Chronic Kidney Disease (CKD) in Dogs & Cats - The Pivotal Role of Phosphorus Control

Dennis J. Chew, DVM Dipl ACVIM

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Introduction

Chronic kidney disease is diagnosed commonly in cats – from 2 to 3 times as frequently as in dogs and is especially common in geriatric cats. CKD is clinically characterized by the development of variably progressive irreversible intrarenal lesions and loss of renal functions. A variety of interventions (diet and drugs) can slow the progression of the renal disease, improve the quality of life for the patient, and/or extend the quantity of life. Compensatory increases (so called adaptations) in glomerular hemodynamics and glomerular volume may actually be maladaptive in some instances as shown in the figure below.

Figure 1. Concept of increased protein-trafficking as a consequence of intraglomerular hypertension and glomerular hypertrophy that occur in remnant nephrons associated with advanced CKD. Protein in urine is both a marker and a creator or more renal disease as shown in the graphic below.

Table 1: Serum creatinine concentrations for assignment of IRIS stage of CKD in dogs and cat

Stage	Serum creatinine concentration (mg/dl)	Serum creatinine concentration (μmol/L)	Comments
1	< 1.4 (dog) < 1.6 (cat)	< 125 (dog) < 140 (cat)	Nonazotemic. Often discovered fortuitously during routine examination. May have evidence of decreased urinary concentrating ability or proteinuria. Usually no obvious clinical signs. May be polyuric.
2	1.4-2.0 (dog) 1.6-2.8 (cat)	125-179 (dog) 140-249 (cat)	Mildly azotemic. Decreased urinary concentrating capacity. May have proteinuria. Clinical signs minimal. May have polyuria and polydipsia.
3	2.1-5.0 (dog) 2.9-5.0 (cat)	180-439 (dog) 250-439 (cat)	Moderate azotemia. Decreased urinary concentrating capacity. May have proteinuria. Many systemic clinical signs may be present.
4	> 5.0 (dog) > 5.0 (cat)	> 440 (dog) > 440 (cat)	Severe azotemia. Decreased urinary concentrating capacity, proteinuria. Systemic clinical signs present and may be severe.

Table 2: Proteinuria (assessed by urine protein/creatinine ratio) for assignment of IRIS sub-stage of CKD in dogs and cats

Urine protein/creatinine ratio	Classification
< 0.2 (dogs) < 0.2 (cats)	Nonproteinuric
0.2-0.5 (dogs) 0.2-0.4 (cats)	Borderline proteinuric
> 0.5 (dogs) > 0.4 (cats)	Proteinuric

 

Table-3: Systemic blood pressure for assignment of IRIS sub-stage of CKD in dogs and cats

Systolic blood pressure (mm Hg)	Diastolic blood pressure (mm Hg)	Risk level
< 150	< 95	Minimal
150-159	95-99	Low
160-179	100-119	Moderate
≥ 180	≥ 120	High

 

Table 4. Treatment Considerations for CKD

Total Body Phosphate Burden Control: Dietary Modification Intestinal Phosphate Binders

H2-Receptor Blockers or Proton Pump Inhibitors

Systemic Hypertension Control: Calcium Channel Blocker (Amlodopine) ACE-Inhibitor (Enalapril/Benazepril)

Hypokalemia/Kaliopenia Control Potassium Supplementation

Metabolic Acidosis Control Alkali Supplementation

Control of UTI

Reduction of Intraglomerular Hypertension ACE-Inhibitor

Reduction of Renal Proteinuria ACE-Inhibitor Spironolactone Control of Systemic Hypertension

Renoprotection – anti adverse remodeling: ACE-Inhibitor, Spironolactone

Further control of renal secondary hyperparathyroidism Activated Vitamin D Metabolites (calcitriol) Calcimimetics (cinacalcet)

Adsorbents of Uremia Toxins Kremezin – AST-120

Recombinant Erythropoietin

Enteric Dialysis® - Azodyl

Ant-Fibrotics

 

Survival with CKD

Most cats with CKD live considerably longer than do dogs with CKD of similar severity based on IRIS staging. Renal survival time is usually defined as the time from the start of treatment to the time when parenteral fluid therapy is necessary, or when euthanasia or death occurs as a consequence of the advancing CKD. Increased serum creatinine, increased UPC, and increased WBC count were independent variables that were associated with shorter renal survival times in a study of 95 cats with CKD (58 were censored as they were still alive or owners failed to follow protocol; King JVIM 2007)). Entry into the study required a serum creatinine of 2.0 and higher along with a urinary specific gravity of 1.025 or lower. The median survival for all 95 cats was 319 days and 644 days in the censored cats. Increased risk not to survive was seen in cats at all levels of proteinuria > 0.2. Increased serum phosphate, urea nitrogen concentration, and lower hemoglobin or hematocrit concentrations were also associated with a shorter renal survival times, but are considered dependent variables since they correlated with serum creatinine at base line. Cats with 4.7 to 6.8 mg/dl serum phosphorus were at increased risk for shorter renal survival despite the fact that these values were still within the normal reference range. Cats with greater than 6.8 mg/dl serum phosphorus were at much greater risk for shorter renal survival. Cats with serum phosphorus of 2.8 to 4.7 mg/dl had the longest renal survivals (many censored since were still alive).

In another study, CKD (Boyd JVIM 2008) was followed in 211 cats with a serum creatinine greater than 2.3 mg/dl and urinary specific gravity less than 1.035 in most cats. IRIS staging based on initial serum creatinine predicted survival. Median survival in IRIS stage 2b (2.3 to 2.8 mg/dl creatinine was 1,151 days; stage 3 was 778 days; stage 4 was 103 days. Median survival for all 211 cats was 771 days. At the time of diagnosis, 37% cats were in stage 2b, 33% were in stage 3, and 30% were in stage 4. Thirty % of the cats diagnosed in stage 4 were later classified to a lower stage after fluid therapy corrected volume deficits. Median survival was 401 days in 142 cats identified with progressive weight loss , 273 days in 142 cats starting SQ fluids, 123 days in 145 cats with onset of a serum creatinine > 4.0 mg/dl, 44 days with onset of creatinine greater than 5.0 mg/dl in 98 cats, 83 days in 81 cats with >25% weight loss, 100 days in 121 cats with PCV < 25%, and 25 days in 42 cats with the start of specific treatment for anemia. IRIS stage alone was predictive for survival but individual serum creatinine values did NOT predict survival. The only parameter in this study that did predict survival was serum phosphorus concentration – unfortunately details of the phosphorus levels and their effect on survival were not provided.

