To “Pee” or not to “Pee”—the KIDNEY in health and disease

“It is no exaggeration to say that the composition of the blood is determined not by

what the mouth takes in but by what the kidneys keep.” Homer W. Smith (1895-1962)

Some numbers…

• Renal diseases are responsible for a great deal of morbidity but are not major causes of mortality.

• Approximately 45,000 deaths are attributed to renal disease per year (as compared to 650,000 deaths due to heart disease, 560,000 due to cancer, and 145,000 due to stroke) (National Center for Health Statistics, 2002)

Some numbers…• Millions of persons are affected annually by

nonfatal kidney diseases, most notably infections of the kidney or lower urinary tract, kidney stones, and renal obstruction.

• Twenty percent of all women have a urinary tract infection or kidney infection at some time in their lives

• 20% of all women and 10% of all men 65 and older have bacteriuria; double those #’s in nursing homes (25-50% of women, and 15%-40%) in men

Some numbers…

• 10% of men and 5 % of women will have a kidney stone by the age of 70; about one million Americans are treated each year for a kidney stone

• BPH is a major cause of bladder outlet obstruction

• Kidney cancer, bladder cancer, prostate cancer are major urologic cancers (especially as the population ages)

Some numbers…

• Urinary incontinence is estimated to affect between 15% and 30% of independent adults ages 65 and older

• Costs the US about $20 billion per year to be incontinent

Kidney failure

• Bones can break, muscles can atrophy, glands can loaf, even the brain can go to sleep, without immediately endangering our survival; but should the kidneys fail…neither bone, muscle, gland nor brain could carry on. --Idem

CKD and renal failure…• From 1988 to 2004 the rates of chronic kidney disease

climbed from 10 percent to 13 percent of the US population

• Contributing factors? Diabetes, hypertension, obesity, and the aging U.S. population (JAMA 2007; 298:2038)

• Chronic kidney disease affects 16.8% of the U.S. population over 20

• Only about 1 in 8 men and 1 in 16 women with moderate (stage 3) kidney disease know they have it—YIKES! If we can pick it up, we can slow it down or reverse it!

Renal failure and renal dialysis

• If renal failure is left untreated it will cause death within two to three weeks

• Dialysis—from the Greek word for “separation”—Willem Kolff, M.D. devoted his entire medical career to the treatment of renal failure after watching the death of a 22-year old patient die from the disease. He invented the first dialysis machine in 1941 (using materials from a local factory) and in 1945 he successfully treated the first patient, a 67 year-old woman who lived another 7 years on dialysis

Renal failure and renal dialysis

• 1960—Scribner and colleagues at the University of Washington developed a blood-access device using Teflon-coated plastic tubes, which facilitated the use of repeated hemodialysis as a life-sustaining treatment for patients with uremia

• It was called the Scribner shunt…led to the development of AV fistulas and grafts and to long-term renal replacement therapy and the era of the “artificial kidney”

A little more history…

• Gustav Simon, in 1869, performed the first successful removal of a human kidney, the patient survived and the remaining kidney “picked up the slack” so to speak

• FACT: The healthy kidney can grow enough to handle 80% of the load that 2 kidneys used to handle

Dr. Joseph Murray, Boston

• During WWII Murray treated burn patients and wondered why skin rejection occurred when grafts were donated by other people. He and another colleague surmised that the closer the genetic relationship the longer the graft would last

• December 23, 1954 the first transplanted kidney from a 23 year-old man to his identical twin; the recipient lived another 8 years; Murray won the Nobel Prize in 1990

Looking for a kidney somewhere else because the waiting list in the U.S. is too long?

• India for $15,000; China? $62,000• U.S.? $262,900• Organ harvesting rings around the world; latest one

from Kosovo (2008)• China—convicts on death row are routinely tested,

typed, and held for on-demand “donations”• Pakistan, India, and Indonesia—slum dwellers sell

their body parts (Scott C, The Red Market, Wired, 2011)

• ARE YOU AT RISK FOR CKD?

The SCORED questionnaire—to identify patients at high risk for kidney disease

• I am between 50 and 59 years of age—2• I am between 60 and 69 years of age—3• I am 70 years or older – 4• I am a woman – 1• I had or have anemia – 1• I have high blood pressure – 1• I am diabetic – 1• I have a history or heart attack or stroke--1

The SCORED questionnaire—to identify patients at high risk for kidney disease

• I have a history of CHF or HF – 1• I have circulation disease in my legs – 1• I have protein in my urine – 1• If you score 4 or higher on the test you have a

1 in 5 risk of chance of having chronic kidney disease

• Get it checked out! (88-95% accuracy in identifying kidney disease)

• Arch of Intern Med 2008 (Feb 29)

Let’s start at the very beginning…

• How much embryology did you get in nursing school?

• The sperm meets the egg and then…

Embryologic development

• Kidneys appear during the 3rd week of fetal development; Three sets of kidneys develop; first two are discarded and the third time is the charm

• By the 3rd month the fetus is excreting urine into the amniotic fluid; urine becomes the main component of amniotic fluid

Embryology—the development of the kidney

• The kidneys and the ears from the same mesenchymal tissse

• The otorenal axis• Nephrotoxic drugs and ototoxc drugs

Location, location, location…

• Kidneys located in the retroperitoneal space between T12 and L3

• Right lower than the left

Kidney size is NOT affected by body build

• The kidneys grow at the same rate that the entire body grows, until ~25-26. This is the age that internal organs reach their final dimensions.

• The mean dimensions of the kidneys upon maturation are: length~12cm (~4.7 inches), width~6 cm (~2.4 inches) and thickness~ 3 cm (~1.2 inches).

• The weight of one kidney averages about 120-150 g (4.5-5 oz).

PEARL:

• The kidney makes up less than 0.5% of the body’s weight, yet takes in 20-25% of the resting body’s cardiac output and uses 20-25% of the body’s oxygen

• It’s busy…

Kidney size• Any decrease in size (atrophy) is not normal. An

enlarged kidney is normal only in cases when one kidney is removed and the remaining kidney enlarges to compensate for the functional absence of the first.

• THE MOST IMPORTANT NON-INVASIVE TEST FOR RENAL DISEASE is a renal ULTRASOUND to determine renal size

The kidney…retroperitoneal space

• CVA tenderness• Acute pyelonephritis• Glomerulonephritis• Palpation? Can you palpate the kidney in an

adult?• Not unless the kidney is HUGE…(tumor)• Polycystic kidney disease (PKD)

The kidney…retroperitoneal space

• Palpation? Can you palpate the kidney in an adult?

