9/22- Cases: Diabetic NP, Focal Segmental Glomerulonephritis, and Malignant HTN

Question 1

Case)

• A 54 year-old woman presented with peripheral edema

Laboratory tests:

• Serum creatinine of 1.8 mg/dl
• 24 hour protein excretion of 4.1 grams
• The serum creatinine was 1.5 mg/dl and the 24-hour protein excretion was 1.3 grams 6 months previously

PMH:

• The patient had adult-onset diabetes diagnosed about 5 years ago. The diabetes was reported to be well controlled. There was no retinopathy
• Serologic tests for hepatitis C viral infection was positive; but other serologic tests were negative.
• A renal biopsy was performed.

What renal syndrome is this? Possible causes?

Answer 1

NEPHROTIC syndrome

• Proteinuria > 3.5 g/day
• Peripheral edema

Possible causes (in adults):

• Idiopathic focal segmental glomerulosclerosis
• Membranous glomerulopathy
• Diabetic nephropathy
• Amyloidosis

Question 2

Why is renal biopsy needed in this pt?

Answer 2

Patient may have diabetic nephropathy or Hep C related glomerulonephritis

• Clinical features can’t distinguish and treatments are very different

Question 3

What do you see in this renal biopsy?

Answer 3

Diabetic nephropathy

• Glomerulus characterized by diffuse and nodular enlargement of mesangial areas
• There is diffuse and uniform thickening of the GBM, and thickening of tubular BM
• Some glomeruli are completely sclerosed
• This biopsy clearly shows features of diabetic nephropathy and rules out the possibility of Hepatitis C-related glomerulonephritis (see following images)

Question 4

What is seen here?

Answer 4

Diabetic nephropathy

• A glomerulus with predominantly nodular mesangial enlargement (Kimmelstiel Wilson)

Question 5

What is seen here?

Answer 5

Diabetic nephropathy:

• A glomerulus characterized by diffuse enlargement of mesangial areas
• There is also diffuse thickening of the glomerular basement membranes
• Arteriolar changes are also seen (*)

Question 6

What is seen here?

Answer 6

Diabetic nephropathy

• Global glomerular sclerosis
• Thickening of the tubular basement membranes (arrows).

Question 7

What do you see in EM in diabetic nephropathy?

Answer 7

Thickening of glomerular basement membranes and foot process effacement

Question 8

How do the renal biopsy findings guide therapy?

What is the treatment for:

• Hep C related GN
• Diabetic nephropathy

Answer 8

• If the patient had Hepatitis C-related glomerulonephritis, antiviral therapy including alpha interferon is indicated.
• Treatment for diabetic nephropathy is quite different and includes control of diabetes, control of hypertension, and pharmacologic blocking of the renin-angiotensin system

Question 9

Case 2)

• A 24 year-old woman presented to her primary care physician seeking referral to a bariatric surgeon for a gastric bypass procedure.
• Physical examination revealed a normotensive obese female (BMI 44) with acanthosis nigricans

Labs:

• Abnormal lipid and liver function tests
• Serum creatinine was normal but urinalysis was abnormal with 2+ proteinuria and 24 hour protein excretion of 1.4 grams
• Liver biopsy findings were consistent with non-alcoholic steatohepatitis
• The renal biopsy findings are provided.

What syndrome is this?

Answer 9

This is NOT nephrotic syndrome

• Proteinuria is under 3.5 g/day and no peripheral edema

Her “abnormal” lipid studies (likely elevated triglycerides and low HDL), skin findings, and liver biopsy results suggest metabolic syndrome (insulin resistance syndrome).

Question 10

What is shown in this LM of renal biopsy in this (case 2) pt?

Answer 10

• Glomerular enlargement (compare the diameters of both glomeruli)
• Tubules and vessels appear normal here (H&E stain)

Question 11

What is seen here?

Answer 11

Focal Segmental Glomerulosclerosis

• Size variation persists but there are also segmental regions of tuft agglutination or scarring (*)
• Tubules and vessels still appear normal (PAS stain)

Question 12

What is seen here?

Answer 12

Focal Segmental Glomerulosclerosis

• Segmental sclerosis (*)
• Focal tubular atrophy (arrow) with normal vessel. (PAS stain)

Question 13

What is seen here?

Answer 13

• In addition to segmental regions of tuft agglutination or scarring (*) there are now collections of atrophic tubules (arrow). (PAS stain)

Question 14

What is more predictive of ESRF: glomeruli or tubule damage?

Answer 14

Tubules?

Question 15

What is seen in EM of renal biopsy in Focal Segmental Glomerulosclerosis? What does this signify?

Answer 15

• Visceral epithelial cell foot processes are preserved in this case (big dense dark spots are RBCs here)
• This suggests the injury is a secondary FSGS rather than primary or idiopathic FSGS (which can also present as asymptomatic proteinuria)

Treatment varies between the two types.

Question 16

What are the two types of FSGS?

Answer 16

1. Primary/Idiopathic
2. Secondary FSGS

Question 17

What is the proposed pathogenesis of secondary FSGS?