Dietary Intervention

Several evidence based medicine studies of clinical cats with chronic renal failure have emerged showing salutary effects of dietary modification to increase survival time and to decrease the number of uremic crises. “Renal-friendly” veterinary diets are generally restricted in protein, phosphorus, calcium, and sodium while supplemented with carbohydrates, sources of alkali (potassium citrate), and polyunsaturated fatty acids in a favorable ratio of omega-6:omega-3 fatty acids. Canned foods are generally more restricted in phosphorus than their dry counterparts and substantial differences exist amongst the available products. The survival time was 16 months for cats with CRF that were eating any of 7 renal kidney diets compared to 7 months when maintenance foods were fed. What exactly is in these renal diets that confers the extension in life is not known. Traditionally, benefits of such diets are attributed to the well-known protective effects of dietary phosphorus restriction (with or without lowering of PTH), but diets with higher eicosapentaenoic acid content may also confer protection.

In a randomized blinded prospective clinical study, dogs with mild to moderate renal failure fed a renal diet had a median survival time of 594 days and fewer uremic crises compared to a median survival time of 188 days in dogs fed the conventional diet. The observed results were compatible with a slower rate of progression of renal disease in the dogs fed the modified diet.

Phosphorus Retention and Renal Secondary Hyperparathyroidism
Renal secondary hyperparathyroidism (2-HPTH) occurs when parathyroid hormone (PTH) synthesis and secretion become excessive during kidney disease and is the result of increased secretion of PTH by each chief cell as well as the increased number of chief cells due to parathyroid gland hyperplasia. Ionized calcium is either normal or low. Parathyroid gland hyperplasia is the primary cause of increased PTH secretion. Underlying calcitriol deficit is the most important factor leading to uncontrolled synthesis and secretion of PTH.

Renal 2-HPTH is commonly documented in dogs and cats with chronic kidney disease (CKD). Overall frequency of renal 2-HPTH was 76% in a recent study of dogs with CKD, encountered in 36% of IRIS stage 1, 50% in stage 2, 96% in stage 3 and 100% in IRIS stage 4 (Cortadellas et al., 2010). An increasing frequency of renal 2-HPTH was similarly found in cats with CKD (Barber and Elliott, 1998), affecting 84% of cats overall (47% of cats with stable azotemia without clinical signs to 100% of cats with decompensated CKD). Hyperphosphatemia is commonly found in CKD patients with 2-HPTH but 2-HPTH can be encountered in both dogs and cats with serum phosphorus within the normal reference range. Hyperphosphatemia was noted in 18% and 2-HPTH in 36 % of dogs in IRIS stage 1 dogs (Cortadellas et al., 2010). The concept that renal 2-HPTH can precede development of hyperphosphatemia in CKD has not been well appreciated in veterinary medicine. Serum phosphorus in the upper normal reference range has recently been associated with increased PTH in CKD dogs (Cortadellas et al., 2010) confirming an earlier report of this association (Nagode et al., 1992). Correction of hyperphosphatemia normalized PTH in many early uremic cats (Barber and Elliott, 1998) but was successful in only a portion of uremic dogs many of which required calcitriol to normalize PTH (Nagode et al., 1996).

Phosphorous is retained in chronic kidney disease, promoting renal secondary hyperparathyroidism, and eventually resulting in hyperphosphatemia. Phosphate retention is a major contributor to the progression of chronic kidney disease and it is well known that hyperphosphatemia is associated with significant mortality risk in humans with end-stage renal disease. With careful monitoring of serum phosphate and PTH and implementation of phosphate-restricted dietary management and intestinal phosphate binders, progression of chronic kidney disease and degree of hyperparathyroidism in cats may be reduced.

Figure 2- Development of Renal Secondary Hyperparathyroidism - calcitriol trade-off hypothesis

Serum phosphorous concentration depends on the dietary phosphorous intake, the degree of gastrointestinal absorption across the duodenum and jejunum, translocation into intracellular sites, and excretion of phosphorous into the urine. The kidney plays a crucial role in regulating serum phosphorous concentrations. Serum phosphate levels are maintained within a narrow range in health. Young growing animals often have higher levels of serum phosphorous than adults. The normal serum phosphorous range of many laboratories includes that of adults and growing animals which may make it difficult to detect early rises in serum phosphorous above normal. The typical normal range for phosphorous in the cat is 2.5-6 mg/dL (0.81 to 1.94 mmol/L). Phosphate retention and hyperphosphatemia are primarily due to impaired renal phosphate excretion. In the early stages of chronic kidney disease increased levels of parathyroid hormone (PTH) keep serum phosphorous within the normal range by increasing phosphate excretion into urine. This allows for normalization of serum phosphorous at the expense of hyperparathyroidism.

Pathophysiological Consequences of Hyperphosphatemia

Deleterious effects of phosphate accumulation in cats are most often recognized to be a direct consequence of phosphate from calcium phosphate precipitates into the tissues (increased calcium x phosphate product). Indirect effects that increase PTH and decrease ionized calcium may also be important. It has been known since the early 1980s that dietary phosphorous restriction provided dramatic benefits to the histologic renal architecture of cats with the remnant model of chronic renal failure. Serum phosphorous and PTH concentrations were considerably increased in cats fed the normal phosphate diet compared to those fed the restricted phosphate diet. Hyperphosphatemia and renal secondary hyperparathyroidism are common in cats with IRIS stage 3 and 4 chronic kidney disease and can be documented in some with IRIS stage 2. Interestingly, thirteen percent of cats in this study had increased PTH despite normal concentrations of both ionized calcium and serum phosphorous.

Treatment of Hyperphosphatemia

Conventional wisdom and evidence dictates the importance of correcting hyperphosphatemia of CKD. Early phosphorus restriction in CRF has been shown in dogs and cats to blunt or reverse renal secondary hyperparathyroidism. In a study of cats with naturally-occurring CRF, renal secondary hyperparathyroidism was successfully managed by dietary restriction of phosphorus; one-third of the cats also required treatment with phosphorus binders. Survival times in CKD cats eating the renal diet was over twice that of those eating maintenance diets – this effect was attributed to phosphorus control and control of PTH. Renal diets may provide sufficient dietary phosphate restriction during early stages of CKD but often dietary phosphate binders are needed. Diet and binders should be prescribed to effect of serum phosphorus and PTH levels. Normal serum phosphorus concentrations are desirable but do not guarantee that PTH is normal. Restoration of normophosphatemia is an initial and main goal but phosphorous restriction may be beneficial in reversing existing renal secondary hyperparathyroidism in cats that are not hyperphosphatemic at the time of initial evaluation. Secondary hyperparathyroidism can exist despite normal ionized calcium and serum phosphorous status.