• Not unless the kidney is HUGE…(tumor)• Polycystic kidney disease (PKD)

Polycystic kidney disease

• Autosomal dominant polycystic kidney disease (ADPKD)• 1/1000; C>AA; 4-10% of patients w/ kidney failure on dialysis

or needing transplant• 50% by age 50 have renal failure• Kidneys can be the size of a football

Associated structures

• Ureters• Bladder• Urethra

Ureters• 10 – 12 inches (25 – 30 cm) and about 0.04 to 0.4 inches

(1 – 10 cm) in diameter• When the bladder fills, the distal end of the ureter closes

to prevent urine from backing up into the kidney• If this mechanism is not working properly bacteria can

reflux into the ureters and up to the kidneys—vesicoureteral reflux

• Muscularis layer of the ureter propels urine via peristalsis to bladder—1 to 5 contractions per minute

Ureters

• Pregnancy--progesterone slows down peristalsis• Kidney stones—the pain?? On a scale from 1 to

1,000? • The incidence of kidney stones increases with age

and it’s higher in Caucasians than African-Americans. There is a significant regional variation in kidney stone formation with the highest prevalence in the Southeastern part of the United States.

Digression…kidney stones• Does fluid intake make a difference? YES• This approach increases urine flow rate and decreases

the urine solute concentration—both mechanisms prevent kidney stones. In warmer climates, inadequate fluid intake causes dehydration, which increases the acidity of urine and stone formation. (Southeastern U.S.= hot=increased kidney stones)

• This time-honored recommendation for reducing the risk of kidney stones is to take two or more liters of fluids per day. And, not just any fluids…

Fluids and kidney stones…

• Certain fluids have been associated with a high risk of kidney stones—these include soft drinks and tea. (Southeastern U.S.=lots of tea) Grapefruit juice has also been linked to an increased risk of kidney stones but the mechanism is unknown.

The good news…

• Alcohol, especially wine, and coffee consumption have been negatively associated with kidney stones. YES!! there is a God.

Kidney stones

• Foods that are high in potassium decrease urinary calcium and increase urinary citrate excretion.

• Some vegetables, such as spinach and rhubarb, as well as peanuts, cashews, and almonds, have high oxalate content and should be avoided.

Bladder • Medium-full bladder holds about 1 pint (500

mL) of urine and measures 5 inches (12.5 cm) in length

• Fully expanded, the bladder can hold 1 quart (1 L) or more and YES, it can burst

• Newborns void 5-to 40 times a day• At 2 months a baby voids 400 mL (14 fl oz) per

day• Adolscents and adults—1.5 quarts (1500 ml)

per day

Urination

• Awareness of urination starts at about 15 months

• Control of nighttime urination sometimes takes until age four

• Girls vs. boys and potty training

Urethra

• 1.5 inches (4 cm) in women• MEN? Depends on who you ask…hahaha…• 6-8 inches (15-20 cm)

Cystitis

• Lower urinary tract infections• Lots of reasons—back to front wiping (E. coli

and the rectum), pH changes, lack of estrogen, vesicoureteral reflux

• Young girls? Old girls?

The importance of estrogen and the maintenance of urinary tract health

• Estrogen receptors and the urethra• Prepuberty , perimenopause, and

postmenopause• E.Coli and the rectum

Treatment of urinary tract infections

• TMP-SFX—Bactrim/Septra—watch out for K+ levels in patients on ACE inhibitors or patients with CKD and ESRD

• Fluoroquinolones – the “floxacins” – used when greater than 20% resistance to TMP-SFX

• Side effects: C. difficile, tendonitis with acute ruptured Achilles’ tendons in high-risk patients (elderly and patients on Prednisone)

The antibiotics—the fluoroquinolones, the “floxacins”…

• Ciprofloxacin (Cipro)*(2) (↑ INR)

• Lomefloxacin (Maxaquin)(2)• Norfloxacin (Noroxin)*(2)• Ofloxacin (Floxin)(2)**uncomplicated UTI if resistance to TMP/SMX is ≥20%

• Levofloxacin (Levaquin) (3)—too broad spectrum for UTI

Gross anatomy• Renal capsule• Renal cortex (glomeruli—

80-85% of nephrons lie in cortex)

• Renal medulla (collecting ducts and some Loops of Henle)

• renal papillae• the renal interstitium

(columns) • renal pelvis (pyelo)/calyces

The anatomy of a nephron—greater detail

• The basic functioning unit of the kidney• The nephron—1.5 million per kidney in

normal birth weight individuals**

Premature babies/LBW babies

• LBW babies are much more likely to develop hypertension later on in life and it may be due to the fact that they have less nephrons to start with

• Autopsies on patients between 35-59• 10 kidneys w/ known hypertension; 10 w/

normal BP• Average number of nephrons in people w/

HBP was fewer than ½ that of people w/ normal BP

Premature babies/LBW babies

• Couldn’t find damaged nephrons or nephrons that had dropped out—suggesting inherited # of nephrons

• Good prenatal nutrition and the # of nephrons—restricting proteins ↓ # of developing nephrons

• (N Engl J Med 9 Jan 2003)

Premature babies/LBW babies

• Another implication• Screening kidney donors for LBW may be important

when deciding who might be a candidate as an appropriate donor

• The donor loses 50% of nephrons—if remaining kidney has fewer #’s due to LBW, this increases the risk of hypertension in the donor—overworked and underpaid triggering the release of renin-angiotensin-aldosterone

The anatomy of a nephron—greater detail

• Afferent arteriole → glomerulus → basement membrane → Bowman’s capsule → tubular system (proximal convoluted tubule (PCT), Loop of Henle, distal convoluted tubule (DCT), collecting duct)

• Peritubular capillaries (the vasa recta)

The nephron and the filtration membrane

• The filtration membrane—3 layers 1) the endothelial cells of the glomerulus 2) the basement membrane between the

glomerulus and the, 3) epithelial cells of Bowman’s capsule• Diseases—1) Lupus nephritis 2) “sugar” diabetes 3)

nephrotic syndrome

The glomerular filtration membrane

1.The glomerular capillary wall (lined with endothelial cells)

