renal3 Flashcards

Question

Alpha-1 blockers

Answer 1

(prazosin, terazosin, doxazosin)

Answer 2

Selectively block alpha-1 adrenergic receptors. This blockade causes a reduction in systemic vascular resistance, thus causing an antihypertensive effect. Blockade of the alpha-1 adrenergic receptor (which is present in high density in the prostatic stroma, prostatic capsule, and bladder neck) decreases urethral resistance and may relieve the obstruction and improve urine flow and BPH symptoms

Answer 3

Orthostatic hypotension - headache -peripheral edema. Positive or no effect on serum TG/LDL/HDL

Answer 4

Benign prostatic hypertrophy (BPH). HTN: 3 or 4th line agent or sooner for patients with BPH

Answer 5

Stimulation of alpha-2 adrenergic receptors in CNS and periphery. reducing sympathetic nerve impulses resulting in a decrease in peripheral vascular resistance. increase parasympathetic outflow from vasopressor center (dec HR). presynaptic inhibition of peripheral norepinephrine release

Answer 6

Orthostatic hypotension, dry mouth, sedation, rebound HTN if high dose discontinued abruptly (reduce dose over 2-4 days)

Answer 7

HTN (3 or 4th line ), ADHD, smoking cessation, ETOH withdrawal

Answer 8

transformed to alpha methylnorepinephrine (false transmitter) – alpha 2 adrenergic agonist. Older agent with safety data in pregnancy - Rarely used due to adverse effects (hepatotoxicity, mental status changes, sedation), Produces positive direct Coomb's test and hemolytic anemia (1%).

Answer 9

defined as a permanent reduction in glomerular filtration rate (GFR). The National Kidney Foundation has now divided CKD into 5 stages. The purpose of this classification is to foster recognition of chronic kidney disease early in it course and to give clinicians guidelines for effective interventions at various stages of kidney disease. Biochemical and physiologic derangements are detectable at varying stages of CKD and therapeutic interventions need to be directed accordingly. Symptoms directly related to CKD typically do not occur until chronic kidney disease is advanced, often not until the GFR falls below 15 ml/min/1.73m2. End stage renal disease (ESRD) is the term often used when chronic kidney disease has deteriorated to the point where renal replacement therapy (dialysis or transplantation) is needed. Any process that permanently damages the kidneys can result in CKD. There are estimated to be about 7.4 million people with stage 3 CKD and there are over 400,000 patients with end stage kidney disease on dialysis. A list of the most common causes of CKD follows. The cost to care for each patient with ESRD on dialysis is $50-100,000 per year.

Answer 10

Diabetic nephropathy- most common, Hypertensive nephrosclerosis & Renal vascular disease, Glomerulonephritis, Polycystic kidney disease, Interstitial nephritis, Obstruction

Answer 11

Perhaps the most intriguing aspect of CKD is that compensatory mechanisms exist that allow the loss of 90% of GFR before many manifestations of the uremic syndrome are evident. It should be noted that there is essentially no evolutionary pressure to adapt to chronic kidney disease as people with CKD have decreased fertility. Therefore, the adaptive mechanisms are essentially the chronic stimulation of the mechanisms we use to respond to acute environmental stresses. Such mechanisms include intact nephron hypothesis, magnification phenomenon, individual solute control systems, trade-off hypothesis.

Answer 12

Nephrons functioning in diseased kidneys maintain glomerulotubular balance comparable to all other nephrons. That is, filtration and net excretion are coordinated.

Answer 13

Although nephrons in diseased kidneys function homogeneously, they alter their handling of given solutes as needed to maintain external balance of that solute if possible. That is, they magnify their excretion of a given solute.

Answer 14

Each solute appears to have a specific control system that is geared to maintain external balance in CKD. Each solute system has individual tubular handling and hormonal influences.

Answer 15

The mechanisms that are magnified to maintain individual solute control may have deleterious effects on other systems. This trade-off is seen in the increased parathyroid hormone (PTH) secretion seen in CKD that helps to maintain normal serum calcium and enhances renal phosphorus excretion. PTH has been implicated in the pathogenesis of many disturbances of uremia (sleep, sex, bone disease, anemia, lipidemia, vascular disease). The corollary of the trade-off hypothesis is the concept of proportional reduction of solute, that is, reduction of solute intake (e.g. phosphorus) in proportion to decrements in GFR could prevent the compensatory changes (e.g. increased PTH) that themselves may contribute to the development of uremia.

Answer 16

For the most part, balance of nitrogenous wastes such as creatinine and urea depends on their rates of filtration (i.e., GFR). Balance (rate of filtration) is maintained for creatinine and urea at the expense of elevated plasma concentrations of these waste products in other words, the excretion rates for urea and creatinine remain constant in the face of diminished clearance.

Answer 17

In order to maintain balance, the fraction of water reabsorbed by the kidney must decrease. Thus, an increased flow per nephron ensues. With progressive CKD, the ability to excrete a water load is compromised and the patient may develop hypoosmolality. Urine concentrating ability is fixed around 300 mOsm/kg H2O and thus the patient is also susceptible to dehydration if water intake is lowered. Thus, a CKD patient is prone to both water excess (hyponatremia) and water deficiency (hypernatremia). Nocturia is common in CKD due to the inability of the kidneys to concentrate the urine at night.

Answer 18

In order to maintain balance the fraction of sodium reabsorbed must be decreased and the fraction excreted increased. A humoral natriuretic peptide has been described that helps to increase sodium excretion in CKD along with other adaptive mechanisms. In CKD, the kidneys are unable to rapidly adjust sodium excretion in response to sudden changes in sodium intake or extrarenal losses. Thus, major increases in sodium intake result in edema and major decreases in intake or increases in extrarenal losses result in volume depletion. The hallmark of CKD is the loss of flexibility in responding to changes in the external balance of solutes and water.

Answer 19

excretion in the cortical collecting duct is regulated by flow, sodium delivery and aldosterone. Increased tubular secretion of potassium helps maintain potassium balance until kidney disease is severe. Around this time fecal excretion of potassium increases to assume perhaps 50% of the load for potassium excretion. Thus, plasma potassium and total body potassium are maintained on normal dietary intake, but the patient is susceptible to hyperkalemia from sudden potassium loads.

Answer 20

In CKD functioning nephrons produce more NH4+ to compensate for the loss of nephron mass This increase in NH4+ production (about a 4-fold increase) keeps acid balance normal until the GFR falls below 20-25 ml/min. At that time there is a continuous positive balance (retention) of hydrogen ion that titrate down the serum bicarbonate and result in a non-anion gap metabolic acidosis.

Answer 21

Literally, uremia means urine in blood- by implication, it is the clinical syndrome resulting from retention of certain substances that are normally excreted into the urine and thus accumulate causing toxicity.

Answer 22

Since the uremic syndrome resembles a systemic intoxication, the search for a putative uremic toxin has been the subject of intensive investigation. However, multiple factors may contribute to the pathogenesis of this syndrome.

Answer 23

Many chemical compounds have been suspected to be responsible for the uremic syndrome. Urea and other nitrogenous products of metabolism have been suggested to play a role in causing uremic symptoms, and their plasma concentrations are useful in assessing adequacy of dialysis therapy. However, a distinct relationship between one or a combination of these substances and the entire syndrome has not been established.

Answer 24

overproduction of parathyroid hormone in response to hypocalcemia and natriuretic hormone in response to volume overload could contribute to many aspects of the uremic state.

Answer 25

Decreased erythropoietin production causes anemia. Decreased 1-hydroxylation of vitamin D contributes to bone disease and secondary hyperparathyroidism. Clearly, these and other such deficiencies could play a role in the uremic state.

Answer 26

Neurological Disorders: encephalopathy, peripheral neuropathy. Hematological Disorders: anemia, bleeding tendency- due in part to platelet dysfunction. Cardiovascular Disorders: pericarditis, hypertension, congestive heart failure, coronary artery disease, vascular calcification. Pulmonary Disorders: pleuritis, pulmonary edema. Gastrointestinal Disorders: anorexia, nausea, vomiting, gastroenteritis, gastrointestinal bleeding. Metabolic-Endocrine Disorders: glucose intolerance, hyperlipidemia, hyperuricemia, malnutrition, sexual dysfunction and infertility. Bone, Calcium, Phosphorus Disorders: hyperphosphatemia, hypocalcemia, dystrophic calcification, secondary hyperparathyroidism, 1,25-dihydroxy vitamin D3 deficiency, osteomalacia, osteitis fibrosa. Skin Disorders: pruritus, hyperpigmentation, easy bruising. Psychological Disorders: depression, anxiety. Fluid and Electrolyte Disorders: edema, hyponatremia, hyperkalemia, hypermagnesemia, metabolic acidosis, volume expansion or depletion.

Answer 27

Anemia is almost universal as GFR falls below 25 ml/min; it may occur with mild CKD. Several factors may contribute: Erythropoiesis is markedly depressed, probably due to reduced erythropoietin production, also, there may be reduced end-organ response to erythropoietin with reduced heme synthesis. Red cell survival is shortened with a mild to moderate decrease in red cell life span, possibly due to a "uremic" toxin. Blood loss is common in uremic patients, possibly secondary to abnormal coagulation due, in large part, to decreased platelet function. Marrow space fibrosis occurs with the osteitis fibrosa of secondary hyperparathyroidism and can contribute to decreased erythropoiesis, especially in patients with longstanding ESRD.

Answer 28

Hypertension occurs in 80%-90% of patients with chronic kidney disease. Several factors contribute: Expansion of extracellular fluid volume; this may arise because of reduced ability of the kidneys to excrete ingested sodium. Increased activity of the renin-angiotensin system is common; many patients with advanced CKD have renin levels that are not completely suppressed by the elevated blood pressure; this renin may contribute to the increased blood pressure. Dysfunction of the autonomic nervous system; frequently, the baroreceptors are insensitive, with increased sympathetic tone. Possible diminished presence of vasodilators; there may be decreased renal generation of prostaglandins or of factors in the kallikrein-kinin system.

Answer 29

This classic hypothesis states that as the kidney fail phosphorus is retained which through a physio-chemical relationship drives down the ionized calcium. The fall in ionized calcium stimulates PTH release. The PTH in turn increases excretion of phosphate and helps restore calcium levels to normal. However, this occurs only at the expense of elevated serum PTH levels. This cycle repeats itself with continued declines in GFR and PTH levels increase progressively. Ultimately, the renal tubules can no longer respond to higher levels of PTH with a further decrease in phosphorus reabsorption. When this occurs, hyperphosphatemia develops, hypocalcemia may become prominent and PTH levels can increase to very high levels. High PTH levels cause bone disease with severe osteitis fibrosa and may have systemic toxicity. As our understanding has increased we realize that this theory is a significant oversimplification. It is now clear that there are two and probably three independent regulators of PTH. The primary regulator is calcium which is sensed via a transmembrane calcium sensing receptor. When calcium is bound to this receptor it inhibits PTH secretion and downregulates PTH production. 1,25 vitamin D downregulates PTH gene transcription by binder to its cytoplasmic sterol receptor that migrates to its site of action in the nucleus. Phosphorus may also have a direct action to increase PTH secretion although the mechanism is unclear.

