Week 10 Flashcards
68-year-old male with no significant medical history presents with five months of right-sided flank discomfort and abdominal fullness. He mentions weight loss of approximately 40 pounds over the last year and intermittent blood-tinged urine. His physical examination reveals right-sided abdominal tenderness. Urinalysis shows 2+ hematuria, but no protein, glucose, or leukocytes. Abdominal CT reveals a fairly well-circumscribed mass in the upper pole of the right kidney. The patient is unaware of any family history of renal tumors.
- Predict the most likely histologic classification and the associated cytogenetic and genetic abnormalities of the tumor.
- The tumor is likely a primary clear cell carcinoma, which most commonly presents as a solitary, spherical, unilateral mass in either pole of the kidney, with a yellow color due to the high lipid content in the “clear” cells. Clear cell carcinoma is the most common type (accounting for up to 80%) of renal cell carcinoma.
- The associated cytogenetic abnormality is a loss of sequences on the short arm of chromosome 3.
- The deleted region contains the von Hippel-Lindau (VHL) gene.
Despite undergoing a radical nephrectomy, the patient’s cancer metastasizes. His oncologist recommends a single-agent chemotherapy, sunitinib. Explain why sunitinib is considered an effective single-agent chemotherapy for this indication. Include at least one specific receptor target for sunitinib in your explanation.
- Sunitinib exhibits antitumor and antiangiogenic properties by inhibiting multiple receptor tyrosine kinases (RTK), including at least one of the following examples: platelet-derived growth factors (PDGFRα and PDGFRβ), vascular endothelial growth factors (VEGFR1, VEGFR2, and VEGFR3), FMS-like tyrosine kinase-3 (FLT3), colony-stimulating factor type 1 (CSF-1R), and glial cell-line-derived neurotrophic factor receptor (RET).
- Broad (non-selective) inhibition of multiple receptor tyrosine kinases significantly inhibits angiogenic signaling resulting in decreased tumor vascularization (via VEGFR), cellular proliferation, and survival via inhibition of RTK-mediated protein kinase B (denoted as Akt) signaling, leading to decreased tumor size and cancer cell metastasis, respectively.
A transurethral biopsy is obtained of a 3 x 3 cm papillary tumor in the posterior wall at the trigone of the bladder (Image 2). Describe the architectural and cytological features of the tumor. Based on your description, explain how would you classify the tumor.
The image of the tumor displays a papilla with architectural disarray and loss of polarity of the urothelium. The urothelium consists of dyscohesive, anaplastic cells with marked nuclear pleomorphism and atypia, including large hyperchromatic nuclei with coarse chromatin and irregular borders. These architectural and cytological features are consistent with a high-grade papillary urothelial carcinoma.
patient receives Bacillus Calmette-Guérin (BCG) as an early-stage treatment to manage their condition. Describe how BCG is thought to prevent the cancer from metastasizing and identify its route of administration.
Bacillus Calmette-Guérin (BCG) is a live vaccine (originally formulated for tuberculosis immunization), which is now being used to treat early-stage bladder cancers. When the medication is administered into the bladder, it attaches to urothelial cells and causes inflammation via immune cell recruitment and cytokine production. The inflammation leads to immune-mediated cytotoxicity (via macrophages, natural killer cells, and other immune cells), which destroys the cancerous urothelial cells, therefore helping to stop the cancer from growing and spreading.
BCG is an intravesicular therapy; delivered through a catheter directly into the bladder.
19-year-old female presents to the clinic with persistent nausea and vomiting. She has also noticed progressive fatigue and arthralgias over the past month. Significant findings on examination include mild fever and a malar rash. Her initial laboratory values are notable for hemoglobin of 9.0 g/dL (11.6-15.0), platelet count 116,000/μL (157,000-371,000), and serum creatinine 2.08 mg/dL (0.59-1.04) with 1+ protein and 3+ hemoglobin on urinalysis. Spot urine protein is 175 mg/dL and spot urine creatinine is 155 mg/dL with a protein:creatinine ratio of 1129 mg/g creatinine (ref: 21-161), consistent with proteinuria of >1g per 24 hours. Additional studies reveal a positive antinuclear antibody (ANA) with decreased C3 and CH50.
- Name the two most likely possible etiologies for this patient’s renal disease and describe how fractional excretion of sodium (FeNa) would help differentiate the two.
The patient appears to have autoimmune disease (SLE). Persistent vomiting may have also contributed to hypovolemia. The question is, which of the two is causing the renal impairment (possibly both!).
FeNa <1% would indicate a prerenal etiology (hypovolemia), whereas FeNa >1% would be more suggestive of an intrarenal cause (such as lupus glomerulonephritis) in this patient.
Discuss the rationale for obtaining a renal biopsy in a patient with lupus nephritis
The patient meets criteria for systemic lupus erythematosus and the presence of microscopic hematuria with a spot protein:creatinine ratio > 1000mg/g creatinine is consistent with proteinuria secondary to glomerular injury (e.g. glomerulonephritis). Renal biopsy allows for diagnostic confirmation of the glomerulonephritis and, most importantly, classification to determine the need for immunosuppression.
Renal biopsy shows a compressed glomerular tuft with crescent formation. Immunofluorescent staining is performed on the renal biopsy. Predict the staining pattern for IgG and C3 and describe the immunologic process that accounts for this staining pattern.
The expected immunofluorescence staining pattern would be granular staining for both IgG and C3. Glomerulonephritis in the setting of autoimmune disease is caused by immune complex deposition. Positively-charged immune complexes deposit in the size (capillary endothelium) and charge (basement membrane and slit membrane) barriers in the glomerulus, which results in spotty staining throughout the glomerulus. C3 staining would mirror that of IgG as complement becomes activated at the sites of immune complex deposition.