2. The basement membrane (a glycoprotein layer)

3. The fenestrated wall (epithelial) cells of Bowman’s capsule into the first part of the tubule (the proximal tubule)(epithelial cells)

1) Lupus nephritis 2) diabetic nephropathy 3) nephrotic syndrome

Glom BM BC PCT

12 3

3

A note on the tubules of the kidney…

• The tubules of Bowman’s capsule and the PCT—proximal convoluted tubule) are lined with epithelial cells

• The epithelial cells are extremely vulnerable to hypoxia

• Without oxygen, the epithelial cells become necrotic and slough into the tubule; clogging the works resulting in

• Acute tubular necrosis (ATN)

Ethylene glycol nephrosis results in acute tubular necrosis

• Dogs and cats love the sweet taste of antifreeze

• Crystals precipitate in the tubular lumen resulting in intrarenal obstruction, degeneration and necrosis of the lining of the tubular epithelium

• Irreversible renal failure

Kidney disease

• Traditional approach is to divide the kidney into 4 basic morphologic components

• 1) Glomeruli--glomerulonephritis• 2 + 3) Tubules—tubulointerstitial diseases

including pyelonephritis)• 3) Interstitium• 4) Blood vessels

Kidney disease

• Early manifestations of each component tend to be distinct and some components seem to be more vulnerable to specific forms of renal injury

• Most glomerular diseases are immunologically mediated

• Most tubular and interstitial disorders are frequently caused by toxins (drugs) or infectious agents (pyelonephritis)

• Blood vessel disease—atherosclerosis or HTN, blood flow problems (hypovolemic shock, septic shock, HF)

The kidney as an innocent bystander…

• In addition to primary kidney disease, the kidney is involved in many systemic diseases and conditions

• Hypertension • Diabetes mellitus• The deadly duo--“Sugar” diabetes and hypertension• HF (Heart failure)• Septic shock, hypovolemic shock• DIC (Disseminated intravascular coagulation)• HUS (Hemolytic uremic syndrome)

The kidney as an innocent bystander… • Autoimmune diseases—lupus, autoimmune

glomerulonephritis, Goodpasture’s disease, Wegener’s granulomatosis, sarcoidosis, amyloidosis (? Autoimmune)

The kidney as an innocent bystander…

• Toxic effects of drugs—aminoglycosides, radiocontrast agents, amphotericin, cisplatinum, acetaminophen, NSAIDS, methicillin, ampicillin, rifampin, allopurinol, cimetidine (Tagamet)

• Cancer—malignant infiltration, multiple myeloma

• Others—rhabdomyolysis, gout

Blood supply of the kidney

• Aorta→renal artery→branches into arcuate→interlobular artery to the afferent arteriole …

What can go wrong? atherosclerosis

• Fatty plaques in the renal artery--chronic decreased blood flow to the kidney

• Renal artery stenosis• Renal atrophy

Who’s at risk for atherosclerosis and kidney disease?

• Family History• Diabetics• Coronary artery disease• Peripheral arterial disease• Erectile dysfunction• Hypertension• Smoking• Geriatric patients

Can we reduce atherosclerosis and kidney disease? Say yes to drugs

The statin “sisters”…• lovastatin (Mevacor)• simvastatin (Zocor)• atorvastatin (Lipitor)• fluvastatin (Lescol)• pravastatin (Pravachol)• pitavastatin (Livalo)• rosuvastatin (Crestor)—( boosts HDLs by 12-

14% vs. ~6% for the other statins) **

The “Statins”—what do they do?• Reduce total cholesterol levels• Decrease LDL levels--LDL is the most atherogenic

of the cholesterols and puts fat right smack dab into all of the arterial walls; therefore, statins decrease plaque formation

• Statins also stabilize plaques and prevent plaque rupture, and…

• Statins shrink plaques in all arteries improving blood flow to all vital organs such as the brain, the heart, and the kidneys…

• And as mentioned, Crestor (rosuvastatin) in particular, increases HDLs

Why are HDLs good for you?1) HDL’s clear excess cholesterol from the blood;

HDL’s are also potent “anti-oxidants” and prevent LDL from oxidizing; the HDLs are also potent “anti-inflammatory” lipoproteins; keep levels above 40 mg/dL (1.04 mmol/L) and above 60 mg/dL (≥ 1.55 mmol/L) would be ideal

2) For every 5 mg/dL (0.13 mmol/L) decrease in HDL below the mean, the risk of heart disease increases by 25%

3) For every 21-mg/dL (0.5 mmol/L) increase in HDL, patients are 50% less likely to develop albuminuria (Diabetes Care January 06)

Drugs your patients might be on that INCREASE the risk of atherosclerosis

• Progestins, androgens, cyclosporines, tacrolimus, thiazide diuretics, setraline (Zoloft), and the atypical antipsychotics (clozepine/Clozaril, risperidone/Risperdal, olanzapine/Zyprexa)) increase LDLs

• New ones—Block D2 receptors and 5-HT2C• Blocking 5-HT2c serotonin receptor increases weight

gain; increased susceptibility to insulin resistance and type 2 diabetes AND heart disease

What else can go wrong with the blood supply into and out of the kidney?

• Hypertension with decreased blood flow (treat with PRILS or ARBS)

• Diabetes with hypertension and atherosclerosis (STATINS, PRILS or ARBS)

• Clamping the aorta above the renal artery (AAA surgery)

• Sudden cessation of blood flow with a renal artery embolus

What can go wrong with the blood supply to and from the kidney?

• Decreased blood pressure with acute blood loss and hypovolemic shock, heart failure, dehydration, septic shock

• Afferent arteriole vasoconstriction with NSAIDs; efferent arteriole vasodilation with ACE inhibitors in a patient with renal insufficiency

• Microthrombosis of glomeruli—DIC (disseminated intravascular coagulation)

• Immune complex deposition in the glomerulus triggering the inflammatory response (lupus nephritis)

How about blood flow OUT of the kidney?

