Case 1

Question 1

Where do the kidneys lie?

Answer 1

on the posterior wall of the abdomen, outside the peritoneal cavity.

Question 2

Each kidney of the adult human weighs about ____________ and is about the size of the ___________.

Answer 2

Each kidney of the adult human weighs about 150 grams and is about the size of the clenched fist.

Question 3

The medial side of the kidney contains an indented region called the ______ through which passes the renal artery and vein, lymphatics, nerve supply, and ureter.

Answer 3

Hilu

Question 4

If the kidneys are bisected from top to bottom, two major regions can be visualized, the outer ______ and the inner region referred to as the ______.

Answer 4

If the kidneys are bisected from top to bottom, two major regions can be visualized, the outer cortex and the inner region referred to as the medulla.

Question 5

The medulla is divided into multiple coned shaped masses of tissue called:

Answer 5

Renal pyramids

Question 6

The base of each pyramid originates at the border between the cortex and the medulla and terminates in the __________, which projects into the space of the renal pelvis is divided into open-ended pouches called __________, which collect urine from the tubules of each papilla.

Answer 6

The base of each pyramid originates at the border between the cortex and the medulla and terminates in the papilla, which projects into the space of the renal pelvis is divided into open-ended pouches called major calyces, which collect urine from the tubules of each papilla.

Question 7

Each kidney in the human contains about how many nephrons and what is its capability?

Answer 7

1 million nephrons, each capable of forming urine

Question 8

TRUE OR FALSE. The kidney cannot regenerate new nephrons.

Answer 8

True. The kidney cannot regenerate new nephrons. Therefore, with renal injury, disease of normal aging, there is a gradual decrease in nephron number.

Question 9

Each nephron contains:
■ ____________________ through which large amounts of fluid are filtered from the blood
■ _____________ in which the filtered fluid is
converted into urine on its way to the pelvis of the kidney.

Answer 9

Each nephron contains:

■ Tuft of glomerular capillaries called the
glomerulus through which large amounts of fluid are filtered from the blood

■ A long tubule in which the filtered fluid is
converted into urine on its way to the pelvis of the kidney.

Question 10

What contains a network of branching and anastomosing glomerular capillaries that, compared with other capillaries, have higher hydrostatic pressures (about 60 mmhg)?

Answer 10

Glomerulus

Question 11

Covered by epithelial cells, and that the glomerulus is encased in what?

Answer 11

Bowman’s capsule

Question 12

Fluid filtered from the glomerular capillaries flows into the bowman’s capsule and then into the _________, which lies in the cortex of the kidney.

Answer 12

proximal tubule

Question 13

From the proximal tubule, fluid flows into the __________, which dips into the renal medulla.

Answer 13

Loop of Henle

Each loop consists of a descending and ascending limb.

Question 14

The walls of the descending limb and the lower end of the ascending limb are very thin and therefore called the:

Answer 14

thin segment of the Loop of Henle

Question 15

At the end of the thick ascending limb is a short segment, which is actually a plaque in its wall, known as the

Answer 15

Macula densa

Question 16

Beyond the macula densa, fluid enters the distal tubule that, like the proximal tubule, lies in the:

Answer 16

Renal cortex

Question 17

What leads to the cortical collecting duct?

Answer 17

the connecting tubule and the cortical collecting tubule

Question 18

The initial parts of 8 to 10 cortical collecting ducts join to form a single larger collecting duct that runs downward into the medulla and becomes the:

Answer 18

medullary collecting duct

Question 19

The collecting ducts merge to form progressively larger ducts that eventually empty into the

Answer 19

renal pelvis through the tips of the renal papillae

Question 20

In each kidney, there are about __________________, each of which collects urine from about _____________.

Answer 20

In each kidney, there are about 250 of the very large collecting ducts, each of which collects urine from about 4,000 nephrons.

Question 21

Those nephrons that have glomeruli located in the outer cortex are called:

Answer 21

Cortical nephrons; they have short loops of Henle that penetrate only a short distance into the medulla.

Question 22

About 20 to 30 percent of nephrons have glomeruli that lie deep in the renal cortex and are called

Answer 22

Juxtamedullary nephrons

Question 23

These nephrons have long loops of Henle that dip deeply into the medulla, in some cases all the way to the:

Answer 23

tips of the renal papillae

Question 24

The vascular structures supplying the juxtamedullary nephrons also differ from those of the:

Answer 24

cortical nephrons

For the cortical nephrons, the entire tubular system is surrounded by an extensive network of peritubular capillaries.

