Renal insufficiency & dialysis, urinary incontinence & calculi

Renal Insufficiency and Dialysis Urinary Incontinence Urinary Tract Calculi

From: Kelly CR & Landman J.(Eds.) The Netter Collection of Medical Illustrations, 2E Vol 5- Urinary System.

Philadelphia PA: Saunders, 2012.

Renal Insufficiency and Dialysis

Marc Imhotep Cray, M.D.

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Acute kidney injury (Acute renal failure)  Acute kidney injury is defined as an abrupt decline in renal function as measured by ↑creatinine and ↑BUN Prerenal azotemia Due to ↓ RBF (eg, hypotension)  ↓GFR  Na+/H2O and BUN retained by kidney in an attempt to conserve volume  ↑BUN/Cr ratio (BUN is reabsorbed, creatinine is not) and ↓ FENa Intrinsic renal failure Generally due to acute tubular necrosis or ischemia/toxins; less commonly due to acute glomerulonephritis (eg, RPGN, hemolytic uremic syndrome) or acute interstitial nephritis  In ATN, patchy necrosis  debris obstructing tubule and fluid backflow across necrotic tubule  ↓ GFR  Urine has epithelial/granular casts  BUN reabsorption is impaired  ↓BUN/creatinine ratio Postrenal azotemia Due to outflow obstruction (stones, BPH, neoplasia, congenital anomalies)  Develops only with bilateral obstruction

Acute kidney injury (AKI) cont.

Le T and Bhushan V. First Aid for the USMLE Step 1 2016.McGraw-Hill, 2016.

Marc Imhotep Cray, M.D.

Consequences of renal failure  Renal failure: Inability to make urine and excrete nitrogenous wastes 2 forms of renal failure:  acute (eg, ATN) and  chronic (eg, HTN, DM, congenital anomalies)

Marc Imhotep Cray, M.D.

Consequences (MAD HUNGER): Metabolic Acidosis Dyslipidemia (especially ↑ triglycerides) Hyperkalemia Uremia—clinical syndrome marked by  ↑BUN: o Nausea and anorexia o Pericarditis o Asterixis o Encephalopathy o Platelet dysfunction Na+/H2O retention (HF, pulmonary edema, hypertension) Growth retardation and developmental delay Erythropoietin failure (anemia) Renal osteodystrophy

QUESTION: What is the difference between azotemia and uremia?

Azotemia is a medical condition characterized by abnormally high levels of nitrogen-containing compounds (such as urea, creatinine, various body waste compounds, and other nitrogen-rich compounds) in the blood.

It is largely related to insufficient or dysfunctional filtering of blood by the kidneys. It can lead to uremia if not controlled.

Uremia in current usage represents the entire constellation of signs and symptoms of chronic renal failure, including nausea, vomiting, anorexia, a metallic taste in the mouth, a characteristic odor of breath, pruritus, urea frost on the skin, neuromuscular disorders, pain and twitching in muscles, hypertension, edema, mental confusion, and acid-base and electrolyte imbalances.

Nephrologist prefer to call this the uremic syndrome.

Marc Imhotep Cray, M.D.

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Effect of Renal Insufficiency on Drug Action  Many drugs and drug metabolites are excreted via kidney so changes (e.g., advanced age, disease) that alter renal function affect elimination (half-life) of many agents  Blood levels of a drug or its metabolites are greater when decreased renal clearance exists than during normal renal clearance  This change is clinically relevant for drugs eliminated primarily by kidneys o Even more critical for drugs with a small therapeutic index

 Sometimes effect of renal insufficiency on a drug metabolite (e.g., normeperidine) is more important than that on drug itself (i.e., meperidine) Marc Imhotep Cray, M.D.

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Effect of Renal Insufficiency on Drug Action(2)  Renal function usually declines with age so elderly patients are often given reduced doses of drugs eliminated mainly via kidneys  Examples of altered drug action in renal insufficiency are  enhanced hyperkalemia with K+-sparing diuretics or NSAIDs  delayed or decreased diuretic effectiveness and  greater risk of NSAID-induced GI bleeding

Marc Imhotep Cray, M.D.

