workload on surviving nephrons reaches a point where they can no longer maintain homeostasis and the signs of renal failure become apparent. When total nephron mass is reduced to 1/3 of normal, there is an impaired ability to concentrate and dilute urine. When total nephron mass is reduced to 1/4 of normal azotemia develops.

The causes of CRF are diverse but often by the time a diagnosis of CRF is made, the inciting cause is no longer evident. Some potential causes of CRF include:

• congenital malformation of the kidneys
• chronic pyelonephritis
• renal ischemia due to vascular disease such as the vasculitis of systemic lupus erythematosis
• immunologic injury such as that caused by immune complex disease
• progression of ARF

Often the renal biopsy of patients with CRF discloses nonspecific changes that are called end stage renal disease (ESRD) which is advanced, generalized, progressive irreversible renal disease with no inciting cause evident or chronic interstitial nephritis (CIN) which likewise indicates irreversibility and unknown cause.

An attempt has been made by the International Renal Interest Society to stage CRF including levels of serum creatinine along with other laboratory or clinical signs of kidney malfunction in the staging.

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Because the kidneys perform so many diverse functions the clinical signs of uremia are polysystemic. 

1. The kidneys excrete toxins (urea, creatinine and other nitrogen containing wastes) from the body via glomerular filtration and tubular secretion.
2. The kidneys regulate body fluids, minerals and electrolytes via glomerular filtration, tubular secretion and tubular reabsorption.
3. The kidneys synthesize hormones and chemicals (erythropoietin, active vitamin D) which have local and systemic effects.

Acid-base balance in CRF:

The diet yields acids that are normally renally eliminated in order to maintain acid-base balance. Additionally the kidney must reabsorb bicarbonate that is filtered by the glomeruli. Both the mechanisms for excreting acid and preserving bicarbonate may be impaired resulting in systemic acidosis. One method the kidneys use to eliminate acid is to use ammonia (NH3) to trap hydrogen ions as ammonium ions (NH4+). When nephrons fail, the remaining nephrons increase production of NH3. Increased concentrations of both NH3 and NH4+ stimulate inflammation of renal tissues by cytokines. To some extent acidosis is buffered by mobilization of minerals from the bone which contributes to development of renal osteodystrophy. Chronic acidosis also disrupts potassium homeostasis and may contribute to hypokalemia

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Water balance:

CRF patients often have a negative water balance (another way of saying they are often dehydrated). The polyuria and gastrointestinal losses from vomiting and diarrhea must be matched by increased water intake (polydipsia) in order to remain normally hydrated. As CRF progresses, the patients become systemically depressed and may drink less or may attempt to drink but drinking water may incite vomiting.

The following discussion describes a single nephron but the concept can be extrapolated to the entire population of nephrons. The blood flow to the nephron is via the afferent arteriole. The afferent arteriole supplies blood to the capillary loops that make up the glomerulus. In a state of health ~ 1/4 to 1/3 of the plasma which enters the capillary loops in the glomerulus enter the tubular lumen as glomerular filtrate. The is called the filtration fraction:

filtration fraction = renal blood flow/ glomerular filtration

The blood which does NOT form glomerular filtrate leaves the glomerulus in the efferent arteriole which continues into the medulla of the kidney as the vasa recta capillaries which run parallel to the tubular portions of the nephrons. In health, solute (primarily urea and sodium) are deposited in the interstitium of the kidney (the black dots in the schematic). These solutes make the interstitium hypertonic so that there is a "stimulus" for water to leave the tubular lumen and enter the interstitium. In health the water will enter the vasa recta capillaries as they leave the kidney resulting in return of water to circulation.

As the overall GFR decreases, a greater amount of blood leaves the glomerulus in the efferent arteriole resulting in increased blood flow in the vasa recta capillaries. As blood flow increases, solute (urea and sodium) are "washed" out of the interstitium so that it is no longer hypertonic and there is less "stimulus" for water to leave the tubule and enter the interstitium for subsequent reabsorption. This is called medullary washout.

Additionally the increased amount of solute handled by a smaller number of nephrons osmotically results in more fluid loss.

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Secondary hyperparathyroidism and renal osteodystrophy

Bone lesions occur as a consequence of long term elevation of parathyroid hormone and as a consequence of bone buffering of metabolic acidosis. Parathyroid hormone (PTH) is secreted by chief cells of the parathyroid gland.

The effect of PTH on bone is to mobilize both calcium and phosphorus. The full effect of PTH's action on bone requires the presence of vitamin D.

The effect of PTH on the kidney is more "discriminating". PTH increases tubular Ca reabsorption (decreased excretion) and decreases tubular phosphorus reabsorption (increased excretion).

PTH also stimulates the activation of vitamin D by the kidney to the active form, (1,25 dihydroxycholecalciferol).