Question 25

For the juxtamedullary nephrons, long efferent arterioles extend from the glomeruli down into the outer medulla and then divide into specialized peritubular capillaries called the:

Answer 25

vasa recta that extend downward into the medulla, lying side by side with the loops of Henle

Question 26

The vasa recta returns toward the cortex and empties into the:

Answer 26

cortical veins

Question 27

What plays an essential role in the formation of concentrated urine?

Answer 27

This specialized network of capillaries in the medulla, the VASA RECTA.

Question 28

Two human kidneys harbor nearly how much glomerular capillary tufts?

Answer 28

nearly 1.8 million

Question 29

Each glomerular tuft resides within Bowman’s space. The capsule circumscribing the space is lined by:

Answer 29

Parietal epithelial cells
- these transition into tubular epithelia forming the proximal nephron or migrate to replenish podocytes.

Question 30

The glomerular capillary tuft derives from:

Answer 30

an afferent arteriole that forms a branching capillary bed embedded in mesangial matrix

Question 31

This capillary network funnels into an:

Answer 31

efferent arteriole, which passes filtered blood into cortical peritubular capillaries or medullary vasa recta that supply and exchange with a folded tubular architecture.

Hence, the glomerular capillary tuft, fed and drained by arterioles, represents an arteriolar portal system.

Question 32

The glomerular capillaries filter _______ of plasma water containing various solutes for reclamation or discharge by downstream tubules.

Answer 32

120–180 L/d

Question 33

Humans with normal nephrons excrete on average how much albumin?

Answer 33

8–10 mg of albumin in daily voided urine, ~20–60% of total excreted protein

Question 34

Some glomerular diseases result from genetic mutations producing familial disease or a founder effect:

Answer 34

congenital nephrotic syndrome from mutations in NPHS1 (nephrin) and NPHS2 (podocin) affects the slit-pore membrane at birth

TRPC6 cation channel mutations produce focal segmental glomerulosclerosis (FSGS) in adulthood

Question 35

What are major risk for nearly 70% of African Americans with nondiabetic end-stage renal disease (ESRD), particularly FSGS?

Answer 35

Polymorphisms in the gene encoding apolipoprotein L1, APOL1

Question 36

monogenetic causes of FSGS are increasingly linked to early age of onset and to genes encoding type IV collagen in older adults, suggesting that much of FSGS may be what?

Answer 36

Hereditary

Question 37

mutations in control of the complement pathway increasingly associate with various forms of:

Answer 37

membranoproliferative glomerulonephritis (MPGN) and C3 glomerulopathies including dense deposit disease, or atypical hemolytic-uremic syndrome (aHUS)

Question 38

What can cause a metabolic syndrome associated with MPGN?

Answer 38

Type II partial lipodystrophy from mutations in genes encoding lamin A/C or PPARγ

Question 39

What produces split basement membranes with glomerulosclerosis?

Answer 39

Alport’s syndrome, from mutations in the genes encoding for the α3, α4, or α5 chains of type IV collagen

Question 40

Lysosomal storage diseases, such as α-galactosidase, a deficiency causing what?

Answer 40

Fabry’s disease and N-acetylneuraminic acid hydrolase deficiency causing nephrosialidosis, produce FSGS

Question 41

What can produce pressure stress, ischemia, or lipid oxidants that lead to chronic glomerulosclerosis?

Answer 41

Systemic hypertension and atherosclerosis

Question 42

What can quickly complicate glomerulosclerosis with fibrinoid necrosis of arterioles and glomeruli, thrombotic microangiopathy, and acute renal failure?

Answer 42

Malignant hypertension

Question 43

What is an acquired sclerotic injury associated with thickening of the GBM secondary to the long-standing effects of hyperglycemia, advanced glycosylation end products, and reactive oxygen species?

Answer 43

Diabetic nephropathy

Question 44

Most glomerular or mesangial antigens involved in immune-mediated glomerulonephritis are:

Answer 44

Unknown

Question 45

Autoimmune diseases such as idiopathic membranous glomerulonephritis (MGN) or MPGN are confined to the kidney, whereas systemic inflammatory diseases such as lupus nephritis or granulomatosis with polyangiitis spread to the kidney, causing secondary glomerular injury.

