PBL Exam 11 Case 2-2

The tubulointerstitial changes are fairly characteristic.

The Bence Jones tubular casts appear as pink to blue amorphous masses, sometimes concentrically laminated, often w/a fractured appearance, filling and distending the tubular lumens. Some of the casts are surrounded by multinuclear giant cells that are derived from mononuclear phagocytes.

The histologic features of amyloidosis, light chain deposition disease, and nephrocalcinosis and infection may also be present.

In the most common form, chronic renal failure develops and usually progresses slowly during a period of several months to years.

Another form occurs suddenly and is manifested by acute renal failure w/oliguria. Precipitating factors in these patients include dehydration, hypercalcemia, acute infection, and treatment with nephrotoxic antibiotics.

Benign nephrosclerosis is the term used for the renal pathology associated with sclerosis of renal arterioles and small arteries. The resultant effect is focal ischemia of parenchyma supplied by vessels with thickened walls and consequent narrowed lumens.

Some degree of nephrosclerosis is present at autopsy with increasing age, preceding or in the absence of hypertension.

Hypertension and DM, however, increase the incidence and severity of the lesions.

1. Medial and intimal thickening, as a response to hemodynamic changes, aging, genetic defects, or some combination of these

2. Hyaline deposition in arterioles, caused partly by extravasation of plasma proteins through injured endothelium and partly by increased deposition of basement membrane matrix.

In gross appearance, the kidneys are either normal or moderately reduced in size. The cortical surfaces have a fine, even granularity that sesembles grain leather.

On histologic exam, there is narrowing of the lumens of arterioles and small arteries caused by thickening and hyalinization of the wall (hyaline arteriolosclerosis).

Larger muscular arteries show fibroelastic hyperplasia, with both medial and intimal thickening.

The vascular lesions cause diffuse ischemic atrophy of nephrons; as a result, the kidneys are relatively small and exhibit diffuse granular surfaces due to scarring and contraction of individual glomeruli.

There patchy ischemic atrophy consists of (1) foci of tubular atrophy and interstitial fibrosis and (2) a variety of glomerular alterations.

Benign nephrosclerosis rarely causes renal failure, but can cause mild proteinuria.

Three groups of patients are at increased risk of developing renal failure:
1. Blacks
2. Patients with more severe BP elevations
3. Patients with a second underlying disease, especially diabetes

In these groups, renal insufficiency may supervene after prolonged benign hypertension, but more rapid renal failure results from development of the malignant hypertension.

Malignant nephrosclerosis is the form of renal disease associated with the malignant or accelerated phase of hypertension.

Although occasionally developing in previously normotensive people, most cases are superimposed on preexisting benign essential hypertension, chronic renal disease, or scleroderma.

For instance, it is also a frequent cause of death from uremia in patients with scleroderma.

The initial insult appears to be some form of vascular damage to the kidneys. This might result from long-standing benign hypertension, with eventual injury to the arteriolar walls, or the initiating injury may spring de novo from arteritis or a coagulopathy or some injury causing acute exacerbation of the hypertension.

In any case, the result is increased permeability of the small vessels to fibrinogen and other plasma proteins, endothelial injury, focal death of cells of the vascular wall, and platelet deposition.

*This leads to the appearance of fibrinoid necrosis of arterioles and small arteries, swelling of the vascular intima, and intravascular thrombosis.

These changes cause ischemia, with stimulation of the renin-angiotensin and other vasoconstrictive systems, perpetuating an ever-increasing cycle of escalating blood pressures.

Patients with malignant hypertension have markedly elevated levels of plasma renin.

Aldosterone levels are also elevated, and salt retention undoubtedly contributes to the elevation in BP.

The kidney has a "flea bitten" appearance due to small, pinpoint petechial hemorrhages on the cortical surface.

Pathologic changes include fibrinoid necrosis of arterioles, *hyperplastic arteriolopathy* (*onion-skinning*); and necrotizing glomerulitis, and a glomerular thrombotic microangiopathy.

In addition, sometimes the arteriolar and arterial lesions result in considerable narrowing of all vascular lumens, with ischemic atrophy and at time infarction distal to the abnormal vessels.