Figure 3. Dietary phosphorus intake between dogs and cats eating commercial or renal therapeutic foods compared to average western diet of humans. Note that dogs and cats consume 5 and 6 times as much phosphorus as the average human which makes it difficult to achieve adequate dietary phosphorus restricion (Developed by Nutritional Support Services The Ohio State University CVM, Dr. Tony Buffington 2006)

Phosphorus restriction in CKD patients with phosphate retention is initiated by feeding a low phosphorus, low protein diet. Compared to an average western diet, cats consume six times, and dogs five times as much phosphate on a mg/100kcal basis when eating grocery store pet foods (C. Buffington 2006). Consequently, with such a high starting point, it is difficult to achieve the degree of dietary phosphate restriction advocated for humans with end-stage renal failure. Veterinary renal diets achieve phosphate restriction largely by restriction of dietary proteins that contain phosphorus, especially animal origin proteins. When there are difficulties in achieving the target serum phosphorus or PTH levels during phosphate restriction, it may be due to too much dietary phosphorus intake, an individual patient’s high level of GI absorption, or the formulation of the phosphate in the diet.

Dietary modification and intestinal phosphate binders are pivotal interventions to provide optimal phosphorous and PTH control. Extremely phosphorous-depleted diets may be unpalatable to cats due to the low levels of protein needed to provide this phosphorous restriction. Diets moderately restricted in phosphorous may provide adequate phosphate control during early stages of chronic kidney disease. As kidney disease progresses diet alone is usually not successful in adequate phosphorous control and phosphorous concentration increases above the normal range or stays in the upper half of the normal range.

Goals of Dietary Phosphorous Control

An initial goal is to attempt to return high serum phosphorus concentrations to within the normal range by the feeding of a phosphate-restricted renal diet. Intestinal phosphate binders should be added if serum phosphate remains increased after one month of consuming the renal diet or if the switch to the renal diet is not accepted by the animal. A serum phosphate concentration in the mid-normal range (< 4.5 mg/dL ; < 1.45 mmol/L) is the recommended target. It is important to serially measure serum phosphate concentrations in cats with CKD usually monthly until the target concentration has been achieved and then every 2 to 4 months thereafter if the cat is stable. Serum phosphorus concentration may increase in CKD cats that increase their food intake following other supportive CKD treatments. It is more difficult to achieve mid-reference range target phosphate concentrations in those with more advanced CKD.

Table 5. Target Serum-Pi Concentration in CKD by IRIS Stage

IRIS Stage	Target Phosphate
Stage 1	Any Pi- Restriction ?
Stage 2 0	.81 to 1.45 mmol/l 2.5 to 4.5 mg/dl
Stage 3	0.81 to 1.61 mmol/l 2.5 to 5.0 mg/dl
Stage 4	0.81 to 1.94 mmol/l 2.5 to 6.0 mg/dl

 

Figure 4. Algorithm for Feeding and Pi-Binders to Gain Control of Phosphorus

A second goal is to restore PTH to normal levels or to prevent it from increasing even if serum phosphorus is in the normal range. Further phosphorus restriction with diet and phosphorus binders can be titrated to the effect of lowering PTH if possible. In some instances, PTH cannot be controlled despite dietary intervention and use of intestinal phosphate binders. Other treatments with calcitriol and calcimimetics may be indicated in these cases. In addition to serial serum phosphate measurements, serial measurement of PTH and ionized calcium from the same time may be considered a gold standard for assessment of sufficient relief of body phosphorus burden and PTH control.
Adverse effects of phosphate restriction potentially can occur. Although hypophosphatemia is one such possible consequence, it is difficult for this to develop in those with initially high concentrations of serum phosphorus and reduced GFR. Hypercalcemia can be encountered when calcium salts are used for intestinal phosphate binding. Constipation and GI effects can occur following use of some of the intestinal phosphate binders. Absorption of chemicals from the intestinal phosphate binder may occur with resulting accumulation in the tissues in some instances.

Intestinal Phosphate Binders

Phosphorus binding agents are given orally to trap phosphorus in the gut and increase insoluble phosphate salt excretion into feces. Phosphate binders work because the cation in the binder combines with dietary phosphate, producing insoluble, non-absorbable, phosphate compounds. Intestinal phosphate binders work best when given with meals or within 2 hours of feeding to maximize their binding of dietary phosphorus. Due to varying effects of intestinal phosphate binders to limit absorption of drugs, it is advisable to give other drugs 1 hour before or 3 hours after any intestinal phosphate binder is given. The dose of any phosphate binder should be based on the meal size (phosphorus intake) and the prevailing serum phosphorus level for each CKD patient; the dose is titrated to effect. Commonly employed oral phosphorus binders include aluminum hydroxide, calcium carbonate, calcium acetate, chitosan, and lanthanum carbonate but no drug is yet licensed for phosphate binding in veterinary medicine.

Figure 5. Effect of orally administered phosphate binder to bind phosphate within the intestinal lumen preventing its absorption across the intestinal tract. Some binders undergo absorption across the intestine and others do not.

Aluminum Salts

Aluminum salts are the most widely used phosphate binders in cats. Aluminum based phosphate binding agents (aluminum hydroxide, aluminum carbonate) are highly effective in lowering serum phosphate levels, forming insoluble and nonabsorbable aluminum phosphate precipitates in the intestinal lumen. In humans with CKD, significant aluminum may be retained in the body, especially the bone, leading to osteomalacia, adynamic bone disease, microcytic anemia, and encephalopathy. THERE IS NO KNOWN SAFE DOSE OF ALUMINUM SALTS FOR HUMANS WITH CKD. Detrimental effects of aluminum based phosphate binders as described in humans seen in humans have not been systematically evaluated in small animal patients and are rarely clinically appreciated. As cats with CKD can live for years on treatment, concerns for aluminum accumulation deserve more study as to long-term safety.

Despite concerns for toxicity and stringent use guidelines in humans, aluminum salts remain the most commonly prescribed intestinal phosphate binders in veterinary medicine as they are very effective phosphate binders and are inexpensive. Aluminum hydroxide or aluminum carbonate is used at an initial dosage of 30 mg/kg q8h or 45 mg/kg q12h given with food. Constipation is the most common side effect encountered during treatment with aluminum phosphate binders. Lactulose treatment may help to alleviate constipation but may also contribute to dehydration due to extra fluid loss in the stool.