Question 46

Antiglomerular basement membrane disease producing Good pasture’s syndrome primarily injures both the:

Answer 46

Lung and kidney

because of the narrow distribution of the α3 NC1 domain of type IV collagen that is the target antigen.

Question 47

Local activation of Toll-like receptors on glomerular cells, deposition of immune complexes, or complement injury to glomerular structures induces mononuclear cell infiltration, which subsequently leads to:

Answer 47

An adaptive immune response attracted to the kidney by local release of chemokines.

Question 48

What are drawn by chemokines into the glomerular tuft, where they react with antigens and epitopes on or near somatic cells or their structures, producing more cytokines and proteases that damage the mesangium, capillaries, and/or the GBM?

Answer 48

Neutrophils, macrophages, and T cells

Question 49

While the adaptive immune response is similar to that of other tissues, ____________ plays an important role in the mechanism of glomerulonephritis.

Answer 49

While the adaptive immune response is similar to that of other tissues, early T-cell activation plays an important role in the mechanism of glomerulonephritis.

Question 50

Antigens presented by _____________ on macrophages and dendritic cells in conjunction with associative recognition molecule engage the CD4/8 T-cell repertoire.

Answer 50

Antigens presented by class II MHC molecules on macrophages and dendritic cells in conjunction with associative recognition molecule engage the CD4/8 T-cell repertoire.

Question 51

What are typically are associated with immune deposits along the GBM, while anti-GBM Ab produce the linear binding of anti-GBM dse?

Answer 51

Poststreptococcal glomerulonephritis, lupus nephritis, and idiopathic membranous nephritis

Question 52

What can precipitate along the subendothelial side of the GBM, while other immune deposits from in situ on the subepithelial side of the GBM?

These latter deposits accumulate when circulating autoantibodies find their antigen trapped along the subepithelial edge of the GBM.

Answer 52

Preformed circulating immune complexes

Question 53

Immune deposits in the glomerular mesangium may result from the:

Answer 53

Deposition of preformed circulating complexes or in situ antigen-antibody interactions.

Question 54

Immune deposits stimulate the release of:

Answer 54

Local proteases and activate the complement cascade, producing C5-9, attack complexes.

Question 55

Local oxidants damage glomerular structures, producing what?

Answer 55

Protenuria and effacement of the podocytes

Question 56

Persistent glomerulonephritis that worsens renal function is always accompanied by:

Answer 56

• interstitial nephritis
• renal fibrosis
• tubular atrophy

Question 57

What is not so obvious, however, is that renal failure in glomerulonephritis best correlates histologically with the:

Answer 57

Appearance of tubulointerstitial nephritis rather than with the type of inciting glomerular injury.

Question 58

Loss of renal function due to interstitial damage is explained hypo- thetically by several mechanisms. The simplest explanation is that urine flow is impeded by tubular obstruction as a result of:

Answer 58

Interstitial inflammation and fibrosis

Question 59

Thus, obstruction of the tubules with debris or by extrinsic compression functionally results in

Answer 59

Aglomerular nephrons

Question 60

A second mechanism suggests that interstitial changes, including

Answer 60

interstitial edema or fibrosis, alter tubular and vascular architecture and thereby compromise the normal tubular transport of solutes and water from tubular lumen to vascular space.

Question 61

This failure increases the solute and water content of the tubule fluid, resulting in

Answer 61

Isosthenuria and polyuria

Question 62

Adaptive mechanisms related to tubuloglomerular feedback also fail, resulting in a

Answer 62

reduction of renin output from the juxtaglomerular apparatus trapped by interstitial inflammation.

Consequently, the local vasoconstrictive influence of angiotensin II on the glomerular arterioles decreases, and filtration drops owing to a generalized decrease in arteriolar tone.

Question 63

A third mechanism involves changes in vascular resistance due to

Answer 63

damage of peritubular capillaries.

The cross-sectional volume of these capillaries is decreased by inter- stitial inflammation, edema, or fibrosis.

Question 64

These structural alterations in vascular resistance affect renal function through two mechanisms:

Answer 64

First, tubular cells are very metabolically active, and as a result, decreased perfusion leads to tubular ischemic injury.

Second, impair- ment of glomerular arteriolar outflow leads to increased intravascular hypertension in less-involved glomeruli; this selective intraglomerular hypertension aggravates and extends mesangial sclerosis and glomerulo- sclerosis to less-involved glomeruli.

Regardless of the exact mechanism, early acute tubulointerstitial nephritis (see Fig. A4-27) suggests poten- tially recoverable renal function, whereas the development of chronic interstitial fibrosis prognosticates permanent loss (see Fig. A4-30).