Answer 30

The calcium sensing receptor is a transmembrane receptor that senses extracellular free calcium. When calcium is bound to the receptor it results in a decrease in PTH release and a downregulation of PTH production. Both activating mutation and inactivating mutations of this receptor have been discovered. Medications targeted at this receptor are being studied and used to decrease PTH in patients with both primary and secondary hyperparathyroidism.

Answer 31

As the GFR falls renal production of 1,25 vitamin D falls. While this may in part be due to the reduction in kidney mass there is now strong evidence that FGF-23 (see below) down regulates 1,25 vitamin D production in a compensatory manor to decrease serum phosphorus by decreasing gut phosphorus absorption. 1,25 vitamin D has several actions that include: stimulating the absorption of calcium and phosphorus from the intestine; and at the level of the parathyroid gland down-regulates PTH gene transcription. Therefore, a lack of this hormone would: decrease calcium absorption from the diet thereby stimulating PTH and directly increasing PTH production by releasing the PTH gene from inhibition.

Answer 32

Recently, a new class of hormones called phosphotonins were discovered. These are phosphorus regulatory hormones and the best studied is FGF-23. It is predominately produced by osteocytes in bone and causes phosphaturia (increased phosphorus excretion) and decreases the kidneys production of 1,25 vitamin D, presumably as a compensatory mechanism to prevent phosphorus overload. The relative role and importance of each of these factors for parathyroid gland proliferation and PTH secretion remains somewhat controversial. However, the central role that phosphorus plays early in the disease process suggests that early attention to phosphorus balance may be important in CKD. Dialysis patients have difficulty eliminating aluminum (usually excreted by the kidney), and are also subjected to aluminum loads (e.g., aluminum from poorly treated dialysate or aluminum binding antacids). Aluminum toxicity may ensue that in addition to causing osteomalacia may also result in brain disease (aluminum encephalopathy) and anemia.

Answer 33

It is suggested that compensatory events secondary to the loss of nephrons may accelerate the rate of destruction of the remaining nephrons in a diseased kidney. The evidence for this is considerable, although the exact pathophysiologic mechanisms involved are still debated. At a clinical level, it has been appreciated for some time that patients tend to lose kidney function at a relatively constant rate during the slowly progressive phase of the disease. In other words, the 1/Scr vs. time plot for a given patient with progressive chronic kidney disease tends to follow a straight line. This observation can be used clinically to ascertain when a patient is likely to require dialysis therapy (e.g. when their kidney function will fall to less than 1/10th of normal) or whether an experimental maneuver is actually successful in slowing the rate of progression (i.e. changes the slope of this line). Regarding the mechanisms operant in the progression of CKD, the most well studied phenomenon is that of glomerular hyperfiltration and hypertension in surviving nephrons.

Answer 34

The compensatory event to increase SNGFR that is mediated via the dilatation of the afferent arteriole, allows increased flow and pressure to be transmitted to the glomerular tuft. It has been suggested that this glomerular hypertension leads to the destruction of the glomerulus. Although glomerular hypertension is associated with progressive kidney failure in some animal models, tubular factors may also be important, but are less well characterized. In particular, increases in the oxygen consumption of remaining nephron units that is out of proportion to the amount of sodium that they transport has been demonstrated in animal models of progressive chronic kidney disease.

Answer 35

is prevented by the administration of converting enzyme inhibitors or angiotensin receptor blockers. Hypertension has also been shown to be especially injurious to a diseased kidney. The injury, again, is felt to be mediated by the increased pressure being transmitted to the remaining nephrons. Studies show that treatment of hypertension with converting enzyme inhibitors or angiotensin receptor blockers is more effective than using other antihypertensive medications. The decrease in efferent arteriolar tone reduces elevated glomerular capillary pressure and thereby may reduce glomerular injury. The implications of this observation to clinical medicine has been demonstrated in controlled clinical trials.

Answer 36

Although no clinical approach can completely stop the progression of CKD, there is now excellent data to support aggressive therapy of hypertension with angiotensin converting enzyme inhibitors (ACE-I) and angiotensin receptor blockers (ARBs). In addition, it is standard of care to maintain serum phosphorus in a near normal range with dietary counseling and phosphate binders. Advanced chronic kidney disease will eventually be accompanied by the uremic syndrome. This can be treated by several approaches including hemodialysis, peritoneal dialysis and renal transplantation. The advantages and disadvantages of these approaches will be discussed during your third year clerkship and fourth year elective in renal diseases.

Answer 37

[Bioavailability (F) or fraction of dose administered that reaches systemic circulation from non-IV (primarily oral) route of administration]. Limited clinical evidence regarding effect of CKD on drug absorption although it can be assumed that factors seen in CKD such as altered gastrointestinal transit time, changes in gastric pH, nausea/vomiting, and diarrhea all have the potential to affect drug bioavailability. Drug-drug interactions are possible and even likely given the large number of drugs a typical CKD patient is taking, especially with cation-containing phosphate binders (for hyperphosphatemia) and bile acid sequestrants (for hyperlipidemia) that can bind concomitantly administered drugs and reduce their bioavailability.

Answer 38

[Estimated by volume of distribution (Vd) that allows conversion of administered dose (MD: maintenance dose or LD: loading dose) to a plasma concentration (Cp) value.] DOSE (mg)/ Vd (L) = Cp (mg/L).

Answer 39

A drug like the congestive heart failure agent digoxin has a relatively large Vd due to extensive tissue binding. In CKD patients, the Vd has been shown to decrease by as much as 50% in stage 5 as a result of decreased tissue binding (mechanism uncertain). Thus, any given dose of digoxin will result in a higher Cp due to the smaller Vd and as CKD progresses it will be necessary to gradually reduce the daily dose of digoxin to prevent toxic accumulations.

Answer 40

The anticonvulsant phenytoin (DilantinÒ) is highly protein bound in patients with normal kidney function. In CKD, organic acids are excreted less efficiently and accumulate in plasma competing with phenytoin for albumin binding sites (analogous to protein-binding displacement drug-drug interaction). Hypoalbuminemia may also occur in CKD and these changes result in less phenytoin binding to proteins, greater levels of free phenytoin and greater ability to distribute outside of the plasma and greater potential for toxicity. Generally, these effects would be of potential clinical significance only in the acute initialization of dose phase.

Answer 41

At steady state, the MAINTENANCE DOSE (MD) represents the dose that is designed to equal the amount of drug that has been eliminated by the body in the preceding dosage interval (tau [τ]), thus maintaining the steady state plasma level [Cpss (avg)]. MD / tau [mg/hr] = Cpss (avg) [mg/L] x CL [L/hr]. Most dosing adjustment recommendations are based on arbitrary GFR values, often set by drug manufacturers from clinical trials. Dosing reductions are generally not recommended until GFR falls below 50 ml/min/1.73 m2 (stage 3 to stage 5), thus patients in stage 1 or 2 of CKD will generally not require any change in maintenance dose.

Answer 42

In combination with excretory processes, major contributor to drug clearance (CL) from plasma and a determinant of maintenance dose (MD). Although majority of drug metabolism occurs in the liver, up to 20% of phase I CYP450 reactions can occur in the kidney. The kidneys also contribute to phase II reactions such as conjugation with glucuronide, sulfate, or glutathione. In diabetic patients without CKD, renal metabolism is responsible for removal of 30% of an insulin dose. Insulin metabolism decreases markedly in CKD and requires a 25% insulin dose reduction in stage 3 / 4 and as much as a 50% reduction in stage 5. Hepatic metabolism can result in active metabolites that are renally excreted and can accumulate in CKD resulting in drug toxicity. Examples include the excitatory metabolite of meperidine (normeperidine) and the hepatotoxic metabolite of acetaminophen (N-acetyl- p-benzoquinonimine).

Answer 43

Renal excretion is the primary means of clearance (CL) for many drugs. As renal function deteriorates in CKD, renal drug clearance will decrease and drug half-life will increase necessitating dosage adjustments to prevent toxic accumulations. Estimating renal function (i.e., ability to excrete drugs or active metabolites) in CKD. NOTE: The kidney’s ability to excrete (clear) drugs is dependent on the combined processes of glomerular filtration, renal tubular secretion, and tubular reabsorption. Only glomerular filtration rate can be reliably measured clinically and it is recommended as the marker for quantifying renal function in adults for the purposes of both staging CKD and determining drug dosage.

Answer 44

measures creatinine clearance [CLcr], which has been shown to correlate closely with GFR. Currently, the C-G equation is more widely used to assess kidney function and adjust drug dosage. CLcr (ml/min) = [(140 - Age) (ABW)] / Scr X 72. For females result is multiplied by 0.85 Age (in years) ABW (actual body weight in kg; use ideal body weight (IBW) in obese patients) Scr (serum creatinine, mg/dL)

Answer 45

are recommended first line treatment for hypertension. As the GFR falls in CKD patients, less drug reaches the site of action in the nephron and diuretic efficacy decreases. At a GFR below 30, a more potent loop diuretic (e.g., furosemide) is necessary to maintain the anti- hypertensive effect.

Answer 46

can occur in later stages of CKD. This can often be overcome by use of synergistic combinations of diuretics that act at different sites in the nephron (e.g., the loop diuretic furosemide with the thiazide diuretic metalozone). Clinical observations have noted that adverse effects of some drugs may occur in CKD patients at doses and plasma levels that are safe and effective in patients with normal renal function. Not well studied.