Patients have a diastolic BP greater than 130 mm Hg, marked proteinuria, hematuria, papilledema, encephalopathy, cardiovascular abnormalities, and eventually renal failure.

There are marked increases in plasma renin, angiotensin, and aldosterone.

With current interventions, about 75% of patients will survive 5 years, and 50% survive with pre-crisis renal function.

Unilateral renal artery stenosis accounts for 2-5% of cases of renal hypertension, resulting from excessive renin secretion by the involved kidney.

*A large proportion of patients with renovascular hypertension have elevated plasma or renal vein pressure levels, and almost all show a reduction of BP when given competitive antagonists of angiotensin II.

The most common cause of renal artery stenosis (70% of cases) is occlusion by an atheromatous plaque at the origin of the renal artery. This lesion occurs more freq in men, and the incidence increases w/advancing age and DM.

The plaque is usually concentrically placed, and superimposed thrombosis often occurs.

The second type of lesion leading to stenosis is so called fibromuscular dysplasia of the renal artery, which is characterized by nonarteriosclerotic intimal, medial, or adventitial thickening. These stenoses, as a whole, are more common in women and then to occur in younger age groups.

The ischemic kidney is usually reduced in size and shows signs of diffuse ischemic atrophy, with crowded glomeruli, atrophic tubules, interstitial fibrosis, and focal inflammatory infiltrates.

The arterioles in the ischemic kidney are usually protected from the effects of high pressure, thus showing only mild arteriolosclerosis. In contrast, the contralateral nonischemic kidney may exhibit more severe arteriolosclerosis, depending on the severity of the hypertension.

On occasion, a bruit can be heard on auscultation of the kidneys.

Elevated plasma or renal vein renin, response to ACE inhibitors, renal scans, and IV pyelography may aid with Dx, but arteriography is required to localize the stenotic lesion.

The cure rate after surgery is 70-80% in well selected cases.

The overlapping symptoms are:
1. Thrombosis in capillaries and arterioles throughout the body
2. Microangiopathic hemolytic anemia
3. Thrombocytopenia
4. Renal failure in certain conditions

1. Classic hemolytic-uremic syndrome (HUS)
2. Adult HUS associated with infection, antiphospholipid antibodies, contraceptives, complications of pregnancy, certain drugs, radiation, and scleroderma.
3. Familial HUS
4. Idiopathic HUS and thrombotic thrombocytocenic purpura (TTP)

(1) Endothelial injury and (2) Intravascular platelet aggregation and coagulation appear to be shared pathogenetic mechanisms.

Both of these events cause vascular obstruction and vasoconstriction and thus precipitate distal ischemia.

They are characterized morphologically by thromboses in the interlobular arteries, afferent arterioles, and glomeruli, together with necrosis and thickening of the vessel walls.

The morphologic changes are similar to those in malignant hypertension, but the changes can precede the development of hypertension or be seen in its absence.

The triggers for endothelial injury and activation can be bacterial endotoxins and cytotoxins, cytokines, viruses, drugs, antiendothelial antibodies, and abnormal multimers or inhibitors of the vWF coagulation factor.

In childhood HUS associated with diarrheal infections, verocytotoxin is clearly the culprit. But in many cases, the proximate endothelial toxin is unknown.

Because many thrombi in HUS/TTP are composed largely of aggregated platelets with scant fibrin, serum factors causing platelet aggregation have been sought.

These include unusually large vWF factor multimers that are secreted by endothelial cells. Normally, they are degraded into smaller multimers by the action of ADAMTS-12, a vWF cleaving metalloprotease.

With congenital or acquired loss of ADAMTS-13 activity, very large vWF multimers persist in the circulation and induce aggregation by activating platelet surface glycoproteins.

This is the most well characterized of the HUS syndromes, since as many as 75% of cases occur in children after intestinal infection with verocytotoxin producing E. coli.

This disease is one of the main causes of acute renal failure in children.

1. Sudden onset, usually after a GI or influenza like prodromal episode
2. Bleeding manifestations (especially hematemesis and melena)
3. Severe oliguria
4. Hematuria
5. Microangiopathic hemolytic anemia
6. In some patients, prominent neurologic change.

