equine urinary wilkins.pdf

Goals Acute and Chronic Renal Failure (AKA Acute kidney injury or AKI) Pamela A. Wilkins Acute Renal Failure (AKI) • Usually secondary to some other disease process – Aminoglycoside antimicrobial therapy – NSAID toxicity – Acute enterocolitis – Pleuropneumonia – DIC – Purpura hemorrhagica – Etc………...

Goals Acute and Chronic Renal Failure (AKA Acute kidney injury or AKI) Pamela A. Wilkins Acute Renal Failure (AKI) • Usually secondary to some other disease process – Aminoglycoside antimicrobial therapy – NSAID toxicity – Acute enterocolitis – Pleuropneumonia – DIC – Purpura hemorrhagica – Etc…………… • To understand the difference between acute and chronic renal failure • To understand the underlying pathophysiology of both acute and chronic renal failure • To list the most common causes of acute renal failure and the differential diagnoses for renal dysfunction • To understand the treatment(s) of renal failure Acute Renal Failure (AKI) AKI may be classified into 3 general categories, as follows: • Prerenal - as an adaptive response to severe volume depletion and hypotension, with structurally intact nephrons • Intrinsic - in response to cytotoxic, ischemic, or inflammatory insults to the kidney, with structural and functional damage • Postrenal - from obstruction to the passage of urine • While this classification is useful in establishing a differential diagnosis, many pathophysiologic features are shared among the different categories. Etiology • The driving force for glomerular filtration is the pressure gradient from the glomerulus to the Bowman space. Glomerular pressure is primarily dependent on renal blood flow (RBF) and is controlled by combined resistances of renal afferent and efferent arterioles. • Regardless of the cause of acute kidney injury (AKI), reductions in RBF represent a common pathologic pathway for decreasing GFR. The etiology of AKI consists of 3 main mechanisms. Presentation • Patients who develop AKI can be oliguric or nonoliguric, have a rapid or slow rise in creatinine levels, and may have qualitative differences in urine solute concentrations and cellular content. (Approximately 50-60% of all causes of AKI are nonoliguric.) • Anuria is defined as a urine output of less than 100 mL/d (human) and, if abrupt in onset, suggests bilateral obstruction or catastrophic injury to both kidneys. • This lack of a uniform clinical presentation reflects the variable nature of the injury. Etiology • Prerenal failure - Defined by conditions with normal tubular and glomerular function; GFR is depressed by compromised renal perfusion • Intrinsic renal failure - Includes diseases of the kidney itself, predominantly affecting the glomerulus or tubule, which are associated with release of renal afferent vasoconstrictors; ischemic renal injury is the most common cause of intrinsic renal failure. • Postobstructive renal failure - Initially causes an increase in tubular pressure, decreasing the filtration driving force; this pressure gradient soon equalizes, and maintenance of a depressed GFR is then dependent on renal efferent vasoconstriction Etiology Etiology • Depressed RBF eventually leads to ischemia and cell death. This may happen before frank systemic hypotension is present and is referred to as normotensive ischemic AKI. • The initial ischemic insult triggers a cascade of events that includes production of oxygen free radicals, cytokines and enzymes, endothelial activation and leukocyte adhesion, activation of coagulation, and initiation of apoptosis. • These events continue to cause cell injury even after restoration of RBF. • Tubular cellular damage results in disruption of tight junctions between cells, allowing back leak of glomerular filtrate and further depressing effective GFR. In addition, dying cells slough off into the tubules, forming obstructing casts, which further decrease GFR and lead to oliguria. • The following are common iatrogenic combinations: – Preexisting renal disease with radiocontrast agents, aminoglycosides, NSAIDs – Nonsteroidal anti-inflammatory drugs (NSAIDs) Hypovolemia with aminoglycosides, heme pigments, or radiologic contrast agents • During this period of depressed RBF, the kidneys are particularly vulnerable to further insults. This