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Cystic Diseases of the Kidney

• Renal cystic diseases are a heterogeneous group of hereditary, developmental, or acquired disorders
• Common disorders frequently cause diagnostic problems and some forms cause chronic renal failure
• They are occasionally mistaken for malignant tumors

Renal Dysplasia

• Renal dysplasia is a sporadic disorder which may be unilateral or bilateral, it is also often cystic
• Unilateral multicystic renal dysplasia is the most common cause of a renal mass in childhood
• Bilateral lesions may appear "in utero" or soon after birth, linking them to oligohydramnios and Potter's syndrome

Macroscopic

• Dysplastic kidneys may be unilateral or bilateral, large or small, reniform or irregular, and solid or cystic

Microscopic

• There is disorganized overall architecture including primitive ducts as well as aberrant glomeruli
• Cysts, immature cartilage, and mesenchymal tissue also are typically apparent

Clinical Outlook

• The clinical outlook depends on the extent of dysplasia

Autosomal Dominant Polycystic Kidney Disease (ADPKD)

• ADPKD is the most common cystic renal disease that has an estimated frequency between 1:500 and 1:1,000
• There's nearly complete penetrance by the 5th decade of life
• In Caucasians, ~85% of cases are related to chromosome 16p defects, which causes a mutation of the PKD-1 gene responsible for encoding polycistin-1
• The remaining ~15% have Chr. 4q mutations in PKD-2 gene, encoding polycystin-2.
• The majority of patients present in the third to fourth decade with dull abdominal pain and palpable kidneys
• Hypertension may be the initial manifestation and flank pain may be due to cyst hemorrhage, cyst infection, and/or renal stones
• Extrarenal manifestations include: polycystic liver disease (75%), mitral valve prolapse (25%), pancreatic cysts (10%), and intracranial berry aneurysms (10-20%)
• Renal failure occurs in 50% of patients, typically appearing ~10 years after diagnosis.
• ~10% of dialysis patients in the U.S. and 6% of renal transplants are accounted for by patients with ADPKD.

Macroscopic

• The kidneys are large, at 250-4000 gms maintaining a somewhat reniform shape
• Variable numbers of spherical, unilocular cysts are present within the cortex and medulla
• The calyces, pelvis and papillae often show great distortion

Microscopic

• Cysts originate from the tubules throughout the nephron, resulting in variable lining epithelia

Autosomal Recessive Polycystic Kidney Disease (ARPKD)

• ARPKD occurs in 1:6,000 to 1:14,000 live births with a 2:1 female predominance.
• There is a genetically homogeneous disease that's linked with defects in chromosome 6p which causes PKHD-1 gene mutations
• PKHD-1 gene encodes a protein named fibrocystin, likely acting as a cell surface receptor and contributing to collecting duct and biliary differentiation
• Many affected newborns have severe disease with an enlarged abdomen, kidneys and signs of oligohydramnios
• In the first few days of life, neonates develop fatal respiratory distress and heart failure
• 30% of older children and adults with ARPKD develop chronic renal failure
• Infancy survivors may develop congenital hepatic fibrosis, portal hypertension, and splenomegaly

Macroscopic

• The renal capsule remains smooth, despite the presence of many small cysts
• On section, the cysts extend radially through the cortex

Microscopic

• The cysts have a uniform cuboidal cell lining reflecting their original location in the collecting tubules

Nephronophthisis (Medullary Cystic Disease)

• Presents primarily as an autosomal recessive hereditary disease
• Cysts arise at the corticomedullary junction
• Several genotypic forms exist due to mutations in proteins like nephrocystin present in the primary cilia or basal bodies
• Familial juvenile nephronophthisis is among the more common variants and accounts for 40-50% of cases
• This disease presents as a renal tubular defect that impairs the concentrating capacity of the kidneys which causes polyuria and polydipsia
• Syndromic variants can also be seen as extrarenal abnormalities such as hepatic fibrosis and retinal degeneration
• It considered the most common genetic cause of end-stage renal disease in children and young adults

Macroscopic

• Symmetrically small kidneys with numerous cysts near the corticomedullary junction are found

Microscopic

• Findings include severe, widespread tubular atrophy and interstitial fibrosis
• Cysts are normally lined by cuboidal to flattened epithelium

Medullary Sponge Kidney

• Characterized by dilated collecting ducts in the renal pyramids
• Usually does not significantly compromise renal function
• The majority of cases appear to be sporadic
• Occasional cases are detected due to complications potentially including hematuria, infections, and/or nephrolithiasis

