GLOMERULAR FILTRATION

• Is the first step in urine formation.
• Glomerular filtration is the process by which ultrafiltrate is formed from small, positively charged molecules; large cells and proteins remain in the blood.
• Occurs within the renal corpuscle, which is the first part of the nephron.
• Driven by dynamically opposing pressures (aka, Starling pressures) that are exerted by the contents of the blood and ultrafiltrate.

Filtration membrane

Three layers:

• Glomerular capillary wall; fenestrations allow passage of small and medium-sized molecules.
• Basement membrane allows positively charged molecules only.
• Visceral layer of Bowman’s capsule; podocytes allow passage of only smallest molecules through filtration slit and slit diaphragm.

Selectively permeable:

• Only small and positively charged molecules pass freely.

Key components of blood within the capillary:

– Large molecules (such as blood cells); blocked by capillary wall.
– Negatively charged molecules; blocked by basement membrane.
– Mid-sized molecules (such as proteins), blocked by visceral layer of Bowman’s capsule.
– Small molecules (water, glucose, amino acids, nitrogenous wastes); pass freely through filtration membrane to become part of ultrafiltrate.

Clinical Correlation:

Glomerulonephritis involves inflammation of the filtration membrane, which alters its permeability and inhibits proper filtration, which can be fatal. Signs include the presence of blood or proteins in the urine.

Net Filtration Pressures:

Hydrostatic pressures (P)

• The forces that blood and ultrafiltrate fluids exert on the filtration membrane; “push” things against the filtration membrane.

Oncotic pressures (aka, colloid osmotic pressures)

• The forces that proteins within the blood and ultrafiltrate exert to draw water towards them; they “suck” them through the filtration membrane.

Typical example values:

• Pressures exerted by blood in glomerular capillary:
  – Hydrostatic pressure = 60 mmHg.
  – Oncotic pressure = 29 mmHg; remember that this is the force blood proteins exert to “suck” water into the capillaries.
• Pressures exerted by the ultrafiltrate in Bowman’s capsule:
  – Hydrostatic pressure = 15 mmHg.
  – Oncotic pressure = approximately 0 mmHg because the filtration membrane prohibited the passage of large proteins into Bowman’s capsule.

Thus, high capillary hydrostatic pressure is a major driving force of net filtration pressure.

Net Filtration Pressure Equation (NFP)

• Describes the outcome of opposing pressures across the filtration membrane.
• A positive net filtration pressure value means that filtration will occur.
  (Glomerular hydrostatic pressure + Bowman’s capsule oncotic pressure) – (Bowman’s capsule hydrostatic pressure + Glomerular oncotic pressure)
• First half of the equation measures forces that favor filtration.
• Second half measures forces that oppose it.
• When we plug in the values from our diagram, we get:
  (60 + 0) – (15 + 29) = 16 mmHg.

Key features of the urinary system:

Kidneys

• Paired, right is lower than left
• Hilum is medial cleft for vessels and ureters to pass
• Supplied by renal artery and vein
• Filter the blood to produce urine

Ureters

• Carry urine away from the kidneys, to the urinary bladder

Urinary bladder

• Lies within the pelvis
• Stores and expels urine

Urethra

• Carries urine to the external environment
• Orifices are regulated by internal and external sphincters

Regulatory functions

• Regulates blood volume, and indirectly, blood pressure; in dialysis patients, the amount of blood volume removed has a significant impact on their blood pressure.
• Regulates erythrocyte production
• Regulates ion balance, and, therefore, the acid/base balance (pH) of the blood.

Clinical Correlations:

• Urinary tract infections (UTI) are one of the most common forms of infection and can involve any part of the urinary system; infection that spreads to the kidneys, called pyelonephritis, can have serious health consequences.
• Kidney stones are hard mineral deposits that form within the kidney and pass through the urinary system; they can be quite painful, and if they become lodged, they may require surgical extraction.