• renal vein → inferior vena cava → right atrium• Patient presented with atrial fibrillation.• Checked all of the usual causes; c/o flank pain,

hematuria• Renal cell carcinoma growing into the renal

vein, IVC, right atrium

Major functions of the kidney

• Fluid and electrolyte balance• Acid-base balance• Vitamin D and calcium metabolism• RBC production via the hormone

erythropoietin• Maintain blood pressure via Renin-

Angiotensin-Aldosterone System (RAAS)

Secretes renin from the juxtaglomerular apparatus—RAAS system

• Baroreceptors in the afferent arteriole sense pressure and volume…low pressure? Low volume? I CAN HELP by releasing renin (a messenger)

• Angiotensinogen to angiotensin I (liver); ACE (angioconverting enzyme) converts I to….• angiotensin II (tissues, primarily lung)—”angie” zips to the

adrenal cortex…can “al” come out to play?• aldosterone (primarily from the adrenal cortex; some tissue

aldosterone production as well)• Angiotensin II is a potent vasoconstrictor and aldosterone

reabsorbs water and sodium (excretes potassium)

Bottom line

• Vasoconstriction via angiotensin II—blood pressure goes up

• Sodium and water retention (with K+ excretion) via aldosterone—blood pressure goes up…

Essential hypertension and the kidney

• It’s estimated that ~70% of all patients with “essential hypertension” have an up-regulation of the RAAS – too much “angie” resulting in vasoconstriction and too much “al” resulting in sodium and water retention and potassium excretion

The RAAS

• Too much RAAS?• Too much “angie” and too

much “AL”• Too much vasoconstriction

and too much sodium and water retention

• The ACE inhibitors to the rescue!!

ANGIOTENSIN 1

ANGIOTENSIN 2

RENIN

ALDOSTERONE

The ACE inhibitors

• Block the conversion of angiotensin I to angiotensin II

• No ANGIE?• No AL-dosterone• Vasodilate and blood

pressure drops• Inhibit aldosterone and

sodium and water are excreted and potassium is retained

ANGIOTENSIN 1

ANGIOTENSIN 2

RENIN

ALDOSTERONE

ACE--

“Prils”—The ACE inhibitors

• Captopril (Capoten)• Enalapril (Vasotec)• Lisinopril (Prinivil, Zestril)• Fosinopril (Monopril)• Perindopril-- (Aceon)• Moxepril (Univasc)• Benazepril (Lotensin)• Quinapril (Accupril)• Trandolapril (Mavik)• Ramipril (Altace)

“Sartans”--ARBs• Angiotensin receptor blockers (bypass ACE) and work by

blocking the angiotensin-II receptors on tissues• Who are they? The “Sartan Sisters”…• losartan—Cozaar• valsartan—Diovan • candesartan—Atacand• irbesartan—Avapro• telmisartan—Micardis• olmesartan—Benicar• eprosartan—Tevetan• azilsartan -- Edarbi

Normal function: Angiotensin II helps maintain glomerular filtration pressure in the nephron

• Afferent arteriole (vasodilated via (prostaglandins)• Blood entering glomerulus• Glomerulus→filter• Efferent arteriole (vasoconstricted via (angiotensin II)• Blood exiting glomerulus

Prostaglandins

Angiotensin II

Toilet

filter

The Diabetic Kidney…hyperglycemia/HTN (the deadly duo)

• Hyperglycemiaand/or hypertensionboost prostaglandins and vasodilate the afferentarteriole • Hyperglycemia and hypertension increaseangiotensin II and vaso-constrict the efferentarteriole • Intraglomerular hypertension causes microalbuminuria

Microalbuminuria --10-fold > risk of RD & CKD)

Why is microalbuminuria a “bad” thing?

• The presence of microalbuminuria suggests that large vessel walls are more permeable to lipoproteins (causing atherosclerosis) and/or damage from the local release of growth factors

• There is a 4-fold increase in acute coronary syndromes in Type 1 DM greater than 35 years old;

• When microalbuminuria is present the risk is increased by a factor of 140!

• Aggressive treatment demonstrates beneficial effects not only on macrovascular disease but on microvascular disease as well (retinopathy and nephropathy)

SO, what is “aggressive treatment”?

• Reduce the albumin in the urine with the PRILS (ACE inhibitors) or ARBs by reducing intraglomerular hypertension

• Decrease the cardiovascular risk and fat deposition in the renal arteries with the STATINS (to lower LDL-cholesterol)(more later)

Other drugs and the RAAS

• Direct renin inhibitor (DRI)--anti-hypertensive drug known as aliskirin/ Tekturna

• spironolactone/Aldactone and eplerenone (Inspra)—aldosterone antagonists

SO, PICK A PRIL, any PRIL or, if they can’t tolerate the side effects, pick an ARB (angiotensin receptor blocker)

PRILS• Captopril (Capoten)• Enalapril (Vasotec)• Lisinopril (Prinivil, Zestril)• Fosinopril (Monopril)• Perindopril (Aceon)• Moxepril (Univasc)• Benazepril (Lotensin)• Quinapril (Accupril)• Trandolapril (Mavik)• Ramipril (Altace)

ARBs• losartan (Cozaar), • valsartan (Diovan),• candesartan (Atacand)• telmisartan (Micardis)• irbesartan—Avapro• olmesartan—(Benicar)• eprosartan—Tevetan• azilsartan -- Edarbi

The Diabetic Kidney…hyperglycemia/HTN (the deadly duo)

• Any drug that blocks angiotensin II is going to “open” up the efferent arteriole and reduce pressure in the glomerulus

• For each 1 gm decrease in proteinuria, kidney disease progression is slowed by 1 mL/min/year—PRILS and SARTANS can decrease the decline by 50% or MORE

•

Major functions of the kidney

• Fluid and electrolyte balance• Acid-base balance• Vitamin D and calcium metabolism• RBC production via the hormone

erythropoietinMaintain blood pressure via Renin-

Angiotensin-Aldosterone System (RAAS)

RBC production and erythropoietin• Secretes erythropoietin to stimulate the bone marrow to

produce RBCs—the failing kidney does not secrete erythropoietin therefore one of the earliest signs of declining renal function is the presence of anemia

• Anemia has been independently associated with an increased risk of left ventricular dilation, left ventricular hypertrophy, coronary artery disease, heart failure

• Each 1 gm ↓ causes LV dilation by 42%)(50% lower survival rates with LVH)

• Almost half of all stage 3 CKD, are anemic (Stage 3—is characterized by a GFR of 30-60 mL/min/1.73 m²)

Anemia and CKD• The link between heart failure, CKD, and renal failure

is known as cardiorenal anemia syndrome• In the “old” days renal patients had to receive

packed RBCs frequently to give them adequate RBCs• Synthetic erythropoietin known as the ESAs

(erythropoiesis stimulating agents) have been available since 1989

• Epoetin alfa (1989) and darbopoetin alfa (2001)

Anemia and CKD

• BUT…fully restoring hemoglobin (to greater than 13 g/dL) in patients with CKD increases their risk of all-cause mortality, poorly controlled BP, and AV access thrombosis…so partial restoration of Hb is advised.