Acquired Renal Cystic Disease

• Diagnosed commonly in patients undergoing long-term dialysis
• Most cases are asymptomatic
• Painful cyst hemorrhage, retroperitoneal hemorrhage or infection can occur
• The most serious complication is developing renal cell carcinoma over the span of several years, with a ~100-fold increased risk

Simple Cysts

• Incidental autopsy and CT scan findings are common
• Solitary or multiple cysts may occur unilateral or bilaterally
• Cysts may be found anywhere in the kidney, including the cortex and medulla
• Most cysts are asymptomatic and are not associated with significant complications
• Discovery of simple renal cysts is usually related to the need to exclude a renal neoplasm

Renal Vascular Disorders

• The kidneys receive approximately 25% of the cardiac output
• The kidneys can be greatly affected by diseases of the blood vessels

Vacular Diseases of Kidney

• Ischemic renal disease causes a notable reduction in the glomerular filtration rate
• This occurs due to significant renovascular occlusive disease affecting the entire renal parenchyma
• Diseases of the larger arteries include atherosclerosis, etc.
• Smaller arteries and arterioles are commonly affected by hypertension and thromboembolism
• Since arteries in the kidneys are considered to be end-organ type with typically no collateral circulation, sudden occlusion usually causes infarction
• Renal ischemia, due to the narrowing of intrarenal arteries or stenosis of main renal arteries, can activate the renin-angiotensin system
• This system results in increased blood pressure

Essential Hypertension

• This condition is the most common cause of systemic hypertension
• It is divided in mild to moderate, or benign hypertension and severe also known as malignant hypertension
• Benign hypertension is a key risk factor or cerebrovascular accidents, coronary artery disease, myocardial infarction and renal disease
• Malignant hypertension causes pressure exceeding 190/120 also including papilledema, congestive heart failure, stroke, encephalopathy and renal insufficiency

Benign Hypertension

• Normal size to moderately reduced in size and weight kidneys
• Capsular surface is granular
• Thin cortex
• Ischemic nephropathy changes may be present
• Arteries may demonstrate intimal fibroplasia and internal elastic lamina reduplication
• Arteriolosclerosis made of homogeneous eosinophilic material replacing the media of arterioles may occur

Malignant Hypertension

• Cortical surface petechial hemorrhages can be found
• Ischemic nephropathy changes may be present
• Arterial intimal fibroplasia can occur
• Presence of fibrinoid necrosis of arterioles, w/ or w/o necrotizing arteriolitis
• Hyperplastic arteriolitis (onion-skin lesion) of interlobular arterioles and larger arterioles

Renal Artery Stenosis

• Significant cause of secondary hypertension
• Atherosclerosis can cause occlusion of large renal arteries, most often affecting older men.
• Occlusion often involves the proximal renal arteries with 50% of cases originating in the aorta
• Bilateral disease is present in up to 60% of presented cases
• Thromboembolic disease and vasculitis may also occur
• Thrombosis of the main renal arteries, and fibromuscular dysplasia also rarely occurs
• Occurs more often in young women
• Usually causes concentric narrowing of the artery
• Alternating constrictions are aneurysmal dilations may present
• Medial fibroplasia is a more common variant
• Is often found bilaterally and it rarely causes total arterial occlusion

Clinical Course

• Consequences of occlusion depends on vessel size an number
• The consequences that are brought upon by the occlusion are affected be vessel size/ number, rate of closure etc...

Treatment

• If found early, it can be reversed by angioplasty/bypass graft
• In long-standing unilateral renal artery stenosis, stenosis correction might not relieve hypertension

Thrombotic Microangiopathies

• Hemolytic uremic syndrome (HUS) and thrombotic thrombocytopenic purpura (TTP) are closely related entities with almost identical renal pathology
• Distinguishing between these two conditions is not always possible
• Characterized by microangiopathic hemolytic anemia, thrombocytopenia and renal failure
• Disease progression is related to endothelial injury, alongside activated coagulation

Hemolytic Uremic Syndrome

• Occurs mainly in young children and is associated with prodromal Diarrhea
• Most common cases are linked with infection from verotoxin-producing strains of E. coli (0157:H7)
• Diarrhea-negative disease can be classified as sporadic or familial
• Sporadic is associated with endotelial injury and complications (pregnancy, SLE, HIV)
• Familial is linked to mutations in complement regulatory protein factor H