is when iatrogenic renal injury is most common. Aminoglycoside Toxicity • Despite extensive study, the exact mechanisms of aminoglycoside nephrotoxicity remain elusive. • After glomerular filtration, approximately 15% of a filtered load of an aminoglycoside is reabsorbed into the kidney. • The uptake of aminoglycosides into the proximal tubule (a key step in the pathogenesis of kidney injury) is saturable, although the level of this effect depends upon the aminoglycoside • After uptake, a number of cellular processes are activated, culminating in apoptosis. This contributes to loss of the renal tubular epithelium and thus kidney dysfunction but, conversely, shedding and urinary excretion of apoptotic bodies may excrete aminoglycosides. NSAID Toxicity • Renal effects of NSAIDs are based on their pharmacologic mechanism of action. • These effects are relatively mild and rare in healthy individuals but can be serious in patients whose renal function is prostaglandin-dependent. • Patients with contracted effective intravascular fluid volume as a result of congestive heart failure, cirrhosis, diuretic use, or restricted sodium intake, are more likely to experience NSAID-related changes in renal function • Renal papillary necrosis is the least common but potentially most severe NSAID-related renal adverse effect, as it represents permanent renal parenchymal damage. This can be caused acutely by a massive overdose of an NSAID in a dehydrated individual. • Chronic renal papillary necrosis is associated with long-term use of multiple high doses of a single analgesic or combinations of analgesics. Acute Kidney Injury Diagnostics Acute Kidney Injury Physical Examination Findings, Clinical Signs, Complaints • • • • • • Weight loss Dullness Poor performance Depression Odor Anorexia • • • • Polyuria Oliguria Pigmenturia Signs consistent with primary disease process • Can be SILENT Acute Kidney Injury Diagnostics • Urinalysis: – Renal tubular casts – Moderate proteinuria – +/- hematuria – Pigmenturia – Increased white blood cells – Increased uGGT, uGGT:Cr – Abnormal fractional excretion of electrolytes – Isostenuria • Urinalysis – Normal equine urinalysis: • • • • • Specific gravity 1.025-1.050 Color: yellow to clear, thick, syrupy pH: alkaline Protein: negative to 1+ Blood: negative SDMA • SDMA (symmetric dimethylarginine) is a novel kidney test that has recently been enabling veterinarians to diagnose kidney disease earlier than traditional diagnostics in dogs and cats. • It has been shown to increase in both acute kidney injury (AKI) and chronic kidney disease (CKD). SDMA is also specific for kidney function and has been shown to be less impacted by extrarenal factors, including body condition, advanced age, and disease state. • The SDMA reference interval for horses was determined to be 0–14 ug/dL (IDEXX) Acute Kidney Injury Diagnostics Acute Kidney Injury Diagnostics • Urine osmolality: – Normal 727-1456 mOsm/L – ARF decreases osmolality to 226-495 mOsm/L Acute Kidney Injury Diagnostics Acute Kidney Injury Diagnostics • Serum chemistry analysis – Azotemia: BUN> 20mg/dl, Cr>2.0 – Hyponatremia, hypchloremia,hyperkalemia – Fractional excretion of electrolytes • {(UNa/Pna) / (UCr/PCr)} x 100 • Na usually < 1.0% • • • • Ultrasonography Radiography Nuclear scintigraphy Renal biopsy Acute Kidney Injury Treatment Acute Kidney Injury Pathophysiology • Acute tubular necrosis – Aminoglycoside toxicity – Pigment nephropathy • Acute interstitial nephritis – ? delayed hypersensitivity • Acute glomerulonephritis • • • • Focus on reversing or treating the inciting cause Prevention is important Restore and maintain intravascular fluid volume Maintain glomerular filtration and urine production • Monitor closely – Ag:Ab complex deposition? • Post-renal acute renal failure Restoration of renal blood flow and associated complications • Recovery from AKI is first dependent upon restoration of RBF. – Early RBF normalization predicts better prognosis for recovery of renal function. • In prerenal failure, restoration of circulating blood volume is usually sufficient. • Rapid relief of urinary obstruction in postrenal failure results in a prompt decrease of vasoconstriction. • With intrinsic renal failure, removal of tubular