Question 65

Persistent damage to glomerular capillaries spreads to the tubu- lointerstitium in association with proteinuria. There is a hypothesis that efferent arterioles leading from inflamed glomeruli carry for- ward inflammatory mediators, which induces downstream interstitial nephritis, resulting in fibrosis. Glomerular filtrate from injured glo- merular capillaries adherent to Bowman’s capsule may also be misdi- rected to the periglomerular interstitium. Most nephrologists believe, however, that proteinuric glomerular filtrate forming tubular fluid is the primary route to downstream tubulointerstitial injury, although none of these hypotheses are mutually exclusive.

Answer 65

The simplest explanation for the effect of proteinuria on the development of interstitial nephritis is that increasingly severe proteinuria, carrying activated cytokines and lipoproteins producing reactive oxygen species, triggers a downstream inflammatory cascade in and around epithelial cells lining the tubular nephron. These effects induce T lymphocyte and macrophage infiltrates in the interstitial spaces along with fibrosis and tubular atrophy.

Tubules disaggregate following direct damage to their basement membranes, leading to more interstitial fibroblasts and fibrosis at the site of injury; recent comprehensive evidence suggests that renal fibroblasts increase through several mechanisms: epithelial or endothe- lial-mesenchymal transitions (15%), bone marrow–derived fibrocytes (35%), and the proliferation of resident fibroblasts (50%). Transform- Disorders of the Kidney and Urinary Tract
ing growth factor β (TGF-β), fibroblast growth factor 2 (FGF-2), hypoxemia-inducible factor 1α (HIF-1α), and platelet-derived growth factor (PDGF) are particularly active in this transition. With persistent nephritis, fibroblasts multiply and lay down tenascin and a fibronectin scaffold for the polymerization of new interstitial collagen types I/III. These events form scar tissue through a process called fibrogenesis. In experimental studies, bone morphogenetic protein 7 and hepatocyte growth factor can reverse early fibrogenesis and preserve tubular archi- tecture. When fibroblasts outdistance their survival factors, apoptosis occurs, and the permanent renal scar becomes acellular, leading to irreversible renal failure.

Question 66

APPROACH TO THE PATIENT
Glomerular disease

Answer 66

HEMATURIA, PROTEINURIA, AND PYURIA
Patients with glomerular disease usually have some hematuria with varying degrees of proteinuria. Hematuria is typically asymp- tomatic. As few as 3–5 red blood cells in the spun sediment from first-voided morning urine is suspicious. The diagnosis of glom- erular injury can be delayed because patients will not realize they have microscopic hematuria, and only rarely with the exception of IgA nephropathy and sickle cell disease is gross hematuria present. When working up microscopic hematuria, perhaps accompanied by minimal proteinuria (<500 mg/24 h), it is important to exclude anatomic lesions, such as malignancy of the urinary tract, partic- ularly in older men. Microscopic hematuria may also appear with the onset of benign prostatic hypertrophy, interstitial nephritis, papillary necrosis, hypercalciuria, renal stones, cystic kidney dis- eases, or renal vascular injury. However, when red blood cell casts (see Fig. A4-34) or dysmorphic red blood cells are found in the sediment, glomerulonephritis is likely. A mean of 8–10 mg/24 h of albumin appears in the urine in the absence of kidney disease. In early nephropathy, such as in diabetic nephropathy, proteinuria increases to 30–300 mg/24 h and is called microalbuminuria and represents the presence of renal disease. Greater than 300 mg/24 h of albuminuria represents frank proteinuria and more advanced renal disease (Table 314-1).

Sustained proteinuria >1–2 g/24 h is also commonly associated with glomerular disease. Patients often will not know they have proteinuria unless they become edematous or notice foaming urine on voiding. Sustained proteinuria has to be distinguished from lesser amounts of so-called benign proteinuria in the normal popu- lation. (Table 314-1). This latter class of proteinuria is nonsustained, generally <1 g/24 h, and is sometimes called functional or transient proteinuria. Fever, exercise, obesity, sleep apnea, emotional stress, and congestive heart failure can explain transient proteinuria. Proteinuria only seen with upright posture is called orthostatic proteinuria and has a benign prognosis. Isolated proteinuria sustained over multiple clinic visits is found in many glomerular lesions. Proteinuria in most adults with glomerular disease is nonselective, containing albumin and a mixture of other serum proteins, whereas in children with minimal change disease (MCD), the proteinuria is selective and composed largely of albumin.

