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The Azotemic Cat

Jonathan Elliott, MA, VetMB, PhD, Cert SAC, Dipl. ECVPT, MRCVS - 24/06/2017

The Azotaemic Cat

A case study

A 15 year old neutered female domestic short haired cat presents to your practice with a three month history of polydipsia. The owners had also noted some weight loss over the same period but were primarily concerned that over the last week the cat’s appetite had decreased and she seemed weak and lethargic. On physical examination your findings include:

• Condition score 2/5 – underweight (3.0 kg)Table 1

• Dull hair coat

• Hydration status – slightly dehydrated (mucous membranes a little tacky)

• A systolic heart murmur loudest over the sternum on the left side (grade 2/6)

• Small and slightly irregular kidneys on palpation

• A moderately full bladder was detected on abdominal palpation.

Blood was taken for a chemistry screen and a complete blood count. Urine was collected by cystocentesis and an in-house urinalysis performed.

The results of the chemistry screen were as shown in Table 1...

The haematology profile was all within the reference range – the haematocrit was 33% (27-48%).

The urinalysis results undertaken in your laboratory were as follows: Urine specific gravity: 1.014, Protein: +2, Blood: +2, pH: 5.0.

All other stick test results were negative.

Ask yourself...

• How would you classify the azotaemia identified in this case and on what basis would you make this classification?

• What further routine diagnostic tests would you undertake in this case, and what is the justification for these tests?

Azotaemia...

Azotaemia indicates a ‘failure’ of the kidney to excrete nitrogenous waste products from the body and can be categorized as:

• Pre-renal: reduced glomerular filtration rate (GFR) due to reduced blood flow to the glomeruli; often secondary to hemodynamic disturbances resulting from circulatory shock and/or severe dehydration leading to systemic hypotension.

• Primary intrinsic renal: primary disease of the kidneys leading to loss of functioning nephrons and, as a result, a reduced GFR. The kidney disease could be affecting the vascular supply, the glomeruli, the tubules or the interstitial compartment and might be acute or chronic (see below).

• Post-renal: (i) obstructive problem in the urinary drainage/storage systems leading to back pressure in the urinary system that is transmitted to Bowman’s space in the glomeruli and reduces or prevents filtration; (ii) leakage of urine from the collection/storage system into the peritoneal cavity preventing elimination of waste products from the body.

In this case, the azotaemia should be tentatively classified as due to primary intrinsic renal disease leading to failure to excrete waste products although we do not have all the necessary information that would be desirable. There are no clinical signs suggestive of obstructive urinary tract disease leading to azotaemia nor is there a history of blunt abdominal trauma that often accompanies cases where there is leakage of urine into the abdomen. Further investigation would help to rule out bilateral ureteral obstruction as a cause of the azotaemia in this case (see below under further diagnostic tests). The cat does not have clinical signs of severe circulatory compromise leading to reduced GFR although it is clinically mildly dehydrated. Despite this, however, the cat is producing dilute urine (based on its urine specific gravity) and so is not able to respond to the dehydration by conserving water and concentrating its urine. In the face of dehydration, cats should concentrate to a urine specific gravity of ≥1.040.

Having decided this case is most likely to have azotaemia due to a primary intrinsic kidney disease, one should then ask whether this is an acute or chronic problem... It is important to recognize that none of the laboratory tests in this case can distinguish between a decompensated chronic kidney disease (CKD) case and an acute renal failure case. The cat has become inappetant, weak and lethargic over the last few days prior to presentation but there are several features that suggest it has a CKD including:

• Chronic history of weight loss and polydipsia that has existed for three months or more

• The finding of small shrunken and irregular kidneys on physical examination

• The finding of a dull hair coat and low body condition score on physical examination

All these features suggest this cat has a CKD leading to azotaemia and has recently suffered an exacerbation of the problem leading to decompensation (loss of appetite, mild dehydration, weakness and lethargy). Whether this decompensation is due to a further extrinsic insult to the kidneys (another episode of the primary disease that damages the kidney) or intrinsic progressive renal injury caused by the adaptive mechanisms of the remaining functioning nephrons is not possible to determine in many cases although attempts to identify an active extrinsic disease process should be made (see below).

 What further routine diagnostic tests would you undertake in this case?

Having identified this case as a case of decompensated CKD, further diagnostic tests should be aimed at:

• Identifying a primary (hopefully treatable) extrinsic disease that may be responsible for this episode of decompensation

• Identifying complications of the uraemic syndrome that lead to:

- Reduced quality of life of the cat

- May contribute to the process of progressive renal injury and so intrinsic progression of the renal failure towards end stage.