toxins and initiation of therapy for glomerular diseases decreases renal afferent vasoconstriction. Acute Kidney Injury Treatment • IV fluids @ 40-80 ml/kg/day until Cr decreases dramatically • Decrease fluid rate to 1-20 ml/kg/day until Cr normal Acute Kidney Injury Treatment Furosemide and AKI • Persistent oliguria: 10-12 hrs after initiating fluid therapy: – Dopamine CRI: ‘renal dose’ 3µg/kg/min – Diuretic agents: • Mannitol: osmotic diuretic ONCE filtered: no longer recommended • Furosemide: loop diuretic • Maintenance of volume homeostasis and correction of biochemical abnormalities remain the primary goals of treatment. Furosemide can be used to correct volume overload when the patients are still responsive; this often requires high intravenous (IV) doses. • Furosemide plays no role in converting an oliguric AKI to a nonoliguric AKI or in increasing urine output when a patient is not hypervolemic. Furosemide in AKI • However, the response to furosemide can be taken as a good prognostic sign. At this stage, the kidneys remain vulnerable to the toxic effects of various chemicals. • All nephrotoxic agents (eg, radiocontrast agents, antibiotics with nephrotoxic potential, heavy metal preparations, cancer chemotherapeutic agents, NSAIDs) are either avoided or used with extreme caution. • Similarly, all medications cleared by renal excretion should be avoided or their doses should be adjusted appropriately. • Once RBF is restored, the remaining functional nephrons increase their filtration and eventually hypertrophy. • GFR recovery is dependent upon the size of this remnant nephron pool. – If the number of remaining nephrons is below some critical value, continued hyperfiltration results in progressive glomerular sclerosis, eventually leading to increased nephron loss. – A vicious cycle ensues; continued nephron loss causes more hyperfiltration until complete renal failure results. – This has been termed the hyperfiltration theory of renal failure and explains the scenario in which progressive renal failure is frequently observed after apparent recovery from AKI. Intrinsic Acute Kidney Injury • Structural injury in the kidney is the hallmark of intrinsic AKI, and the most common form is ATN, either ischemic or cytotoxic. Frank necrosis is not prominent in most human cases of ATN and tends to be patchy. • Less obvious injury includes loss of brush borders, flattening of the epithelium, detachment of cells, formation of intratubular casts, and dilatation of the lumen • Although these changes are observed predominantly in proximal tubules, injury to the distal nephron can also be demonstrated. • In addition, the distal nephron may become obstructed by desquamated cells and cellular debris. • A physiologic hallmark of ATN is a failure to maximally dilute or concentrate urine (isosthenuria). This defect is not responsive to pharmacologic doses of vasopressin. • The injured kidney fails to generate and maintain a high medullary solute gradient, because the accumulation of solute in the medulla depends on normal distal nephron function. – (Failure to excrete concentrated urine even in the presence of oliguria is a helpful diagnostic clue in distinguishing prerenal from intrinsic renal disease; in prerenal azotemia, urine osmolality is typically more than 500 mOsm/kg, whereas in intrinsic renal disease, urine osmolality is less than 300 mOsm/kg.) Post-renal Acute Kidney Injury • Mechanical obstruction of the urinary collecting system, including the renal pelvis, ureters, bladder, or urethra, results in obstructive uropathy or postrenal AKI. • If the site of obstruction is unilateral, then a rise in the serum creatinine level may not be apparent due to contralateral renal function. Although the serum creatinine level may remain low with unilateral obstruction, a significant loss of GFR occurs, and patients with partial obstruction may develop progressive loss of GFR if the obstruction is not relieved. Causes of obstruction include stone disease; stricture; and intraluminal, extraluminal, or intramural tumors. • Diseases causing urinary obstruction from the level of the renal tubules to the urethra include the following: – Tubular obstruction from crystals (eg, uric acid, calcium oxalate, acyclovir, sulfonamide, methotrexate, myeloma