Hypertension is present in about half the patients.

The pathogenesis of this syndrome is clearly related to the Shiga-like toxin. The toxin has a variety of effects on endothelium, causing increased adhesion of leukocytes, increased endothelin production and loss of endothelial NO; and in the presence of cytokines, such as TNF, endothelial lysis.

The resultant endothelial effects enhance both thrombosis and vasoconstriction, resulting in the characteristic microangiopathy. Verocytotoxin also binds to platelets and can directly activate them.

In gross appearance, the kidneys may show patchy or diffuse renal cortical necrosis. On micro exam, the glomeruli show thickening and sometimes splitting of capillary walls, due largely to endothelial and subendothelial swelling, and deposits of fibrin-related materials in the capillary lumens, subendothelially, and in the mesangium.

Mesangiolysis is a common finding. Interlobular and afferent arterioles show fibrinoid necrosis and intimal hyperplasia and are often occluded by thrombi.

1. In association with infection, such as typhoid fever, E. coli septicemia, viral infections, and shigellosis.
2. In the antiphospholipid syndrome, either primary or secondary to SLE.
3. Related to complications of pregnancy (placental hemorrhage) or the postpartum period. So called postpartum renal failure usually occurs after an uneventful pregnancy.
4. Associated with vascular renal diseases, such as systemic sclerosis and malignant hypertension.
5. In patients treated with chemotherapeutic and immunosuppressive drugs, such as mitomycin, cyclosporine, bleomycin, cisplatin, and radiation.

So called postpartum renal failure usually occurs after an uneventful pregnancy, 1 day to several months after delivery, and is characterized by microangiopathic hemolytic anemia, oliguria, anuria, and initially mild hypertension.

The condition has a grave prognosis, although recovery can occur in milder cases.

About 5-10% of cases of HUS present with recurrent thromboses, and have a much higher mortality rate (about 50%) than classical childhood HUS (less than 5%).

Most patients with familial HUS have an inherited deficiency of the complement regulatory protein Factor H, which normally breaks down the alternative pathway C3 convertase and protects cells from damage by uncontrolled complement activation.

Idiopathic TTP is manifested by fever, neurologic symptoms, hemolytic anemia, TTP, and the presence of thrombi in glomerular capillaries and afferent arterioles.

It is caused by an acquired or genetic defect in ADAMTS-13, the protease that celaves large vWF multimers.

The abnormal (uncleaved) forms of vWF promote platelet aggregation.

The disease is more common in women and most patients are younger than 40.

Idiopathic TTP and various forms of HUS overlap considerably. In classic TTP, however, CNS involvement is the dominant feature, whereas renal involvement occurs in only about 50% of patients.

In the kidney, eosinophilic granular thrombi are present predominantly in the terminal part of the interlobular arteries, afferent arterioles, and glomerular capillaries.

Other glomerular changes are similar to those described for HUS.

Untreated, the disease was once highly fatal, but exchange transfusions and corticosteroid therapy have reduced mortality to less than 50%.

Bilateral disease, usually diagnosed via arteriography, now appears to be a fairly common cause of chronic ischemia with renal insufficiency in older individuals, sometimes in the absence of hypertension.

The important of recognizing this condition is that surgical revascularization is beneficial in reversing further decline in renal function.

Cholesterol crystals and debris embolize from atheromatous plaques after manipulation of severely disease aortas, usually for repair of aortic aneurysms or during intraaortic cannulation.

They lodge in intrarenal vessels, causing arterial narrowing and focal ischemic injury.

Rarely, renal function becomes compromised.

Sickle cell disease in both the homo- and heterozygous forms may lead to hematuria and a diminished concentrating ability.

These are thought to be due largely to accelerated sickling in the hypertonic hypoxic milieu of the renal medulla, which increases the viscosity of the blood during its passage thru the vasa recta, leading to plugging of vessels and decreased flow.

Patchy papillary necrosis may occur; this is sometimes associated w/cortical scarring.

Proteinuria is also common in sickle cell disease, occurring in about 30% of patients.

