Urinary tract I - the kidney

The relationship between GFR and creatinine is non-linear and a plot of the reciprocal of creatinine concentration with GFR approximates a straight line. What does this mean?

When GFR is near normal, relatively large changes in GFR do not result in much alteration in creatinine concentration but once GFR is low, even small changes will alter creatinine concentration. This means that creatinine concentration is generally insensitive to mild, early renal dysfunction

Give examples of non-renal influences on urea

Fasting

Dietary protein content

GI haemorrhage

Liver function

Hyperthyroidism

Where in the kidney is urea reabsorbed from?

Passive re-absorption in the proximal tubule. It is also reabsorbed in the inner medulla.

What factors can enhance urea uptake?

Slow tubular flow rates

Activation of RAAS and SNS

Release of ADH

Creatinine concentrations tend to increase or decrease with body weight?

Increase - so in dogs there is quite marked breed variation

What are the limitations of using creatinine as a marker for GFR?

• Poorly sensitive

• Relies on the endogenous production of creatinine (eg relating to the thyroid)

• Muscle mass

What is the critical difference for creatinine measurements?

35umol/l

What is cystatin C?

It is a cysteine protease inhibitor. It is produced by all nucleated cells and its rate of production is reportedly more stable than that of creatinine.

It is freely filtered by the glomerulus and reabsorbed by the tubular epithelial cells where it is catabolised.

= [Urinary] is low and an increase has been proposed as a marker of tubular dysfunction

Dysfunction of what organ is known to cause problems when evaluating cystatin C measurements in humans?

Thyroid, particularly in the cat.

Is serum cystatin C a useful marker for identification of reduced renal function in the cat?

No

What is SDMA?

Symmetric dimethylarginine and is a marker of GFR.

How is SDMA formed?

When proteins that have been methylated within nucleated cells are broken down. This is then eliminated almost exclusively by renal filtration.

The production of SDMA is altered in what hormone condition?

HYperthyroidism

In clinical practice, GFR is estimated by measuring the plasma clearance of an injected substance which can be achieved in what two ways?

• Repeated blood samples can be taken to monitor the disappearance of an injected analyte from the blood

• If radioactive, then it’s rate of accumulation within the renal parenchyma (which related to its rate of filtration) can be monitored using a gamma camera.

What filtration markers are most commonly used for estimating GFR?

Exogenous creatinine and iohexol

On ultrasound is a thin renal cortex more likely to be associated with AKI or CKD?

CKD, if thick then more likely to be associated with acute. Renal cortical thickness: Aorta ratio has a stronger association with AKI/CKD.

The distinction between pre-renal and renal azotaemia is most often made on USG. If the USG IS >1.030 in a dog and >1.035 in a cat, then the azotaemia is usually considered to be pre-renal. What are some caveats to this tule?

• Cats with CKD will sometimes retain significant urine concentrating ability

• Dogs & cats with primary glomerular disease also sometimes retain concentrating ability even once they have developed azotaemia

• Patients will only be able to concentrate urine in the face of pre-renal azotaemia if the tubular and collecting duct mechanisms are intact. If there is a lack of medullary hypertonicity (such as in patients with hAC or a very protein restricted diet) or an interference with tubular (patients receiving diuretics) or collecting ducts (patients with primary or secondary causes of DI) function then creation of concentrated urine will not be possible even when azotaemia is pre-renal. In these patients, the -re-renal nature of the azotaemia is usually confirmed by administering IVFT and documenting the resolution

In an animal with urinary tract rupture, a creatinine concentration of the fluid greater than X of the circulation?

Twice

In a urinary tract rupture, what kind of fluid is usually present?

Transudate, protein poor/protein rich or exudate due to the presence of haemorrhage or inflammatory cells. A non-septic, neutrophilic inflammation is common

Non-regenerative anaemia may be present n patients with CKD due to a relative EPO deficiency. However, anaemia may also occur in patients with AKI for what reasons?

• Overhydration

• Leptospirosis

• hAC

• Haemorrhage or haemolysis resulting in hypoxia/hypotension

Hyperkalaemia is most often associated with AKI, particularly with post-renal causes of AKI. However, it can also develop in dogs with CKD that are eating renal diets especially if they are concurrently treated with what?

ACE inhibitors or angiotension-receptor blockers.

What is the function of an intact glomerular barrier?

To prevent macromolecules (primarily proteins) from being lost into the urine.