Sucralfate

Sucralfate is an aluminum hyrdoxide complex used mostly for treatment of GI ulcer disease. It has known phosphorous binding properties much like that from aluminum salts in general. Sucralfate has been used empirically by some clinicians as a phosphate binder though there are no reports of its use for such in cats or dogs. Sucralfate is reported to be an effective phosphate binder in humans with CKD though it is more expensive than aluminum hydroxide. Increased aluminum in the circulation and tissues is still of concern despite lower aluminum intake from sucralfate.

Calcium Salts

Calcium-based binders are not as effective as aluminum salts, having a lower affinity for phosphorous, thus effective binding of dietary phosphorous requires large doses of calcium, often enough to induce hypercalcemia in humans.

The most commonly used calcium based phosphate binders are calcium carbonate and calcium acetate. Calcium carbonate can be used in cats at a starting dosage of 30-mg/kg q8h or 45-mg/kg q12h given with food. Calcium carbonate binds phosphorous best in an acidic environment (pH approx. 5) and binding capacity is reduced in the neutral pH range. Many CKD patients receive inhibitors of gastric acid secretion potentially reducing calcium carbonates ability to bind phosphorous. Calcium acetate can bind phosphate over a wide range of pH, has about twice the phosphate binding capacity of calcium carbonate and as such can be used at lower dosage, and has been shown to cause less hypercalcemia than calcium carbonate when activated vitamin D metabolites are not also being used. Doses of 20, 30, or 40 mg/kg given with each meal approximate doses of calcium acetate recommended for humans with dialysis dependent CKD. Animals should be monitored for development of hypercalcemia whenever calcium-containing phosphorus binders are used.

Sevelamer

Sevelamer hydrochloride (Renagel®, Genzyme Corporation) and the very recently FDA approved Sevelamer carbonate (Renvela®, Genzyme Corporation) organic polymers that do not contain aluminum or calcium and are not absorbed from the gastrointestinal tract (excreted entirely in feces). These compounds are exchange resins that bind dietary phosphorous and release the counterion chloride (sevelamer hydrochloride) or carbonate (sevelamer carbonate). Many human clinical studies have demonstrated the ability of sevelamer hydrochloride to lower serum phosphorous, and parathyroid hormone levels, and control Ca x P product in dialysis patients compared with calcium containing phosphate binders. Their effects on dogs and cats with clinical CRF, however, have not been reported.

Sevelamer hydrochloride is hydrophilic and sevelamer carbonate is hygroscopic but both are insoluble in water. Pills should be given intact and will expand in water. Sevelamer may be associated with gastrointestinal side effects including constipation, and at extremely high dosages in dogs (6 to 100 times the recommended dosage in humans) sevelamer may be associated with impaired absorption of folic acid and vitamins K, D, and E.Sevelamer HCl is available in 400 mg and 800 mg tablets and Selelamer carbonate is available in 800 mg tablets. Sevelamer hydrochloride can also be compounded into a suspension. Sevelamer hydrochloride has been used effectively in children with end-stage renal failure. Reported doses of sevelamer hydrochloride used in children are extrapolated from adult humans ranging from initial dose of 100 mg/kg/day to 121 mg/kg/day divided every 8 hours and titrated to a final dose of 130 mg/kg/day to 163 mg/kg/day divided every 8 hours. These doses may be applied to small animal patients with careful monitoring for side effects and serial serum phosphate measurements with titration of the dose as needed.

Chitosan

Epakitin® (Vetoquinol USA, Inc.) is marketed as a complementary feed on the veterinary market. It contains the adsorbent chitosan (8% crab and shrimp shell extract), 10% calcium carbonate, and 82% lactose and is designed to reduce GI phosphorus absorption and to lower urea nitrogen due to effects of reduced protein digestibility. One short-term study of a small number of normal and CKD cats showed a reduction in protein and phosphorus digestibility along with the decreases in BUN and serum phosphorus in cats eating a normal maintenance diet supplemented with the chitosan and calcium carbonate product.Another longer-term study showed the ability of a chitosan and calcium carbonate intestinal phosphate binder to significantly decrease serum phosphorous and plasma parathyroid hormone levels when added to a maintenance diet for cats with CKD created by 11/12. The results of these two studies suggest that this supplement could be an alternative to prescription of renal veterinary diets thereby allowing some cats to continue on their regular diets while still reducing the risks for progression of CKD associated with total body phosphorus burden. We have, however, observed the development of hypercalcemia in a few CKD cats with the use of this product probably as a consequence of the calcium carbonate.

Lanthanum Salts

Lanthanum carbonate (Fosrenol®, Shire Pharmaceuticals) is another newly developed non-aluminum and non-calcium containing intestinal phosphate binder and is indicated for use in human patients with end-stage renal failure to reduce serum phosphorous. Very little lanthanum is absorbed across GI tract and lanthanum accumulates to a far less degree following absorption compared to aluminum since lanthanum undergoes extensive hepatic excretion whereas aluminum is excreted mostly by the kidneys. Lanthanum appears to have minimal toxicity in humans. Toxicity studies performed in dogs show that lanthanum increases in many tissues (especially GI tract, bone and liver) during treatment. Intact tablets should not be swallowed. Tablets may be crushed to aid in chewing. Initial daily doses of Fosrenol® that may be extrapolated from humans for use in cats range from 12.5 mg/kg/day to 25 mg/kg/day (based upon an average human weight of 60 kgs). However doses of 35 mg/kg/day to 50 mg/kg/day are often needed since commercial cat foods contain more phosphate proportionally than what an average human consumes daily.

Several reports of the use of lanthanum carbonate in cats have recently been published. Studies of normal European Shorthair cats that were given lanthanum carbonate in maintenance food or a veterinary renal diet showed similar results when compared to findings in cats eating the same diets without supplementation. Phosphorus excretion into feces increased while phosphorus excretion into urine decreased in a dose-related manner; serum phosphorus did not differ between dose groups. Food intake did not change during treatment with lanthanum carbonate.In 2007, based upon reports of efficacy and safety in cats, the European Food Safety Authority (EFSA) approved lanthanum carbonate octahydrate (Lantharenol® Bayer HealthCare AG) as a feed additive for adult cats in order to decrease intestinal phosphate absorption. The approved dose was 1500 to 7500 mg per kg of complete feed. Renalzin® (Bayer HealthCare AG) is the proprietary name for the delivery system of Lantharenol® was launched in 2008. In addition to Lantharenol®, Renalzin® also contains kaolin, for uremic toxin binding effects, and vitamin E, for its anti-oxidant effects, but the benefits of these other compounds have not yet been demonstrated. It comes as a liquid with a pump to deliver the appropriate liquid dose to food.