light chains) – Ureteral obstruction - Retroperitoneal tumor, retroperitoneal fibrosis (methysergide, propranolol, hydralazine), urolithiasis, or papillary necrosis – Urethral obstruction - Benign prostatic hypertrophy; prostate, cervical, bladder, colorectal carcinoma; bladder hematoma; bladder stone; obstructed Foley catheter; neurogenic bladder; or stricture Post-renal Acute Kidney Injury • Ureteric obstruction – stone disease, tumor, fibrosis, ligation during pelvic surgery • Bladder neck obstruction – benign prostatic hypertrophy [BPH], cancer of the prostate [CA prostate or prostatic CA], neurogenic bladder, tricyclic antidepressants, ganglion blockers, bladder tumor, stone disease, hemorrhage/clot • Urethral obstruction – strictures, tumor, phimosis • Intra-abdominal hypertension Renal vein thrombosis Acute Renal Failure Treatment • Monitoring: – Therapeutic drug monitoring – Blood pressure – Central venous pressure – Urinalysis – Electrolytes – Creatinine – Etc. Acute Renal Failure Prognosis • Depends on underlying event. Length of time present • Severe ischemic failure, AIN carry worst prognosis • ATN prognosis good if basement membrane intact • Patients recover but may not be able to fully concentrate urine. Chronic Renal Failure Chronic Renal Failure • Infrequently recognized in horses • Primarily a problem in older patients • Many older patients have renal lesions: large renal reserve prevents clinical signs – Requires 2/3 to ¾ of functional parenchyma be lost • Underlying causes can be congenital or acquired Chronic Renal Failure Causes Physical Examination Findings, Clinical Signs, Complaints • • • • Gradual weight loss Poor performance Pendent edema PU/PD • • • • Excessive dental tartar Oral ulcerations Stunted growth Abdominal pain • Two broad classes of causation: – Primary glomerular disease • Glomerulnephropathy, glomerulopathy, renal glomerular hypoplasia, amyloidosis – Tubulointerstitial disease • Incomplete recovery from ARF, pyelonephritis, nephrolitiasis, hydronephrosis, renal dysplasia, papillary necrosis (rare) Chronic Renal Failure Causes – Chronic interstitial nephritis in most common cause: • • • • • • • ATN Drug induced Obstruction NSAID toxicity Pigmenturia Ischemic causes Nephrolitiasis Chronic Renal Failure Diagnostics • As for ARF but include: – BUN:Cr usually > 10 with CRF – Red cell parameters: CRF patients frequently anemic – Albumin: < 2.5 gm/dl – More electrolyte abnormalities – Blood gas parameter: acidosis common – Hypercholesterolemia/hyperlipidemia – Rectal exam and US to evaluate renal size Chronic Renal Failure Treatment • • • • • • • • • Treat any acute component as ARF Supportive care, IV fluid support Adequate feed, decrease protein Unlimited water access Oral NaCl Or NaHCO3 Avoid NSAIDs and steroids Remove calculi if present Pyelonephritis: antimicrobial therapy All efforts are palliative Chronic Renal Failure Prognosis • GRAVE Goals • To understand the difference between acute and chronic renal failure • To understand the underlying pathophysiology of both acute and chronic renal failure • To list the most common causes of acute renal failure and the differential diagnoses for renal dysfunction • To understand the treatment(s) of renal failure Goals • To understand common causes of urinary tract infections in horses, treatment and prognosis • To understand the clinical presentation and underlying causes of urolithiasis in horses and prescribe appropriate treatment • To understand the common causes of PU/PD in horses, it diagnosis and its management. Urolithiasis, Urinary Tract Infection, PU/PD Pamela Wilkins Hematuria Hematuria Causes • • • • • • • • Pyelonephritis Cystitis Idiopathic renal Urolithiasis Sabulous bladder Urethral rent Blister beetle toxicosis Trauma Physical Examination Findings, Clinical Signs, Complaints • • • • • • • Lower Urinary Tract Altered urine flow Urine scalding Dysuria Pollakuria Gross hematuria Calculi at end of urination • • • • • Upper urinary tract Fever Weight loss Signs of systemic illness Other like LUTI Urinary Tract Infections Urinary Tract Infections Diagnostics Pathogenesis • Urinalysis – > 20 organisms/hpf, > 10 WBC/hpf in mid-stream catch or catheterized sample • • • • Urinary Tract