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Effect of Renal Insufficiency on Drug Action (3)

Raff RB, Rawls SM, Beyzarov EP. Netter's Illustrated Pharmacology, Updated Edition. Saunders, 2014

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Effect of Hemodialysis on Drug Action Hemodialysis is used  as maintenance therapy for patients with renal failure and  to clear toxic substances from blood of patients who ingested poisons or overdoses of drugs  Fundamental physiologic principle in dialysis is that of a solute moving across a semipermeable membrane in a direction and at a rate consistent with concentration and osmotic gradients  Principle is basis for operation of artificial or mechanical kidneys  If a patient receives therapy with a drug that can be dialyzed (i.e., pass through membrane), amount lost during dialysis must be considered, and supplementary doses may be needed to replace lost drug Marc Imhotep Cray, M.D.

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Hemodialysis, Peritoneal Dialysis, and Continuous Therapies When kidney dysfunction is severe enough to cause homeostatic abnormalities that cannot be corrected with diet or medications, dialysis is performed to artificially replace kidney’s major functions The major goals of dialysis are to support the elimination of nitrogenous waste products To restore fluid and electrolyte homeostasis, and restore normal plasma pH The major indications are listed in the following slide

Marc Imhotep Cray, M.D.

Hemodialysis Indications:  Metabolic acidosis that is refractory to medical treatment  Electrolyte abnormalities, such as hyperkalemia, that are refractory to medical treatment  Intoxication with dialyzable drugs (e.g., salicylates, lithium)  Volume overload that is refractory to diuretics  Uremia and its complications (encephalopathy, pericarditis, bleeding)

In patients with chronic kidney disease:  Glomerular filtration rate <10–15 mL/min/1.73 m2  Weight loss, anorexia, loss of appetite  Any of sequelae of impaired renal function listed above Marc Imhotep Cray, M.D.

Principles of Dialysis  Dialysis employs a semipermeable membrane to alter composition of blood  Bld is located on one side of membrane, whereas a wash solution, known as dialysate, is on opposite side  Objective is for desirable electrolytes to move from dialysate to bld and for undesirable electrolytes to move in opposite direction  Movement of fluid and solutes across membrane depends on two physical forces:  diffusion and  convection

Marc Imhotep Cray, M.D.

Hemodialysis  In hemodialysis, bld leaves patient and flows through tubing into a dialyzer  dialyzer contains numerous hollow fibers composed of semipermeable membranes  As bld flows through these fibers, dialysate flows around them in opposite direction  Molecules are exchanged across fiber walls  bld then returns to patient

 b/c blood and dialysate flow in opposite directions concentration gradients are maintained across entire length of dialyzer  As a result, potassium, nitrogenous waste products, phosphorus, and other substances that have accumulated in blood diffuse into dialysate  substances that are concentrated in dialysate, such as bicarbonate and other electrolytes at specific concs., diffuse into blood to restore desired levels  Patient’s vasculature can be accessed using either a central venous catheter (CVC) or a connection between an artery and vein (fistula or graft) Marc Imhotep Cray, M.D.

Hemodialysis

Raff RB, Rawls SM, Beyzarov EP. Netter's Illustrated Pharmacology, Updated Edition.

Saunders, 2014

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Vascular Access for Hemodialysis

From: Kelly CR & Landman J.(Eds.) The Netter Collection of Medical Illustrations, 2E Vol 5- Urinary System. Philadelphia PA: Saunders, 2012.

Marc Imhotep Cray, M.D.

Peritoneal Dialysis (PD)  In PD, dialysate is instilled into intraperitoneal space  Bld in peritoneal capillaries exchanges material with dialysate using peritoneal membrane as a natural semipermeable membrane  Dialysate dwells in peritoneum for 2 to 12 hrs and is then removed  Each sequence of instillation, dwelling, and draining is known as a cycle (or exchange)  Dialysate is a sterile solution that contains variable concs. of glucose  While dialysate is in peritoneum, substances such as urea and potassium diffuse from capillaries into dialysate, whereas  glucose and lactate diffuse in the opposite direction Marc Imhotep Cray, M.D.

Peritoneal Dialysis

Marc Imhotep Cray, M.D.

From: Kelly CR & Landman J.(Eds.) The Netter Collection of Medical Illustrations, 2E Vol 5- Urinary System. Philadelphia PA: Saunders, 2012.