Answer 47

Glyburide: Half-life prolonged. Glipizide: No adjustments necessary Thiazolidinediones: No adjustments necessary Metformin: Use NOT recommended if SCr > 1.5

Answer 48

Half-life prolonged

Answer 49

Thiazides may lose effectiveness as renal function declines; more potent loop diuretics (e.g., furosemide) are recommended Avoid potassium-sparing diuretics

Answer 50

Used through all CKD stages; monitor for hyperkalemia and elevations in serum creatinine; may cause ARF in hypovolemic patients

Answer 51

Atenolol: Half-life prolonged. Metoprolol, Carvedilol: No adjustments necessary

Answer 52

No adjustments necessary

Answer 53

No adjustments necessary

Answer 54

No adjustments necessary; dry mouth side effect can increase thirst contributing to volume overload

Answer 55

No adjustments necessary

Answer 56

No adjustments necessary

Answer 57

Gemfibrozil recommended fibrate in CKD stage

Answer 58

No adjustments necessary

Answer 59

No adjustments necessary

Answer 60

Kidney synthesizes and secretes 90% of circulating erythropoietin, the red blood cell growth factor. As kidney function declines, the serum concentration is reduced and anemia results. Increase in prevalence at Stage 3 CKD, even more prevalent in Stages 4 and 5

Answer 61

Epoetin Alfa (Epogen) and Darbepoetin Alfa (Aranesp) and iron supplements

Answer 62

Glycoproteins prepared with recombinant DNA technology with biologic activity identical to erythropoietin 

Answer 63

Given parenterally (SC) every week (epo) or every 1-2 weeks (darbepoetin) 

Answer 64

Generally well tolerated; hypertension most common event reported

Answer 65

Iron deficiency is most common cause of resistance to erythropoietic therapy. Supplements provide iron for production of hemoglobin and incorporation into red blood cells

Answer 66

Oral route commonly used, but absorption is generally poor (bid-tid). IV administration often required, especially in Stage 5 CKD 

Answer 67

Oral – constipation, nausea, abdominal cramping, often leading to reduced compliance. IV – allergic reactions, hypotension, headaches, anaphylactoid reactions (1.8% to iron dextran) 

Answer 68

Absorption decreased by calcium and by drugs that increase gastric pH (antacids, proton pump inhibitors, H2 antagonists)

Answer 69

Declining kidney function results in decreased phosphate elimination and elevated serum phosphate levelsàlowers serum calciumàstimulates release of PTH. PTH initially normalizes serum calcium and phosphate concentrations by increasing renal calcium reabsorption and decreasing renal phosphate reabsorption BUT long term elevation of PTH leads to osteodystrophy (“trade-off hypothesis”). Problem is compounded by the failing kidney’s decreased ability to convert 25-hydroxy vitamin D to the most active 1,25-dihydroxy vitamin D resulting in a vitamin D deficiency and a further reduction in serum calcium levels and increased release of PTH

Answer 70

phosphate binding agent, vitamin D compounds, calcimimetics

Answer 71

Most commonly used are calcium compounds (calcium acetate [PhosLo]) or non-elemental agents (sevelamer HCl [Renagel], sevelamer bicarbonate [Renvela] àreduced incidence of metabolic acidosis)

Answer 72

Bind dietary phosphate in GI tract to form insoluble magnesium, calcium, or aluminum phosphate, which is excreted in the feces, thus decreasing phosphate absorption and serum levels.

Answer 73

Given orally, best taken with meals.

Answer 74

Primarily GI side effects – constipation (Al+++ or Ca++), diarrhea (Mg++), nausea, vomiting, abdominal pain. Hypercalcemia possible with Ca++ salts; CNS toxicity with Al+++ salts limits use.

Answer 75

Best choice is agent that does not require renal conversion to the most biologically active form, i.e., 1, 25-dihydroxy vitamin D (calcitriol [RocaltrolÒ])

Answer 76

Suppresses PTH secretion indirectly by stimulating intestinal calcium absorption and directly by decreasing PTH synthesis in parathyroid gland.

Answer 77

Available in oral (Stage 1-4) and intravenous (Stage 5) dosage forms

Answer 78

Hypercalcemia and hyperphosphatemia possible.

Answer 79

Absorption reduced by concomitant administration of cholestyramine.

Answer 80

Cinacalcet (SensiparÒ), alternative to vitamin D in patients developing hypercalcemia.

Answer 81

Binds to calcium-sensing receptors on parathyroid cells, increasing sensitivity to plasma Ca++ levels, resulting in reduced release of PTH directly.

Answer 82

Available orally, metabolized by CYP450 

Answer 83

Hypocalcemia (monitor plasma Ca++); GI side effects.

Answer 84

Potent inhibitor of CYP2D6.

Answer 85

Failing kidney cannot excrete sufficient potassium to maintain homeostasis. Hyperkalemia is most common in stage 5 CKD. RECALL: Drugs that can cause hyperkalemia Potassium sparing diuretics: aldosterone antagonists (spironolactone, eplerenone) - collecting duct Na+ channel blockers (triamterene, amiloride) ACE inhibitors: lisinopril, enalapril, captopril, and more Angiotensin receptor blockers: losartan, valsartan, candesartan, and more Digoxin (toxic doses)

Answer 86

Acute (symptomatic): Hemodialysis is definitive treatment; temporizing therapies include IV calcium gluconate, insulin and glucose, sodium bicarbonate, and nebulized albuterol. MOA: Shift of K+ into intracellular fluid compartment (insulin / glucose, albuterol, sodium bicarbonate), antagonism of cardiac conduction abnormalities (calcium). Chronic (asymptomatic): Sodium polystyrene sulfonate (Kayexalate) MOA: Cation exchange resin that binds (exchanges) potassium for sodium in intestine. Pharmacokinetics: Oral (more effective) and rectal. Side effects: Constipation, fecal compaction, nausea, vomiting.

Answer 87

The kidney develops in 3 stages in 3 different locations through development, so really we have three sets of kidneys temporally and spatially related. The pronephros (about 3 to 4 weeks), the mesonephros (about 4 weeks-2 months), and the metanephros (about 5 weeks to maturity). Some of the nephrons of the metanephros are partially functional within about 2 1/2 to 3 months, but the majority develop continuously until birth and afterwards.

Answer 88

All of these develop initially from the nephrogenic cord within the urogenital ridge, a tissue that runs laterally and ventrally to the dorsal aorta lengthwise along the coelom of the embryo. The primordia begin as an undifferentiated group of mesodermal cells along the length of the nephrogenic cord and first develop into small groupings of cells or nephrotomes within each somite during segmentation of the embryo along its length (which includes, of course, for- mation of myotomes and the spinal ganglia as well). These are usually single nephrotomes near the anterior end of the pronephros but become progressively less distinctly associated with unique somites caudally. The nephrotomes then vesiculate and join, along their more lateral re- gions, to form a duct which originates as the pronephric duct and is then added to by nephro- tomes further caudally to become the mesonephric duct. The mesonephric duct grows cau- dally to join with the developing cloaca. The remaining mesonephric duct is also referred to medically as the Wolffian duct. It is important to point out that although the mesonephric duct is crucial in development of the kidney, the duct will eventually become a part of the male re- productive system (the epididymus and ductus deferens) and will largely degenerate in females (remnants may persist as Gartner’s duct and vestiges of tubules in the broad ligaments of the uterus, which may become cystic later in life).

Answer 89

The vesicular tubules of the pronephros degenerate and disappear by approximately 4 weeks, but the tubules of the mesonephros actually come in contact with small vessels that branch from the dorsal aorta, and it is thought that for a short time period in develop- ment these tubules may actually be functional nephrons. The urogenital ridge further develops into the Wolffian body that protrudes further into the coelom. It is relevant to point out that in lower vertebrates such as many species of fish the mesonephros functions for the entire lifetime of the animal and in some primitive fish (like the hagfish) the pronephros also functions in early stages of life. The metanephros is more well developed in land-dwelling vertebrates.

Answer 90

Another duct worth mentioning that develops along the urogenital ridge is the paramesoneprhic duct or Mullerian duct. This duct develops from an invagination of the coelom wall and runs along most of the length of the Wolffian body (Fig. 2) to also join with the cloaca. This duct is the duct from which the oviducts and uterus will eventually develop in females. In males this duct will largely degenerate. What is vital to recognize is that although the pronephros will degenerate and the meso- nephros may become part of the male reproductive ductwork, without these stages of development the metanephros, or definitive adult kidney, could not originate.

Answer 91

The metanephros, which becomes the final functioning kidney we know and love, begins as a tiny bud of epithelial cells from a portion of the mesonephric duct near where it joins with the cloaca. The bud, called the ureteric bud, is enveloped by a small re- gion of cells called the metanephric blastema, which will develop into some portions of the kidney. During development, the ureteric bud will grow lengthwise and branches will develop within the tis- sue of the metanephric blastema to initially form the ureter and the regions of the renal pelvis and major and minor calyces.

Answer 92

The regions of developing epithelia from the ureteric bud that will eventually line the calyces (about 8-9 weeks) generate a series of epithelial-lined out- growths as tubules that run roughly parallel to each other from the medulla into the cortical regions of the kidney. At this stage of development this grouping of aligned tubules are called the Malpighian pyramids. The epithelia of these outgrowths will become the collecting ducts of the kidney. In addition, these tubules also branch and give rise to short branching tubules that will become the collecting tubules. These tubules then stop elongating. Consequently, the epithelium of the ureteric bud, which branches successively during kidney development in several stages, gives rise to the ureters, the pelvis, the calyces, the collecting ducts, and the collecting tubules. However, interestingly, the remaining portions of the nephrons are not derived from the ureteric bud.

Answer 93

A most fascinating part of kidney development is that at the tips of the collecting tubules, which stop growing, the mesoderm that originated in the metanephric blastema is now induced to differentiate. The mesoderm organizes near the tips of collecting tubules as a group of cells called the metanephric spheroid, simply a cluster of metanephric mesodermal cells. This group of cells then vesiculates to form a metanephric vesicle. The vesicle then begins to elongate and initially forms a short tubule which folds on itself reminiscent of the shape of the letter “S”, the beginnings of the metanephric tubule that will form the rest of the epithelium of the nephron. Meanwhile, during the development and elaboration of the tissues derived from the ureteric bud, the renal artery and vein begins to supply the developing metanephric blastema. These branch between the Malpighian pyramids as the intralobar vessels, giving rise to the arcuates, interlobular vessels, the glomerular capillaries, efferent arterioles and vasa recta.

Answer 94

The localized gomerular capillary beds are present in the cortex during the elongation of the metanephric tubules, and these tubules undergo interactions at both ends: 1). At the end nearest the collecting tubules, they fuse with the collecting tubule forming a single elongated epithelial tubule. 2). At the other end the tubule reaches a glomerulus and the tissues of the tubule branch to envelop the glomerular capillary. The entire process, from induction of the mesodermal cluster of cells to formation of a functional nephron. The cells in direct contact with the glomerulus differentiate into podocytes. The cells of the outer epithelial layer differentiate into the squamous cells of the outer portion of Bowman’s capsule. The tubule also elongates in various regions and differentiates along it’s length to form the different cell types of the proximal tubule, ascending and descending portions of the loops of Henle, and the distal tubule. The fully developed nephron, finally, takes its place alongside others, de- pending on their approximate site of origin in the cortex.

Answer 95

lobular in appearance—the outer connective tissue that delineates the shape of mature kidney does not form early on as the kidney is rapidly growing. The lobular form is diminished at the time of birth through progressive filling in of the interlobar grooves.