Thrombotic Thrombocytopenic Purpura

• Occurs most commonly in women in the fourth and fifth decades
• Characterized as presents with neurological symptoms (seizures and altered states of consciousness)
• Severe renal damage is very uncommon in patients

Etiologic Classification of the Major Forms of Primary Thrombotic Microangiopathy

• Shiga toxin-mediated HUS - Acquired: Shiga toxin-producing E. coli, Shigella dysenteriae serotype 1.
• Atypical HUS (complement-mediated TMA) - Inherited: Complement dysregulation due to genetic abnormalities and acquired complement dysregulation due to autoantibodies
• TTP - Inherited: Genetic ADAMTS13 deficiency and acquired ADAMTS13 deficiency due to autoantibodies

Treatment and clinical course of Thrombotic Microangiopathies

• Renal function is able to recover in classic HUS cases
• Cases are effectively managed by dialysis
• Plasma can be exchanged and used as a single main treatment
• This is used for TTP, with survival rates are above 80%

Cholesterol Emboli

• The kidneys are the most common organs affected by cholesterol embolization
• These emboli usually occur in older people with atherosclerosis of the thoracic or upper abdominal aorta
• They set in weeks after angiography and cardiovascular surgery or other events
• These effect the smaller arteries and arterioles

Clinical Manifestations

• Renal manifestations are typically accompanied by increased serum BUN and creatinine
• Renal involvement ranges in severity but might be progressive
• Severe renal failure will require the use of dialysis

Renal Cortical Necrosis

• It is an uncommon cause of renal failure that can occur in the setting of severe circulatory failure
• The disease is frequently bilateral
• The most common causes are obstetric complications (placenta abruption or eclampsia)

Clinical Manifestations

• Causes acute renal failure
• Histologic appearance is similar to renal infarction
• Hemodialysis can lead to number of patients surviving, but leave with considerable renal insufficiency

Renal Infarction

• The the most major is linked to embolism (usually on left side of heart)
• The majority of renal infarcts are clinically silent
• Severity affects the size of the vessel, and the resulting amount of renal tissue infarction

Urinary Tract Obstruction and Urolithiasis

• Causes urinary tract obstruction are varied and multiple
• Intrinsic causes are often found that occur (nephrolithiasis, sloughed renal papilla, strictures etc.)
• Among extrinsic causes, carcinoma of the uterine cervix/endometrium, prostatic hyperplasia, tumors, and retroperitoneal fibrosis may occur
• More prevalent in males during childhood, typically due to ureteropelvic and vesicoureteral obstruction
• Between childhood and age 60, it is more common in females, stemming from gynecological pathology
• For individuals after the age of 60, men are at higher risk, due to diseases of prostate

Pathophysiology behind Urinary Tract Obstruction

• Obstruction damages include increased medullar pressure
• Mechanisms: intrarenal reflux of urine; direct medulla blood pressure; and vessel obstruction

Clinical Manifestations of Urinary Tract Obstruction

• Clinical presentation exhibits diversity; indications such loss concentrating, complete obstruction and leading renal failure

Treatment of Urinary Tract Obstruction

• Treatment depends on the primary condition
• Duration is a factor that dictates the degree of recovery

Urolithiasis

• The development is dependent of supersaturation, debris, epithelial casts; absence of stone inhibitors (nephrocalcin)

Three Main Types of Renal Calculi

• ~75% Calcium oxalate
• 10-15% Struvite
• 5-6% Uric acid
• 15% are made of Other substances
• Vast majority are calcium oxalate-based
• Calcium oxalate is associated with hypercalcemia.
• ~ one fifth are associated w/ hyperuricosuria

Struvite Stones

• Composed of magnesium ammonium phosphate stones
• The stones are associated with urease infection (typically proteus)
• Alkaline urine results precipation of magnesium ammonium phosphate salts
• Large staghorn calculi exhibit this stones

Uric Acid Stones

• Patients are neither hyperuricemic/ hyperuricosuric
• Typically, patients have hyperuricemia (gout, rapid cell etc).
• Formation results in excreted urine, ph< 5.5, and insolubility of acidic urine

Clinical features of Urolithiasis

• Renal colic syndrome manifested by flank/groin excruciating pain; nausea/emesis
• Calculi are painless if they remain in the pelvis
• Hematuria is a frequent manifestation

Clinical Course

• Small stones cause complications by the release throughout ureter
• Calculi predispose to infection due to obstruction and trauma

Treatment

• < 5mm stones are spontaneously passed
• < 2cm cases are treated with lithotripsy
• Larger stones require nephrolithotomy