Infections Ultrasound Chemistry screen Hematology with fibrinogen Urine culture • Neurologic disorders – EPM, EHV-1, cauda equine neuritis, botulism • Urolithiasis • Foaling trauma • Poor perineal conformation • Common organisms: – E. coli, Proteus spp, Klebsiella spp, Pseudomonas spp. Urinary Tract Infections Urinary Tract Infections Treatment Parasite • Treat any associated ARF/CRF • Antimicrobial therapy based on urine culture and sensitivity – TMS, penicillin, ceftiofur sodium Urethral Rents • Urethral rents that occur on the convex surface of the urethra at the level of the ischial arch cause hematuria in geldings and hemospermia in stallions. • Urethral rents communicate with the corpus spongiosum penis (CSP). • Hemorrhage through the rent into the urethral lumen occurs when pressure within the CSP increases at the end of urination or during ejaculation. • The 5-10-mm rent is identified endoscopically on the convex surface of the urethra, near the level of the ischial arch. • Urethral rents often heal without treatment. • • • • • Uncommon Strongylus vulgaris Halicephalobus gingivalis (deletrix) Dioctophyma renale Klossiella equi Urolithiasis • Urinary calculi or stones may form in any part of the equine urinary tract, but the most common site is the bladder (cystic). • Calculi are formed by material dissolved in the urine (solutes) being precipitated upon a collection of bladder or other cells, such as tubular epithelial, renal papillary or red or white blood cells. • Usually only one calculus occurs at a time, often composed of calcium carbonate. Urolithiasis • The factors favoring this precipitation are not well understood but include urine pH; alkalinity increases the formation of carbonate calculi; and the concentration of urine solutes. – This can be affected by diet, water intake and loss. – If the diet or water has a high mineral content, urine solute content increase. – A high-concentrate, low-roughage ratio may allow the deposited solute to cement together more easily. Urolithiasis • All breeds and both sexes are equally likely to develop calculi, athough in mares they become very large before symptoms appear. – These are similar to those seen in cases of cystitis, which often is present at the same time. – Affected individuals urinate more frequently, with straining and dribbling of urine. – Less commonly there may be mild recurrent colic, loss of condition and stilted gait. • Occasionally a calculus passes into the male urethra, causing acute obstruction of urine flow. Urolithiasis • Diagnosis of cystic calculi involves: – Urine analysis (the changes are similar to those of cystitis) – Rectal examination – Passage of urinary catheter – Ultrasound of the bladder – Urinary tract endoscopy Urolithiasis • Surgical removal of the calculus is the only effective method of treatment. • The approach and type of surgery is determined by the size of the stone and the sex of the patient. • Some cases may also require treatment for concurrent cystitis. – Pyridium! • Urinary acidification may be attempted but is often unrewarding. Sabulous bladder Incontinence to start….. • Incontinent horses due to neurologic dysfunction dribble urine because effective detrusor contraction is absent and bladder contents are not subject to muscle contraction and forced ejection from the body, as occurs in a normal state. The neurologic circuitry that mediates the micturition reflex is complex, and examples of disease processes that can interfere with various segments of the reflex loop include herpes myelitis, polyneuritis equi (cauda equine syndrome), and equine protozoal myeloencephalitis. Cystitis……sediment Treatment • Bladders that become paralyzed because of these pathologic processes often show deposition of a sandy, crystalloid sediment, a condition called sabulous cystitis, instead of formed uroliths. Bladder paralysis permits settling of deposits onto the bladder floor, where the material's weight prevents it from being extruded during dribbling of urine from the incontinent bladder. The sediment contributes to inflammation and irritation of the mucosal lining, exacerbating cystitis and most likely, the discomfort of the horse. • Treatment of the condition involves lavage of the bladder lumen with isotonic