Secondary hyperparathyroidism (increased levels of PTH) is the price paid (the trade-off) for maintenance of phosphorus and subsequently calcium levels.

Progressive nephron destruction results in a decrease in total GFR which results in a transient increase in serum phosphorus. Increased phosphorus causes reduction in serum ionized calcium by simple mass action (as P increases Ca decreases). Reduction of ionized calcium is the stimulus for the chief cells of the parathyroid gland to increase PTH production. PTH leads to increased kidney reabsorption and intestinal reuptake of Ca, and a return of serum P and Ca to normal. A new steady state is reached with higher serum levels of PTH.

As GFR steadily falls with progressive disease, PTH levels continue to rise. Serum Ca levels are usually normal until terminal states. The response of the parathyroid glands is appropriate as it is properly responding to the stimulus of low Ca.

With time, some patients will develop autonomously functioning parathyroid glands which do not respond to the return of serum Ca to normal and continue secreting PTH resulting in hypercalcemia. Some call this tertiary hyperparathyroidism which is not common in dogs and cats as they usually don't live as long with renal disease as do people who can be maintained by dialysis and transplantation.

As functional renal mass declines to 10-15% or normal, active vitamin D is no longer produced, thus reducing intestinal Ca uptake and mobilization of Ca from bone resulting in a low serum Ca and further stimulation of PTH release

Clinical signs that may be attributable to PTH include:

• soft tissue calcification which can manifest as pruritus
• metabolic bone disease (renal osteodystrophy)
• anemia due to marrow fibrosis as a consequence of cortical bone remodeling encroaching upon the marrow cavity. PTH also increases the fragility of RBC making them more susceptible to lysis
• neuromuscular disturbances. PTH has been shown to cause disturbances in the electrical activity in neurons and muscle cells leading to mental dullness/lethargy and muscle weakness
• decreased reabsorption of amino acids
• anorexia. PTH causes a state of partial insulin resistance. Blood glucose levels are mildly increased which gives the animal the sensation of not being hungry.
• PTH impairs both cellular and humeral immunity which predisposes CRF patients to infections.
• PTH can contribute to the progression of renal dysfunction.

The bony changes of renal osteodystrophy can be subtle or striking. As bone mineral is reabsorbed under the influence of PTH, fibrous tissue may be deposited in an attempt to   "strengthen" the bone weakened by loss of mineral. The  most marked gross changes in bone structure occur in young dogs.The bones may become more flexible due to loss
of mineral: "rubber jaw"

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Anemia of CRF is nonregenerative, normocytic and normochromic. It is caused by deficiency of erythropoietin releasing factor, erythroblast inhibition, reduced survival of RBC, iron deficiency (blood loss, impaired absorption), myelofibrosis, chronic infection, or loss due to coagulation abnormalities.

Coagulation abnormalities arise from abnormal function of normal numbers of platelets which is called thrombocytopathia.

Sodium handling by diseased kidneys: The kidneys still try to maintain sodium balance by excreting excess or conserving in states of limited intake. Each nephron must excrete more sodium to maintain balance and there is a narrower range of response which leads to an inability of the chronically diseased kidney to adapt to rapid changes in sodium intake (increases or decreases).

Blood pressure: Renal failure patients are often hypertensive. Hypertension is defined as a systolic pressure > 180 mmHg (dog) > 200 mmHg (cat) and a diastolic pressure > 95 mmHg (dog) > 145 mmHg (cat).

Blood pressure can be measured by indirect techniques using oscillometric or Doppler methods from the cranial tibial/dorsal pedal artery, metacarpal artery or the coccygeal artery. Indirect readings are comparable to direct measurements obtained by arterial puncture.

Blood pressure monitoring equipment is not uniformly reliable in dog sand cats. Several readings should be obtained to confirm consistency of the measured values.

Blood pressure can be measured using a Doppler blood pressure unit which measures systolic
pressure only or an oscillometric blood pressure unit with inflatable cuffs. The cuff size must be appropriate for the size of the patient or the readings will be inaccurate.

Normal blood pressure in dogs (direct technique)

• 148 + 16 mmHg systolic
• 87 + 8 mmHg diastolic
• 102 + 9 mmHg mean

Normal blood pressure in cats (direct, awake, 5-10 mmHg lower under anesthesia)

• 171 +/- 22 mmHg systolic
• 123 +/- 17 mmHg diastolic
• 149 +/- 24 mmHg mean

50-93% of dogs with renal failure are hypertensive. 80% of dogs with glomerular disease are hypertensive. Hypertension may play a role in the self perpetuation of renal failure. Hypertension can also cause cardiac disease, CNS dysfunction and retinal detachment leading to blindness.