Some patients with inflammatory glomerular disease, such as acute poststreptococcal glomerulonephritis or MPGN, have pyuria characterized by the presence of considerable numbers of leuko- cytes. This latter finding has to be distinguished from urine infected with bacteria.

CLINICAL SYNDROMES
Various forms of glomerular injury can also be parsed into sev- eral distinct syndromes on clinical grounds (Table 314-2). These syndromes, however, are not always mutually exclusive. There is an acute nephritic syndrome producing 1–2 g/24 h of proteinuria, hematuria with red blood cell casts, pyuria, hypertension, fluid retention, and a rise in serum creatinine associated with a reduc- tion in glomerular filtration. If glomerular inflammation devel- ops slowly, the serum creatinine will rise gradually over many weeks, but if the serum creatinine rises quickly, particularly over a few days, acute nephritis is sometimes called rapidly progres- sive glomerulonephritis (RPGN); the histopathologic term crescentic glomerulonephritis is the pathologic equivalent of the clinical presentation of RPGN. When patients with RPGN present with lung hemorrhage from Goodpasture’s syndrome, antineutrophil cytoplasmic antibody (ANCA)–associated small-vessel vasculitis, lupus erythematosus, or cryoglobulinemia, they are often diag- nosed as having a pulmonary-renal syndrome. Nephrotic syndrome describes the onset of heavy proteinuria (>3.0 g/24 h), hypertension, hypercholesterolemia, hypoalbuminemia, edema/anasarca, and microscopic hematuria; if only large amounts of proteinuria are present without clinical manifestations, the condition is sometimes called nephrotic-range proteinuria. The glomerular filtration rate (GFR) in these patients may initially be normal or, rarely, higher than normal, but with persistent hyperfiltration and continued nephron loss, it typically declines over months to years. Patients with a basement membrane syndrome either have genetically abnormal basement membranes (Alport’s syndrome) or an autoimmune response to basement membrane collagen IV (Goodpasture’s syndrome) associated with microscopic hematuria, mild to heavy proteinuria, and hypertension with variable elevations in serum creatinine. Glomerular-vascular syndrome describes patients with vascular injury producing hematuria and moderate proteinuria. Affected individuals can have vasculitis, thrombotic microangiopathy, antiphospholipid syndrome, or, more commonly, a systemic disease such as atherosclerosis, cholesterol emboli, hypertension, sickle cell anemia, and autoimmunity. Infectious disease–associated syndrome is most important if one has a global perspective. Save for subacute bacterial endocarditis (SBE) in the Western Hemisphere, malaria and schistosomiasis may be the most common causes of glomerulonephritis throughout the world, closely followed by HIV and chronic hepatitis B and C. These infectious diseases produce a variety of inflammatory reactions in glomerular capillaries, ranging from nephrotic syndrome to acute nephritic injury, and urinalyses that demonstrate a combination of hematuria and proteinuria.

These six general categories of syndromes are usually determined at the bedside with the help of a history and physical examination, blood chemistries, renal ultrasound, and urinalysis. These initial studies help frame further diagnostic workup that typically involves testing of the serum for the presence of various proteins (HIV and hepatitis B and C antigens) or antibodies (anti-GBM, antiphospho- lipid, antistreptolysin O [ASO], PLA2R, THSD7A, anti-DNAse, antihyaluronidase, ANCA, anti-DNA, cryoglobulins, anti-HIV, and anti-hepatitis B and C antibodies) or depletion of complement com- ponents (C3 and C4). The bedside history and physical examination can also help determine whether the glomerulonephritis is isolated to the kidney (primary glomerulonephritis) or is part of a systemic disease (secondary glomerulonephritis).
When confronted with an abnormal urinalysis and elevated serum creatinine, with or without edema or congestive heart fail- ure, one must consider whether the glomerulonephritis is acute or chronic. This assessment is best made by careful history (last known urinalysis or serum creatinine during pregnancy or insurance physical, evidence of infection, or use of medication or recreational drugs), the size of the kidneys on renal ultrasound examination, and how the patient feels at presentation. Chronic glomerular dis- ease often presents with decreased kidney size. Patients who quickly develop renal failure are fatigued and weak and often have uremic symptoms associated with nausea, vomiting, fluid retention, and somnolence. Primary glomerulonephritis presenting with renal failure that has progressed slowly, however, can be remarkably asymptomatic, as are patients with acute glomerulonephritis with- out much loss in renal function. Once this initial information is collected, selected patients who are clinically stable, have adequate blood clotting parameters, and are willing and able to receive treat- ment are encouraged to have a renal biopsy.