solutions to remove the sediment load, administration of systemic antibiotics chosen with regard for culture results and sensitivity testing of a catheterized urine sample, anti-inflammatories, and urine acidification. Lavage can be achieved through a catheter. Placement of an indwelling catheter for a brief initial period helps lower urine stasis and maintains the bladder in a fairly decompressed state, abating further detrusor damage. Adding acetic acid to decrease luminal pH during lavage is advocated. Pharmacologic intervention Phenazopyridine • The parasympathomimetic drug bethanechol augments contractility of the detrusor smooth muscle. – Bethanechol (20-40 mg or 0.07 mg/kg SQ q 8 hours, 80 mg PO q 8 hours do not give I.V. or I.M.) is not currently available as a proprietary formulation but can be obtained from compounding pharmacies. • Phenoxybenzamine, (0.2-0.7 mg/kg PO, q 6-8 hrs) is an adrenergic antagonist, and may be given to help relax the distal urethral sphincter in cases where the condition is determinedly due to upper motor neuron damage. • (4 mg/kg PO q 8-12 hours), an azo dye compound that acts to confer relief from irritation or spasm of the urinary tract mucosa via local anesthetic activity, may also be administered in the initial management of the cystitis caused by the sedimentary accumulation. • This compound discolors urine. – Owners should be warned that it will stain skin and textiles which inadvertently come into contact with the substance. • In humans with urinary tract inflammation the agent alleviates symptoms of dysuria, frequency, burning, and the sensation of urgency. Estrogen PU/PD • Mares in which urinary incontinence is from hypoestrogenism may enjoy a better prognosis for response to treatment. Successful management of the condition in such mares has been observed in association with administration of estradiol cypionate or benzoate (5-10 _g/kg I.M. q 48 hours). PU/PD • Rare, indicates a failure of normal homeostatic mechanisms controlling water balance • Can be caused by either increased water intake or increased urine production • Establishing if a horse is really PU/PD can be a challenge PU/PD • Rule out: – Diarrhea – Acute Renal Failure – Horse on High Salt Diet Diagnostics • • • • • • • History Clinical Examination Clinical Pathology Renal function tests Water deprivation test Modified water deprivation test ADH (vasopressin) stimulation test Causes • Psychogenic polydipsia • Thirst • Compulsive salt or glucose consumption • • • • • • Diabetes mellitus Diabetes insipidus Hyperadrenocorticism Sepsis/endotoxemia Iatrogenci Primary renal insufficiency Nephrogenic diabetes insipidus • Decreased sensitivity of collecting ducts to vasopressin • Rare in horses Neurogenic diabetes insipidus • Hyposthenuria in the face of dehydration • Positive response to vasopressin Syndrome of Inappropriate ADH Secretion (SIADH) • • • • Most common in neonates Associated with perinatal asphyxial syndrome Very concentrated urine Hyponatremia secondary to increased water retention, ‘dilutional’ • Excessive weight gain • Usually resolves, treatment is appropriate fluid restriction. Psychogenic polydipsia • Psychogenic water (common) or salt (rare) consumption • Drink 2-3 times that of others horses in same environment • Respond to water deprivation by concentrating urine Urinary Incontinence • Causes: – Neurological diseases – Intramural bladder/urethral disease – Hormonal – Ectopic ureter – Bladder tumor – Adhesions – Urolithiasis – Sorghum toxicity – Etc…… Urinary Incontinence Urinary Incontinence Treatment Prognosis • Depends on underlying problem • Upper motor neuron: – Phenoxybenzamine – Bethanacol • Poor to guarded • May fully recover from EHV-1, botulism with time • Lower motor neuron: – Phenylpropanolamine • Older mares: – Estradiol Urinary Tract Tumors • Bladder: – Squamous cell carcinoma, transitional cell carcinoma (RARE) • Kidney: – Renal cell carcinoma, lymphosarcoma Goals • To understand common causes of urinary tract infections in horses, treatment and prognosis • To understand the clinical presentation and underlying causes of urolithiasis in horses and prescribe appropriate treatment • To understand the common causes of PU/PD in horses, it diagnosis and its management.