This is an uncommon condition that occurs most freq after an obstretic emergency, septic shock, or extensive surgery.

When bilateral and symmetric, it can be fatal in the absence of supportive therapy, but patchy cortical necrosis may permit survival.

The gross alterations of massive ischemic necrosis are sharply limited to the cortex. The histologic appearance is that of acute ischemic infarction. The lesions may be patchy, with areas of coagulative necrosis and apparently better preserved cortex.

Intravascular and intraglomerular thromboses may be prominent but are usually focal, and acute necroses of small arterioles and capillaries may occasionally be present.

Hemorrhages occur into the glomeruli, together with the formation of fibrin plugs in the glomerular capillaries.

The kidneys are favored sites for the development of infarcts.

B/c the arterial supply to the kidney is of the end-organ type, most infarcts of the the "white" anemic type. They may occur as solitary lesions or may be multiple and bilateral.

Within 24 hours, infarcts become sharply demarcated, pale, yellow-white areas that may contain small irregular foci of hemorrhage discoloration. They are usually ringed by a zone of intense hyperemia.

Many renal infarcts are clinically silent. Sometimes, pain with tenderness localized to the costovertebral angle occurs, and this is associated with showers of red cells in the urine.

Large infarcts of one kidney are likely associated with narrowing of the renal artery or one of its major branches, which in turn may be a cause of hypertension.

Obstruction increases susceptibility to infection and to stone formation, and unrelieved obstruction almost always leads to permanent renal atrophy, termed hyponephrosis or obstructive uropathy.

1. Congenital anomalies
2. Urinary calculi
3. BPH
4. Tumors
5. Inflammation
6. Sloughed papillae or blood clots
7. Normal pregnancy
8. Uterine prolapse and cytocele
9. Functional disorders (neurogenic and other functional abnormalities)

Hydronephrosis is the term used to describe dilation of the renal pelvis and calyces associated w/progressive atrophy of the kidney due to obstruction to the outflow of urine.

Obstruction also triggers and interstitial inflammatory reaction, leading eventually to interstitial fibrosis.

When the obstruction is sudden and complete, the reduction of GFR usually leads to only mild dilation fo the pelvis and calyces but only somtimes cause atrophy.

When the obstruction is subtotal or intermittent, GFR is not suppressed, and progressive dilation ensues.

In gross appearance, the kidney may have slight to massive enlargement. The pelvis and calyces may be dilated and there is often interstitial inflammation.

Progressive blunting of the apices of the pyramids occurs, and these eventually become cupped.

In far-advanced cases, the kidney may become transformed into a thin-walled cystic structure having a diameter of up to 15-20 cm with striking parenchyma atrophy, total obliteration of the pyramids, and thinning of the cortex.

Unilateral obstruction may remain silent for long periods of time, since the unaffected kidney can usually compensate to maintain adequate renal function.

In bilateral partial obstruction, the earliest manifestations are inability to concentrate the urine; this is reflected by polyuria and occasionally acquired distal tubular acidosis, salt wasting, renal calculi, tubulointerstitial nephritis, atrophy, and hypertension.

Complete bilateral obstruction is incompatible with long survival unless the obstruction is relieved. Curiously, after relief of complete urinary tract obstruction, postobstructive diuresis occurs.

1. Most stones (about 70% are calcium containing, composed largely of calcium oxalate or calcium oxalate mixed with calcium phosphate
2. Another 15% are so-called triple stones or struvite stones, composed of magnesium ammonium phosphate
3. 5-10% are uric acid stones
4. 1-2% are made up of cystine

The most important determinant is an increased urinary concentration fo the stones' constituents, such that it exceeds their solubility in urine (supersaturation)

A low urine volume in some metabolically normal patients may also favor supersaturation.

These stones are associated in about 5% of pts with both hypercalcemia and hypercalciuria, caused by hyperparathyroidism, diffuse bone disease, sarcoidosis, and other hypercalcemic states.

About 55% have hypercalciuria without hypercalcemia.

Hyperoxaluria (in vegetarians) and hyperuricosuria are associated in others.

Struvite stones are associated with infection by urea-splitting bacteria that convert urea to ammonia.