What are the three layers of the glomerular filtration barrier?

• Fenestrated endothelium which lines the glomerular capillaries

• Glomerular basement membrane

• Slit diaphragm which is formed by the interdigitating food processes of the podocytes

Damage to any one of these 3 layers will result in loss of barrier function resulting in glomerular proteinuria. Which one is most likely to have the biggest impact if damaged?

Basement membrane or podocytes

How else can glomerular barrier function be compromised?

Increased hydrostatic pressure within the glomerular capillaries. This can be due to systemic hypertension of due to adaptive hyperfiltration that ocurs when the number of functioning nephrons is significantly reduced.

There is no cut off point for the magnitude of proteinuria that signifies primary glomerular disease is present but UPCR values are typically greater than what?

2 or 3

What is measurement of fractional excretion of solutes (usually electrolytes) considered an indicator of

Tubular function

What changes associated with tubular function can be seen on urinalysis?

Glucosuria

• Isolated or as a component of Fanconi’s

• Primary tubular defect or due to AKI

Changes in urine pH & hyperchloraemic metabolic acidosis

• Renal tubular acidosis

• Proximal type 2 and distal type 1 forms

Crystalluria

• Cysteine

• Urate

• Xanthine

Enzymuria increases with injury to which part of the nephron?

Tubules

What enzymes can be detected in urine in tubular disease?

N-acetyl-beta-D-glucosaminidase (NAG) and GGT and they arise from proximial tubular cells

Enzymuria increases with tubular injury. In clinical practice this is useful when?

Repeatedly administering a drug that is known to be nephrotoxic so this can be detected when repeatedly administering a drug that is known to be nephrotoxic so this can be discontinued as soon as renal injury is detected.

They may also increase in more chronic disease states representing ongoing tubular injury or increased cellular workload

Neutrophil gelatinase-associated lopocaline (NGal) is a promising biomarker for the detection of AKI. It is markedly increase when what kind of injury occurs?

Tubular. An ELISA for blood & urine has been validated for use in dogs but does not detect NGal in feline samples .

You can perform a NGal/creatinine ratio or measure NGal on blood. These increase in AKI and to a lesser exten in CKD and with URIs

In the IRIS kidney guidelines, if there is a discrepancy between creatinine and SDMA the stage is usually whichever is higher or lower?

Higher

What increase in creatinine is likely to represent a decline in GFR in AKI?

26.5umol/l

List causes of CKD in the cat

Lymphoma

Polycystic kidney disease

FIP

Amyloidosis

Glomerulonephritis/PLN

Pyelonephritis

Toxins

Recovery from AKI

Obstructive uropathy/nephropathy

Chronic tubulointerstitial nephritis

What breed is most commonly affected by polycystic kidney disease?

Persians due to an autosomal-dominant inheritance

Describe obstructive uropathy/nephropathy or ‘big kidney, little kidney’ syndrome

1. Obstruction of the first kidney is usually asymptomatic = little/CKD

2. Clinical signs occur when the second kidney obstructs = large/acute injury. Results in renal injury and development of fibrosis

Increasing frequency of calcium oxalate stones is thought to have resulted in emergence of this condition

List the causes of CKD in dogs

• Tubulointerstitial nephritis

• Familial nephropathies

• Glomerular disease

• Other eg pyelonephritis

• Post AKI

In CKD, when should you consider renal biopsy?

• Kidneys are enlarged

• Glomerular proteinuria is present

• Specific diagnosis is suspected (eg due to a mass lesion)

List some mechanisms for disease progression in CKD

Secondary renal hyperparathyroidism

Glomerular hyperension

Direct proteinuria induced renal injury

Acidosis/increased renal ammoniagenesis

Hypokalaemia

What is FGF23 and what does it do?

It is a 251 amino acid polypeptide hormone that is secreted by osteocytes and osteoblasts

It increases Phosphate excretion and it inhibitis 1-a-hydroxylase which reduces intestinal phosphate absorption

What is the most common side effect of intestinal phosphate binding drugs?

Constipation

What are the side effects of aluminium hydroxide preparations at high doses?

Microcytosis, encephalopathy and weakness

What initially happens following the loss of a critical amount of renal mass?

Local changes within the kidney result in hyperfiltration of the remaining functional nephrons.

Hyperfiltration of the remaining nephrons is detrimental and can lead to what?