Answer 96

The urogenital sinus originates as endoderm, from a caudal portion of the endoderm called early on the cloaca. The mesonephric duct joins the cloaca in a region that will eventually become a part of the urogenital sinus. The urogenital sinus separates from the hindgut at approximately 6-7 weeks (Fig. 5). Eventually, the portion of it called the allantois degenerates to form a fibrous cord called the urachus and the bladder and urethra develop from the urogenital sinus. In males, the portion of ureteric duct connected to the mesonephric duct moves to directly contact the bladder, so the mesonephric duct (which now formally becomes a part of the male reproductive system) separates fully from the insertion of the ureter to the bladder. It eventually connects with the urethra at the region that will become the prostatic urethra and a portion of the bladder called the trigone or trigonal vesicle between the insertion of the ureter and Wolffian duct is actually of mesonephric origin, rather than endodermal like the rest of the bladder. In females, the Mullerian duct develops into the oviducts and uterus which will be covered in reproductive development. It is important to point out that as the ureteric bud elongates, the kidney normally ascends from the sacral region into its normal retroperitoneal location. In males, the testes, connected to the Wolffian duct, undergo a descent, eventually to the scrotum.

Answer 97

The kidney undergoes a complex series of morphogenetic events, and there are a large number of genes that contribute to the various inductive processes that occur. Pax-2 and WT-1 are involved in mesonephric duct elongation and metanephric mesoderm specification, Wnt-4 and Bmp-7 are involved in metanephric vesicle formation, BF-2 and and PDGF-B are involved in nephron epithelial differentiation and tubulogenesis, etc—there are many other genes involved. This process is very complex and not well understood in terms of how each gene product affects others, their transcriptional/translational controls and the entire cascade of expression that must occur.

Answer 98

a treatment for patients with advanced chronic kidney disease. While dialysis cannot duplicate many functions of a normal kidney, the goals of dialysis are to remove toxins that are normally cleared by the kidney and to maintain euvolemia in the patient. Ideally, chronic dialysis will improve signs and symptoms of uremia and allow patients to return to pre‐dialysis functional status. There are two major types of dialysis: hemodialysis (performed in a dialysis unit or at home) and peritoneal dialysis (usually performed at home). There are no well‐ performed prospective clinical trials comparing the two modalities so the choice of modality depends mainly on the preferences of a patient or possible contraindications to either modality.

Answer 99

In general, life‐threatening conditions, such as severe hyperkalemia, severe volume overload or uremic pericarditis, will mandate initiation of dialysis. If the patient does not have appropriate dialysis access (see below), dialysis would be initiated with a vascular catheter. Less severe symptoms, such as mild cognitive changes associated with uremia, would warrant dialysis initiation if the patient has appropriate dialysis access (AV fistula or PD catheter); if the patient does not have access, the benefits of dialysis must be weighed against the risk of a catheter infection. Ideally, dialysis should be initiated before life‐threatening symptoms develop. Although most patients with a severely depressed GFR (

Answer 100

Hemodialysis is the most common modality in the United States (93% of patients) and can be performed either at an outpatient dialysis unit or at home. Most patients in the US receive hemodialysis at a dialysis center. Hemodialysis at dialysis units is usually performed thrice weekly with each treatment lasting three to four hours. Some patients receive longer, nocturnal sessions at dialysis units. Home dialysis patients do shorter treatments more frequently (five or six times weekly) or nocturnal treatments. During the hemodialysis procedure, blood is rapidly moved through an extracorporeal circuit. Blood is removed by a needle or through a catheter port and enters a tube with a semi‐permeable membrance. On the outside of the tube is dialysate moving in a counter‐current fashion. Solutes in the blood (high concentration) move into the dialysate (low concentration) by diffusion. Blood is then returned via a separate needle or port. Fluid can be removed (ultrafiltration) by applying positive pressure to the blood compartment.

Answer 101

To perform hemodialysis regularly, it is necessary to have dialysis access through which blood can removed at a fast flow rate. The preferred access for dialysis is an arteriovenous fistula (AVF). AVFs are created by surgical anastomoses of artery to vein. Most AVFs are placed in the arm. AVFs have the lowest infection rate and, on average, can be used longer than other types of access. However, AVFs take time to mature (at least 6‐8 weeks but up to 6‐9 months) and sometimes are never suitable for dialysis. Arteriovenous grafts (AVGs) are synthetic grafts that are connected to the artery and vein. AVGs can be used more quickly and have a higher primary success rate. However, AVGs fail quicker than AVFs due to neointimal hyperplasia, require frequent interventions to maintain patency, and have a higher infection risk. Finally, dual lumen catheters can be used for dialysis. Catheters are most often placed in the internal jugular vein and can be used immediately for dialysis. Catheters have a much higher infection rate than AVFs or AVGs and also have a high rate of dysfunction. Since AVFs are the preferred access yet take time to mature, patients with stage IV CKD should be referred for fistula placement prior to starting dialysis. Accesses are preferably placed in non‐dominant arm so preserving the non‐dominant arm from needle sticks and IVs is important in patients with CKD.

Answer 102

has many advantages. With modern filters, the treatment provides for rapid and effective removal of small molecular weight solutes (urea) over a 4‐hour treatment. Also, hemodialysis machines allow for precise control of ultrafiltration, allowing providers to prescribe a specific amount of fluid removal. In dialysis centers, patients can have trained health care professionals perform the treatment and the total treatment time is roughly 12 hours/week. However, in‐center hemodialysis does have some limitations as well. Since it is not a continuous treatment, fluid removal is not physiologic and often necessitates removing large volumes of fluid during a 4‐hour treatment. Hemodialysis is also not terribly effective at removing larger molecules or solutes that are protein‐bound.

Answer 103

Hemodialysis can also be associated with numerous complications. Infectious complications are relatively common in HD patients and lead to significant morbidity. Most commonly, HD patients develop bloodstream infections with gram positive bacteria, such as Staph aureus and coagulase‐negative staphylococci. The dialysis procedure itself can cause hypotension, angina, or myocardial ischemia. During the first few treatments, patients starting dialysis can develop disequilibrium syndrome, characterized by headache, somnolence, or rarely seizures and coma. Very rare but potentially fatal complications to the dialysis procedure are air emboli and anaphylaxis.

Answer 104

Peritoneal dialysis is a common dialysis modality worldwide but only used in about 7% of US patients. PD is usually done by the patient or caregiver at home and is designed to be a continuous therapy.

Answer 105

To perform peritoneal dialysis, a coiled catheter is placed in the peritoneal cavity and tunneled through the subcutaneous portion of the abdominal wall to an exit site. Sterile, pre‐packaged dialysate is infused into the peritoneal cavity and dwells in the cavity. Peritoneal dialysate has a high dextrose concentration providing a high oncotic pressure. Therefore, fluid moves from the bloodstream to the peritoneal cavity by osmosis. Solutes move with fluid by convection. The dialysate and ultrafiltered fluid are then drained from the peritoneal cavity and a new dwell with fresh dialysate is a started. There are two main types of peritoneal dialysis. Continuous ambulatory peritoneal dialysis (CAPD) is a manual therapy. The patient does three to four manual exchanges of dialysate daily. Continuous cycling peritoneal dialysis (CCPD) is an automated therapy. A cycler machine instills and drains dialysate many times throughout the night and leaves a dwell of dialysate in the peritoneum in the morning.

Answer 106

PD is the preferred dialysis method in many countries due to lower cost. PD often provides the patient with more freedom and autonomy than HD. The patient is responsible for performing the exchanges, taking vital signs, weighing themselves, and using their judgment to determine dextrose concentrations for the dwells (thereby affecting their fluid removal). Although many patients on HD also continue their employment, PD may make it easier to continue one’s job due to an uninterrupted day when one performs CCPD. Fluid removal is also more gradual and continuous than with HD, potentially making it more tolerable from a hemodynamic standpoint. PD also does not require vascular access and may be easier to perform than HD in a patient without adequate veins.

Answer 107

PD also has significant complications. Due to increase in intra‐abdominal pressure, PD can cause hernias. As a result, patients who have a hernia will need to have the hernia repaired prior to initiating PD. Also, in very large patients, it may be difficult to have adequate solute removal using conventional prescriptions. While peritoneal dialysis is usually not associated with bloodstream infections, patients can develop infectious peritonitis. The severity of peritonitis varies. Mild cases due to pathogens such as coagulase‐negative staphylococci will usually resolve quickly with antibiotics. Infectious peritonitis associated with fungi usually requires catheter removal. Since peritoneal dialysis contains hypertonic dextrose, patients typically receive a moderate carbohydrate load daily with therapy. Finally, catheter problems, such as kinking or malposition, can lead to problems with dialysis and may require surgical correction.

Answer 108

Unfortunately, neither peritoneal dialysis nor hemodialysis can completely replace the function of native kidneys. Also, patients on maintenance dialysis frequently have numerous medical co‐morbidities. Thus, the long‐term survival for patients on dialysis is quite poor. In the United States, patients beginning dialysis have a mortality rate greater than 20% for their first year on dialysis and 50% after five years. Dialysis patients most commonly die from cardiovascular disease and infections. Preventing cardiovascular death in dialysis patients is difficult; two large studies showed that cholesterol lowering with statin drugs does not decrease mortality on dialysis. Some small studies have shown that frequent dialysis, beta blockers, and ACE inhibitors may improve mortality in selected patients but these results have not been reproduced with large numbers of patients

Answer 109

Patients with ESRD receiving dialysis are subject to many comorbid factors that reduce survival compared to the general population including advanced age, high incidences of diabetes, coronary artery disease, peripheral vascular disease, COPD, and cancer. On dialysis life expectancy of 8 years (age 40-44) and 4.5 years (age 60-64), compared to general population life expectancy of 30-40 years and 17-22 years, respectively. Transplant improves long term patient survival vs. dialysis, however not to that of the general population. a higher mortality in the peri- and immediate post-operative period (due to the transplant procedure and initiation of immunosuppression) with a long-term survival benefit. Additional advantages associated with transplant include significant quality of life improvements as well as financial benefits vs. dialysis

Answer 110

Transplanted kidneys can come from either a living or deceased donor. Potential living donors undergo extensive medical, social, and psychological assessment prior to becoming an approved donor. Live donor nephrectomies are commonly laparoscopic, often with hand-assisted technique. Left kidney is preferred for donation due to longer length of the renal vein. Renal vein and artery anastomosis to recipient external iliac vein and artery, commonly on the right due to accessibility of the right external iliac vein. Donor ureter anastomosed to recipient bladder. Deceased donor organ retrieval occurs in a controlled setting at the institution where the deceased donor is located. Donor kidneys are then flushed with cold preservation fluid and transported to the transplanting institution, either on ice or under machine perfusion. Due to the nature of this process,deceased donor kidneys are subject to several types of ischemia: Warm ischemia: time from cardiac death to cold perfusion (max ~60 min) Cold ischemia: time from cold perfusion to recipient anastomosis (max 24-36 hours)

Answer 111

Standard criteria (SCD): Donor brain death, organs remain perfused until cross- clamping (minimizing warm ischemia). Donation after cardiac death (DCD): Organ recovery occurs after cardiopulmonary death. Increases warm ischemia time and risk of delayed function once transplanted. This is “controlled” in the US (ventilator and/or pressor support is withdrawn in the OR) and often uncontrolled in Europe (asystolic in the field after attempts at resuscitation). Extended criteria donor (ECD): -Donor > 60 years old, or -Donor age 50-59 with at least two of either 1) history of hypertension, 2) death by stroke, or 3) elevated terminal creatinine Associated with 70% increased risk of graft failure within 2 years vs. SCD. For this reason, ECD kidneys are generally reserved for patients with especially high mortality while on dialysis (older patients and patients with diabetes) as the waiting time is shorter vs. SCD.