The tests undertaken so far have identified hypokalaemia, hyperphosphataemia and metabolic acidosis as complications of the uremic syndrome which may be influencing the quality of life of the cat and certainly could be addressed in the therapy of this case. There is reasonable evidence to suggest that hyperphosphataemia contributes to progressive renal injury and equivocal evidence to suggest hypokalaemia and metabolic acidosis could contribute. As a routine in these cases, the following additional diagnostic tests should be undertaken:

Figure 1  • Urine sediment examination (+/- urine culture)

Quite often we find the presence of significant bactiuria, particularly in female cats presenting to us for the first time. Bacteria are often visible on sediment examination as they are usually rod-shaped bacteria (Figure 1). It is difficult to say whether bacterial infection of the urinary tract caused the decompensation in these cases but it is a treatable problem and infected cats often improve clinically on antibacterial drug therapy. This cat had evidence of a bacterial urinary tract infection despite the fact it was not showing clinical signs of lower urinary tract disease. This is typical and is why this problem is often missed unless urine sediments are routinely examined in these cases or urine collected by cystocentesis is routinely cultured.

• Assessment of urine protein excretion

If the urine sediment examination is inactive and/or the culture results are negative, we would usually measure the urine protein to creatinine ratio, regardless of the results on the dipstick analysis. Most cat urine samples screened by standard dipstick analysis show 1+ protein in the urine. This can be associated with normal levels of protein (urine protein to creatinine ratio <0.2), borderline proteinuria (UPC >0.2 but <0.4) or significant proteinuria (UPC >0.4) (1). Urine protein to creatinine ratio is an important parameter to determine when assessing or staging a case of CKD since it has been shown to be predictive of all cause mortality (2). The implication of this finding is that proteinuric animals (provided this is renal proteinuria) might benefit from anti-proteinuric therapy (e.g. ACE inhibitor treatment). In this case, because the urine sediment was active and evidence of a bacterial urinary tract infection was present, we delayed assessing proteinuria until this had been successfully treated and the infection had resolved.

• Measurement of arterial blood pressure

Doppler assessment of systemic arterial blood pressureAll cats with a diagnosis of CKD are at risk of being hypertensive and should have their blood pressure measured by one of the available indirect methods. We use the Doppler technique and measure systolic arterial blood pressure (SABP) only (Figure 2). Blood pressure measurement is undertaken in conjunction with a retinal examination to determine whether there is evidence of target organ damage. SABP below 150 mmHg is considered normotensive in our clinic (minimal risk of target organ damage). If the SABP is between 150 and 159 mmHg the cat would be considered to be at mild risk of target organ damage; SABP between 160 and 179 mmHg is associated with moderate risk of target organ damage and pressures >180 mmHg are associated with high risk of target organ damage (3). This particular cat has a heart murmur which is not uncommon in normotensive cats with CKD (30% prevalence in our clinic (4)) but is more common in cats with hypertension (70% prevalence). In addition, hypokalemia is a significant risk factor associated with feline hypertension (4). Blood pressure was measured initially in this case and was 146 mmHg. It is important to monitor blood pressure in these cases over time particularly in those cats which have decompensated and present in a dehydrated state. Assessment of their blood pressure after they have been rehydrated and are back in a more compensated state would be very important.

• Diagnostic imaging of the kidneys and urinary tract +/- renal biopsy

figure 3When looking for a primary disease process, the use of diagnostic imaging of the kidneys and ureters can sometimes yield useful diagnostic information (Figure 3). The likelihood of finding abnormalities on such investigations increases in younger cats and in cats with palpably enlarged kidneys on physical examination. For example, ureteral obstruction by calcium oxalate ureteroliths can occur - bilateral obstruction can lead to azotemia and this tends to occur in younger cats (<10 years of age), possibly with a history of recurrent lower urinary tract signs. Renal biopsy would be the ultimate diagnostic test to identify the pathological processes going on in the kidney. However, aged cats presenting as this one did often only have evidence of chronic interstitial fibrosis with glomerular sclerosis and renal biopsy does not inform the management or prognosis of these cases.

How would you manage this case?