Cats with experimental sub-total nephrectomy (asymptomatic, mildly azotemic, and normophosphatemic following renal mass reduction)were fed wet cat food supplemented with Lantharenol® for two weeks. Food intake was not altered in cats of this study and a dose-dependent decrease in phosphorus availability was demonstrated. Urinary phosphorus excretion was increased unlike that seen with decreased urinary phosphorus excretion in normal cats. This may be due to excretion of phosphate from cellular stores that accumulated during renal failure. In another study of experimental cats, cats with subtotal nephrectomy were fed a standard feline maintenance diet supplemented with Renalzin® (5mg/kg original moist feed) for 6 months. Serum urea, creatinine, and phosphorous values were significantly improved and pH was increased, from starting values, after two months of Renalzin® administration. These parameters, however, tended to deteriorate towards the end of the six month trial period possibly due to a progressive decline in kidney function. Renalzin® was tolerated by all cats and did not affect body weight.

In a dose tolerance study, normal cats were fed an escalating dose of Lantharenol. A dose of 1 g/kg bodyweight was well tolerated by all cats. However at 2 g/kg Lantharenol® repeated vomiting of feed occurred in all cats which resolved 2 days after discontinuation of test item and re-occurred with re-challenge of 2 g/kg Lantharenol®. A dose of Lantharenol® of 1 g/kg bodyweight corresponds to a concentration of 84 g Lantharenol® per kg complete feed. Given the approved feed concentration range of 1.5 to 7.5 g/kg complete feed Lantharenol® has a safety margin of ten.

Twenty-three cats with naturally-occurring CKD (decreased urinary specific gravity, increased BUN and serum creatinine) finished an 8-week study comparing those fed a veterinary renal diet (9 cats) or a maintenance diet supplemented with Renalzin® at 400-600 mg Lantharenol ® per day (14 cats). The Renalzin® treated group showed an improvement in serum phosphorus control, overall clinical status, and behavioral scores for quality of life compared to cats fed the veterinary renal diets. Due to an unintended but relavant group difference at randomization and enrolment into the study – the Renalzin® group comprised a higher proportion of animals with hyperphsophatemia as well as impaired quality of life and overall clinical status – a comparison of the effects in Renalzin® and the renal diet in this study became impossible and requires further testing. Nevertheless, the evidence suggests that Renalzin®, similar to Epakitin ®, may be beneficial in cats on regular maintenance diets.

TABLE 4. Treatment of cats with intestinal phosphate binders: dose rates and approximate costs

Intestinal Phosphate Binder	Dose (Cat)	Approximate Cost	Approximate cost for 4 kg cat/mo.
Aluminum hydroxide (Alternagel® 600 mg/5ml)	30 mg/kg PO q 8 hr; 45 mg/kg PO q 12 hr (give with meal)	$8.50/360 mls* (£0.60) (€0.69)	$1.42-$2.13 (£0.86–1.29) (€0.98–1.47)
Calcium carbonate (Tums® regular strength 500 mg/tablet)	30 mg/kg PO q 8 hr; 45 mg/kg PO q 12 hr (give with meal)	$0.04/tablet* (£0.02) (€0.03)	$1.00 (£0.60) (€0.69)
Sevelamer hydrochloride (Renagel® 400 mg tablets)	33-54 mg/kg PO q 8 hr; 50-80 mg/kg PO q12 hr (give with meal)	$1.40/tablet* (£0.84) (€0.97)	$42.00-$68.00 (£25.37–41.07) (€28.98–46.92)
Epakitin®	1 gm/10lbs twice daily with food	$15/50 gms# (£9.05) (€10.35)	$18.00 (£10.87) (€12.42)
Lanthanum (Fosrenol® 500 mg chewable tablets)	12.5-25 mg/kg/day PO; 6.25-12.5 mg/kg PO q12 hr starting dose (give with meal, do not swallow tablet whole)	$6/tablet* (£3.62) (€4.14)	$45.00-$90.00 (£27.18–54.36) (€31.05–62.10)
Lanthanum (Renalzin®) Not available in US	2 mls applied to cats food once or twice daily	$10/50 mls^ (£6.04) (€6.90)	$12.00-$24.00 (£7.25–14.50) (€8.28–16.56)
* Prices obtained from drugstore.com (accessed April 6, 2009) # Price obtained from amazon.com (accessed April 6, 2009) ^ Price obtained from petdrugsonline.co.uk/ (accessed April 6, 2009) Currency conversions correct as of September 8, 2009 (1$ ≡ £0.604/€0.690)

ACE-Inhibition

Figure 6. - ACE-Inhibition Provides Glomerular Afterload Reduction. High pressures of the supernephron (left panel) are created by dilatation of the afferent arteriole. In the right panel, intraglomerular pressure has been restored to normal during treatment with ACE-inhibition. ACE-inhibitors reduce the effect of angiotensin-II to cause intrarenal vasoconstriction but the effect is greater on the efferent arteriole which lowers resistance to outflow from the glomerular beds.

Angiotensin-II plays a pathophysiologic role in proteinuria and the progression of renal disease. Angiotensin-converting enzyme (ACE) inhibitors (e.g. enalapril, benazepril) may have protective effects in patients with chronic renal disease due to their ability to block adverse effects of angiotensin II. ACE-inhibition reduces glomerular capillary hydraulic pressure by decreasing postglomerular arteriolar resistance. Proteinuria is decreased secondary to decreased glomerular hydraulic forces and development of glomerulosclerosis is limited when protein trafficking across the glomerulus is decreased. Remnant nephrons in animals with CRF have glomerular hypertension that can benefit from reductions in transglomerular forces. An additional potential benefit from ACE-inhibition is improved control of systemic blood pressure. This beneficial effect must be balanced against their potential to worsen azotemia since glomerular pressure provides the driving force for GFR in the “super-nephron”.