Interstitial fibrosis, inflammation and further nephron loss

What are the factors that drive hyperfiltration?

Glomerular capillary hypertension due to local activation of the renin-angiotensin system. There is increased local concentration of angiotensin II which results in selective constriction of the efferent arteriole and stimulation of nephron hypertrophy.

Glomerular hypertension also results in a low level what?

Proteinuria

What are the risk factors for proteinuria?

Plasma creatinine concentration

Increased systolic blood pressure

Why does systolic blood pressure cause an increase in severity of proteinuria in cats?

Due to an inability of the kidney to autoregular renal blood flow appropriately which results in a resultant transmission of the elevated systemic blood pressure to the glomerulus

OR

Proteinuric renal diseases are more likely to cause systemic hypertension

What is the rationale behind treatment of renal diseases with ACE inhibitors?

They cause preferential dilation of the efferent arterioles, resulting in reduction of glomerular capillary pressure, reduce glomerular capillary permeability to protein = reducing proteinuria and preventing the development of glomerulosclerosis

Why can ACE inhibitors cause AKI (in late 3, early 4 CKD particularly)

Because they reduce GFR

What commonly happens to the creatinine levels when you start ACE inhibitors?

There is a decrease in GFR = an increase in creatinine concentration

ACE inhibitor therapy has been evaluated in dogs with what kind of kidney disease?

Biopsy proven glomerulonephritis, where it has been shown to prolong survival time

At what PCV levels should you consider treating anaemia due to CKD in cats and dogs?

<20% in cats and 25% in dogs

The cause of anaemia in CKD is multifactorial, with a lack of EPO being an important factor. If the severity of the anaemia does not tolerate with the severity of the anaemia, what does this suggest?

That it is, at least in part, caused by some other condition.

What should be given alongside Darbepoetin?

Iron supplementation

What does a HIF-prolyl hydroxylase inhibitor do?

They are transcription factors that upregulate the synthesis of erythropoietin and multiple other factors to increase oxygen carrying capacity. They increase PCV

What medications increase the likelihood of hyperkalaemia in animals with CKD?

ACE inhibitors

About 20-30% of cats with CKD are hypokalaemic. Why does potassium wasting occur?

In animals fed an acidifying diet, there is displacement of K+ from intracellular potassium from intracellular fluid. This allows cellular proteins to buffer excess hydrogen ions, and the subsequent loss of K+ in the urine.

Decreased appetite

Treatment of significant hypokalaemia leads to a clinical improvement in what?

Appetite, muscle strength and activity

Measurements of concentrations of what will identify cases suffering from metabolic acidosis and help to identify cases where dietary alkali supplementation is necessary?

Plasma bicarbonate.

Describe how NSAIDs can be harmful to the kidney?

Prostaglandins cause afferent vasodilation and by inhibiting PG production, NSAIDs can cause afferent arteriole vasoconstriction and reduce GFR.

How can ACE inhibitors cause AKI?

Angiotensin II causes efferent vasoconstriction and it helps to maintain GFR when renal perfusion is low. Blocking the effect of angiotensin II with ACE inhibitors and ARBs in these situations can cause acute renal failure.

What ocular change are seen in cats with hypertension?

• Retinal detachment

• Retinal haemorrhage

• Hyphaemia

What neurological signs can be associated with hypertension?

Ataxia

Weakness

Disorientation

Amaurosis

Vestibular signs

Paraparesis

Decorticate posturing

Stupor

Seizures

Sudden death

What is the recommended treatment for hypertension in cats?

Amlodipine (± telmisartan)

How does amlodipine work?

It. isa dihydropyridine calcium channel blocker, with preferential affinity for the L-type channels that are found in vascular smooth muscle, rather than the calcium channels present in the myocardium or nodal tissue. It’s main effect is to reduce TPR

Amlodipine has a long duration and a slow onset of action. Why is this clinically important?

Because it means that once daily dosing is possible & patients do not suffer from initial hypotension with reflex tachycardia immediately after dosing.

Amlodipine is metabolised through urine & faeces and this process is not affected by reduced renal function. However, it should be avoided in cats with significant dysfunction of?

The liver

When is peak plasma level of amlodipine reached?

3-6h post dosing

When is steady state reached when using amlodipine?

2 weeks after starting treatment

What drug is better for use in emergency management of very severe hypertension of rapid onset?