There are several problems that have been identified in this case that require immediate attention. These are the things that may be related to the acute decompensation of CKD. They consist of:

Dehydration which will be exacerbating the azotaemia

Hypokalaemia probably resulting from the anorexia and continued polyuria

Urinary tract infection which, if untreated may extend to the kidneys (it could already have done so)

Fluid therapy to rehydrate the cat and correct the metabolic acidosis and hypokalaemia is important in this case. It should be remembered that cats with CKD are susceptible to over-hydration as well as to dehydration since their kidneys can not excrete a large fluid over-load. Great care is necessary to make sure fluid therapy is accurately administered (e.g. use of an infusion pump). This cat is not vomiting and so the oral route can be used to replace potassium and it may be possible to follow-up initial intravenous treatment in hospital with subcutaneous fluid on an out-patient basis. Most cats are happier in their own environment and are far more likely to eat when at home than when in the hospital environment.

One approach would be to provide sufficient fluids to rehydrate the cat over 48 hours. In this case assuming the cat is 10% dehydrated this would be 300 mL (0.1 x 3 = 0.3 mEq) plus 75 x 3 x 2 (maintenance requirements – 75 mL/kg/24 h)*. The total fluid requirements over the first 48 hr would be 750 mL. Lactated ringers solution would be appropriate to rehydrate the cat although its sodium concentration is high and for prolonged maintenance, a lower sodium containing fluid (with added potassium chloride) would be ideal. Depending on the cat’s response to treatment, subcutaneous fluids could be continued to provide part of the maintenance requirements each day on an outpatient basis.

* Usually the maintenance requirements are set at 50 mL/kg/24 h. With a cat with CKD that is polyuric, urinary losses will be high and 75 mL/kg takes this into account.

To correct the hypokalaemia an oral potassium supplement was used. Potassium gluconate is the one most commonly used in clinical practice in the UK. A dose rate of 3 mEq of potassium twice a day would be appropriate initially in this cat with a follow-up blood test being advisable after 5 to 7 days. The owner of this cat felt unable to administer the potassium gluconate tablets and the gel form was not available at the time. As the cat was not eating much at all initially the powdered form added to the food was not an option. We used potassium citrate (available from pharmacies) since tablets can be dissolved to make a liquid formulation to syringe-dose the cat by mouth. Both citrate and gluconate are bicarbonate precursors so act to provide bicarbonate replacement therapy, addressing the problem of metabolic acidosis demonstrated by the low total CO2 in this cat.

Antibiotic treatment was essential in this case. The choice of antibiotic should be made on the basis of culture and sensitivity testing in this case since a long course of treatment is usually recommended (at least 4 week) on the assumption that the infection has extended to the kidneys and we are dealing with pyleonephritis. The organisms cultured in our clinic are usually E coli and the majority are sensitive to amoxicillin potentiated with clavulanate. Palatable tablets are available containing this drug combination and the owner was able to administer these in this case. We would routinely follow-up with an examination of the urine sediment after a week on treatment. Assuming there is no evidence of inflammation in the urine sediment at that stage we would treat for 4 weeks and culture the urine again after the cat had been off treatment for 7 days to determine whether there had been a bacteriological cure.

Potentiated amoxicillin is well concentrated in urine and even in cats with CKD reaches urine concentrations which are 100 times higher than its plasma concentration. It also has a time dependent bactericidal action. Prolonged treatment is required to clear any pockets of infection within the renal parenchymal tissue. It is not uncommon for urinary tract infections to recur in cats with CKD and routine monitoring of the urine sediment on a regular basis (+/- routine cultures) are to be recommended. If potentiated amoxicillin is not effective in managing these infections our second line treatment would be a fluoroquinolone. We have most experience of using marbofloxacin for this purpose and most uropathogenic E coli seem to be sensitive to this group of antibiotics.

No attempt was made to change the cat’s diet at this stage to address the hyperphosphataemia. The most important treatment targets are to get the cat over the acute exacerbation of its CKD, correcting the dehydration, managing the hypokalaemia and treating the urinary tract infection. Once the cat is back in a more stable state, management of the more chronic problems associated with chronic kidney disease is then appropriate.

Progression of this case with the above management...

After a week of the treatment described above, this cat was much improved and was eating more of her normal diet. The urine sediment was nonactive. Systolic arterial blood pressure measured at this point was 192 mmHg, placing her in the high risk group for target organ damage. A retinal examination (not performed when the cat first presented) revealed evidence of hypertensive choroidoretinopathy with patchy areas of oedema and small retinal hemorrhages around the retinal blood vessels in both eyes.

A repeat plasma biochemistry profile showed the values presented in Table 1.