• Target Hb of 11-12 g/dL; Monitor Hb at least monthly when on ESAs

Major functions of the kidney

• Fluid and electrolyte balance• Acid-base balance• Vitamin D and calcium metabolismRBC production via the hormone

erythropoietinMaintain blood pressure via Renin-

Angiotensin-Aldosterone System (RAAS)

Vitamin D metabolism

• The kidney converts the vitamin D from the skin and diet to the active form of vitamin D (calcitriol)

• Vitamin D is necessary for the absorption of calcium from the GI tract

• Calcium and phosphorus must always be “in balance” in the blood

• If the kidneys fail, phosphate is retained and results in hyperphosphatemia

Aids in Vitamin D metabolism• With increased phosphate retention due to kidney

failure or decreased calcium absorption due to lack of vitamin D, the parathyroids increase their production of Parathyroid Hormone (PTH)

• PTH breaks down bone to replace the calcium to balance the hyperphosphatemia—known as secondary hyperparathyroidism and it wreaks havoc with bones causing the osteomalacia of chronic renal failure

• Phosphate binders in patients with renal failure• Decrease foods that contain phosphates (a registered

dietician is your best friend)

Treatment of hyperphosphatemia

• Phosphate binders• Sevelamer carbonate (Renvela) a buffered

form of the anion-exchange resin sevelamer hydrochloride (Renagel) has been approved for use by hemodialysis patients. Renvela will replace Renagel, which has been shown to induce or exacerbate metabolic acidosis in patients on dialysis.

• Medical Letter, February 25, 2008, Vol. 50 (1280): 13.

Some notes on Vitamin D• 10-15 minutes of exposure to sunlight on face,

hands, and arms 2-3 days per week is required to synthesize sufficient amounts of vitamin D (in shorts and a t-shirt, people can soak up enough UV-B rays to produce 12,000 U of vitamin D within 20 minutes)

• Sunscreen? SPF-8?• Food—fatty fish, cod liver oil, and egg yolks• Fortified foods—milk, breakfast cereals, margarine,

butter, certain brands of OJ and yogurt

Major functions of the kidney

Fluid and electrolyte balance and acid base balance

Vitamin D and calcium metabolismRBC production via the hormone

erythropoietinMaintain blood pressure via Renin-

Angiotensin-Aldosterone System (RAAS)

Fluid and electrolyte and acid-base balance

• Regulation of water, • Electrolytes: Sodium, chloride, potassium, and phosphorus

• Excretion of excess urea and creatinine

• Excretion of excess hydrogen ions

If the kidney fails…

• Retention of water—edema, weight gain, HBP• Retention of urea (BUN) and creatinine (as measured

by serum creatinine and creatinine clearance)• Retention of Na+ resulting in hypertension• Retention of K+ resulting in hyperkalemia and

potentially life-threatening cardiac arrythmias• Retention of phosphorus resulting in

hyperphosphatemia• Retention of H+ ions—metabolic acidosis

Free water is regulated by ADH (anti-diuretic hormone)

• Conservation of free water • Diurnal rhythm—kicks in around midnight

with water conservation and reduced urination at night

• NO ADH at night? Clinical sign of NOCTURIA

Anti-diuretic hormone

• ADH is produced by the hypothalamus and released from the posterior pituitary in response to osmoreceptors located in the hypothalamus

• ADH receptors on the distal tubule and collecting duct

Free water is regulated by ADH (antidiuretic hormone)

• Early a.m. specimen is concentrated (as measured by the specific gravity)—1.025

• One of the earliest signs of renal insufficiency is the inability to concentrate urine at night—early a.m. specimen, 1.010; mid-day specimen, 1.010, evening specimen, 1.010…GET IT?

Anti-diuretic hormone

• OR…beer and ETOH inhibit ADH—a 6-pack of beer before bedtime? urinating all night

• And morphine increases ADH as well as tightens the urinary sphincter (urinary retention—problem after surgery in patients on PCA pumps or anyone receiving morphine)

Other causes of nocturia?• Inability of the kidney to respond to ADH—immaturity?

Enuresis in kids? (DDAVP--desmopressin); • Nephrogenic diabetes insipidus—genetic lack of receptors• “sugar” diabetes—glucose is an osmotic diuretic• Enlarged “prostrate”• UTI• CHF (“funny things happen in the middle of the night”)• Pregnancy• Diuretics at bedtime—lasix, HCTZ• Drugs can cause the Syndrome of Inappropriate ADH

Aldosterone• Aldosterone (part of the RAA system) is

produced by the adrenal gland primarily in response to angiotensin II

• Low sodium, high potassium, low BP or low volume and the RAAS kicks into action

• Aldosterone interacts with receptors on the distal tubules to conserve water AND sodium; the sodium is exchanged for potassium; potassium is secreted into the distal tubules and excreted

Too much sodium and water?

• Aldosterone antagonists (blockers)—spironolactone (Aldactone) and eprelrenone (Inspra)

Now that you know what the kidney is supposed to do…

What do YOU do?• Accurate intake and output• Daily weights• Check for signs of fluid retention—peripheral

edema, jugular vein distention, S3• Blood pressure• Interpretation of lab tests

Doin’ the double-dub—S3 (also listen for an S4 with LVH; Apical impulse is displaced laterally)

Lab tests

• BUN• Serum creatinine• Estimated glomerular filtration rate (GFR) as

measured by the MDRD formula or the Cockcroft-Gault equation

Blood urea nitrogen (BUN)

• Urea is a commonly used marker for the diagnosis of renal failure/kidney injury; by-product of protein metabolism (not produced at a constant rate

• BUN (8-18 mg/dL)—three reasons for an elevated BUN– decreased GFR– Increased tissue metabolism (burns, crush injuries,

rhabdomyolysis)– increased load of urea for excretion from the diet

(protein)

What about the Atkin’s diet?