Question 67

RENAL PATHOLOGY

Answer 67

A renal biopsy in the setting of glomerulonephritis quickly identifies the type of glomerular injury and often suggests a course of treatment. The biopsy is processed for light microscopy using stains for hematoxylin and eosin (H&E) to assess cellularity and architecture, periodic acid–Schiff (PAS) to stain carbohydrate moieties in the membranes of the glomer- ular tuft and tubules, Jones-methenamine silver to enhance basement membrane structure, Congo red for amyloid deposits, and Masson’s trichrome to identify collagen deposition and assess the degree of glomerulosclerosis and interstitial fibrosis. Biopsies are also processed for direct immunofluorescence using conjugated antibodies against IgG, IgM, and IgA to detect the presence of “lumpy-bumpy” immune deposits or “linear” IgG or IgA antibodies bound to GBM, antibodies against trapped complement proteins (C3 and C4), or specific anti- bodies against a relevant antigen (PLA2R, THSD7A, and DNAJB9). High-resolution electron microscopy can clarify the principal location of immune deposits and the status of the basement membrane.
Each region of a renal biopsy is assessed separately. By light micros- copy, glomeruli (ideally 20) are reviewed individually for discrete lesions; <50% involvement is considered focal, and >50% is diffuse. Injury in each glomerular tuft can be segmental, involving a portion of the tuft, or global, involving most of the glomerulus. Glomeruli having proliferative characteristics show increased cellularity. When cells in the capillary tuft proliferate, it is called endocapillary, and when cellular proliferation extends into Bowman’s space, it is called extracapillary. Synechiae are formed when epithelial podocytes attach to Bowman’s capsule in the setting of glomerular injury; crescents, which in some cases may be the extension of synechiae, develop when fibrocellular/ fibrin collections fill all or part of Bowman’s space; and sclerotic glo- meruli show acellular, amorphous accumulations of proteinaceous material throughout the tuft with loss of functional capillaries and normal mesangium. Since age-related glomerulosclerosis is common in adults, one can estimate the background percentage of sclerosis by dividing the patient’s age in half and subtracting 10. Immunofluores- cent and electron microscopy can detect the presence and location of subepithelial, subendothelial, or mesangial immune deposits, or redu- plication or splitting of the basement membrane. In the other regions of the biopsy, the vasculature surrounding glomeruli and tubules can show angiopathy, vasculitis, the presence of fibrils, or thrombi. The tubules can be assessed for adjacency to one another; separation can be the result of edema, tubular dropout, or collagen deposition resulting from interstitial fibrosis. Interstitial fibrosis is an ominous sign of irre- versibility and progression to renal failure.

Question 68

producing 1—2 g/24 h of proteinuria, hematuria with red blood cell casts, pyuria, hypertension, fluid retention, and a rise in serum creatinine associated with a reduction in glomerular filtration

Answer 68

Acute nephritic syndrome

Question 69

describes the onset of heavy proteinuria (>3.0 g/24 h), hypertension, hypercholesterolemia, hypoalbuminemia, edema/anasarca, and microscopic hematuria; if only large amounts of proteinuria are present without clinical manifestations, the condition is sometimes called nephrotic-range proteinuria. (Harrisson’s Internal Medicine 18 ed.)

Answer 69

Nephrotic syndrome

Question 70

DIFFERENT TREATMENT MODALITIES FOR ACUTE GLOMERULONEPHRITIS

● Treatment involves specific pharmacologic and supportive therapy to prevent and/or treat the sequelae, such as edema, hypertension, and progression of renal disease.

Answer 70

ANTIBIOTICS THERAPY
- Penicillin

NONSELECTIVE BETA-BLOCKER WITH CARDIOSELECTIVE ALPHA1 BLOCKER
- Labetalol

LOOP DIURETICS
- Furosemide (Lasix)

CORTICOSTEROIDS
- Methylprednisolone

ANTINEOPLASTICS AND IMMUNOSUPPRESSANTS
- Cyclophosphamide

Question 71

ANTIBIOTICS THERAPY

Answer 71

● Antibiotic Therapy must cover all likely pathogens in the context of the clinical setting.