Currently Known Dialyzable Substances

Raff RB, Rawls SM, Beyzarov EP. Netter's Illustrated Pharmacology, Updated Edition. Saunders, 2014 19

Continuous Therapies Continuous renal replacement therapy (CRRT) is similar to hemodialysis in some respects  however, sessions are continuous, rather than discrete, and flow rate is lower (100 to 300 mL/min)

CRRT is performed when patients require dialysis but are hemodynamically unstable or have homeostatic abnormalities that cannot be addressed with an individual hemodialysis session  For example, if a pt. in renal failure is expected to receive a large volume load (in form of transfusions or antibiotics), it may be advantageous to receive CRRT

As in hemodialysis, a connection is established between patient’s vasculature and an extracorporeal apparatus  Access is established using a central venous catheter  AV fistulae or grafts cannot be used b/c constant presence of needles in these vessels (in contrast to episodic presence associated with hemodialysis sessions) could lead to Marc Imhotep Cray, M.D. damage and infection, which would prevent future use

Urinary Incontinence Urinary Tract Calculi

Marc Imhotep Cray, M.D.

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Urinary Incontinence Urinary retention is normally under autonomic or voluntary control  Incontinence (an increased stimulus to void, a decreasedability to prevent voiding, or both) results when these pathways are interrupted or are overactivated or underactivated, or when smooth muscle of bladder contracts weakly, incoordinately, or inappropriately Although incontinence is not life threatening, it has significant medical and social consequences  It is often cited as a primary reason for inability of families to care for elders at home Marc Imhotep Cray, M.D.

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Urinary Incontinence (2)  Drug treatment options (far from ideal) include:  those that reduce bladder contraction, such as cholinergic antagonists o (e.g., oxybutynin, prophantheline, tolterodine)  those that increase bladder outlet function, such as αadrenoceptor agonists o (e.g., phenylpropanolamine, pseudoephedrine); and  those for which mechanism is not fully understood, such as o tricyclic antidepressants (possibly related to anticholinergic actions) and o estrogens (in postmenopausal women) Marc Imhotep Cray, M.D.

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Urinary Incontinence (3)

Marc Imhotep Cray, M.D.

Raff RB, Rawls SM, Beyzarov EP. Netter's Illustrated Pharmacology, Updated Edition. Saunders, 2014

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Case 55-Urinary Incontinence A 48-year-old Caucasian woman you have been treating for several years comes to your family medicine practice and seems embarrassed. She complains of urinating at least 10 times a day and 3 to 4 times at night and states it is interfering with her business and social life. She indicates her problem, which she says is â&#x20AC;&#x153;due to her getting older,â&#x20AC;? began about 2 years ago. She has tried several things to help, including drinking only one cup of coffee in the morning and total avoidance of liquid after 6 PM. She has begun wearing pads to avoid the embarrassment of leakage. She describes being in an important business meeting and having to get up and leave to go to the bathroom. She constantly worries about the location of the nearest bathroom and has avoided social events like her sonâ&#x20AC;&#x2122;s soccer games, which are on an open field with no facilities.

Marc Imhotep Cray, M.D.

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Case 55 cont.

Upon further questioning she denies leakage with coughing, sneezing, or laughing. She denies any dysuria, hematuria, or feeling of incomplete voiding.

She is monogamous without any prior history of sexually transmitted infections (STIs). You assure her the problem is not due to â&#x20AC;&#x153;getting oldâ&#x20AC;? and that there are treatable medical causes for the problem. Your physical examination is negative for STIs, vulvar or vaginal inflammation/infection/ trauma, and cystocele. You order a urinalysis which comes back normal. You prescribe a trial of oxybutynin. _ What are the causes of overactive bladder? _ What is the mechanism of action of oxybutynin? _ What are the different classes of agents used in the treatment of the different kinds of urinary incontinence?

Marc Imhotep Cray, M.D.

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Summary: â&#x20AC;˘ Urge incontinence (see following for other forms of UI) is caused by contraction of the bladder such that urine passes the urethral sphincter at the wrong time. â&#x20AC;˘ Oxybutynin is an anticholinergic drug that blocks muscarinic cholinergic receptors. M3 cholinergic receptors are responsible for the direct activation of the detrusor muscle. Oxybutynin decreases frequency of symptoms, and delays initial desire to void.

Marc Imhotep Cray, M.D.