Answer 112

The major histocompatibility complex (MHC) is a group of genes located on the short arm of chromosome 6. MHC gene products, termed HLA antigens in humans, bind peptide antigens for presentation to T cells via the T cell receptor. A T cell receptor will not be activated unless the peptide in question, such as a viral, bacterial, or tumor antigen, is presented by anHLAprotein. The MHC complex encodes two clinically relevant classes of HLA antigens, class I and class II. The polymorphic nature of the vertebrate MHC system is a necessary evolutionary response to the constant threat of microbial invasion and ensures the continuity of species by retaining the ability to present a large variety of “non-self” microbial particles to T cells. This highly conserved system, however, provides a barrier to transplanting organs across non-HLA-identical individuals. In this scenario donor HLA antigens will be recognized by the recipient’s immune system as “non-self”, resulting in an immune response, or rejection, unless the recipient undergoes immunosuppression.

Answer 113

include HLA-A, HLA-B, and HLA-C and are present on all nucleated cells. Class I antigens are mainly responsible for presenting cytosolic peptides, including viral antigens, to CD8+ cytotoxic T cells.

Answer 114

include HLA-DR, HLA-DP, and HLA-DQ and are usually only present on specific antigen-presenting cells (dendritic cells, B cells, macrophages). Class II antigens usually present extracellular proteins (that have entered the cell as a result of endocytosis) to CD4+ helper T cells. Unlike most proteins, HLA molecules are highly polymorphic. The HLA-A locus, for example, contains over 1800 possible alleles across the population. The ability of a particularHLA protein to bind an antigen depends on the amino acid structure of both the HLA protein and the immunogenic epitope within the antigenic peptide molecule.

Answer 115

You may hear talk of how many “matches” are associated with a patient’s kidney transplant. 6 HLA matches are taken into account in kidney transplantation. Historically, matching at the HLA-A, HLA-B, and HLA-DR loci has been deemed the most important in terms of graft survival. We receive one set of HLA genes from each parent and they are co-dominantly expressed, thus the 6 matches refer to two each from HLA-A, B, and DR. Interestingly and for reasons not completely understood, the degree of HLA matching does not impact the risk of acute rejection. It does, however, impact long term graft survival. For example, the mean 5 year graft survival rate for a 6 out of 6 HLA match kidney transplant is 79% compared to 66% for 0 out of 6 match transplant. The clinical decision of whether or not to proceed with a given transplant is not routinely dependent upon the HLA match, however decisions regarding degree of immunosuppression required after the transplant has occurred are more likely to be affected by this information.

Answer 116

Recipient T cell activation begins with recognition of a foreign donor HLA molecule, which can be presented by either recipient or donor (shed from within the allograft) derived antigen presenting cells. After the initial activating pathway and a second co-stimulatory event, a series of intracellular signaling cascades results in dephosphorylation of NFAT by calcineurin and subsequent cytokine (IL-2) production,leading to T cell proliferation and clonal expansion. The mechanism by which T cells cause graft damage during a rejection episode depends on the T cell subset

Answer 117

cytotoxic T cells confer direct cytotoxicity by either inducing cell apoptosis or by releasing cytotoxic proteins such as FasL and granzyme B.

Answer 118

helper T cells provide proliferation signals for CD8+ T cells, macrophages, and B-cells (some of which will eventually differentiate into antibody-producing plasma cells).

Answer 119

For the reasons described above, without immunosuppression organ transplant between non- HLA-identical individuals will result in a recipient immune response and subsequent allograft rejection. Immunosuppressive pharmacotherapy is therefore necessary in order to protect allografts from the recipient’s immune response. The standard pharmacologic approach for patients undergoing kidney transplantation includes triple therapy using three classes of immunosuppressive agents: a calcineurin inhibitor, a proliferation signal inhibitor, and prednisone. In addition to drug-specific side effects listed below, all immunosuppressive agents increase the risk of infection and malignancy. Memorizing all side effects is not as important as the general concept that these drugs are not without potential toxicity, sometimes severe.