Benazepril is licensed for treatment of CRF in cats in many regions of the world (Fortekor®), but not in the USA. Average survival of benazepril treated cats of one study was 501 days vs. 391 days for placebo treated cats but this effect did achieve statistical significance. When a subset of cats in this study with proteinuria (UPC > 1.0) was considered, survival was not significantly improved for those treated with benazepril (401 days in benazepril treated cats vs. 126 days for control cats) but this subgroup only contained 13 cats. Plasma protein concentration was maintained at higher levels in CKD cats treated with benazepril if the initial UPC < 1; better appetite was maintained in those with UPC > or = 1. Benazepril consistently reduces proteinuria in various stages of chronic kidney disease in cats in this and other studies even when the base line level of proteinuria is seemingly trivial. In another study of 61 cats with CKD, benazepril treatment for 180 days appeared to stabilize those in IRIS stage 2 or 3 with less transition to stage 4 compared to treatment with placebo though this effect did not achieve statistical significance (low number of cats and short duration of study). The overall efficacy of treatment rated by the attending veterinarian was statistically higher during benazepril compared to placebo treatments. In another study of cats, fewer with CKD progressed from IRIS stage 2 or 3 to IRIS stage 4 when treated for 6 months with with benazepril compared to placebo (Mizutani 2006) suggesting stabilization of renal function during this period.

In a 6 month study of dogs with modest azotemia and moderate to severe proteinuria, enalapril treatment (0.5 mg/kg PO q12-24h) reduced proteinuria (as assessed by urine protein/creatinine ratio), decreased blood pressure, and slowed progression of renal disease in dogs with biopsy-proven glomerulonephritis compared to treatment with placebo (Grauer 2000). Results from this study provided enough clinical evidence to make the use of ACE-inhibition standard of care for protein-losing nephropathy in dogs caused by glomerulonephritis. In a placebo controlled study of dogs with CKD not selected for proteinuria, benazepril treatments for 6 months resulted in higher GFR and lower magnitude of proteinuria (Tenhundfeld 2009).

General guidelines for use of ACE-inhibitors in CKD include rechecking renal function in 1 week following start of ACE-inhibition to make sure that GFR has not been reduced too much. It is common to see a small increase in serum creatinine at this time (20 to 30% increase over baseline). If creatinine has increased too much, reduce the dose of the ACE-inhibitor. Some dogs and cats are ACE-inhibitor intolerant in that their renal function will be much worse during initial treatments so that treatment must be discontinued. We also recommend to recheck the UPC 1 and 3 months after the start of ACE-inhibition. The goal is to achieve a 50% decrease in UPC in those in which it was initially increased. There does not appear to be much difference between benazepril or enalapril for clinical use in the dog or cat with CKD. Benazeprilat is cleared by both the kidney and liver compared to enalaprilat being cleared only by the kidney.

Hormone replacement: Calcitriol

Calcitriol treatments help to decrease PTH or prevent its increase in those with renal secondary hyperparathyroidism. This occurs mostly by genomic effects to block PTH synthesis in addition to a mild calcemic effect, and antiproliferative effect that prevents parathyroid gland hyperplasia. During treatment of CRF patients with calcitriol, simultaneous monitoring of serum ionized calcium, serum phosphorus and PTH concentrations is the ideal way to document successful and safe control of renal secondary hyperparathyroidism.

Calcitriol should not be administered until hyperphosphatemia has been controlled. If the Ca X P solubility product exceeds 60-70, calcitriol should be avoided because of the risk of soft-tissue mineralization. The beneficial effects of calcitriol are also lessened within the parathyroid gland when ionized calcium remains low. Phosphorus restriction relieves phosphate-mediated inhibition of the renal 1α-hydroxylase system, resulting in enhanced endogenous synthesis of calcitriol and subsequent inhibition of PTH synthesis. The effectiveness of calcitriol in control of hyperparathyroidism has been noted to increase in patients in whom serum phosphate was lowered.

Supplementation with calcitriol in CRF was initially designed as a daily therapy for life in veterinary patients as long as serum phosphorus remains within the normal range and serum calcium does not become increased. An extremely low dosage of calcitriol (2 to 3 ng/kg/day) has been used in dogs and cats with stable CRF to reverse renal secondary hyperparathyroidism. Serum PTH concentrations decrease during calcitriol administration over a period of weeks to months. Calcitriol is manufactured in capsule (250 or 500 ng) and liquid (1000 ng/mL) forms. Reformulation by a compounding pharmacy may be necessary to provide accurate dosing. In a recent study, dogs with CRF treated with calcitriol survived for a median of 365 days compared to 250 days in dogs treated with placebo. Similar studies were done in cats by the same investigators who concluded that there is no advantage to calcitriol treatments in cats with CRF but the study followed cats for just one year. In order to show a difference in treatment effect if one exists, studies in cats with CRF must be conducted for at least 2 and possibly 3 years due to the inherently slow nature of the progression of chronic renal disease in this species.

Intermittent rather than daily dosing treatment protocols are likely to become the standard of care since less hypercalcemia occurs during this protocol. The equivalent dose given at 2.5 ng/kg daily is given instead every 3.5 days. This works out to a dose of 9 ng/kg (8.75 ng/kg rounded to 9 ng/kd). It is important to give the dose every 3.5 days, rather than on day 1 & 4. For example if a dose is given Tuesday PM the next dose should be given Saturday AM. This is the longest time in between dosing that will still suppress the parathyroid gland. This method of dosing is especially attractive for cat owners since medication will only be given twice weekly.

Hormone replacement: erythropoietin

Recombinant human erythropoietin (rhEPO) has been used to successfully correct nonregenerative anemia in CKD cats. Treated animals demonstrate resolution of anemia, weight gain, improved appetite, improved haircoat, increased alertness, and increased activity. Therapy may be started in symptomatic cats with PCV values < 20% if clinical signs of anemia are present and problematic. The starting dosage is 100 U/kg administered subcutaneously 3 times per week. Iron deficiency is avoided by monitoring serum iron and total iron binding capacity and providing oral supplementation with ferrous sulfate (5 to 50 mg per cat per day). When the lower end of the target PCV range (30-40%) is reached, frequency of administration is reduced to twice a week. Depending upon the severity of anemia, it may require 3-4 weeks for the PCV to enter the target range. Although initially effective in correcting the anemia of CRF, use of rhEPO is associated with antibody formation in up to 50% of treated dogs and cats after 1 to 3 months of treatment. The resulting anemia can be more severe than that present before treatment because the induced antibodies can cross-react with the animal’s native EPO. The canine EPO gene has been isolated, and recombinant canine EPO has been used to stimulate erythropoiesis in normal dogs and in those with naturally occurring CRF. It is not as effective when used in dogs that have developed red cell aplasia from previous treatment with rhEPO. Feline recombinant EPO also has been produced, but unfortunately unexplained red cell aplasia developed in some treated cats. Other adverse effects have been observed during administration of rhEPO to dogs and cats including vomiting, seizures, hypertension, uveitis, and hypersensitivity-like mucocutaneous reaction.

