Loop diuretics block Na⁺-K⁺-2Cl^- symporters at the thick ascending limb of the loop of Henle, preventing reabsorption of 25% of Na⁺ filtered by the glomerulus.  Since nephron segments distal to this location are incapable of reabsorbing sodium, naturesis and diuresis result. 

Other renal effects of loop diuretics include:

increased renin secretion

increased K⁺ and H⁺ excretion

increased PGE₂ formation

decreased Ca²⁺ and Mg²⁺ reabsorption

decreased hypertonicity of medullary interstitium

Volume depletion, hypokalemia, metabolic alkalosis, ototoxicity

Aminoglycosides - additive rsik for nephrotoxicity

NSAIDs -     additive risk for nephrotoxicity

      inhibit PGE₂ formation

compete for OATs

Edema of cardiac, renal or hepatic origin

Hypercalcemia or hyperkalemia

EIPH in horses (if legal)

Induction of diuresis in oliguric renal failure

Decreased capillary oncotic pressure

Increased capillary hydrostatic pressure

Increased capilary permeability

Decreased lymphatic drainage

  A.  Decreased cardiac output:

1) stimulates the RAAS which causes retention of Na⁺ and H₂O

2) stimulates baroreceptors which causes ADH release and retention of Na⁺ and H₂O

B.  Increased LV end diastolic pressure leads to increased capillary hydrostatic pressure

A.  Hepatic fibrosis causes portal hypertension, leading to increased capillary hydrostatic pressure

B.  Hypoalbuminemia results in decreased capillary hydrostatic pressure.

A.  Proteinuria leads to decreased capillary oncotic pressure

B.  Reduced Na⁺ excretory ability of the renal tubules leads to Na⁺ and H₂O retention, increasing capillary hydrostatic pressure

1.  Used prophylactically in ARF to prevent renal tubular damage by administration of a renal toxin

2.  Used to reduced intracranial pressure (except when due to hemorrage)

3.  Used to reduce intraocular pressure in glaucoma

1.  Chronic dehydration and electrolyte disturbances.

2.  Chronic extracellular hyperosmolarity causes formation of intracellular idogenic osmoles; if treatment is discontinued abruptly, can result in cerebral edema

Hyperkalemia

Dehydration and hyponatremia

Idiosyncratic hypersensitivities (facial puritis in cats, mucocutaneous reactions in dogs)

Low: binds DA1 and DA2 receptors only, causing vasodilation and inhibition of peripheral sympathetic neurons (respectively).

Moderate: binds beta adrenergic receptors, increasing heart rate and contractility

High: binds alpha adrenergic receptors, causing vasopressive effects.

By blocking angiotensin converting enzyme, ACE inhibitors prevent the formation of angiotensin II, a vasoconstrictor.  The result is vasodilation in patients with an activated RAAS.

ACE inhibitors also preferentially dilate the efferent arteriole more than the afferent arteriole in the glomerulus, reducing pressure within the glomerulus and the amount of protein passed into the filtrate.

Reduction of proteinuria in patients with glomerular disease

Cardiovascular disease

Pre-renal azotemia; maintain patient hydration and monitor BUN/creatinine

Increased bradykinin levels due to reduced metabolization by angiotensin resulting in cough and angioedema (allergic subcutaneous reaction); monitor for these signs

Other nephrotoxic drugs (aminoglycosides, NSAIDs, cisplatin)

Other hypotensive drugs (all diuretics)

Enalapril, Benazapril and Lisinopril

Enalapril because it is excreted almost exclusively by the kidney

The antithrombotic dose of aspirin is about 50 times less than the antiinflammatory dose.  At antiinflammatory doses, negative renal effects occur (reduced renal perfusion)

For other NSAIDs, the anticoagulant dose is roughly equal to the antiinflammatory dose, causing reuced renal perfusion and GI ulceration.  Thus NSAIDs other than aspirin are not indicated for use as antithrombotics in glomerular disease.

In chronic renal failure, tubular cells that make calcitriol are lost, reducing blood calcitriol levels.  Hyperphosphatemia that occurs in renal failur also inhibits the formation of calcitriol

Calcitriol inhibits PTH secretion, therefore CRF patients have excessive PTH levels

Easy to cause hypercalcemia by giving greater than 2.5ng/kg/day

Can promote soft tissue mineralization if given to a patient with a blood phosphorus above 6.0mg/dL

Aluminum-based and calcium-based

Both bind phosphorus in the GI tract, preventing its absorption

Aluminum-based: chronic use can cause aluminum toxicity (encephalopathies, microcytic anemia, osteomalacia)

Calcium-based: hypercalcemia (especially when used with calcitriol)

Concurrent use of calcium-based phosphate binders with calcitriol carries an additive risk of hypercalcemia.

Both calcium-based and aluminum-based forms interfere with oral drug, such as fluoroquinolone and tetracycline, absorption.

Aluminum hydroxide: Amphojel®

Polyaluminum hydroxide: sucralfate

Calcium carbonate: Tums®

Erythropoietin is produced by the peritubular fibroblasts of the renal cortex and is reduced in CRF, resulting in a normocytic, normochromic non-regenerative anemia.

EPO should be given when the patient has a PCV of <20% and symptomatic (pale MMs, lethargy, etc.)

Treatment with EPO can result in iron deficiency; monitor serum iron and TIBC

EPO has direct vasoconstrictive effects and can cause hypertension if too much is given

If dose is too high or two frequent, hyperviscosity can result from polycythemia

Treatment with EPO has the potential to cause anti-EPO antibody formation resulting in severe refractory anemia; requires months of blood transfusions to pull the patient through

Epogen®: rhEPO (recombinant human EPO)

Darbepoietin: chemically modified EPO (longer T_1/2)

Start with a renal diet.  As disease progresses, implement (in order): phosphate binders, anti-ulcer medications, potassium supplementation (in cats), calcitriol w/ intensive monitoring, EPO therapy/blood transfusions.

Quality of life declines as each of the above therapies becomes necessary.