Answer 120

``` Includes cyclosporine (neoral, gengraf) and tacrolimus (prograf). Dose: Twice daily, based on blood level at trough (12 hours after last dose, immediately before next dose) and varies depending on time out from transplant and individual immunologic risk of the patient. Adverse effects: Nephrotoxicity Acutely due to vasoconstriction of the afferent arteriole, chronically due to interstitial fibrosis and arteriolar nodular hyaline sclerosis. Cyclosporine: gingival hyperplasia, gout, hypertrichosis, HTN, hyperlipidemia Tacrolimus: neurotoxicity (tremor), alopecia, diabetes ```

Answer 121

include Mycophenolate Mofetil (MMF, cellcept, myfortic, MPA) and mTOR Inhibitors (sirolimus, everolimus)

Answer 122

Mechanism of action: inhibits purine synthesis. Dose: 1 g BID (MMF) or 720 mg BID (myfortic). Adverse effects: Gastrointestinal (nausea, diarrhea), hematologic (leukopenia, anemia)

Answer 123

Mechanism of action: inhibits mTOR proliferation signaling. Dose: 1-2mg/day (sirolimus) and .5-3 mg bid (everolimus). Like the calcineurin inhibitors, dose is adjusted based on trough concentrations. Adverse effects: Renal: potentiating effect on CNI nephrotoxicity, proteinuria, ↓K+, PO4, Mg -Impaired wound healing. Hyperlipidemia. Pulmonary: BOOP. Edema. Mucositis (mouth ulcers)

Answer 124

Mechanism of action:Multiple, exact mechanism is unclear Dose: 20 mg daily tapered to 5 mg daily by 4-6 months post-transplant Adverse effects: Numerous, HTN, hyperlipidemia, cataracts, weight gain are prevalent

Answer 125

The differential diagnosis of AKI in patients with transplanted kidneys includes all the possibilities you have learned about previously in native kidney disease in addition to a number of potential surgical, immunological, and infectious complications. Transplant AKI should be approached in a similar fashion as native disease, i.e. organized as pre-renal, intra-renal, and post-renal. In addition to the differential diagnosis for AKI in native kidney disease, the following is abrief list of etiologies to be considered in the setting of kidney transplant:

Answer 126

Volume depletion from post-operative fluid shifts, blood loss, etc. Thrombosis of the transplanted renal artery or vein (surgical emergency) Calcineurin inhibitor effects on the afferent arteriole

Answer 127

Transplant ureter obstruction due to fluid collection: requires surgical drainage. Lymphocele. Hematoma. Urine leak: most commonly due to break down of transplant ureter to bladder anastomosis. Creatinine rises due to absorption through peritoneal membrane (Cr concentration is much higher in urine vs. serum). Requires ureteral stenting and often surgical repair.

Answer 128

Recurrence of primary renal disease: some renal diseases carry significant risk of recurrence in the transplanted kidney. Primary FSGS: 20-50% recurrence. MPGN II: approaches 100% recurrence. Atypical HUS: approaches 100% recurrence. Membranous nephropathy, IgA nephropathy, SLE, diabetic nephropathy tend to recur though are often not clinically significant. Infection: Urinary tract infection and pyelonephritis very common, CMV virus: often will cause systemic disease with gastrointestinal symptoms, can cause interstitial nephritis as well. Treatment: ganciclovir. BK virus nephropathy: causes mild respiratory illness in children and remains dormant in native kidney tissue in 80% of the population. Can re-activate following transplantation with immunosuppression and lead to interstitial nephritis (acute) and fibrosis/tubular atrophy (chronic). Treatment: reduction of immunosuppression. Rejection: Either T-cell or B-cell (antibody) mediated. Diagnosed by renal biopsy. T cell rejection causes tubular and/or large vessel inflammation (lymphocytes).

Answer 129

represent some of the most common infections in humans. Although the vast majority of them remain confined to the lower urinary tract (bladder, urethra), they may involve the upper urinary tract (ureter, pelvis, kidney) and have the propensity to cause permanent kidney damage and even renal failure.

Answer 130

ascending vs. blood borne. Ascending infection is the most common cause of UTI. Organisms which normally colonize the lower GI tract and perineal skin become  introduced into the urethral meatus and progressively ascend to the urinary tract. colonization not enough to produce infection. balance between organism virulence and host defenses. Coliform bacteria are the usual causative organisms: E. coli most common (∼ 70%), Klebsiella, Proteus, Pseudomonas, Serratia, Strep species also, especially in recurrent or hospital acquired infections. E. coli only ∼ 1% of fecal flora. Strain-specific virulence factors (see below) must therefore play a role. Hematogenous infection is much less common. Occurs mainly in debilitated patients or in kidneys previously damaged by some  other process. Involves different organisms: S. aureus, group A strep. Clinical setting: septicemia, endocarditis

Answer 131

Bacterial adhesion – certain strains of E. coli have “P” pili which allow for attachment to glycosphingolipid receptors on urothelial cells. These so called “uropathogenic” strains more commonly cause UTI, particularly pyelonephritis. E. coli with P-pili agglutinate human RBCs (basis for test). Persons with blood group P1 carry these uropathogenic strains more often than those with blood group P2. They have a relative risk of recurrent pyelonephritis that is eleven times that of the general population. Other bacterial antigens may offer resistance to host factors. Endotoxins produced by E. coli may inhibit ureteral peristalsis.

Answer 132

Secretions of urethral glands. Mucosal factors. Hydrokinetic factors - urine flow. Functional “valve” between bladder and ureter that prevents retrograde flow. . Urine (poor culture medium).

Answer 133

Normally, host defenses are enough to oppose organism virulence and prevent infection. Some predisposing factor may trip this balance and allow for UTI. Females more frequently affected than males: Shorter urethra, Urethra more easily irritated (“honeymoon cystitis”), Vagina and introitus likely to be colonized by bacteria. Post-menopause: Lack of estrogen enhances colonization of vagina. Instrumentation: Catheterization – especially indwelling catheters, Cystoscopy. Decreased urine flow/urinary stasis: Urinary tract obstruction, Incomplete voiding, Infrequent micturition, Low flow, Bladder/ureteral diverticula, Neurologic diseases affecting bladder control. Calculi: Cause obstruction, Perpetuate infection – inhibit effectiveness of therapy, Facilitate spread. Vesical-ureteral reflux – backflow of urine from bladder to ureters, renal pelvis, etc. Pregnancy - UTI's are more common during pregnancy because of changes in the urinary tract. The uterus sits directly on top of the bladder. As the uterus grows, its increased weight can block the drainage of urine from the bladder, causing an infection. Diabetes - The presence of high glucose concentration in urine provides a rich culture medium for bacteria to grow. Women with diabetes have more frequent and more severe UTIs than women without the disease. Other underlying diseases of kidney and urinary tract (e.g., polycystic kidneys, congenital anomalies, vascular disease, etc).

Answer 134

Covert bacteriuria: 30:1 F:M, 15-20% have chronic pyelonephritis, Scarring mostly occurs early in life (

Answer 135

For conceptual purposes, it is useful to categorize symptoms according to the level to which micro-organisms have ascended and caused an inflammatory reaction. Urethra and vesical-urethral valve:  dysuria, difficulty voiding, incomplete emptying, incontinence. Bladder (cystitis): frequency, suprapubic pain. Ureters and kidneys (acute pyelonephritis): flank pain & tenderness-abdominal pain, fever, chills, oliguria. Note: For the individual patient, clinical data are not reliable indicators of the level of infection.

Answer 136

Urinalysis: Many WBC’s, WBC casts (pyelonephritis), RBC’s (variable). urine culture: usually > 100,000 bacteria/ml; always > 10,000 bacterial/ml

Answer 137

Acute pyelonephritis – suppurative inflammation of the kidney and renal pelvis caused by bacterial infection (less often fungal).  Patchy, wedge-shaped regions of suppuration with microabscesses.  Tubules filled with aggregates of PMNs. Tubular destruction. Interstitium – edema, PMNs, lymphs and plasma cells (may predominate in areas away from abscesses or during resolution).  Glomeruli preserved until late in course. Papillary necrosis – especially in diabetics and obstructive pyelonephritis. Perinephric abscess – usually an extension of acute pyelonephritis. Renal scarring.  Recurrence.  Stones - especially with Proteus infection.

Answer 138

There are two major circumstances that when combined with chronic or recurrent infections are associated with renal scarring and progressive renal impairment. This includes urinary tract obstruction and vesical-ureteral reflux. Recurrent infections without obstruction, reflux or some other underlying urinary tract disease (e.g., stones, diabetes) rarely if ever cause chronic pyelonephritis.

Answer 139

Obstruction predisposes to infection (see above). . Obstruction makes it difficult to eradicate infection and predisposes to  recurrence.  Combination of obstruction and infection causes structural damage to the kidney  and urinary tract with loss of renal function (chronic obstruction pyelonephritis). Probably a result of pressure-induced ischemia and tubular atrophy combined with tissue injury from organisms and inflammatory reaction.

Answer 140

Intrinsic (intraluminal) masses of the urinary tract:  exophytic tumors, calculi, sloughed necrotic papilla, blood clots. Inflammation, stricture of urethra or ureters. Urethral valves. Extrinsic compression:  tumors (esp. pelvis, retroperitoneal), retroperitoneal fibrosis, hemorrhage (trauma), iatrogenic (surgical ligation, adhesions). Functional:  neurological disease, diabetes mellitus. Idiopathic

Answer 141

Structural changes – unilateral or bilateral depending on level of obstruction.   Dilatation of the urinary collecting system (hydroureter, hydronephrosis). Atrophy and flattening of renal papillae and medulla: X-ray dx  Fibrosis and atrophy of renal cortex. Microscopically:  tubular atrophy, fibrosis with patchy infiltration of lymphs & plasma cells, focal edema and PMNs if superimposed acute infection. Functional changes: Decreased GFR – irreversible after weeks to months and Hypertension.

Answer 142

Retrograde flow of urine from bladder into ureter and renal pelvis during micturition. Although there is no anatomical valve at the ureterovesicle junction, the oblique  course of the ureter through the bladder wall forms an effective “valve” in which the ureter is compressed during situations of increased intravesicular pressure, especially during micturition. If the intramural segment of ureter is shortened or displaced such that it enters the bladder perpendicularly, this functional valve is lost allowing urine to reflux into ureter. VUR is most commonly apparent as an isolated abnormality in infancy and decreases in frequency and severity throughout early childhood (most resolved by age 5) – spontaneous remission. familial, some cases may be associated with congenital malformations, posterior  urethral valves, neurogenic bladders, etc., renal scarring occurs early in life with little or no progression if reflux abates  (

Answer 143

The consequences of VUR include chronic or recurrent infections with non- obstructive pyelonephritis and renal scarring, termed reflux nephropathy. This is usually associated with hypertension. VUR allows the pelvicaliceal system to be subjected to high pressure during  micturition, and allows organisms to gain access to the renal parenchyma. Coarse, segmental scars lying directly over dilated calyces.  Thinning of both cortex and medulla. Often unilateral or unequally bilateral. More extensive scarring at poles of kidney. Related to papillae morphology – simple vs. compound papillae. Compound papillae have “open” ducts of Billini allowing for pelvic-tubular  reflux. Compound papillae tend to be found at poles. Children without compound papillae resistant to renal scarring. Small percentage of patients develops focal segmental glomerulosclerosis.

Answer 144

Both benign and malignant tumors occur in the kidney. With the exception of oncocytoma, the benign tumors rarely cause clinical problems. Malignant tumors, on the other hand, are of great importance clinically and deserve considerable emphasis. By far the most common of these malignant tumors is renal cell carcinoma (RCC), followed by Wilms tumor, which is found in children and will be discussed in a separate lecture, and finally urothelial tumors of the calyces and pelves. Although some tumors that occur more commonly in adults may also occasionally be encountered in children and vice versa, a broad separation of renal tumors according to patient age is an arbitrary but widely accepted practice whose usefulness has been validated by many years of experience. Most of the pathological categories of neoplasms have been documented as primary tumors of the kidney, particularly in adults, but most tumors are carcinomas that conform to a rather narrow range of histologic lesions differentiating in whole or in part toward renal tubular epithelial structures.

Answer 145

Renal Papillary Adenoma: Well circumscribed nodules within the cortex, 7 – 22 % at autopsy, small (5 mm diameter). Surgically removed since they are considered “early cancers.” Renal Fibroma or Hamartoma (Renomedullary Interstitial Cell Tumor): Fibrous, less than 1 cm, within pyramids, no malignant tendency. Angiomyolipoma: Vessels, smooth muscle and fat. 25 -50% in patients with tuberous sclerosis. Oncocytoma: Eosinophilic epithelial cells, numerous mitochondria, 5 – 15% of all renal neoplasms. Some cases are most common within family groups. Metanephric adenoma. Very rare, only one case in a child known to produce metastases.