Control of Systemic Hypertension

Systemic hypertension occurs in 20 to 65% of cats with chronic renal failure when determined by methods that indirectly measure blood pressure. It is essential that cats be in a quiet environment before and during blood pressure measurements. Cats especially are prone to “white coat artifact” making it difficult to determine if a given cat is truly hypertensive. The correlation of unregulated arterial hypertension to the progression of CRF has not been established in cats, but there are some studies in dogs and humans that suggest a positive relationship. It is likely that high systemic blood pressure is transmitted to the glomerular vessels, which promotes further injury. Cats that have systemic hypertension from a variety of causes have been shown to survive longest when their blood pressure is well controlled.

Patients with systolic blood pressure readings > 170 mm Hg or those CKD patients with lower levels of blood pressure readings that also have fundic lesions consistent with hypertensive retinopathy (e.g., retinal edema, retinal hemorrhages, arterial tortuosity, retinal detachment) are candidates for anti-hypertensive therapy. Angiotensin-converting enzyme (ACE) inhibitors (e.g. enalapril, benazepril) may have protective effects in patients with CRF due to their ability to block adverse effects of angiotensin II. Beneficial effects include reduction in proteinuria, limitation of glomerular sclerosis and slowing of progression of renal failure as well as improvement in systemic blood pressure. Enalapril has not been very effective for treatment of hypertensive cats. The calcium channel blocker, amlodipine has been used successfully in cats at a dosage 0.625 to 1.25 mg per cat given orally once per day. Follow-up evaluations should be scheduled for one week after beginning treatment with amlodipine. Adverse effects (including hypotension) are very uncommon with the use of amlodipine in cats.

Control of Proteinuria

The detection of proteinuria is a diagnostic index in cats with CRF. Based on the theories of glomerular hypertension that occur in “super nephrons” of the adapted kidney, protein gaining access to tubular fluid and the mesangium is also a creator of further renal injury. The magnitude of proteinuria is a function of the integrity of the glomerular barrier, GFR, tubular reabsorptive capacity, and effects from elevated systemic and intraglomerular blood pressure.

Cats with CRF increased their risk for death or euthanasia when the UPC was 0.2 to 0.4 compared to <0.2 and was further increased in cats with UPC of >0.4. The prognosis for survival is influenced by the UPC despite what has traditionally been thought to be low-level proteinuria. The effect of treatment that lower proteinuria on survival have not been specifically studied.

Since even low-level proteinuria is a risk factor to not survive, it is prudent to consider treatments that lower the amount of proteinuria in those with CKD and CRF. Benazepril has been shown in two recent clinical studies to reduce the UPC in cats with CRF. Cats treated with benazepril in one study did not progress from IRIS stage 2 or 3 to the next stage as rapidly as those treated with placebo but over 6 months. Despite reduction in proteinuria in CKD cats with initial UPC > 1.0 that were treated with benazepril in another study, a significant increase in survival time was not found over placebo.

Selected Reading

1. Boyd LM, Langston C, Thompson K, Zivin K, Imanishi M: Survival in Cats with Naturally Occurring Chronic Kidney Disease (2000-2002). J Vet Intern Med, 2008.
2. Brown SA, Brown CA, Jacobs G, Stiles J, Hendi RS, Wilson S: Effects of the angiotensin converting enzyme inhibitor benazepril in cats with induced renal insufficiency. Am J Vet Res 62(3): 375-383, 2001.
3. Brown SA, Rickertsen M, Sheldon S. Effects of an intestinal phosphorous binder on serum phosphorous and parathyroid hormone concentrations in cats with reduced renal function. Intern J Appl Res Vet Med 2008; 6: 155-160.
4. Cortadellas O, Fernandez del Palacio MJ, Talavera J, Bayon A: Calcium and phosphorus homeostasis in dogs with spontaneous chronic kidney disease at different stages of severity. J Vet Intern Med 24: 73-79, 2010.
5. Elliott J, Rawlings JM, Markwell PJ, Barber PJ: Survival of cats with naturally occurring chronic renal failure: effect of dietary management. J Small Anim Pract 41(6): 235-242, 2000.
6. Elliott J, Barber PJ, Syme HM, Rawlings JM, Markwell PJ. Feline hypertension: clinical findings and response to antihypertensive treatment in 30 cases. J Small Anim Pract 2001; 42:122-9.
7. Grauer GF, Greco DS, Getzy DM, Cowgill LD, Vaden SL, Chew DJ, Polzin DJ, Barsanti JA: Effects of enalapril versus placebo as a treatment for canine idiopathic glomerulonephritis. J Vet Intern Med 14(5): 526-533, 2000.
8. Jepson RE, Elliott J, Brodbelt D, Syme HM: Effect of control of systolic blood pressure on survival in cats with systemic hypertension. J Vet Intern Med 21(3): 402-409, 2007.
9. King JN, Gunn-Moore DA, Tasker S, Gleadhill A, Strehlau G: Tolerability and efficacy of benazepril in cats with chronic kidney disease. J Vet Intern Med 20(5): 1054-1064, 2006.
10. King JN, Tasker S, Gunn-Moore DA, Strehlau G: Prognostic factors in cats with chronic kidney disease. J Vet Intern Med 21(5): 906-916, 2007.
11. Mizutani H, Koyama H, Watanabe T, Kitagawa H, Nakano M, Kajiwara K, King JN: Evaluation of the clinical efficacy of benazepril in the treatment of chronic renal insufficiency in cats. J Vet Intern Med 20(5): 1074-1079, 2006.
12. Plantinga EA, Everts H, Kastelein AM, Beynen AC: Retrospective study of the survival of cats with acquired chronic renal insufficiency offered different commercial diets. Vet Rec 157(7): 185-187, 2005.
13. Ross SJ, Osborne CA, Kirk CA, Lowry SR, Koehler LA, Polzin DJ: Clinical evaluation of dietary modification for treatment of spontaneous chronic kidney disease in cats. J Am Vet Med Assoc 229(6): 949-957, 2006.
14. Spiecker-Hauser U, Kraemer F, Epe C, Schmidt B. Efficacy of Lantharenol to reduce intestinal phosphorous absorption from feline renal diet. Proceedings of the 11th European Society of Veterinary and Comparative Nutrition Congress; 2007 Nov 2-3; Leipzig, Germany, p.133.
15. Nagode LA, Chew DJ, Podell M: Benefits of calcitriol therapy and serum phosphorus control in dogs and cats with chronic renal failure. Both are essential to prevent of suppress toxic hyperparathyroidism, Vet Clin North Am Small Anim Pract 26:1293-1330, 1996.
16. Nagode LA, Chew DJ, Steinmeyer CL: The use of low doses of calcitriol in the treatment of renal secondary hyperparathyroidism. In Proc 15th Waltham Symposium (Endocrinology), Columbus, OH, 1992.
17. Schmidt B, Delport P, Spiecker-Hauser U: Bay 78-1887, a novel lanthanum-based phosphate binder, decreases intestinal phosphorus absorption in cats. J Vet Pharmacol Therap 29((Supplement 1)): 206-207, 2006.
18. Schmidt B, Spiecker-Hauser U, Gropp, J: Effect of Lantharenol® on apparent phosphorus absorption from a conventional feline maintenance diet and a renal diet for cats. Proc Soc Nutr Physiol 17:87, 2008.
19. Schmidt B, Spiecker-Hauser U, Murphy M: Efficacy and safety of lantharenol® on phosphorus metabolism in cats with chronic kidney disease. J Vet Intern Med 22(3): 798, 2008.
20. Schmidt B, Adler K, Hellmann K. The use of Renalzin, a new intestinal phosphate binder, in feline chronic renal failure. Proceeding of the Vetoalp 2008 Conference; 2008 March 31; Chamonix, France; p.69.
21. Schmidt BH, Murphy M. A study on the long-term efficacy of Renalzin® (Lantharenol® suspension 20%) in cats with experimentally induced chronic kidney disease. Vet Clin Pathol. In Press 2009.
22. Schmidt B, Spiecker-Hauser U. Overdose acceptance and tolerance of Lantharenol in adult healthy cats. J Vet Pharmacol Ther. In Press 2009
23. Syme HM, Markwell PJ, Pfeiffer D, Elliott J: Survival of cats with naturally occurring chronic renal failure is related to severity of proteinuria. J Vet Intern Med 20(3): 528-535, 2006.
24. Tenhundfeld J, Wefstaedt P, Nolte IJ: A randomized controlled clinical trial of the use of benazepril and heparin for the treatment of chronic kidney disease in dogs. J Am Vet Med Assoc 234(8): 1031-1037, 2009.
25. Wagner E, Schwendenwein I, Zentek J: Effects of a dietary chitosan and calcium supplement on Ca and P metabolism in cats. Berl Munch Tierarztl Wochenschr 117(7-8): 310-315, 2004.
    