The urine sediment examination at this visit was unremarkable with very few red cells or white cells seen and no bacteria identified. Thus the response to treatment has been good and the acute problems are under control in this case allowing us to turn our attention to the more chronic problems associated with CKD. Antibiotic therapy should continue for a further 3 weeks before assessment of whether a bacteriological cure has been achieved and at that point, an assessment of the urine protein to creatinine ratio would be appropriate also. Potassium supplementation was reduced from 3 mEq twice a day to 3 mEq once a day at this point.

Management of more chronic problems associated with chronic kidney disease...

At this point there are two longer term problems identified namely hyperphosphataemia and hypertension. This cat has been stabilized with a plasma creatinine concentration of 283 μmol/L (3.71 mg/dL). This would place it in the early Stage 3 of CKD according to the IRIS classification (5). Its blood pressure gives it a high risk of suffering target organ damage and ocular complications associated with this are evident. Sub-staging based on proteinuria should be postponed until treatment for the urinary tract infection has been completed.

Anti-hypertensive treatment... Our preference is to institute treatments one at a time and assess response to these treatments, getting the owner used to each new treatment. This also means that not too many changes are made too suddenly so the response of the cat to these treatments can be adequately assessed. In this case we prescribed amlodipine besylate to treat the hypertension. The starting dose was 0.625 mg once daily and the response to this treatment was assessed after 14 days of therapy. Empirically, our post-treatment target blood pressure is 160 mmHg. If the SABP is above this value we would increase the dose to 1.25 mg once a day and reassess. Usually this is sufficient to achieve the target, if not we would consider adding benazepril as an additional treatment to aid in achieving the target. Hypotension is a theoretical possibility with antihypertensive treatment but one we rarely see provided these drugs are not started in cats that are dehydrated and decompensated. Hypotension would be a SABP of <110 mmHg measured under clinic conditions.

Management of hyperphosphataemia... In this case when we measured the SABP after 14 days on amlodipine it was 142 mmHg. At this point it was appropriate to address the hyperphosphataemia problem. This was done initially by reducing phosphate intake in the diet and prescribing a renal clinical diet. The owner was advised to introduce this gradually by mixing a small quantity of the clinical diet with the cat’s normal food and gradually increasing the proportion of the clinical diet and reducing the proportion of the cat’s normal food over a period of 7 to 14 days. We recognize that palatability can be an issue with these clinical diets and suggest owners find the maximum proportion of clinical diet that is acceptable and feed this if it is not possible to transfer the cat onto the clinical diet as the sole source of food. The post-treatment target in this case is to achieve a plasma phosphate concentration of <1.6 mmol/L (4.95 mg/dL) (for Stage 3 cats) and ideally less than 1.45 mmol/L (4.49 mg/dL) (for Stage 2 cats). In Stage 3 cats it may be necessary to use both clinical diets and intestinal phosphate binding agents to achieve this post-treatment target. There are a number of intestinal phosphate binding agents available (calcium carbonate, aluminium hydroxide, lanthanum carbonate). These need to be mixed with the ration that is fed so they can interact with the phosphate in the food and reduce its bio-availability.

When we have changed the diet we measure plasma phosphate concentration after 4 to 6 weeks to assess response to treatment. This is a chronic therapy that reverses the whole body phosphate overload that occurs in chronic kidney disease and leads to hyperparathyroidism and soft tissue mineralization (including nephrocalcinosis). It has been shown to be associated with increased interstitial fibrosis and mineralization in experimental cats (6) and phosphate restriction through diet and phosphate binders is associated with improved survival in cats with naturally occurring chronic kidney disease (7). In addition to monitoring plasma phosphate concentration against the post-treatment targets, it is also important to monitor plasma calcium concentration as some cats (5% of those treated) develop hypercalcaemia (total calcium >3 mmol/L) (12 mg/dL) when dietary phosphate is restricted. Theoretically it might also be possible to induce hypophosphataemia, which would be undesirable although that is much less likely to occur particularly in a cat in Stage 3 chronic kidney disease.

Response to dietary treatment...