Overview

• Primary lung tumors can cause chest pain, cough, dyspnea, and hemoptysis, particularly in the later stages. Early stages are often asymptomatic, which contributes to the difficulty in early diagnosis.
• Complications of lung cancer depend on the location and/or cell type of the tumors.
• Diagnosis
  – Initial diagnosis is via chest x-ray or CT scans, and is often incidental.
  – Sputum collection and biopsies are performed so that histopathology and molecular analyses can tell us the type of lung cancer.
  –Unfortunately, many patients are diagnosed in advanced stages, when metastasis has already begun and prognosis is poorer.
  –Thus, screening is recommended for high-risk individuals (patients with a history of heavy smoking and who are between 55 and 80 years old).
• Treatment
  – Varies by patient, cancer type, and stage; list the following options, which are often combined for maximal efficacy:
  Surgical removal of tumor
  Radiation
  Chemotherapy
  Targeted drug therapy – this is particularly useful in non-small cell lung carcinomas harboring specific genetic mutations – for example, Tyrosine Kinase Inhibitors (such as erlotinib and gefitinib) are effective for patients with EGFR mutations, and ALK inhibitors (such as crizotinib) for ALK mutations.
  Targeted therapies are celebrated for their relative safety and tolerability, since they only act against cancer cells; however, be aware that resistance to targeted inhibitors can occur,which is another reason for combination therapy.
  Immunotherapy is another form of targeted therapy; immune checkpoint inhibitors (such as nivolumab) amplify the immune response to cancer cells.

Paraneoplastic syndromes and complications

Small-cell lung cancer

• Ectopic Cushing syndrome; we draw a “moon face” to remind ourselves that Cushing syndrome is caused by over-secretion of ACTH and is associated with fat accumulation in the head, neck, and trunk, which can produce an exaggerated roundness in the face.
• SIADH (syndrome of inappropriate anti-diuretic hormone secretion); remind ourselves that this leads to retention of body water and, therefore, reduced urine output.
• Lambert-Eaton myasthenic syndrome and other immune-mediated neurologic syndromes. To illustrate this, show antibodies attacking the neuromuscular junction

Adenocarcinoma

• Nonbacterial verrucous endocarditis.

Squamous cell carcinoma

• Hypercalcemia due to production of parathyroid hormone-related protein; common symptoms of hypercalcemia include weakness, nausea, vomiting, abdominal cramps, and dehydration.

Large cell lung cancer

• Gynecomastia.

Non-small cell lung cancers, as a group

• Hypertrophic pulmonary osteoarthropy, (aka, Marie-Bamberger syndrome), which is a rare condition comprising the following triad: periostitis, arthropathy, and digit clubbing.

Small and Non-Small lung cancers

• Hematological disorders including anemia, disseminated intravascular coagulation, granulocytosis (increased granulocytes), and thrombocytosis (increased platelets).
• Dermatomyositis

Complications of lung cancer more broadly

• *Superior vena cava syndrome is obstruction of blood flow through the superior vena cava due to direct tumor invasion or external compression of the vessel.
  – Patients present with facial and neck swelling, edema, and jugular venous distention.
  – SVC syndrome is more likely to occur in small-cell lung cancer, but, because non-small cell lung cancer is more common than small-cell, it is a frequent cause of SVC syndrome.
• Pancoast tumors, aka, superior sulcus tumors, occur when tumors at the lung apex compress nearby structures.
  – We think about Pancoast tumors in brachial plexopathies, which cause shoulder pain and weakness, and also in proximal ulnar neuropathies, which cause weakness and atrophy of the intrinsic hand muscles.

– Pancoast tumors are also responsible for Horner syndrome, which is characterized by ptosis (eyelid drooping), miosis (pupil constriction), and facial anhidrosis (lack of sweating).

• Lastly, indicate that lung tumors can cause compression of the recurrent laryngeal nerve (from CN 10)

STAGING

• Tumor staging determines treatment options and prognosis. Staging can involve imaging studies as well as surgical resections and biopsy.

Non-Small Cell Lung Cancer

• Uses the TNM system to asses Tumor size/invasiveness, lymph Node involvement, and Metastasis to distant sites.
• The stages I-IV progress from cancer in the lungs, then the lymph nodes, then other body sites.
• Stage I: tumor is present only in the lungs (no lymph node involvement or metastasis).
• Stage II: tumor is present in the lungs and there is nearby lymph node involvement (but no metastasis).
• Stage III: tumor in the lungs is accompanied by cancer in the lymph nodes in the middle of the chest (but no metastasis).
  –Stage IIIa involves lymph nodes on the same side as the original tumor.
  – Stage IIIb involves lymph nodes on the opposite side.
• Stage IV tumors are in both lungs, the pleural fluid, and/or has metastasized (most often to the brain, liver, or bones).