● Penicillin is the DOC in treating acute glomerulonephritis of a post streptococcal group A beta-hemolytic etiology.

● Derivative of 6-aminopenicillanic acid with a beta-lactam ring structure essential for bactericidal activity. Inhibits enzymes and cell wall receptors, resulting in cell wall synthesis inhibition.

● Other autolytics enzymes also are activated, degrading the bacterial cell wall.

● Bacterial resistance via beta-lactamase can be prevented with addition of clavulanic acid, sulbactam, or tazobactam.

● Other forms of bacterial resistance include alteration of bacterial PBPs and decreased permeability of cell wall to penicillin.

● Adult Dose 500 mg PO q6h
● Pediatric Dose <12 years: 40 mg/kg/d PO divided
q4-6h; not to exceed adult dose
● >12 years: Administer as in adults

● Contraindications documented:
○ Hypersensitivity;
○ Renal function impairment;
○ Bleeding disorder, Congestive heart failure;
○ Cystic fibrosis;
○ GI disease or antibiotic-associated colitis;
○ Mononucleosis
○ Interactions Probenecid may increase effectiveness
by decreasing clearance;
○ Tetracyclines are bacteriostatic, causing decrease in effectiveness of penicillins when administered concurrently

Question 72

NONSELECTIVE BETA-BLOCKER WITH CARDIOSELECTIVE ALPHA1 BLOCKER

Answer 72

● Labetalol is used for hypertensive encephalopathy and malignant hypertension.

● Drug Name Has nonselective beta-antagonist and cardioselective alpha1 antagonist effects. Beta-blocking effects predominate, particularly when used IV.

● Low lipid solubility means bioavailability is reduced by first pass metabolism and enhanced by coadministration of food.

● Drug is not removed by hemodialysis.

● Adult Dose 20 mg (0.25 mg/kg for 80-kg patient) IV microdrip labetalol hydrochloride injection slowly over 2 min; desired BP may be achieved with continued injections of 40-80 mg at 10-min intervals or until 300 mg has been administered prn; to reduce possibility of postural hypotension, patients should remain supine for 3 h after administration.

● Pediatric Dose - Not established
● Suggested dose: 0.4-1 mg/kg/h IV, not to exceed 3 mg/kg/h.

● Contraindications Documented
○ Hypersensitivity;
○ Cardiogenic atrioventricular block;
○ Uncompensated congestive heart failure;
○ Pulmonary edema;
○ Bradycardia;
○ Reactive airway disease;
○ Severe bradycardia
○ Interactions Decreases effect of diuretics and
increases toxicity of methotrexate, lithium, and
salicylates;
○ May diminish reflex tachycardia, resulting from
nitroglycerin use, without interfering with hypotensive effects;
○ Cimetidine may increase labetalol blood levels;
○ Glutethimide may decrease labetalol effects by inducing microsomal enzymes.

● Precautions: Caution in impaired hepatic function; discontinue therapy if signs of liver dysfunction; in elderly patients, lower response rate and higher incidence of toxicity may be observed

Question 73

LOOP DIURETICS

Answer 73

● Used for hypertensive encephalopathy with CNS signs and circulatory congestion or pulmonary edema.

● Furosemide is DOC for this — Inhibits resorption of sodium indication.

● Drug Name Furosemide (Lasix) and water in ascending limb of loop of Henle by interfering with Na+/K+/Cl- channel.

● An antihypercalcemic effect is mediated by an increased excretion of calcium.

● Plasma volume, blood pressure, and cardiac output are reduced Calcium excretion is increased.

● Absorption of oral furosemide is reduced with renal disease or nephrotic syndrome as a result of edematous bowel.

● Parenteral administration may be indicated in patients with compromised kidneys; metabolized by hepatic biotransformation and renal excretion; onset of action is 20-60 min PO and 5 min

● Adult Dose 20-80 mg PO/IV once initially, followed by once qd, or once qd after titrating for optimum efficacy, or by dividing daily dose bid/tid

● Pediatric Dose Initially: 2 mg/kg PO/IV once; titrate with additional 1-2 mg/kg q6h.