Answer 146

In the broadest sense, most renal tumors could be classified as adenocarcinoma, but current usage prefers the term renal cell carcinoma (RCC) to distinguish them. In the USA, renal cancer is the 7th leading malignant condition among men and the 12th among women, accounting for 2.6 % of all cancers. About 2% of cases of renal cancer are associated with inherited syndromes. In the USA, more than 36,000 new cases of renal cancer are predicted to occur every year, many of which are being discovered earlier because of the widespread availability of radiographic testing. Nevertheless, more than 12,000 deaths from the disease are predicted to occur every year. RCC arise from the renal epithelium and account for about 85 % of renal cancers. A quarter of the patients present with advanced disease, including locally invasive or metastatic RCC. Moreover, a third of the patients who undergo resection of localized disease will have a recurrence. Median survival for patients with metastatic disease is about 13 months. Thus, there is a great need for more effective surgical and medical therapies. The biological behavior of RCC is generally malignant, but the few benign tumors in the group cannot be distinguished by size alone. The classification of RCC has recently undergone revision, based on correlative cytogenetic, genetic, and histologic studies of both familial and sporadic tumors.

Answer 147

Most common type, accounting for 70% to 80% of renal cell cancers (third most common urologic malignancy, found in 3% of the adult population). Male to female ratio 3:1.

Answer 148

Hematuria. Renal mass may be incidental finding on imaging study.  Arises in the renal cortex, has a propensity to invade the renal vein and can extend into the inferior vena cava up to the heart. Regional lymph nodes may be enlarged. Hematogenous spread to lungs may occur, too. Metastatic disease often as multiple nodules in the lungs.

Answer 149

Ball-like mass of renal cortex; tumor enhances less than normal parenchyma. Engorged, tumor-filled renal vein with extension to inferior vena cava. Look for metastatic disease.

Answer 150

Gross: Most often as single tumor (multifocal and bilateral in Von Hippel-Lindau  disease), somewhat spherical, yellowish gray mass, variegated appearance, focal  hemorrhage, 20% are cystic.

Answer 151

In clear cell RCC three cell types are generally recognized -clear, granular, and spindle. Most tumors are composed of clear cells, granular cells, or a mixture of these two cell types. Nuclear grade of tumor cells is assigned according to Fuhrman's criteria, and varies from 1 to 4. Nuclear grade in RCC is an important independent predictor of survival; that is tumors of grades 1-2 carry a better prognosis than tumors of grades 3-4. Spindle cell types or sarcomas tend to grow and spread more quickly than the other kinds of RCCs. They can be associated with any of subtype mentioned and this subtype portends poorer prognosis.

Answer 152

Current studies implicate the VHL gene in the development of both familial and sporadic clear cell tumors.  Familial, associated with VHL (Von Hippel-Lindau) disease (4% of cases) Most cases (95%) are sporadic. 98% of tumors: loss of sequences on short arm chromosome 3 by deletion (3p-) or by unbalanced chromosomal translocation (3;6, 3;8, 3;11) resulting in loss of chromosome 3 spanning 3p12 to 3p26. This region harbors the VHL gene (3p25.3). A second non-deleted allele of the VHL gene shows somatic mutations or hypermethylation-induced inactivation in about 80% of clear cell cancers, indicating that the VHL gene acts as a tumor-suppressor gene in both sporadic and familial cancers.

Answer 153

encodes a protein that is part of a ubiquitin ligase complex involved in targeting other proteins for degradation. Important among the targets of the VHL protein is hypoxia-inducible factor-1 (HIF-1). When VHL is mutated, HIF-1 levels remain high, and this constitutively active protein increases the transcription and production of hypoxia-inducible, pro-angiogenic proteins such as VEGF and TGF-β1. In addition, insulin-like growth factor-1, another VHL target, is upregulated. Thus, both cell growth and angiogenesis are stimulated.

Answer 154

The average 5-year survival rate of patients with renal cell carcinoma is about 45% and up to 70% in the absence of distant metastases. With renal vein invasion or extension into the perinephric fat, the figure is reduced to approximately 15% to 20%. Nephrectomy has been the treatment of choice, but partial nephrectomy to preserve renal function is being done with increasing frequency and similar outcome.

Answer 155

Represent 10% to 15% of renal cancers.

Answer 156

Gross: Unlike clear cell RCCs, papillary carcinomas are frequently multifocal.  

Answer 157

Papillary growth pattern.

Answer 158

Occurs in both familial and sporadic forms. Not associated with 3p deletions. Most common cytogenetic abnormalities are trisomies 7, 16, and 17 and loss of Y in male patients in the sporadic form, and trisomy 7 in the familial form. The gene for the familial form has been mapped to a locus on chromosome 7 (MET locus, a protooncogene that serves as the tyrosine kinase receptor for hepatocyte growth factor). This gene has also been shown to be mutated in a proportion of the sporadic cases of papillary carcinoma.

Answer 159

Better than clear cell RCC.

Answer 160

Represents 5% of renal cell cancers

Answer 161

Cells with prominent cell membranes and pale eosinophilic cytoplasm, usually  with a halo around the nucleus. Histologic distinction from oncocytoma can be difficult.

Answer 162

multiple chromosome losses and extreme hypodiploidy. They are, like the benign  oncocytoma, thought to grow from intercalated cells of collecting ducts.

Answer 163

Excellent compared with that of the clear cell and papillary cancers; similar to  oncocytomas.

Answer 164

Represents approximately 1% or less of renal epithelial neoplasms. They arise from collecting duct cells in the medulla.

Answer 165

Nests of malignant cells enmeshed within a prominent fibrotic stroma, typically in a medullary location.

Answer 166

A number of chromosomal losses and deletions have been described for this tumor, but a distinct pattern has not been identified.

Answer 167

Associated with aggressive behavior and poor prognosis. For the majority of patients surgical treatment will not result in a cure. Previously recommended chemotherapy and/or immunotherapy appear to have a limited role in treatment of this disease, and early detection may be the best method for prolonging patient survival.

Answer 168

Although they account for only 4% of renal cancers, familial variants have been enormously instructive in studying renal carcinogenesis. Includes VHL, hereditary clear cell carcinoma, and hereditary papillary carcinoma.

Answer 169

1/2 to 2/3 of VHL patients: hemangioblastomas of the cerebellum and retina, develop renal cysts and bilateral, often multiple, renal cell carcinomas (nearly all, if they live long enough). Current studies implicate the VHL gene in the development of both familial and sporadic clear cell tumors. 

Answer 170

confined to the kidney, without the other manifestations of VHL but with abnormalities involving the same or a related gene.

Answer 171

This autosomal-dominant form is manifested by multiple bilateral tumors with papillary histology. These tumors exhibit a series of cytogenetic abnormalities and, as will be described, mutations in the MET protooncogene.

Answer 172

The most important factor in predicting prognosis is the stage. The stage describes the cancer's size and how deeply it has spread beyond the kidney. The Staging System of the American Joint Committee on Cancer (AJCC) is sometimes known as TNM system. The letter T followed by a number from 1 to 3 describes the tumor's size and spread to nearby tissues. Higher T numbers indicate a larger tumor and/or more extensive spread to tissues near the kidney. The letter N followed by a number from 0 to 2 indicates whether the cancer has spread to lymph nodes near the kidney and, if so, how many are affected. The letter M followed by a 0 or 1 indicates whether or not the cancer has spread to distant organs (for example, the lungs or bones) or to lymph nodes that are not near to the kidneys.

Answer 173

The tumor is 7 cm (about 2 3/4 inches) or smaller, and limited to the kidney. There is no spread to lymph nodes or distant organs.

Answer 174

The tumor is larger than 7.0 cm but still limited to the kidney. There is no spread to lymph nodes or distant organs.

Answer 175

There are several combinations of T and N categories that are included in this stage. These include tumors of any size, with or without spread to fatty tissue around the kidney, with or without spread into the large veins leading from the kidney to the heart, with spread to one nearby lymph node, but without spread to distant lymph node or other organs. Stage III also includes tumors with spread to fatty tissue around the kidney and/or spread into the large veins leading from the kidney to the heart, that have not spread to any lymph nodes or other organs.

Answer 176

There are several combinations of T, N, and M categories that included in this stage. This stage includes any cancers that have spread directly through the fatty tissue and the fascia ligament-like tissue that surrounds the kidney. Stage IV also includes any cancer that has spread to more than one lymph node near the kidney, to any lymph node not near the kidney, or to any other organs such as the lungs, bone, or brain.

Answer 177

Primary tumor cannot be assessed

Answer 178

No evidence of primary tumor

Answer 179

Tumor 7 cm or less, limited to kidney

Answer 180

Tumor greater than 7 cm, limited to kidney

Answer 181

Tumor extends into major veins/adrenal/perinephric tissue; not beyond Gerota's  fascia

Answer 182

Tumor invades adrenal/perinephric fat

Answer 183

Tumor extends into renal vein(s) or vena cava below diaphragm

Answer 184

Tumor extends into vena cava above diaphragm

Answer 185

Tumor invades beyond Gerota's fascia

Answer 186

Regional nodes cannot be assessed 

Answer 187

No regional lymph node metastasis 

Answer 188

Metastasis in a single regional lymph node 

Answer 189

Metastasis in more than one regional lymph node

Answer 190

Distant metastasis cannot be assessed

Answer 191

No distant metastasis 

Answer 192

Distant metastasis

Answer 193

About 95% of urinary tract tumors are of epithelial origin, the remainder being mesenchymal tumors. Most epithelial tumors are composed of urothelial (transitional) type cells and are thus interchangeably called urothelial or transitional tumors, but squamous and glandular carcinomas also occur. A small number of benign neoplasias of the urinary tract are represented by small tumors generally of mesenchymal origin. The two most common are fibroepithelial polyps and leiomyomas. The fibroepithelial polyp is a tumor-like lesion that grossly presents as a small mass projecting into the lumen. The lesion occurs more commonly in the ureters (left more often than right) but may also appear in the bladder, renal pelves, and urethra. The polyp presents as a loose, vascularized connective tissue mass lying beneath the mucosa.

Answer 194

80% patients between 50 -80 years. Male to female ratio 3:1. More frequent in urban areas. Fifty to 80% of all bladder cancers are in smokers. Industrial exposure to acrylamide (2-snaphthylamine). Schistosoma haematobium infections in Egypt and Sudan. Exposure to radiation.

Answer 195

Comprise more than 90% of tumors that arise from the urinary tract, other cell types include squamous cell and adenocarcinomas. Clinical presentation includes hematuria and irritative bladder symptoms such as dysuria, urinary frequency and urgency. The hematuria may be episodic, gross or microscopic. May be an incidental finding on urinalysis. TCC may arise from the renal calyces, pelvis, ureters, bladder, urethra and urothelium lined ducts in the prostate. The tumor can extend to the pelvic sidewalls and metastases can go to the lungs, bones and liver. The tumor can cause ureteral obstruction leading hydronephrosis, unilateral or bilateral depending on its location.

Answer 196

Multiple modalities, CT, MRI, cystography, IVP can demonstrate the tumor. Tumors appearas filling defects in the urinary tract. Appearance depends on the size of the tumor and whether it is polypoid or sessile

Answer 197

The gross patterns of urothelial cell tumors vary from purely papillary to nodular or flat. The tumors may also be noninvasive or invasive. The level of invasion has prognosis significance and can involve the lamina propria, muscularis propria, peri-cystic fat tissue and other organs. Papillary lesions appear as red, elevated excrescences varying in size from less than 1 cm in diameter to large masses more than 5 cm in diameter. Multicentric origins may produce separate tumors. The histologic changes encompass a spectrum from benign papilloma to highly aggressive anaplastic cancers. Overall, the majority of papillary tumors are low grade. Most arise from the lateral or posterior walls at the bladder base.

Answer 198

There is no familial tendency.

Answer 199

Depending on grade and stage.

Answer 200

Urothelial papilloma (benign). Urothelial neoplasm of low malignant potential (Grade 0). Papillary urothelial carcinoma, low grade (Grade 1). Papillary urothelial carcinoma, high grade (Grades 2 and 3)

Answer 201

Noninvasive, papillary (Ta). Carcinoma in situ (noninvasive, flat) (Tis). Lamina propria invasion (T1). Muscularis propria invasion (T2). Microscopic extra-vesicle invasion (T3a). Grossly apparent extra-vesicle invasion (T3b). Invades adjacent structures (T4)