 

Table 5. Checklist of Possible Treatments for Compensated Chronic Renal Failure.

First Level of Treatment
Change to renal therapeutic diet– reduced phosphorus intake is most important – commercially available or home-made – wet foods better than dry if possible
Fresh water available at all times
H2 receptor or proton pump blocker – combat gastric hyperacidity
Intestinal phosphate binders to effect of serum phosphorus – aim for mid-normal range; aluminum or calcium salts used most often
Treat serious hypertension now (> 180 mm Hg systolic) – get below 180 mm Hg soon
Treat urinary or systemic infection
Avoid anesthesia or exposure to nephrotoxicants when possible
Second Level of Treatment
Subcutaneous fluids if not maintaining hydration
Add in metoclopramide or other anti-emetic to reduce vomiting and nausea effects if needed
Potassium supplementation if hypokalemia is overt or borderline
Optimize phosphate restriction (diet or binders) based on PTH or serum Pi – consider dose or class change for phosphate binders
Further blood pressure control – minimal aim to < 165 mm Hg, optimal < 145 mmg Hg
Provide peri-operative renal protection with IV fluids for several hours before, during, and following anesthetic and surgical procedures
Androgenic steroids for DOGS ONLY when poor body condition persists – monitor liver parameters
Third Level of Treatment
Provide ACE-inhibition for renoprotection and antiproteinuric effects, independent of normal systemic blood pressure
Blood pressure control optimized for renal patient– multiple drug therapy or dose escalation as needed to maintain systolic blood pressure at < 145 mm Hg
Calcitriol – daily or intermittent dosing protocol to control PTH and prevent parathyroid gland hyperplasia– base doses on ionized calcium and PTH
PEG tube placement when patient will not consume adequate nutrition and body condition is poor
EPO if patient approaches transfusion dependency – not for minor anemia
Fourth Level of Treatment
Renal transplantation – consider for selected cats
Chronic dialysis – only for the extremely wealthy
Emerging or Unproven Treatments
Azodyl – probiotic to reduce azotemia following bacterial utilization
Spironolactone – anti-adverse remodeling and further anti-proteinuric effects
Cinacalcet – calcimimetic to lower PTH, calcium, and phosphorus
Kremezin (Covalzin® or AST-120) – non-selective sorbent to remove uremic toxins from intestinal lumen
Epakatin – Chitosan and calcium carbonate phosphate binder
Renalzin – Lanthanum carbonate phosphate binder
Darbopoietin – Stimulate new red blood cell production; may have less antibody production than EPO

 

Table 6. Status Checklist During Treatment of the Patient with CKD or CRF

Nutritional Status
Body Weight Body Condition Score Muscle Condition Score Serum Albumin Total Protein BUN Cholesterol Poor, acceptable, excellent; worse, stable, improving
Serum Phosphorus Control
Poor, acceptable, excellent; worse, stable, improving
Serum Calcium Control
Serum total calcium Serum ionized calcium (preferred) Poor, acceptable, excellent; worse, stable, improving
Serum Potassium Control
Poor, acceptable, excellent; worse, stable, improving
Acid-Base Control
Blood gas (preferred); HCO3 on profile Poor, acceptable, excellent; worse, stable, improving
Systemic Blood Pressure Control
Poor, acceptable, excellent; worse, stable, improving
Proteinuria Control
Urinary protein to creatinine ratio; microalbuminuria testing Poor, acceptable, excellent; worse, stable, improving
PTH Control
Poor, acceptable, excellent; worse, stable, improving
CKD Progression Control
BUNCreatininePhosphorusProteinuriaRenal SizeSystemic blood pressure Poor, acceptable, excellent; worse, stable, improving