Answer 17

“Adaptive” or “hyper-filtering” FSGS

• In obesity there is increased glomerular perfusion and filtration with increased glomerular pressure leading to stretching of the capillary wall and injury to all glomerular compartments
• Endocrine changes (RAS, insulin induced growth factors) also contribute.
• The most common cause of secondary FSGS is obesity (sometimes called obesity related glomerulopathy or nephropathy).

Question 18

What are 3 other scenarios (non obesity/diabetes) that may result in diagnosis of secondary FSGS?

Answer 18

1. Decreased nephron mass due to surgical resections (such as prior nephrectomy for cancer)
2. Impaired nephron development (such as pre-term or low birthweight infants)
3. Progressive impairment due to prior glomerular injury ( such as prior injury from glomerulonephritis)

Question 19

Case 3)

• 65 year-old woman presented to the ER with abdominal pain and vomiting for several months
• In the ER she becomes lethargic and unresponsive
• Her examination is significant for a blood pressure of 270/170 mmHg

Labs:

• BUN 82 and Cr 5.7 mg/dL.
• Urinalysis contains 4+ protein and blood.
• The patient is anemic and thrombocytopenic with a normal ADAMTS13 level

. - EKG changes were consistent with chronic hypertension.

Per family members the patient has had high blood pressure for a long time but isn’t on any anti-hypertensive medications.

• Proteinuria was found one year ago at an ER visit but she had no further work up.
• A renal biopsy was performed

What renal syndrome is this? Possible causes?

Answer 19

Acute renal failure

• It is important to recognize that before the development of acute renal failure, there were already baseline renal abnormalities (previous history of proteinuria) probably related to an underlying hypertensive nephrosclerosis (EKG changes, history of long standing untreated hypertension).
• Acute renal failure developed from the background of impaired renal function in this patient (acute on chronic renal failure)

Possible causes of ARF may be pre-renal, renal, or post-renal

• Renal causes: mainly related to severe involvement of one of the 3 main renal compartments (i.e. glomerular, tubulointerstitial, or vascular)
• Other diseases can present with neurologic changes, renal failure, anemia, and thrombocytopenia (including HUS and TTP)

Question 20

What does this renal biopsy show?

Answer 20

(Inset = normal)

• Vascular changes consistent with malignant hypertension: thrombosed and thickened vessels; chronic changes (no blood flow)
• The background kidney is end-stage
• The etiology of the chronic renal injury is unclear but may be related to untreated chronic hypertension
• The kidney is too far gone at this point to identify the etiology of underlying renal disease, though no immune complexes were identified (see following images).

Question 21

What is seen here?

Answer 21

• Tortuous arteriole with intimal thickening and pink smudging of vessel wall (arrows) characteristic of fibrinoid necrosis.
• Fibrinoid is red on trichrome staining (green background
• Green = collagen; fibrin = red

Question 22

What is seen here?

Answer 22

An arteriole showing fibrin thrombus (t) and marked intimal thickening (i). A barely discernible sclerotic glomerulus (G) is present.

• Hot pink = thrombus

Question 23

What is seen here?

Answer 23

Involuting glomerular tuft with tubular atrophy and interstitial fibrosis (long standing chronic renal disease). Thrombosed arterioles (arrow).

Question 24

What is seen here?

Answer 24

Shriveled glomerular tuft with wrinkled GBMs and areas of reduplication (arrow)

• Can see “tram-tracking”: black depositions running side by side (something is splitting the membrane)

Question 25

What is seen here?

Answer 25

Electron microscopy shows subendothelial electron lucent areas (**)

• “subendothelial lucency”- seen in microangiopathic disease (?)
• RBCs stuck outside the lumen

Question 26

What is seen here?

Answer 26

Electron microscopy shows subendothelial electron lucent areas (**).

Trapped red blood cells (*) contribute to schistocytes and hemolysis seen in thrombotic microangiopathies. No immune deposits.

Question 27

Based on the previous pictures, what is the diagnosis?

Answer 27

Malignant nephrosclerosis in a background of chronic renal disease

Question 28

What is the underlying disease process in malignant nephrosclerosis and how does it happen?

Answer 28

• Malignant hypertension may be primary (previously normal blood pressure) or secondary (chronic hypertension)
• The high pressure injures the endothelium of the vessels, forcing plasma proteins into the vessel wall and activating the coagulation cascade resulting in thrombosis
• Most patients have underlying severe renal disease, as is this case
• Malignant hypertension must be distinguished clinically from other thrombotic microangiopathies including hemolytic uremic syndrome (HUS) and thrombotic thrombocytopenic purpura (TTP)
• The renal biopsy findings may be similar in all thrombotic microangiopathies
• In this case the ADAMTS13 level was normal, excluding TTP.

Question 29

What is the renal outcome of this patient?

Answer 29

• 1 year survival for untreated malignant hypertension is roughly 10%.
• Intravenous antihypertensive medications must be administered to gradually lower the blood pressure. Mean arterial pressure must stay high because many vessels are narrowed. Dropping the blood pressure too much may lead to organ ischemia.
• The prognosis depends on the degree of underlying renal injury. Many patients develop end-stage renal disease, and become dialysis dependent, as did this patient.