● Contraindications documented:
○ Hypersensitivity
○ Hepatic coma, anuria
○ Renal function impairment
○ Diabetes mellitus, gout
○ MI
○ Pancreatitis;
○ State of severe electrolyte depletion
○ Interactions Metformin decreases furosemide
concentrations;
○ Furosemide interferes with hypoglycemic effect of antidiabetic agents and antagonizes muscle-relaxing effect of tubocurarine;
○ Auditory toxicity appears to be increased with coadministration of aminoglycosides and furosemide (hearing loss of varying degrees may occur);
○ Anticoagulant activity of warfarin may be enhanced when taken concurrently;
○ Increased plasma lithium levels and toxicity are
possible when taken concurrently.

● Precautions: Perform frequent serum electrolyte, carbon dioxide, glucose, creatinine, uric acid, calcium, and BUN determinations during first few months of therapy and periodically thereafter

Question 74

CORTICOSTEROIDS

Answer 74

● Methylprednisolone is used for non-streptococcal etiologies of acute glomerulonephritis, particularly in lupus nephritis and in idiopathic progressive glomerulonephritis.

● Drug Name **Methylprednisolone (Medrol) - Has anti-inflammatory effect and immunosuppressive.

● Metabolized by hepatic transformation and renal excretion.

● Adult Dose Pulse therapy of 30 mg/kg IV over a minimum of 30 min.

● Pediatric Dose - Administered as in adults

● Contraindications documented:
○ hypersensitivity;
○ Viral, fungal, or tubercular skin infections
○ Interactions Coadministration with digoxin may
increase digitalis toxicity secondary to hypokalemia;
○ Estrogens may increase levels of methylprednisolone,
phenobarbital, phenytoin, and
○ Rifampin may decrease levels of methylprednisolone (adjust dose);
○ Monitor patients for hypokalemia when taking
medication concurrently with diuretics.

● Precautions
Adverse effects include allergy, cataracts,
Cushing syndrome, severe acne, GI irritation, and pancreatitis Hyperglycemia, edema, osteonecrosis, peptic ulcer disease, hypokalemia, osteoporosis, euphoria, psychosis, growth suppression, myopathy, and infections are possible complications of glucocorticoid use

Question 75

ANTINEOPLASTICS AND IMMUNOSUPPRESSANTS

Answer 75

● Cyclophosphamide is used for etiology-dependent treatment of acute glomerulonephritis due to Wegener Neosar, granulomatosis.

● Drug Name Cyclophosphamide (Cytoxan, Procytox) — Acts as an alkylating agent that cross-links strands of DNA and RNA.

● Other actions include inhibition of protein synthesis, immunosuppression, and cholinesterase inhibition. Not within the scope of ED care.

● Adult Dose For long-term therapy, the following doses are used: 400-1800 mg/m2 (30-40 mg/kg) IV in divided doses over 2-5 d; may repeat at 2- to 4-wk intervals; alternatively, 10-15 mg/kg IV q7-10d or 3-5 mg/kg twice weekly

● Pediatric Dose Long-term therapy: Administer as in adults

● Contraindications documented:
○ hypersensitivity;
○ Severely depressed bone marrow function
○ Interactions Allopurinol may increase risk of bleeding or infection and enhance myelosuppressive effects;
○ May potentiate doxorubicin-induced cardiotoxicity
○ May reduce digoxin serum levels and antimicrobial effects of quinolones
○ Chloramphenicol may increase half-life while decreasing metabolite concentrations;
○ May increase effect of anticoagulants;
○ Coadministration with high doses of phenobarbital may increase rate of metabolism and leukopenic activity;
○ Thiazide diuretics may prolong
cyclophosphamide-induced leukopenia and neuromuscular blockade by inhibiting cholinesterase activity.

● Pregnancy D - Unsafe in pregnancy.

● Precautions
Regularly examine hematologic profile (particularly neutrophils and platelets) to monitor for hematopoietic suppression; regularly examine urine for RBCs, which may precede hemorrhagic cystitis

Question 76

COMPLICATIONS OF GLOMERULONEPHRITIS

Answer 76

● Progression to sclerosis is rare in the typical patient; however, in 0.5-2% of patients with acute glomerulonephritis, the course progresses toward renal failure, resulting in kidney death in a short period.

● Abnormal urinalysis may persist for years (microhematuria). Marked decline in glomerular filtration rate is rare.

● Other complications, resulting in relevant end-organ damage in the central nervous and cardiopulmonary systems, can develop in patients who present with severe hypertension, encephalopathy, and pulmonary edema.

● Those complications include the following:
○ Hypertensive retinopathy
○ Hypertensive encephalopathy
○ Rapidly progressive glomerulonephritis
○ Chronic renal failure
○ Nephrotic syndrome