Factors which contribute to hypertension include:

• failure to excrete salt and fluid
• stiffening of venous capacitance vessels
• altered adrenergic activity
• activation of renin-angiotensin-aldosterone system
• suppression of renodepressor prostaglandins

Other ionic disturbances may be present including an increase in magnesium which can cause drowsiness and increased neuromuscular excitability. Potassium is variable depending on urine output, dietary intake and gastrointestinal losses but is usually normal or low in polyuric CRF.  Cats may develop a painful myopathy as a result of hypokalemia.

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Diagnosis of CRD and CRF:

The history is often nonspecific including signs such as polyuria & polydipsia, nocturia/incontinence, gastrointestinal signs, anorexia, or depression.

On physical examination, dehydration, weight loss, pale mucous membranes, oral ulcers, palpably small kidneys, pathologic fractures or loose teeth may be seen. Oral ulcers are due to the breakdown of urea present in saliva to ammonia by oral bacteria. Hypertensive animals may present with acute blindness caused by retinal detachment.

Hematology often discloses nonregenerative, normochromic normocytic anemia and normal or a stress leukogram. CRF patients may have impaired phagocytic function of neutrophils which may lead to infection and leukocytosis. Anemia may be masked by hemoconcentration (dehydration). Platelets are normal in number but abnormal in function which can lead to bruising at the venipuncture site or other abnormal bleeding.

Biochemical changes include

• increased BUN
• increased creatinine
• increased phosphorus
• Na⁺ and Cl^- usually normal but total body concentration may be increased or decreased
• Ca is usually normal until terminal stage (may be low terminally) unless hypercalcemia caused the renal disease in which case calcium will be increased

Urinalysis will disclose a specific gravity between 1.007-1.017 (Isosthenuria).  Proteinuria is variable and is most often seen in patients with congenital CRD and those in which glomerular disease is the cause of CRF. The urine sediment is usually normal.

Radiology may show a decrease in kidney size, with irregular contours. If the animal is in poor body condition, the absence of abdominal fat may make visualization of the kidneys difficult. Contrast studies of the kidneys are NOT indicated.   Decreased bone density may be appreciated on the radiographs.

Renal function tests are not necessary if the patient is azotemic. Renal biopsy is often low yield in patients with CRF and is not necessary to make a diagnosis. Renal biopsy is of value to make a diagnosis of congenital renal disease.

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Treatment of CRF

The uremic crisis should be managed similar to the patient with ARF. Any prerenal influences should be corrected with fluid therapy. Prerenal insults may precipitate a uremic crisis in a previously compensated CRF patient.

Specific therapy of causative disorders may slow or stop the development of renal lesions including correction of hypercalcemia causing hypercalcemic nephropathy, antibiotics to eliminate bacterial infection, antifungals to eliminate mycotic infections, removal of obstructions (e.g., uroliths or neoplasms), or correction of abnormal renal perfusion that caused ischemia.

Diuretics are not indicated in the CRF patient unless they are oliguric, and then only once the patient is rehydrated. Intensive diuresis protocols using osmotic diuretics may be used if the patient becomes oliguric. See the ARF section for more specific information.

Conservative medical management is formulated to maintain fluid, electrolyte, acid-base, endocrine, and nutrient balance by providing unlimited access to water, decreasing the quantity of metabolic wastes to be excreted by the kidneys and to provide metabolites that the kidneys cannot effectively conserve or produce. This regime is conservative with respect to the cost and effort required compared to more aggressive forms of therapy such as aggressive fluid therapy or dialysis. Conservative medical management is indicated when the clinical signs of renal dysfunction are not severe enough to warrant more intensive forms of therapy and after successful treatment of the uremic crisis by more intensive measures. The initial response to conservative therapy may be relatively slow, taking weeks to months to see a response.

Conservative medical management of CRF includes:

• unlimited access to water
• avoidance of stress and increased renal work ( changes in the environment, nephrotoxic antibiotics, corticosteroids)
• avoidance or correction of circumstances which cause dehydration and prerenal azotemia (e.g. unnecessary surgical episodes, vomiting, diarrhea)
• modification of dietary protein intake
• phosphorus restriction
• control of blood pressure
• water soluble vitamins
• normalization of acid base status
• correction of anemia

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Modification of dietary protein intake: It is generally agreed that reducing dietary protein intake can ameliorate some of the clinical signs of uremia. The controversial aspects of protein modification include when to restrict protein, how much protein is needed, and will protein restriction delay the progression of renal disease? Some studies in rats, humans and dogs demonstrate that high protein diets result in glomerular hyperfiltration that in turn contributes to progression of deterioration in renal function suggesting that protein restriction in patients with CRD may ameliorate glomerular hyperfiltration and delay disease progression. This is not accepted universally regarding dogs with renal failure (see Finco 1989 in Current Veterinary Therapy X).