Hydralazine (works within 15 minutes) but there is a risk of inducing hypotension

What other classes of drug are sometimes used to aid in the management of hypertension in cats?

Beta blockers

Drugs that interfere with the actions of TAAS eg ACE inhibitors / ARB blockers

Why are ACE inhibitors not very effective in reducing BP?

• Plasma renin activity in cats with hypertension is usually low

• Once daily tx is insufficient and twice daily therapy would be more appropriate

What blood pressure do you want to achieve in a hypertensive cat or dog with renal disease?

<160mmHg

What is the most common type of renal tumour in the dog?

Renal carcinoma. Other primary tumour types include

• Haemangiosarcoma

• Fibrosarcoma

• Leiomyosarcoma

• Transitional cell carcinoma

What are the clinical signs in dogs with primary renal tumours?

Nonspecific - anorexia, depression, weight loss, abdominal mass

What paraneoplastic syndromes can occur with the renal neoplasia ?

• Polycythemia

• Hypertrophic osteopathy

• Nodular dematofibrosis

Pulmonary metastasis are radiographically apparent in what % of dogs at diagnosis?

1/3

Histopathology is required for dx of primary renal tumours as cytology is usually unrewarding. Excision of the affected kidney is usually the only treatment option. Why is this difficult?

Because it is common to have invasion of the caudal vena cava

What is the median survival time following surgery in a primary renal tumour?

8 months

What is the most common renal tumour in cats?

Lymphoma

Cats are generally azotaemic at time of presentation (with renal lymphoma). What is generally apparent on physical examination?

Bilateral renomegaly

How can you make a diagnosis of renal lymphoma?

FNA

Azotaemia generally resolves if patients go into remission with renal lymphoma, true or false?

True

Proteinuria tends to be a hallmark of what kind of kidney disease?

Glomerular

What is nephrotic syndrome?

Proteinuria, hypoalbuminaemia, hyperlipidaemia, oedema/fluid accumulation of body cavities

What are the clinical signs of a protein losing nephropathy?

Muscle wasting, weight loss, malaise

Renal failure

Hypertension

Thromboembolism

A urine dipstick is more sensitive to albumin than to globulin and will not detect what type of protein?

Bence-Jones

Blood contamination of a sample needs to be quite severe before protein concentrations will increase - true or false?

True

Significant proteinuria (>3) most often develops due to…

• Glomerulonephritis

• Amyloidosis

Why does glomerulonephritis occur?

Due to the presence of intra-glomerular immune complexes. This may develop when circulating antigen-antibody complexes become trapped in the glomerulus or they may be formed in situ. This inflammatory response results in cellular proliferation, thickening of the glomerular basement membrane, hyalinisation and sclerosis = nephron destruction and renal failure

What is amyloidosis?

When insoluble deposits of a fibrillar protein are deposited into tissue (not just renal tissue, but clinical signs are most frequently related to the development of azotaemia or nephrotic syndrome).

Amyloid is a fragment of an acute phase protein that is produced in response to chronic inflammation or neoplastic stimuli.

What breeds are recognised relatively frequently with regards to amyloidosis?

Sharpei & Abyssinian

What are some other causes of proteinuria?

Leishmaniasis

Lyme’s disease

Drugs > TKIs, sulphonamides, steroids

When should you be suspicious of a PLN?

2+ or 3+protein on dipstick

Hypoalbuminaemia

At risk breed eg Basenji

Azotaemic renal disease

C/s of PLN

Unless a high degree of suspicion exists for familiar amyloidosis or glomerulonephropathy, it is usual to perform a diagnostic workup including… before renal biopsies

• Urea/creatinine/USG

• Albumin/cholesterol

• Urine culture

• BP

• Fundic exam

• Haematology

• Biochemistry

• Imaging

• Serology

• CSF/joint taps

• FeLV/FIV

Glomerular disease cannot be distinguished except by biopsy. What are examples of glomerular diseases?

Amyloidosis

Glomerulonephritis: membranous, membranoproliferative, other

Minimal change disease

Glomerulosclerosis (secondary focal glomerulosclerosis)

Familial glomerulopathies

Why are renal biopsies considered in patients with PLR?

• To determine whether there is any evidence the disease process is immune mediated and therefore would benefit from immunosuppressive therapy

• Breed management

• Prognostic info

What are the risks of renal biopsy?

Haemorrhage

Renal injury

Expense