So-called staghorn calculi are struvite sometimes that are almost always associated with infection.

Uric acid stones are common in pts with a hyperuricemia, such as gout, and diseases involving rapid cell turnover, such as gout, and diseases involving rapid cell turnover, such as the leukemias.

However, more than half of all pts with urate calculi have neither hyperuricemia nor increased urinary excretion of uric acid.

In this group, it is thought that an unexplained tendency to excrete urine of pH below 5.5 may predispose to uric acid stones, b/c uric acid is insoluble in relatively acidic urine.

In contrast to the radio-opaque calcium stones, uric acid stones are radiolucent.

Cystine stones are caused by genetic defects int eh renal reabsorption of AAs, including cystine, leading to cystinuria. Stones form at a low urinary pH.

It has been postulated that stone formation is enhanced by a deficiency in inhibitors of crystal formation in the urine. These include pyrophosphate, diphosphonate, citrate, glycosaminoglycans, osteopontin, and glycoproteins called nephrocalcin.

Stones are unilateral in about 80% of pts. The favored sites for their formation are within the renal calyces and pelves, and in the bladder. If formed in the renal pelvis, they tend to remain small, having an average diameter of 2-3mm. These may have smooth contours or may take the form of an irregular, jagged mass of spicules.

Often, many stones are found w/in one kidney. On occasion, progressive accretion of salts leads to the development of branching structures known as staghorn stones.

Small, discrete, *usually yellow* tumors are seen in 7% to 22% of autopsies.

Histologically, most consist of vacuolated epithelial cells forming tubules and complex branching papillary structures with numerous complex fronds. The cells may be histologically indistinguishable from those of low-grade papillary renal cell CA, and they share some of their cytogenetic features (trisomies 7 and 17).

Most are small (0.5 mm in diameter)

On occasion, at autopsy, small foci of gray-white firm tissue, usually less than 1 cm in diameter, are found w/in the pyramids of the kidneys.

Microscopic exam of these nodules discloses fibroblast-like cells and collagenous tissue. Ultrastructurally, the cells have features of renal interstitial cells. The tumors have no malignant propensities.

The renal cell CA, followed by Wilms tumors, and finally urothelial tumors of the calyces and pelves.

This is a benign tumor consisting of vessels, smooth muscle, and fat.

*Angiomylolipomas are present in 25-50% of patients with tuberous sclerosis, a disease characterized by lesions of the cerebral cortex that produce epilepsy and mental retardation as well as a variety of skin abnormalities.

This is an epithelial tumor composed of large, eosinophilic cells having small, round, benign-appearing nuclei that have large nucleoli. It is thought to arise from the intercalated cells of collecting ducts.

Ultrastructurally, the eosinophilic cells ahve numerous mitochondria. In gross appearance, the tumors are tan or mahogany brown, relatively homogeneous, and usually well encapsulated. They may achieve a size up to 12 cm in diameter.

This tumor is considered benign.

Renal cell CA occur most often in older individuals, usually in the6th and 7th decades of life, showing a male preponderance in the ratio of 2 to 3:1.

B/c of their gross yellow color and the resemblance of the tumor cells to clear cells of the adrenal cortex, they were at one time called hypernephromas. These tumors arise from tubular epithelium and are therefore renal adenocarcinomas.

Tobacco is the most significant risk factor.

Additional risk factors are obesity, hypertension, unopposed estrogen therapy; and exposure to asbestos, petroleum products, and heavy metals.

1. Von Hippel-Lindau (VHL) syndrome
2. Hereditary familial clear cell CA
3. Hereditary papillary CA

Half-to 2/3rds of pts w/VHL, characterized by hemangioblastomas of the cerebellum and retina, develop renal cysts and bilateral, often multiple, renal cell CAs.

Current studies implicate the VHL gene in the development of both familial and sporadic clear cell tumors.

Hereditary papillary CA is an autosomal dominant disease manifested by multiple bilateral tumors w/papillary histology.

These tumors exhibit a series of cytogenetic abnormalities and mutations in the MET protooncogene.