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Clinical Correlation There are several types of urinary incontinence and they have different causes.

Urge incontinence as described in this case is typified as urinating more than eight times a day accompanied by a sudden and intense urge to urinate, frequently followed by involuntary loss of urine. The detrusor muscle contracts well before the bladder has filled and may give a warning of only a few seconds before the bladder sphincter muscle relaxes.

The fundamental problem seems to be neuromuscular in origin.

Contraction of the detrusor muscle is mediated by M3 cholinergic receptors. Urge incontinence may be caused by urinary tract infections, bladder irritants, bowel disease, Parkinson disease, Alzheimer disease, stroke, or nervous system damage associated with multiple sclerosis.

If thereâ&#x20AC;&#x2122;s no known primary cause, urge incontinence is also called overactive bladder.

Marc Imhotep Cray, M.D.

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Clinical Correlation cont.

Stress urinary incontinence (SUI) occurs upon sneezing, laughing, coughing, or other maneuvers that increase intraabdominal pressure in the presence of a weakened bladder sphincter. Urethral pressures, prolapse conditions, and congenital and acquired sphincter dysfunction all contribute to SUI pathophysiology.

In women, childbirth, pregnancy, and menopause can cause stress incontinence.

In men, prostate removal is a cause.

Marc Imhotep Cray, M.D.

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Clinical Correlation cont.

Overflow incontinence is a frequent near-constant loss of urine caused by inability to void. This usually has an anatomical or neural cause that interferes with normal emptying of the bladder.

Mixed incontinence refers to a combination of types.

The most common type of urinary incontinence in older women is a mixture of urge and stress incontinence. Treatments include lifestyle and behavioral modifications, drugs, and surgery.

Often the detailed history and examination is sufficient to give a presumptive diagnosis; however, various testing may be needed to rule out other contributing or causative etiologies. On occasion diagnostic testing, radiographic testing, and laboratory testing may be required as well.

Marc Imhotep Cray, M.D.

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Urinary Tract Calculi (Kidney Stones)  Urinary calculi are hardened crystals composed of a nucleus (often urate) and surrounding layers of precipitated minerals, such as calcium and magnesium salts, and other components of the urine (including metabolites of drugs excreted in the urine)  Stones are usually found in kidney, but they also occur in ureter and bladder (usually passed from kidney)  Urinary calculi occur in all age groups but primarily in persons aged between 20 and 55 years  Treatment (surgical or pharmacologic) depends on the cause, size, and location of the stone Marc Imhotep Cray, M.D.

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Kidney Stones (2)  Two common types for which drugs are used are due to hypercalciuria and hyperuricuria  Drugs for hypercalciuria include  sodium cellulose phosphate (inhibits calcium reabsorption) and  thiazides (mild diuresis stimulates convoluted tubule reabsorption of calcium)  Drugs for hyperuricuria include  allopurinol (decreases urate formation) and  alkali (increases urinary citrate, which inhibits stone formation) Marc Imhotep Cray, M.D.

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Urinary Tract Calculi (3)

Marc Imhotep Cray, M.D.

Raff RB, Rawls SM, Beyzarov EP. Netter's Illustrated Pharmacology, Updated Edition. Saunders, 2014

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See next slide for sources and links to additional study tools and resources.

Marc Imhotep Cray, M.D.

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Sources and further study: eLearning Renal cloud folder tools and resources MedPharm Guidebook: Unit 9 Drugs Used to Affect Renal Function Renal Pharmacology eNotes Clinical Pharmacology Cases 7, 8, & 55 (Learning Triggers) Textbooks Brunton LL, Chabner BA , Knollmann BC (Eds.). Goodman and Gilmanâ&#x20AC;&#x2122;s The Pharmacological Basis of Therapeutics. 12th ed. New York: McGraw-Hill, 2011 Katzung, Masters, Trevor. Basic and Clinical Pharmacology, 12th ed. New York: McGraw-Hill, 2012 Mulroney SE. and Myers AK. Netter's Essential Physiology. Philadelphia: Saunders, 2009 Raff RB, Rawls SM, Beyzarov EP. Netter's Illustrated Pharmacology, Updated Edition.

Philadelphia: Sanders, 2014 Toy E C. et.al. Case Files-Pharmacology Lange 3rd ed. New York: McGraw-Hill 2014.

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