• High content of valine and lysine increases intraglomerular pressure and can accelerate kidney damage in impaired kidneys

• Should a diabetic go on the Atkin’s diet?• How about an 80-year old?• No harmful effect in young people with

normal kidneys• Renal disease and dietary restrictions

Serum creatinine

• Creatinine is released from skeletal muscle at a relatively constant state, is freely filtered at the glomerulus, and is not reabsorbed or metabolized by the kidneys

• Hence, it’s popularity for measuring the ability of the kidneys to filter; if the kidneys are not filtering properly creatinine will be retained and the serum creatinine will be increased

• Normal reference range is 0.5 to 1.0 mg/dL* (to convert to micromoles per liter, multiply by 88.4)

• See Caveats

A few caveats--serum creatinine

• Can be influenced by age, gender, muscle mass, diet, concomitant diseases, circadian rhythm, and stability of renal function, tubular secretion, & drugs (cimetidine/Tagamet increases creat cl)

Serum creatinine (varies with sex and age)

newborn (0.3-1.0)infant (0.2-0.4)child (0.3-0.7)Adolescent (0.5-1.0)Adult Male (0.6-1.3)Adult Female (0.5-1.2) (women have 15% less muscle

mass than men, hence serum creatinine is lower)Elderly patients—less muscle mass, decreased filtration

due to aging kidney

Critically ill patients and serum creatinine

• Patients are not in a steady state and an increase in creatinine lags behind renal injury by as much as 12 hours to 2 days

Important notes…

– The NIH Consensus conference of 1993 recommends that patients with chronic kidney disease be referred to a renal team when the serum creatinine has increased to 1.5 mg/dL in the female and 2.0 mg/dL in the male

– Most nephrologists report that patients are usually referred to a renal healthcare team when their serum creatinine level is 3-4 mg/dL or greater…earlier is better!

serum creatinine and the estimated GFR

– What is the glomerular filtration rate? A determination of how much the glomerulus filters; can be determined by how much creatinine is CLEARED into the toilet (also known as creatinine clearance)

Calculating the eGFR—2 equations• MDRD (modification of diet in renal disease)

formula • ml/min/1.73m2 = 170 x (SCr)-0.999x (age)-0.176

x (BUN)-0.170 x (alb)0.318 x (0.762 if female) x (1.180 if black)

• Cockcroft-Gault equation• OMG! GET A CALCULATOR or• GFR calculators are available at:• http://kidney.org• http://nephron.com/cgi-bin/MDRD.cgi

Estimated GFR

– normal estimated GFR in young adults is 105-130 mL/min/1.73 m² (women 105 mL/min, guys 125 mL/min)

– a GFR of less than 60 mL/min/1.73 m² represents a loss of more than half of normal kidney function

– GFR decreases with age—the 1% rule

Stages of chronic kidney disease based on the GFR

– CKD-1 = GFR>90 mL/min or higher – CKD-2 = GFR 60-89 mL/min=mild renal

insufficiency– CKD-3 = GFR 30-59 mL/min=moderate renal

insufficiency* (refer to nephrologist)– CKD-4 = 16-29 mL/min =severe renal

insufficiency– CKD-5 = 0-15=failure or ESRD (end-stage renal

disease) (dialysis or transplant)

Major causes of end-state renal disease (Cooper, et al.NEJM 2010)

• Diabetes – 33.9%• Glomerulonephritis – 16.1%• Polycystic kidney disease – 10.1%• Hypertension – 7.9%• Analgesic nephropathy – 4.7%• Reflux nephropathy – 4.7%• Renovascular disease – 3.7%• Interstitial nephritis – 2.2%• Obstructive nephropathy –1.2%• Failing kidney transplant – 3.2%• Other – 15.3%

Co-existing conditions

• Diabetes – 42.6%• Hyperlipidemia – 60.9%• Cardiovascular disease – 39.6%• Ischemic heart disease – 29.5%• Peripheral vascular disease – 17.1%• CHF – 4.5%• Stroke – 2.7

Smoking status

• Current smoker – 11.4%• Former smoker – 50.7%• Never smoked – 37.9%

The GFR and the geriatric patient

• 75-year-old = 1.2 mL/min x 45 years = 53 mL/min; 120-53=67 mL/min in a HEALTHY 75-year-old (not taking into account weight, ethnicity, or gender)

The pitfalls of relying on serum creatinine to evaluate renal function

• 85-year-old, 50-kg Caucasian female vs. 55-year-old, 70-kg African American Male

• SCr 1.5 in each of the patients• CrCl as measured by the MDRD (using age,

sex, color and serum creatinine)• 35 mL/min/173m2 in the C female (CKD-3)• 63 mL/min/1.73m2 in the AA male (CKD-2)

Urinalysis

• In addition to ultrasound, the urinalysis is the second part of the ‘non-invasive’ measurement of renal function

• Checking for protein in the urine (and other components) is an essential part of the renal work-up

Urinalysis

• Can tell you all sorts of interesting information• Glucose—transport maximum 180 mg/dL;

over that amount and you’ll have glucosuria (geriatric patients the Tm is 140 mg/dL)

• Proteinuria—trace, 1+, 2+, 3+, 4+ (glomerular injury with higher numbers)

Urinalysis

• Pink or brownish tinge—blood, bile salts, red beets

• Bright yellow—riboflavin in multivitamins• Frothy—bile salts (blocked bile duct, liver

disease); protein (large amounts, glomerular disease)

• Ketones—fruity odor; diabetes, low carb diet, fasting or starvation

Asparagus

• Why does your urine smell when you eat asparagus?

• Or does it?