1. Clear cell CA (most common type - 70-80% of cases)
2. Papillary CA (10-15%)
3. Chromophobe renal CA (5%)
4. Collecting duct (Bellini duct) CA (< 1%)

Most common type - 70-80% of cases. On histologic exam, the tumors are made up of cell w/clear or granular cytoplasm and are nonpapillary.

Whether familial, sporadic, or associated with VHL, there is loss of sequences on the short arm of chromosome 3 that harbors VHL, a tumor-suppressor gene. This occurs by deletion or by unbalanced translocation.

The VHL gene encodes a protein that is part of a ubiquitin ligase complex that targets other proteins for degradation. When VHL is mutated, hypoxia-inducible factor-1 (HIF-1) levels remain high, and this increases cell growth and angiogenesis.

Papillary CA (10-15%) is characterized by a papillary growth pattern and also occurs in both familial and sporadic forms.

The gene for the familial form is on chromosome 7; it encompasses the locus for MET, a proto-oncogene that exhibits both germ line and somatic mutations.

A second gene called PRCC on chromosome 1 is implicated in sporadic tumors, largely in children.

Chromophobe renal CA (5%) is composed of cells w/prominent cell membranes and pale eosinophilic cytoplasm, usually with a halo around the nucleus.

Like the benign oncocytoma, they are thought to grow from intercalated cells of collecting ducts.

On cytogenetic exam, these tumors exhibit multiple chromosome losses and extreme hypdiploidy- they have an excellent prognosis.

Collecting duct (Bellini duct) CA (< 1%) arise from collecting duct cells in the medulla.

Histologically, these tumors are characterized by nests of malignant cells enmeshed w/in a prominent fibrotic stoma, typically in a medullary location.

Clear cell CAs are spherical masses, 3-15 cm in diameter, composed of bright yellow yellow-gray-white tissue that distorts the renal outline.

There are large areas of ischemic opaque, gray-white necrosis, foci of hemorrhagic discoloration, and areas of softening.

*Tumors may bulge into the calyces and pelvis, and invade the renal vein to grow as a solid column of cells w/in this vessel.

Papillary carcinomas.

The growth pattern varies from solid to trabecular (cordlike) or tubular. *The tumor cells have a rounded or polygonal shape and abundant clear or granular cytoplasm that contain glycogen and lipids.*

The tumors have delicate branching vasculature and may exhibit cystic as well as solid areas.

Most tumors are well differentiated, but some show marked nuclear atypia with formation of bizarre nuclei and giant cells.

Papillary CA is composed of cuboidal or low columnar cells arranged in papillary formations.

Interstitial foam cells are common in the papillary cores.

Psammoma bodies may be present.

Chromophobe renal CA is made up of pale eosinophilic cells, often w/a perinuclear halo, arranged in solid sheets with a concentration of the largest cells around blood vessels.

Collecting duct CA is a rare variant showing irregular channels lined by highly atypical epithelium with a hobnail pattern.

Sarcomatoid changes arise infrequently in all types of renal cell CA and are a decidedly ominous feature of these tumors.

1. Costovertebral pain
2. Palpable mass
3. Hematuria

*These are seen in only 10% of cases. The most reliable of the three is hematuria but it may be microscopic.

Pts may show hematuria, fever, constitutional symptoms, or a paraneoplastic syndrome (polycythemia, hypercalcemia, hypertension, feminization or masculinization, Cushing syndrome, esoinophilia, leukemoid reaction, and amyloidosis).

Prognosis depends on tumors size and the extend of spread at Dx.

***Renal cell CA has a tendency to metastasize widely before becoming symptomatic*** On average, 45% survive 5 years, and in the absence of metastatic spread at Dx, up to 70% survive 5 years.

About 5-10% of renal tumors occur in the pelvis, where they manifest relatively early either due to hematuria or obstruction and cause flank pain.

Their histologic type is the same as for urothelial tumors in the bladder, ranging from well differentiated papillary lesions to anaplastic invasive CAs.

They are often multifocal, and in 50% of cases there is a synchronous or metachronous bladder tumors. Evidence suggests they are clonal in origin.

*Pts with analgesic nephropathy have an increased risk of urothelial CAs of the renal pelvis and bladder.