Small-cell Lung Cancer

• Staging is much simpler.
• Limited stage: in which tumors lie within the ipsilateral hemithorax (tumors on one side of the chest only) and can be encompassed within a single radiation port.
• Extensive stage: metastatic cancer that involves both sides of the chest or is present in pleural or pericardial effusions.

Overview

• Lung cancer is the result of tumors that form in the respiratory epithelium of the bronchi, bronchioles, and alveoli.
• Lung cancer is a key cause of cancer death worldwide, in both men and women.
• Although lung cancer is often asymptomatic in the early stages (and, thus, often goes undetected), later stages can be marked by chest pain, cough, dyspnea, and hemoptysis.
• Complications of lung cancer depend on the location of tumors and the cell type; we’ll address complications in more detail, elsewhere.
• Often found incidentally on chest x-ray or CT.
• Once a tumor is found, determination of the type of lung cancer relies on histopathology and molecular analysis.
• Tobacco cigarettes contain multiple toxins and carcinogens, and smoking is the number one cause of lung cancer, accounting for 80-90% of all lung cancer cases.
• Other causes include asbestos, radon, polycyclic aromatic hydrocarbons (produced when coal, wood, etc. are burned), and various metals (ex: nickel, chromium).
  – Although the role of electronic cigarettes in lung cancer in humans is uncertain, studies are showing that electronic cigarettes can induce lung cancer in mice.
• Most genetic mutations associated with lung cancer are non-heritable, and are associated with exposure to carcinogens.
  – Genetic changes are variable, and include driver mutations, amplifications, translocations, deletions, and insertions.
• Pleural mesothelioma is cancer of the lung pleura; it is most often caused by exposure to asbestos (which comprises long, thin fibers found in some building and construction materials).
  – Pleural thickening and effusions are common in mesothelioma, which is notoriously difficult to treat.

LUNG CANCER TYPES

Lung cancer is broadly divided into small-cell lung cancer and non-small cell lung cancer.

Small-cell lung cancer, aka, oat cell carcinoma.

• Accounts for approximately 15% of lung cancer cases.
• Often centrally located, with formation of tumors in the airways submucosa and perihilar masses.
• Aggressive, rapid growth and early dissemination, often to the brain, liver, and bones.
• Histopathology
  – Small, spindle-shaped cells with a high mitotic rate (due to rapid growth).
  – Cells have scant cytoplasm and contain granular chromatin.
  – Necrosis is common.
  – Cancerous cells arise from neuroendocrine cells (called Kulchitsky cells) in the basal bronchial epithelium.
  – Small-cell cancer may be “pure” or “combined” with large cells and/or non-small lung cancer cells.
• Small-cell cancer is almost always caused by cigarette smoking.
• MYC oncogene mutations and RB1 and TP53 inactivations (which facilitate uncontrolled tumor growth).
• We can tie key biomarkers to the fact that these tumors arise from neuroendocrine cells:
  – The following neuroendocrinal markers are often used to help identify small-cell lung cancer:
  Neuron-specific enolase, Chromagranin A, Synaptophysin, and CD56.
• Lastly, this type of lung cancer is associated with a variety of complications, including superior vena cava syndrome, SIADH, Cushing Disease, and Lambert-Eaton syndrome.

Non-small cell lung carcinomas (NSCLC)

Collectively account for approximately 85% of all lung cancers.

Be aware that significant WHO reclassifications occurred in 2004 and 2015 due to advances in immune-histological and molecular techniques. We will follow these updated classification schemes, but be aware of significant intertextual variation.