The optimal dietary protein requirements for dogs and cats with CRF are not established. Current commercial renal failure diets contain

• Dogs - 1.9 - 5.2 grams of protein/100 kcal high biologic value protein
• Cats -  5.4 - 7.2 grams of protein/100 kcal high biologic value protein

The protein source determines the biologic value and usability of the protein. Proteins with high biologic value can be readily converted to body proteins with minimal waste production. Animal proteins have a higher biologic value than vegetable proteins. Eggs have the highest biologic value.

Protein modification can be achieved with homemade diets or commercial diets such as Hills KD and UD.

• Feline KD - 29-30% of dry matter is protein
• Canine KD- 15-16% of dry matter is protein (maintenance diets- 15 -25% protein)
• UD -  9.5-10.4% of dry matter is protein

The goal is to achieve the best compromise between dietary control of clinical manifestations of uremia and prevention of malnutrition. Dietary protein intake must be individualized to meet patient needs. The potential advantages of protein restriction include reduction of nitrogen containing wastes, possibly slower progression, and lower phosphorus intake which may slow the development of renal osteodystrophy.

Potential disadvantages of protein restriction include protein malnutrition characterized by weight loss, reduction in muscle mass, reduced PCV, and reduced albumin. Protein restricted diets are less palatable than higher protein diets. Dogs with CRD that are still eating are more likely to accept a change in diet to a protein restricted diet than are dogs who are very ill and refusing most foods.   Protein restricted diets are more expensive than higher protein diets.

Adequate calories from fat and carbohydrate sources must be supplied to prevent the ingested protein from being catabolized for energy. The minimum caloric intake recommended is  60-100 Kcal/kg/day for dogs and 70-80 Kcal/kg/day for cats. Warming foods may enhance their palatability.

Water soluble vitamins like B and C are lost through diuresis and may need to be supplemented. Commercial diets sold for patients with renal disease contain increased amounts of water soluble vitamins so additional vitamins do not need to be given.

Lack of appetite and loss via polyuria may result in hypokalemia requiring potassium supplementation. Cats are more likely to be hypokalemic than are dogs. Potassium gluconate or citrate administered orally are most commonly used in hypokalemic patients.

Phosphorus restriction may delay the progression of renal failure and will minimize hyperparathyroidism. Protein restricted diets are also restricted in phosphorus. If phosphorus remains increased while feeding a protein restricted diet, phosphate binding agents which bind phosphorus in intestinal tract can be administered. Allow about 2 weeks of feeding just the phosphate restricted diet to determine its impact on blood phosphorus concentration before adding phosphate binders. Samples to analyze serum phosphorus should be obtained after a 12 hour fast. Phosphate binding agents include aluminum carbonate, aluminum hydroxide, calcium citrate and calcium carbonate. Phosphate binding agents are given with meals (or mixed with food) and are dosed to effect to normal serum phosphorus levels. Side effects may include hypophosphatemia, constipation, and aluminum toxicity. Aluminum toxicity causes encephalopathies and bone disease in humans, neither of which have been documented in cats or dogs.  Calcium containing phosphate binding agents (acetate, carbonate, citrate) should not be used until serum phosphorus is reduced to < 6 mg/dl. Monitor blood calcium and phosphorus concentrations at 10 to 14 day intervals while determining the necessary dose, then at 4 to 6 week intervals when serum phosphorus has normalized.

Calcium levels may be controlled by controlling hyperphosphatemia. Active vitamin D or calcium supplements may be given if hypocalcemia persists but only when hyperphosphatemia has been controlled. When Ca x P product exceeds 70, calcium-phosphate salts will precipitate in soft tissues including the kidneys.

Sodium bicarbonate should be administered if serum bicarbonate is < 17mEq/L. The goal is to increase serum bicarbonate to ~18-24 mEq/L. . Sodium bicarbonate should be administered cautiously in patients with cardiac disease or hypertension. Bicarbonate precursors including calcium or potassium salts of acetate, gluconate, lactate or citrate can also be used to alkalinize the acidotic patient. Potassium citrate is a good choice as it limits sodium intake and supplements potassium in addition to its alkalinizing effect.

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Sodium:  Diseased kidneys are less efficient at regulating sodium and plasma volume.Diseased kidneys cannot adapt rapidly to abrupt changes in sodium intake. Make changes in sodium intake gradually over several weeks. Commercial kidney diets contain 0.03 to 0.14 g sodium/100 kcal which is about 2 times the recommended minimum requirement.

Treatment of hypertension: An attempt should be made to confirm hypertension by measuring blood pressure. Hypertension may be treated with:

• reduced sodium intake
• diuretics can be used. furosemide is the diuretic of choice
• beta-adrenergic antagonists (propanolol)
• alpha adrenergic blockers (prazosin)
• ACE inhibitor vasodilator drugs (captopril or enalapril or benazepril)
• calcium channel blocking drugs like verapamil or amlodipine