A 43-year-old man comes to the physician for a 1-week history of swelling around his eyes and decreased urination. His pulse is 87/min, and blood pressure is 152/95 mm Hg. Physical examination shows 1+ periorbital and pretibial edema. Serum studies show a urea nitrogen concentration of 21 mg/dL and a creatinine concentration of 1.4 mg/dL. Urinalysis shows 3+ blood and 1+ protein. Further evaluation of this patient is most likely to show which of the following?

Renal interstitial inflammation

Detached renal tubular epithelial cells

A 42-year-old man presents to his primary care provider complaining of foamy urine for the last 2 weeks. He has also begun to notice swelling in his hands and feet, and he says that his shoes have not been fitting normally. On exam, the patient has a temperature of 98.8°F (37.1°C), blood pressure is 132/84 mmHg, pulse is 64/min, and respirations are 12/min. The patient has 2+ pitting edema bilaterally up to his shins. A 24-hour urine study is found to contain 9.0 g of protein. The patient is referred to a specialist and undergoes a renal biopsy. On light microscopy, the glomeruli demonstrate basement membrane thickening. On electron microscopy, subepithelial deposits are seen. Which of the following is a characteristic of this patient’s disease?

Antibodies to phospholipase A2 receptor

Antibodies to alveolar basement membrane

Loss of podocyte foot processes

A 67-year-old man presents to his primary care provider because of fatigue and loss of appetite. He is also concerned that his legs are swollen below the knee. He has had type 2 diabetes for 35 years, for which he takes metformin and glyburide. Today his temperature is 36.5°C (97.7°F), the blood pressure is 165/82 mm Hg, and the pulse is 88/min. Presence of which of the following would make diabetic kidney disease less likely in this patient?

Normal-to-large kidneys on ultrasound

Gradual reduction of glomerular filtration rate (GFR)

A 66-year-old white man comes to the physician because of a 10-day history of fatigue and lower leg swelling. Over the past 6 months, he has had a 3.6-kg (8-lb) weight loss. He has chronic bronchitis and uses an albuterol inhaler as needed. He has smoked one pack of cigarettes daily for 44 years and drinks one alcoholic beverage daily. His temperature is 37°C (98.6°F), pulse is 88/min, and blood pressure is 120/75 mm Hg. He appears thin. Examination shows 2+ pretibial edema bilaterally. Cardiopulmonary examination shows no abnormalities. Laboratory studies show: Hemoglobin 11.2 g/dL Leukocyte count 8500/mm3 Platelet count 130,000/mm3 Serum Urea nitrogen 23 mg/dL Glucose 77 mg/dL Creatinine 1.6 mg/dL Albumin 1.8 mg/dL Total cholesterol 475 mg/dL Urine Blood negative Glucose negative Protein 4+ WBC 0–1/hpf Fatty casts numerous An x-ray of the chest shows a right upper lobe density. A CT scan of the chest shows a 2.5 x 3.5 x 2-cm right upper lobe mass. Which of the following is the most likely diagnosis?

Granulomatosis with polyangiitis

Rapidly progressive glomerulonephritis

Focal segmental glomerulosclerosis

A 69-year-old white man comes to the physician because of a 15-day history of fatigue and lower leg swelling. Over the past 8 months, he has had a 3.8-kg (8.3-lb) weight loss. He has smoked one pack of cigarettes daily for 48 years. Vital signs are within normal limits. He appears thin. Examination shows 2+ pretibial edema bilaterally. An x-ray of the chest shows a right upper lobe density. Laboratory studies show: Hemoglobin 11.3 g/dL Leukocyte count 8600/mm3 Platelet count 140,000/mm3 Serum Urea nitrogen 25 mg/dL Glucose 79 mg/dL Creatinine 1.7 mg/dL Albumin 1.6 mg/dL Total cholesterol 479 mg/dL Urine Blood negative Glucose negative Protein 4+ WBC 0–1/hpf Fatty casts numerous Light microscopic examination of a kidney biopsy reveals thickening of glomerular capillary loops and the basal membrane. Which of the following is the most likely diagnosis?

Rapidly progressive glomerulonephritis

Granulomatosis with polyangiitis

Focal segmental glomerulosclerosis

Membranoproliferative glomerulonephritis

A 41-year-old African American woman presents to her primary care physician with a 3-week history of lower extremity edema and shortness of breath. She says that she has also noticed that she gets fatigued more easily and has been gaining weight. Her past medical history is significant for sickle cell disease and HIV infection for which she is currently taking combination therapy. Physical exam is significant for periorbital and lower extremity edema. Laboratory testing is significant for hypoalbuminemia, and urinalysis demonstrates 4+ protein. Which of the following would most likely be seen on kidney biopsy in this patient?