Adenocarcinoma

• Accounts for 40% of all lung cancers.
• Most commonly (though not always) found in the peripheral lung tissues, affecting airway epithelial type II alveolar cells.
• Distant metastases are common.
• 5 histological subtypes of adenocarcinoma
  – More than one type may be present in a tumor
  – Mucinous and non-mucinous forms exist.
  –  Lepidic subtype is characterized by cancer cells that follow the lining of the alveolar walls; note that there is no disruption to the respiratory tissue architecture. Adenocarcinomas with predominantly lepidic patterns have the best prognosis.
  – Acinar patterns are, as their name suggests, comprised of cuboidal and/or columnar shaped cells that form acini and tubules.
  – Papillary pattern comprises columnar cells surrounding a fibroblastic core.
  – Micropapillary pattern is similar to papillary but smaller and lack fibroblastic cores – these small “tufts” of cells may appear to float in the alveolar spaces. Micropapillary adenocarcinoma has a relatively poor prognosis.
  –  Solid pattern comprises dense sheets or “nests” of cells;show that ribbons of fibrosis may weave around the nests. This pattern also has a poor prognosis.
• Be aware that the subtypes “bronchoalveolar cell carcinoma” and “mixed adenocarcinoma” are no longer in use, and that “clear cell,” “rhabdoid,” and “signet” are now used as descriptive terms, not subtype labels.
• Invasiveness of adenocarcinoma varies
  – Pre-invasive forms are predominantly lepidic, and include Atypical Adenomatous Hyperplasia (AAH) and Adenocarcinoma in situ (AIS).
  – Minimally invasive carcinomas comprise both lepidic and more invasive cell types that infiltrate the myofibroblastic stroma (but no invasion into the pleura or circulation). These tumors are often non-mucinous.
  – Invasive adenocarcinoma is characterized by a tumor focus greater than 5 mm, and comprises a mixture of histologic patterns. Tumors are classified according to the predominant histologic pattern (for example, invasive adenocarcinoma with predominant papillary pattern). These tumors are often mucinous.
• Key Points:
  – Adenocarcinoma is most common lung cancer overall.
  – It is the most common lung cancer in women and in non-smokers.
  – Genetic mutations, including EGFR, KRAS, and ALK are associated with adenocarcinoma, and are the focus of key targeted therapies.

Squamous cell carcinoma

• Accounts for approximately 30% of lung cancers.
• Most often arises centrally in the bronchial tubes; however, write that peripheral tumors are associated with cavitation.
• 3 Histopathological Subtypes: basaloid, non-keratinized, and keratinized.
  – Some former subtypes have been discontinued, and those subtype names are now used as descriptive terms (ex: clear cell).
• Histopathology
  – *Nests of polygonal cells with eosinophilic cytoplasm and obvious nucleoli
  – Under high magnification, we can see intercellular bridges.
  – Keratin pearls are another common features; these are accumulations of keratin between the nests of polygonal cells.
  – Necrosis may also be present.
• Key Points:
  – Squamous cell carcinoma is strongly associated with cigarette smoking, and with TP53 and P-450 mutations.
  – A notable complication is hypercalcemia due to parathyroid hormone-related protein (PTH-rp) production; common symptoms of this include weakness, nausea, vomiting, abdominal cramps, and dehydration.

Large cell carcinoma

• Accounts for approximately 10% of lung cancers.
• Often peripherally located.
• Histopathology: tumors comprise poorly differentiated, large cells.
• Strongly associated with cigarette smoking.
• It’s important to know that several “subtypes” have been reclassified/reorganized; for example, this group no longer includes Large Cell Neuroendocrine Carcinoma, which is now grouped with small cell neuroendocrine tumors.
• Large cell lung cancer is a diagnosis of exclusion, and diagnosis relies on surgical resection.
• When relying on cytology alone, the term “non-small cell lung carcinoma, not otherwise specified” (NSCLC-NOS) is preferred.

Key Points

• Pulmonary hypertension is defined as increased pressure in the pulmonary vasculature.
  – Pressures of 25 mmHg or above are considered hypertensive.
  – Be aware that some argue that the threshold should be lowered to 20 mmHg.
• Symptoms are nonspecific and may be overlooked.
  – Most patients present with shortness of breath, especially on exertion.
• Serious outcomes, include: right heart failure, arrhythmias, blood clots, and bleeding into the lungs.
  – Early diagnosis and treatment is important.