Urinalysis

• Specific gravity—1.001-1.035; tests the ability of the kidneys to concentrate urine

• ADH and the urine; first morning specimen• If you drink nothing for a full day, your kidneys

continue producing urine at a specifc gravity of 1.025

• Lose the ability to concentrate urine and the specific gravity will be 1.010 at any time of day

Urinalysis

• Marijuana• Cocaine• Alcohol• Steroids• RBCs• RBC casts• WBCs• WBC casts

Acute Kidney Injury (AKI)

• Today the term acute kidney injury has replaced ARF, with an understanding that such an injury is a common clinical problem in critically ill patients and is predictive of an increase in morbidity and mortality

• Acute renal failure is still used but there was no uniform standard for diagnosing and classifying acute renal failure; more than 35 different definitions used in clinical practice

ARF• Comprises a family of syndromes that are characterized by an

abrupt (over hours or days) decrease in the GFR• May occur in the absence of prior renal dysfunction, or it may

represent an acute exacerbation in a patient with known stable chronic kidney disease

• Oliguria (less than 400 to 500 mL/24 h) may be a presenting manifestation, although the urine volume may be variable, ranging from less than 100 mL to greater than 3 L per day

• Primary manifestation is the accumulation of nitrogenous waste products—primarily creatinine and BUN

AKI

• Refers to a sudden decline in kidney function that causes disturbances in fluid and electrolyte, and acid-base balance because of a loss of clearance of small solutes and a decreased GFR

• AKI has a broad spectrum and encompasses the entire renal failure syndrome in all patients—not just those that require renal replacement therapy but also in patients with minor changes in renal function

Criteria for AKI includes assessment of 3 grades of severity

• Risk of acute renal failure— serum creatinine increased 1.5 times normal or GFR decreased > 25%; urine output < 0.5 mL/kg x 6 hours

• Injury to the kidney-- serum creatinine increased 2 times normal or GFR decreased > 50%; urine output < 0.5 mL/kg x 12 hours

• Failure of renal function-- serum creatinine increased 3 times normal or GFR decreased > 75% ; urine output < 0.5 mL/kg for 12 hours or anuria for 12 hours

Two outcome classifications for AKI

• Loss—complete loss of renal function for > 4 weeks

• End-stage renal disease—need for renal replacement therapy for > 3 months

• KNOWN AS THE RIFLE classification• Risk, Injury, Failure, Loss, End-stage kidney

disease

Classification of ARF syndromes (in tertiary care centers)

• Prerenal—insult occurs prior to the kidneys (21%)

• Renal—within the kidnesy (intrinsic)(45% with ATN)

• Postrenal—after (10%)(obstructive uropathy)

Causes of prerenal ARF

• Intravascular volume depletion—• GI losses• Renal—diuretics, osmotic diuresis • Cutaneous (burns)• Hemorrhage (hypovolemic shock)• 3rd spacing (pancreatitis)• Decreased effective blood volume—CHF, cirrhosis, nephrotic

syndrome, sepsis, anesthesia

Causes of prerenal ARF• Altered intrarenal hemodynamics—such as preglomerular

(afferent) vasoconstriction (NSAIDS—COX1, COX 2)(prescription NSAID use increases risk of ARF in elderly by 58%)

• Cyclosporine, tacrolimus, hypercalcemia• postglomerular (efferent) vasodilation (ACE inhibitors,

angiotensin receptor blockers)(older age, NSAIDS + ACE inhibitors, diuretic RX and diabetics highest risk)

• Abdominal compartment syndrome—increased intra-abdominal pressure with increased renal venous pressure (trauma patients requiring massive volumes of fluids; fluid sequestration, pancreatitis, peritonitis)

Intrinsic ARF

• Associated with renal parenchymal injury• Most commonly results from ischemic or toxic injury

to renal tubular epithelial cells• Also includes glomerular diseases (autoimmune) and

vascular and interstitial inflammatory processes (allergic) that are associated with rapid loss of renal function

Intrinsic ARF

• Acute glomerulonephritis— postinfectious GN (ex. Acute poststreptococcal {Group A beta hemolytic strep} GN), endocarditis-associated GN, Hemolytic Uremic Syndrome*, Thrombotic Thrombocytopenic Purpura, rapidly progressive glomerulonephritis (RPGN)

• Acute vascular syndromes—renal artery thromboembolism, renal artery dissection, renal vein thrombosis, atheroembolic disease

• DIC—disseminated intravascular coagulation

Hemolytic uremic syndrome and E. Coli O157:H7

• Mid-70’s, mutation in Venezuela; Shigella + E. coli• Moved up through Central America into Southern Texas in the

early ’80’s (1982 first identified)• 3rd most deadly toxin in the world; 10-100 pathogens to make

you ill or kill you• Produces a toxin that kills the kidneys• The leading culprit in 2006 for food-borne illness• Cook burgers to 160° F• Produce – bagged spinach and lettuce

E. Coli O157:H7

• Very young, very old, very immunocompromised• Acute Renal Failure in Kids• 1993 Jack-in-the-Box in Seattle/Tacoma (500/4

deaths)• Mickey D’s—30 outbreaks per year• Supportive Treatment

Meningococcemia and DIC

• DIC is characterized by microthrombi in the small vessels

• Decreased urinary output is one of the first signs

• Check the platelet counts and coagulation studies (fibrinogen, thrombin time, D-dimers or fibrin split products)

Causes of intrinsic ARF• Acute Tubular Necrosis• Ischemic—hypotension, hypovolemic shock, sepsis,

cardiopulmonary arrest, cardiopulmonary bypass• Nephrotoxic—drug-induced such as the aminoglycosides,

radiocontrast agents, amphotericin, cisplatinum, acetaminophen

• Pigment nephropathy—intravascular hemolysis and rhabdomyolysis (massive muscle damage—trauma, statin drugs (rare)

Causes of intrinsic ARF• Acute interstitial nephritis—drug-induced (penicillins,

cephalosporins, sulfonamides, rifampin, dilantin, furosemide, NSAIDS)

• Infection-related—bacterial infections, viral, rickettsial disease, TB

• Systemic diseases—SLE, Wegener granulomatosis (granulomatous inflammation involving the respiratory tract and necrotizing vasculitis of the small and medium sized vessels; necrotizing glomerulonephritis is common)

• Malignancy—malignant infiltration, multiple myeloma (Bence-Jone’s proteins—what are these?)