Following intensive therapy, the patient survives her initial renal injury. She is started on therapy for SLE prior to discharge but is unable to tolerate her medication regimen and misses her next two follow-up appointments. At her next visit 10 months later, her creatinine is 2.6 mg/dL. Aside from the ongoing immune-mediated damage, describe the physiologic mechanisms that would explain her continued decline in GFR.
With chronic renal injury, declining functional renal mass (due to sclerosis of nephrons) leads to increased intraglomerular pressure in the remaining functioning nephrons. This increased pressure leads to glomerular injury with endothelial and mesangial proliferation, protein leakage, and eventually collagen deposition. The result is focal segmental glomerulosclerosis, which further decreases her functional renal mass.
Pt with CKD caused by diabetic nephropathy, 2 yrs ago labs with GFR at 33 and now GFR is 14.
- The patient’s current renal biopsy shows nodular and diffuse glomerulosclerosis, hyalinosis, and thickening of the basement membranes. Describe the mechanism(s) by which the thickening of the basement membrane occurs in this patient and correlate this finding with the patient’s leg swelling.
Basement membrane thickening occurs as a result of advanced glycated end-products (AGEs) crosslinking the type IV collagen fibers in the basement membrane and subsequent deposition of small proteins such as albumin. Despite the thickening, the membrane remains porous to proteins. Much of the albumin will spill into the urine, leading to decreased serum albumin. The decreased serum albumin decreases intravascular oncotic pressure, pulling fluid into the extravascular space (interstitium) and causing dependent edema
Pt with CKD caused by diabetic nephropathy, 2 yrs ago labs with GFR at 33 and now GFR is 14.
- Based on the patient’s estimated glomerular filtration rate (eGFR), compare the GFR stage of chronic kidney disease (CKD) during her laboratory testing two years ago to her more recent renal function testing, including the general implications of each GFR stage for her medical care.
- Based on the patient’s eGFR two years ago, her renal function was consistent with Stage 3b Chronic Kidney Disease (CKD-3b), which is defined as an eGFR between 30-44 mL/minute/1.73m2. This signifies considerable renal impairment.
- Based on the patient’s more recent eGFR, her renal function is now consistent with Stage 5 CKD, which is defined as an eGFR below 15 mL/minute/1.73m2.
- Many medications are eliminated by the kidneys and require dose adjustment for CKD-3b (e.g., metformin), yet more are renally-dosed for CKD-4 (e.g., rosuvastatin), and some are contra-indicated in CKD-5 (e.g., rivaroxaban). At the point that the patient’s nephrologist diagnoses ESRD, the patient should be considered for invasive management with dialysis and/or renal transplantation.
Evaluate the benefits and risks of hemodialysis
- benefit of hemodialysis is the (transient) removal of waste products (such as urea) and the normalization of electrolyte and fluid levels. This filtration is essential for life, and dialysis will lower the patient’s exposure to azotemia/uremia, hyperkalemia, and fluid overload.
- risk is that annual mortality rate of patients on dialysis remains approximately 20%, impaired quality of life (over two-thirds are unable to return to work) and loss of independence, cognitive decline, and a greater risk of falls for older patients. Medical complications are common and include frequent hospitalizations, clotting and infection of the vascular access, bloodstream infections, and severe exhaustion following hemodialysis sessions.
Paraphrase the regulatory status of ESRD in regard to her financial coverage
Because she has been diagnosed with End-Stage Renal Disease (ESRD), the patient’s dialysis (and other medical treatments) will be paid for by Medicare. Following federal legislation (Section 299I) that was signed into law as part of the Social Security Amendments of 1972, ESRD is considered a disabling condition that automatically qualifies for Medicare (and Social Security) funding.
Describe the three primary documents that should be completed for an Advanced Directive in the state of Texas.
- Medical Power of Attorney (MPOA): designates the patient’s decision-maker for end-of-life care, the MPOA may determine decisions for any treatments not otherwise specified by an Advanced Directive.
- Living Will: designates the patient’s decisions for life support, including whether the patient chooses to pursue life-sustaining treatment or comfort care only, as well as any specified additional requests [such as artificial nutrition/fluids, intravenous antibiotics, dialysis, organ donation, etc.].
- Do Not Resuscitate (DNR) Order: designates the patient’s decisions for life-saving measures, and is limited to the choice to undergo cardiopulmonary resuscitation (CPR), transcutaneous cardiac pacing, and defibrillation (DNR) or advanced airway management and artificial ventilation (DNI: Do Not Intubate). There are two different forms of DNR orders, which include the Out-of-Hospital DNR (OOH-DNR) Order and the separate In-Hospital DNR order. Both orders must be signed by an attending physician.
Discuss one potential limitation to the enactment of an Advanced Directive
- Another potential limitation to the enactment of an Advanced Directive is that an In-Hospital DNR Order is only valid during the patient’s current hospitalization and is not readily transferable outside of the hospital. Likewise, an Out-of-Hospital (OOH) DNR Order is not readily applicable during a hospital admission
- An Advanced Directive may not be readily accessible to emergency personnel (e.g., paramedics and EMTs), who are required to provide every possible life-saving treatment.
Describe the mechanism(s) by which glomerular basement membrane thickening occurs
Membranous nephropathy is characterized by diffuse thickening of the glomerular basement membrane due to immune complex deposition. In this case, the immune complexes may be formed by hepatitis viral particles and antiviral antibodies. The complexes become deposited in a subepithelial location and cause injury to podocytes. Podocytes secrete membrane proteins, including collagen, resulting in thickening of the membrane between and around the subepithelial deposits.