In this cat after 4 weeks of feeding a renal clinical diet, the plasma phosphate concentration had reduced to 1.85 mmol/L (5.73 mg/dL) (from 2.56 mmol/L) (7.93 mg/dL). This was considered to be a good response to treatment and the cat was eating the diet to the exclusion of everything else. We decided to continue to feed the diet and monitor the plasma phosphate concentration rather than trying to introduce phosphate binding agents at this point in time. The plasma creatinine concentration was 275 μmol/L (3.11 mg/dL) and plasma potassium concentration was 4.2 mmol/L. SABP remained below the target at 150 mmHg. Urinalysis post-antibiotic treatment yielded an inactive urine sediment and bacterial culture was negative. At this point a urine protein to creatinine ratio was measured and found to be 0.56. The cat’s body weight had stabilized at 3.2 kg. At this point the potassium supplementation therapy was stopped. After another 6 weeks of dietary and antihypertensive treatment a reassessment of this cat was undertaken. The plasma phosphate concentration was 1.55 mmol/L (4.8 mg/dL) (below the 1.6 mmol/L (4.95 mg/dL) target)), plasma creatinine remained stable at 290 μmol/L (3.28 mg/dL), the blood pressure was still within the target at 138 mmHg, the urine sample had benign (inactive) sediment and the urine protein to creatinine ratio was 0.68.

At this point we discussed with the owners about instituting further treatment to manage the persistent proteinuria. This would involve administering another oral medication (benazepril; 2.5 mg once daily) to manage the proteinuria. The post-treatment target would be to reduce the UPC to below 0.4. We would also need to monitor blood pressure carefully to make sure the combination of amlodipine and benazepril did not induce systemic hypotension. Benazepril does consistently reduce proteinuria in cats with CKD (8) and in our experience does not lead to systemic hypotension when combined with amplodipine.

 Outcome in this case...

This cat remained stable on dietary treatment, amlodipine and benzepril for a further six months. Post-treatment UPCs following initiation of benazepril therapy were 0.36 and 0.42. After six months this cat suffered from another uremic crisis presenting severely dehydrated and suffering from a recurrence of its urinary tract infection. The owners at this point decided euthanasia was the best option rather than a further period of hospitalization and fluid therapy. 

Take home messages!

• The finding of azotaemia (raised creatinine and urea) on a chemistry screen requires careful consideration of the history and physical examination findings to classify the case appropriately.

• A full urinalysis is required in all azotemic patients and this must include microscopic examination of the urine sediment.

• In cats with CKD, which is a heterogeneous syndrome, measurement of urine protein to creatinine ratio (if the urine sediment is benign) and of systemic arterial blood pressure is important to identify therapeutic targets in the management of these cases.

• Re-assessment and monitoring of laboratory test results (including urine protein to creatinine ratio) and blood pressure is important as part of the monitoring process. In animals that have recently deteriorated, reassessment once they have stabilized again is very important as blood pressure and plasma creatinine may change substantially once the cat is feeling better and more stable.

Tailoring treatment to the individual case is important. Dealing with acute problems first and then, once the cat is stable again assessing what chronic therapeutic targets there are and dealing with these sequentially so that responses to treatment can be adequately assessed is important.

 This article was kindly provided by Royal Canin, makers of Royal Canin RENAL:

Royal CaninRoyal Canin Renal diet

 

 

 

 

 

 

References:

1. Lees GE, Brown SA, Elliott J, et al. Assessment and management of proteinuria in dogs and cats; 2004 ACVIM Forum Consensus Statement (Small Animal). J Vet Intern Med 2005; 19(3): 377-385.

2. Syme HM, Markwell PJ, Pfeiffer DU, et al. Survival of cats with naturally occurring chronic renal failure is related to severity of proteinuria. J Vet Intern Med 2006; 20(3): 528-535.

3. Brown S, Atkins C, Bagley R, et al. American College of Veterinary Internal Medicine. Guidelines for the identification, evaluation, and management of systemic hypertension in dogs and cats. J Vet Intern Med 2007; 21(3): 542-558.

4. Syme HM, Barber PJ, Rawlings JM, et al. Incidence of hypertension in cats with naturally occurring chronic renal failure. J Am Vet Med Assoc 2002; 220: 1799-1804.

5. Elliott J. Staging of chronic kidney disease. In: Manual of canine and feline nephrology and urology. Eds. Elliott J & Grauer GF. BSAVA Publication, Cheltenham, Glos 2007.

6. Ross LA, Finco DR, Crowell WA, et al. Effect of dietary phosphorus restriction on the kidneys of cats with reduced renal mass. Am J Vet Res 1982; 43: 1023-1026.

7. Elliott J, Rawlings JM, Markwell PJ, et al. Survival of cats with naturally occurring renal failure: effect of conventional dietary management. J Small Anim Pract 2000; 41: 235-242.

8. King JN, Gunn-Moore DA, Tasker S, et al. Benazepril in renal insufficiency in cats study group. Tolerability and efficacy of benazepril in cats with chronic kidney disease. J Vet Intern Med 2006; 20(5): 1054-1064.

This article was previously published in 2013.

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