Answer 202

BCG, Electrocautery, Surgery

Answer 203

dilation of the renal pelvis by accumulated urine due to obstruction.

Answer 204

most common cause of pediatric hydronephrosis, 1/1000-2000 newborns. obstruction is more common in boys, especially in the newborn period, 2M:1F. left side involved in 67%, bilateral in 10-40%. result of incomplete canalization of ureteric bud at 12 weeks gestation and/or local abnormality of smooth muscle fibers with increased fibrosis impeding peristalsis. signs & symptoms are abdominal mass, pain, urinary tract infection (UTI). antenatal ultrasonography has increased early detection. UPJ obstruction is coexistent with other congenital abnormalities in almost 50% of patients. 10% of patients with UPJ obstruction show ipsilateral reflux. surgeon sees a ureteral narrowing with angulation, resects it then joins the ends (reanastomosis).

Answer 205

dilation of the ureter by accumulated urine due to obstruction.

Answer 206

backflow of urine up the urinary tract upon contraction of the detrusor muscle during micturition.

Answer 207

most common renal abnormality, occurring in approximately 1% of the population, about 10% of children with urinary tract infections (UTI) and more commonly in females. complete ureteral duplication, in which 2 ureters ipsilaterally enter the bladder, has a propensity for vesicoureteral reflux into the lower pole and obstruction of the upper pole, which may insert ectopically into the bladder or end in a ureterocele (80% of the time). signs & symptoms include failure to toilet train or continuous drip incontinence.

Answer 208

a cystic dilation of the terminal intravesical (portion within the bladder wall) ureter. An ectopic ureterocele is at the bladder neck or the urethra, regardless of the position of the orifice. can often be obstructive if the orifice is stenotic or ectopically located and can cause reflux if the orifice is patulous. incidence of 1/5000, 10% bilateral, 70% ectopic, 80% associated with upper pole ureter of duplex kidney, which is often dysplastic. diagnosed prenatally when associated with hydronephrosis or during work up of UTI, or may prolapse through urethra causing bladder outlet obstruction, usually in girls.

Answer 209

the urachus connects the dome of the fetal bladder to the allantois in the umbilical cord. Normally, the urachus involutes to form the median umbilical ligament. a urachal anomaly can cause pain and retraction of the umbilicus during micturition. a cyst forms 30% of the time causing a painful midline mass between the umbilicus and the suprapubic area. a sinus or fistula leads to drainage of clear or purulent urine at umbilicus and sometimes UTI. chronic irritation may lead to umbilical polyp formation

Answer 210

abnormal distention of the bladder by urine due to bladder outlet obstruction

Answer 211

abnormal congenital obstructing membrane located in the posterior male urethra. results from abnormal insertion of mesonephric duct on the cloaca prior to its dividing into the urogenital sinus and the anorectal canal. causes abnormal development of all upsteam structures due to chronic increased intraluminal pressure. most common cause of bladder outlet obstruction, in boys only. incidence approximately 1 in 5000 male births. usually diagnosed prenatally or with anuria and bladder distention. may have a poor urine stream, UTI or urinary incontinence in the older boy

Answer 212

the orifice (meatus) of the penile urethra at a location along the ventral aspect of the penis rather than the tip of the glans (named accordingly-glandular, penile, scrotal, perineal). results from abnormal fusion of urogenital folds in males, often from androgen insufficiency.

Answer 213

a fibrous band causing the penis to curve toward its location, usually associated with hypospadius or epispadius.

Answer 214

location of the urethral opening on the dorsal aspect of the penis.

Answer 215

exposure of the bladder mucosa due to absence of the abdominal wall.

Answer 216

arises from failure of separation by the urorectal septum of the primitive cloaca into the urogenital sinus and anorectal canal at six weeks gestation. incidence is 3/100,000 births, 2-6M:1F

Answer 217

During development the fetus swallows amniotic fluid and produces urine. This fetal urine is a necessary component of the amniotic fluid, which fills the amniotic sac in which the fetus develops. Normal lung development depends of the fetus “breathing” the amniotic fluid. While the maternal circulation through the placenta eliminates metabolic waste products so the fetus can come to term, the consequences of renal agenesis or a urinary tract obstruction can be lethal to the newborn.

Answer 218

Urinary tract obstruction → decreased amniotic fluid (oligohydramnios). pulmonary hypoplasia, deformation of face and limbs, and placental amnion nodosum (Potter facies)

Answer 219

occurs in1 in 35,000-50,000 live births. usually a male with a thin or lax abdominal wall with megalocystis and tortuous, dilated ureters. absence of the muscle wall may be a result of pressure atrophy from the dilated urinary tract. all boys have cryptorchidism due to the urinary bladder blocking descent of the testes into the scrotum. depending on the degree of oligohydramnios, pulmonary hypoplasia may occur.

Answer 220

incidence of unilateral renal agenesis is 1/1000. The opposite kidney hypertrophies to compensate. Left kidney more commonly affected. May be associated with single umbilical artery. incidence of bilateral renal agenesis is 1/3000 births. Incompatible with postnatal life. -due to failure of metanephric diverticulum to develop or its early degeneration.

Answer 221

the under development of a kidney with contralateral compensatory hypertrophy.

Answer 222

abnormal metanephric tissue differentiation of the kidney tissue with cysts and heterotopic tissues such as cartilage due to pleuripotent potential of renal anlage.

Answer 223

failure of the kidney to rise out of the pelvis or to rotate medially. -may result in ureteral obstruction. -kidneys may be discoid in shape.

Answer 224

incidence is 1/500. the anlage of the kidneys is fused (90% of the time at the lower pole). since they are linked together, they are often ectopic and fail to rotate medially. increased incidence of urolithiasis.

Answer 225

Renal cysts may be acquired, genetic or developmental in origin.

Answer 226

acquired cystic kidney disease. the most common renal lesion (65-70% of renal masses), incidence of 25-33% by age 50 years, usually asymptomatic; may be large, up to several centimeters

Answer 227

acquired cystic kidney disease. incidence estimated at 1 in 5000 population. found in approximately 20% of patients with nephrolithiasis. kidneys are normal sized, with at least one enlarged and pale renal pyramid. The disease is bilateral in 70% of cases. 1-3 mm cysts are dilated collecting ducts lined by cuboidal or flattened epithelium in the papillary portions of the pyramids. Roughly half contain calcifications.

Answer 228

occurs in patients with all etiologies of ESRD, particularly those who are dialysis dependent. The incidence, number, and size of cysts all increase with the duration of dialysis. More common in men. most patients are asymptomatic, but gross hematuria, flank pain, renal colic, or a palpable renal mass may occur. Renal cell carcinoma may develop. cortical cysts filled with clear fluid usually 0.5 m in diameter, may grow to 3 cm and later develop in the medulla.

Answer 229

Genetic cystic conditions. due to mutations in PKD1 (90%) on 16p13 and PKD2 (10%) on 4q21 which encode polycystin proteins 1 & 2 respectively; PKD2 progresses about 10 years more slowly. incidence of 1 in 400 to 1 in 1000 population among white people. 25% of patients have no family history. near 100% penetrance with large cysts. kidneys are bilaterally enlarged up to 40 cm weighing 5 kg and are distorted by multiple variably sized renal cysts distributed relatively uniformly through the medulla and cortex containing clear to hemorrhagic fluid. Cystic dilation involves all segments of the nephron. hepatic cysts are observed in 80% of patients older than 50 years, also mitral valve prolapse (25%), diverticulosis (80%), cerebral aneurysms (5-30%), and pancreatic cysts (10%). presents in the fourth decade with chronic flank pain or intermittent hematuria. Hypertension and chronic renal failure in the fifth decade of life, only 50% progress to end-stage renal disease (ESRD) in the sixth decade of life. accounts for 8-10% of all cases of ESRD.

Answer 230

Genetic cystic conditions. due to PKHD1 on 6p21 which encodes fibrocystin. incidence of 1 in 6000 to 1 in 55,000 live births, with a heterozygous carrier frequency of 1 in 70. kidneys are enlarged bilaterally, but still reniform. In neonates the kidneys may be 10-20 times normal size. Radial cysts are less than 3 mm in diameter extend from the papillary tips to the surface of the cortex. Microscopically, cysts are dilated collecting tubules lined by cuboidal epithelium. liver is grossly enlarged, with bile duct proliferation and periportal fibrosis called congenital hepatic fibrosis (CHF) which is always present in ARPKD. renal disease manifests as hypertension in first few years of life, diminished urine concentrating ability, and renal insufficiency. growth retardation has been reported in 25%. can progress to renal failure requiring dialysis or transplantation, 5% of ESRD.

Answer 231

nephronophthisis is autosomal recessive and involves several genes with distinct ages of onset and extrarenal manifestations. the most common genetic cause of ESRD in the first 2 decades of life, accounting for 5- 15% of cases of ESRD. medullary cystic kidney disease (MCKD) is autosomal dominant and involves 2 genes with distinct ages of onset. is a rare case presents with ESRD in adulthood. bilateral small kidneys show cortical atrophy with a thickened, pitted, granular, capsular surface. Spherical cysts are located primarily at the corticomedullary junction. 25% of cases do not have grossly visible cysts. Microscopic evaluation demonstrates the cysts lined by single layers of cuboidal epithelium with a thickened basement membrane.

Answer 232

due to mutation in VHL gene on 3p25. incidence of approximately 1 in 39,000 population. phenotype includes retinal and cerebellar hemangioblastomas, pheochromocytomas, and renal cell carcinoma in 40% of patients. two-thirds develop renal cysts, also pancreatic, hepatic and epididymal cysts. multiple renal cysts lined by glycogen-rich cells develop bilaterally in 75% of patients Atypia and epithelial hyperplasia are common in the cysts.

Answer 233

due to mutations in TSC1 on 9q34 and TSC2 on 16p13. TSC2 is adjacent to PKD1. -incidence of 1 in 10,000 to 1 in 50,000 population. phenotype includes facial nevi, cardiac rhabdomyomas, epilepsy, angiofibromas, and mental retardation and multiple renal angiomyolipomas although diffuse renal cystic disease is rare. renal cysts are present in 20-25% of these patients. cysts vary in size from several millimeters to 3 cm lined by large eosinophilic cells with enlarged, hyperchromatic nuclei.

Answer 234

incidence of 1 in 1000 to 1 in 2000 population. the most common cause of an abdominal mass in the newborn period and is the most common cystic malformation of the kidney in infancy. often associated with ureteral or ureteropelvic atresia. the affected kidney is nonfunctional and will involution over time. usually asymptomatic and can remain undetected into adulthood. multicystic dysplastic kidney is abnormally shaped, and often resembles a bunch of grapes. The numerous and irregularly sized, smooth walled cysts range from less than 1 mm to several centimeters in diameter and contain a clear or yellow fluid. Primitive epithelial ducts and nests of metaplastic cartilage are often seen in addition to characteristic fibrovascular structures. associated ureteral or ureteropelvic atresia is always present. MCDK results from an abnormal induction of the metanephric blastema by the ureteral bud. This abnormal induction might be due to a problem with the formation of the mesonephric duct, malformation of the ureteral bud, or degeneration of the ureteral bud at an early stage.

Answer 235

most common kidney tumor at birth to 6 months of age. can be detected on prenatal sonogram (“ring” sign). solitary firm round infiltrating fibrous mass composed of bland spindle cells. more aggressive cellular variant is associated with t(12;15) ETV6-NTRK3 fusion. clinical behavior is generally benign if completely resected.

Answer 236

most common malignant kidney tumor of childhood (80% of pediatric renal tumors). presents between 4-6 years of age as a solitary abdominal mass, “claw” sign on imaging. usually solitary budging tumor with triphasic histology, meaning it is composed of three cell types in varying proportions: stromal (fibroblastic), blastemal (small round blue cells) and epithelial (tubules) components. treated by resection and chemotherapy (before or after). 4% of Wilms tumors have unfavorable histology because of anaplasia (large, hyperchromatic nuclei and multipolar mitoses) indicating resistance to chemotherapy, which results from mutation of TP53. Bilateral Wilms tumor is frequently associated with genetic syndromes (which give insights into its genetic basis) including: beckwith-weidemann syndrome and WAGR.

Answer 237

phenotype includes gigantism, macroglossia and exomphalmos, due to imprinting abnormalities on chromosome 11p15.5; 5-7% develop Wilms tumor as well as other embryonal tumors.

Answer 238

(Wilms tumor, Aniridia, Genitourinary malformation and mental Retardation) deletion of 11p13 including PAX6 (responsible for aniridia and retardation) and WT1 (involved with the development of the genitourinary system); 30% of these patients develop Wilms tumor.