Birefringence under polarized light

A 36-year-old man comes to the physician for a 4-week history of swollen legs. He has difficulty putting on socks because of the swelling. Two years ago, he was diagnosed with sleep apnea. He takes no medications. He emigrated from Guatemala with his family when he was a child. He is 171 cm (5 ft 6 in) tall and weighs 115 kg (253 lb); BMI is 39 kg/m2. His pulse is 91/min and blood pressure is 135/82 mm Hg. Examination shows periorbital and bilateral lower extremity edema. Serum Albumin 3.1 g/dL Total cholesterol 312 mg/dL Urine Blood negative Protein +4 RBC 1-2/hpf RBC cast negative Fatty casts numerous A renal biopsy is obtained. Which of the following is most likely to be seen under light microscopy of the patient's renal biopsy specimen?

Segmental sclerosis of the glomeruli

Diffuse thickening of glomerular capillaries

Amyloid deposition in the mesangium

Eosinophilic nodules within the glomeruli

Fibrin crescents within the glomerular space

Nephrotic syndrome disorders for USMLE Step 2 CK: High-Yield Pathology Lessons

Nephrotic Syndrome - The Leaky Filter

Core Definition: A state of massive proteinuria (>3.5 g/day), hypoalbuminemia, generalized edema, and hyperlipidemia/lipiduria. Results from glomerular damage that increases permeability to plasma proteins, leading to a "leaky" filter.
Pathophysiology Flowchart:

Fatty cast with Maltese cross under polarized light

⭐ Loss of antithrombin III in the urine creates a hypercoagulable state, predisposing patients to thromboembolism, especially renal vein thrombosis.

Podocytopathies - Foot Process Problems

Characterized by primary injury to the podocyte, causing selective proteinuria.

Podocyte foot process effacement in nephrotic syndrome

Feature	Minimal Change Disease (MCD)	Focal Segmental Glomerulosclerosis (FSGS)
Demographic	Children	Adults (esp. African Americans)
Associations	NSAIDs, Hodgkin lymphoma	HIV, heroin, obesity, sickle cell
LM	Normal glomeruli	Focal & segmental sclerosis/hyalinosis
IF	Negative	Negative (non-specific IgM/C3 possible)
EM	Diffuse foot process effacement	Diffuse foot process effacement
Prognosis	Excellent steroid response	Often steroid-resistant, progresses to CKD

Membranous Nephropathy - Spike & Dome

Microscopy Findings:
- LM: Diffuse thickening of capillary walls and glomerular basement membrane (GBM).
- IF: Granular deposition of IgG and C3 along the GBM.
- EM: Subepithelial immune deposits create the pathognomonic “spike and dome” appearance.
Etiology:
- Primary/Idiopathic (~85%): 📌 Autoantibodies against the phospholipase A2 receptor (anti-PLA2R).
- Secondary: Associated with drugs (e.g., NSAIDs), infections (HBV, HCV), SLE, or solid tumors (lung, colon).

⭐ Membranous nephropathy is the leading cause of primary nephrotic syndrome in non-diabetic Caucasian adults.

Systemic Causes - Collateral Damage

Diabetic Nephropathy:
- Leading cause of End-Stage Renal Disease (ESRD) in the US.
- Pathogenesis involves non-enzymatic glycosylation of the glomerular basement membrane (GBM) and efferent arterioles.
- Histology: Features GBM thickening and pathognomonic Kimmelstiel-Wilson (KW) lesions (nodular glomerulosclerosis).
Amyloidosis:
- Extracellular deposition of misfolded amyloid protein (e.g., AL from multiple myeloma, AA from chronic inflammation).
- Diagnosis: Congo red stain shows amorphous deposits in the mesangium and capillary walls.
- Hallmark: Exhibits classic apple-green birefringence under polarized light.

⭐ In Diabetic Nephropathy, ACE inhibitors are renoprotective. They preferentially dilate the efferent arteriole, reducing intraglomerular pressure and slowing the progression to ESRD.

Syndrome Sequelae - Clots & Infections

Thrombosis/Thromboembolism: Hypercoagulable state from urinary loss of Antithrombin III.
- Leads to ↑ risk of clots, especially renal vein thrombosis.
Infection: Increased susceptibility due to urinary loss of Immunoglobulins (IgG).
- Common pathogens: Encapsulated bacteria (e.g., Streptococcus pneumoniae).

⭐ Renal vein thrombosis is a classic complication, most frequently seen with membranous nephropathy.

High‑Yield Points - ⚡ Biggest Takeaways

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