Postrenal ARF

• Acute obstruction to the urinary tract from the renal pelvis to the urethra

• However, for obstruction proximal to the urinary bladder to result in ARF, it must be bilateral or occur in the setting of a single functional kidney

Causes of postrenal ARF

• Intrinsic—stones, papillary necrosis, blood clot, transitional cell carcinoma

• Extrinsic—aortic aneurysm, retroperitoneal or pelvic malignancy

• Lower tract obstruction—urethral stricture, BPH, prostatic cancer, transitional cell carcinoma of the bladder, bladder stones, neurogenic bladder

Feline urologic syndrome

• Obstructive disease of the urethra—especially in the male feline

• Pathogenesis includes the maintenance of a constant alkaline urinary pH, increased intervals between urination, exclusive use of dog food, and maybe a virus thrown in

• Renal failure

Rx of acute renal failure…the obvious

• Treat the underlying cause…• Measure electrolytes daily, K+ restriction, diuretics and renal

replacement therapy (RRT) as necessary• Acidosis—RRT• Volume—I & O of course; CVP; insensible losses• Daily weights, volume replacement• Pulmonary edema—loop diuretics if ANY renal function is left;

if not, RRT• Nitrates and opiates provide vasodilation in patients with

acute pulmonary edema; oxygen• Maintain hemoglobin above 10 g/dL

Specific syndromes of ATN• RCN—radiocontrast nephropathy is one of the most frequent

etiologies of nephrotoxic ATN accounting for 10% of all cases of hospital-acquired ARF

• Risk factors—baseline renal insufficiency (baseline serum creatinine greater than 2.0 mg/dl), DM, CHF, large volumes of contrast media, volume depletion, concurrent use of NSAIDS or ACE inhibitors

• Risk with normal kidney function=negligible• Mild to mod renal insufficiency with DM=10-40% risk• Advanced renal insufficiency=50% risk• Due to renal vasoconstriction and direct renal tubular

epithelial cell toxicity

RCN (radiocontrast nephropathy)

• Acute rise in serum creatinine 24-48 hours after contrast study• Peaks 3-5 days after onset of renal failure and returns to baseline in 7-10

days• Usually non-oliguric• Prevention—use other imaging techniques in high-risk patients, if

possible; correct hypovolemia, discontinue NSAIDs and ACEI• Administer saline (1 ml/kg/h from 8 a.m. on the day of the procedure to 8

a.m. the following day—reduces RCN by 50%; especially in women, diabetics, and patients receiving more than 250 ml of contrast dye

• Use low-osmolality contrast media• N-acetylcysteine (NAC) (Mucomyst)—potential therapeutic benefit

Aminoglycoside nephrotoxicity• Develops in 10-15% of patients treated for more than several

days• Taken up by PCT where they accumulate in high

concentrations and produce cytotoxicity• Onset of nephrotoxicity usually occurs after 7-10 days of

therapy• Shedding of epithelial cells into urine (tubular cell casts)• Complete recovery is possible—high risk groups are patients

with volume depletion, the elderly, cardiac surgery, preexistent renal disease, and hepatobiliary disease

• Once daily dosing will reduce the nephrotoxicity

Rhabdomyolysis

• Release of muscle cell constituents as the result of traumatic or nontraumatic injury is the principal cause of hemepigment associated ARF (myoglobin)

• Increased CK, AST, LDH• Severe cases result in profound hypovolemia,

metabolic acidosis, electrolyte disturbances• Treat with aggressive volume replacement with

saline• Renal replacement therapy may be necessary

Postoperative Acute Renal Failure

• Most commonly associated with vascular, cardiac and major abdominal surgery, including visceral organ transplants

• Multifactorial in origin• Cardiogenic shock, history of renal disease with CC

less than 60 ml/min), emergency surgery, LVEDP greater than 25 mmHg, age greater than 70, left-main coronary stenosis greater than 70%, and a history of PVD

• Decreased incidence in patients undergoing off-pump bypass vs. grafting vs. bypass grafting with cardiopulmonary bypass

Pharmacologic management of ARF

• Prevention—optimizing vascular hemodynamics to ensure adequate renal perfusion with saline loading

• Discontinue drugs that increase vasoconstriction

• Avoid nephrotoxic drugs when possible• If unavoidable, use dosing schedules and new

preparations

Pharmacologic management of ARF—what doesn’t work…

• Dopamine infusions—there is NO evidence that dopamine is of benefit in the prevention or treatment of ARF; increased risk of arrhythmias, myocardial ischemia, intestinal ischemia…

• Loop diuretics—clinical studies do NOT support the use for loop diuretics; outcomes are not improved

• Atrial natriuretic peptide—the literature does not support the use of ANP

Renal replacement therapy

• Given the lack of effective pharmacologic therapy, the management of ARF remains primarily supportive, with RRT the cornerstone of treatment

• Dialysis is more difficult in ARF patients—they are more hemodynamically unstable, more hypercatabolic, have greater nutritional requirements and have a a larger daily fluid intake (vs. chronic RF patients)

• Multiple modalities to provide RRT

Renal replacement therapy

• When should it start in acute renal failure?• The gold standard was to initiate RRT when the BUN

hit 100 mg/dl• 1999 study showed the early RRT with a BUN less

than 60 mg/dl vs. a BUN greater than 60 mg/dl was associated with a 39% survival as compared to a 20.3% survival

• (Getings, LG, Reynolds HN. Outcome in post-traumatic acute renal failure when continuous renal replacement therapy is applied early vs. late. Intensive Care Med 25:805-813, 1999.)

Renal replacement therapy

• Intermittent hemodialysis or,• Continuous renal replacement therapy (CRRT)?• Insufficient data to favor intermittent vs. CRRT,

however, in hemodynamically unstable patients, CRRT can be more safely performed due to a lesser tendency to exacerbate hypotension

• Peritoneal dialysis (only use if nothing else is available), or

Historical highlight

• The ancient Chinese, Roman, and German societies frequently used urine as mouthwash. Surprisingly, the ammonia in urine is a good cleanser. Do not try this unless desperate measures are necessary.

The end.

• Barb Bancroft, RN, MSN, PNP• CPP Associates, Inc.• www.barbbancroft.com• BBancr9271@aol.com

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Early versus Late Initiation of Dialysis. N Engl J Med 2010; 363;7:609-619.

• Crus DN, Perazella MA. Drug-induced acute tubulointerstitial nephritis. Hosp Practice 1998 Feb 15; 151-164.

• Friedman JM. Ace Inhibitors and congenital anomalies. N Engl J Med 2006 Jun 8; 2498-2500.

Bibliography• Ghanasekaran I, Dimitrov H. Primary care

management of anemia in chronic kidney disease. Patient Care May 2006

• Guzzo TJ, Drach GW. Major Urologic Problems in Geriatrics: Assessment and Management. Med Clin N Am 2011, 95:253-264.

• Himmelfarb J, Ilizler TA. Hemodialysis. N Engl J Med 2010; 363;19:1833-1845.

• Palevsky P. Acute Renal Failure. Journal of the American Society of Nephrology. March 2003; 2(2).

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