Pulmonary arterial pressure and its determinants

Review of flow of blood through the heart and lungs

• Deoxygenated blood is returned to the heart via the vena cavae, passes through the right atrium, and is pumped by the right ventricle into the pulmonary trunk, which bifurcates to give rise to the right and left pulmonary arteries and their branches.
• Pulmonary blood pressure is generated by the right ventricle.
• Normal mean pulmonary arterial pressure is around 15 mmHg at rest.
• Pulmonary circulation is characterized by low pressure, low resistance, and high compliance.
  –  Pulmonary arterial pressure (PAP) is determined by cardiac output, pulmonary vascular resistance, and pulmonary venous pressure.
  Recall that the pulmonary circulation receives the same cardiac output as the systemic circulation; the low pressure and resistance of the pulmonary vasculature allows it to receive this blood without damage.
  –  Low pulmonary vascular resistance is the product of short, wide vessels with relatively little smooth muscle in their walls.
  In our drawing, we compare the less muscular pulmonary arterioles to the systemic arterioles.
  – Key modulators of pulmonary vascular resistance include lung volume, perfusion pressure, oxygen, carbon dioxide, and pH levels.
  For example, hypoxia causes pulmonary vasoconstriction; when chronic, this can lead to hypertension.
  – High compliance of the pulmonary circulation is facilitated by the thin vessel walls with little muscular tone.

5 Groups of Pulmonary Hypertension

The Groups are defined by hemodynamic profiles and causes. These groupings are important because proper treatment of pulmonary hypertension requires that we know its underlying pathobiology.

• Group 1: Pulmonary arterial hypertension (PAH), which accounts for less than 5% of all pulmonary hypertension.
  – Pulmonary arterial hypertension can be idiopathic, or can be due to hereditary causes (for example, mutations of the BMPR2 gene), toxins, HIV, or connective tissue diseases.
  – Hemodynamic profile of pulmonary arterial hypertension is pre-capillary
  Pulmonary arterial wedge pressure of 15 mmHg or less (Be aware that many use pulmonary arterial wedge pressure and pulmonary capillary wedge pressure interchangeably).
  Elevated pulmonary vascular resistance of 3 Wood Units or more.
  (Be aware that many use pulmonary arterial wedge pressure and pulmonary capillary wedge pressure interchangeably).
  – Pulmonary arterial hypertension is characterized by inflammation, fibrosis, thrombosis, and vasoconstriction.

• Group 2: Pulmonary hypertension due to left heart disease; approximately 70% of all cases of pulmonary hypertension are Group 2.
  – Causes include systolic and diastolic dysfunction, valvular disease, and congenital disorders that lead to left heart failure.
  – The hemodynamic profile of Group 2 is characterized by a pulmonary arterial wedge pressure of greater than 15 mmHg; note the contrast with Group 1, which is lower.
  – Group 2 can be further subdivided by pulmonary vascular resistance values:
  Pulmonary vascular resistance of less than 3 Woods Units indicates post-capillary hypertension.
  Pulmonary vascular resistance of greater than 3 Woods Units indicates mixed pre- and post-capillary hypertension; this subtype of Group 2 is sometimes called “reactive.”

To better understand how left heart disease leads to pulmonary hypertension, draw the heart and a lung:

– Indicate that that venous return brings oxygenated blood from the lungs to the left side of the heart.
– Then, show that, when left ventricular end diastolic pressure is elevated, which occurs in left heart failure, that left atrial pressure also increases;
– And, as a result, passive increases in the pulmonary vasculature occur due to venous backflow.
– However, in some individuals, reactive pulmonary hypertension develops when heart disease leads to pulmonary arterial dysfunction and precapillary hypertension; thus, hypertension is “mixed” pre- and post-capillary.
In reactive pulmonary hypertension, we see increased transpulmonary gradients and pulmonary vascular resistance.

• Group 3 pulmonary hypertension is due to underlying lung diseases and other disorders that lead to hypoxia; this accounts for approximately 10% of PH.
  – Some important causes of Group 3 pulmonary hypertension include COPD, interstitial lung disease, and obstructive sleep apnea, all of which cause hypoxic vasoconstriction, and, thus, elevations in pulmonary pressure.

• Group 4 is chronic thromboembolic pulmonary hypertension, which accounts for less than 5% of PH.
  • Review pulmonary embolism

• Group 5 is pulmonary hypertension due to unknown or miscellaneous causes; approximately 15% of PH is in this group.
  – This group includes pulmonary hypertension associated with hematological, systemic, metabolic, and other disorders.
  Thus, patients with sickle cell anemia, renal diseases, sarcoidosis, and other related disorders are at higher risk for PH.

Pre vs Post-capillary

• Let’s summarize the 5 groups in a quick diagram to show pre- and post-capillary pulmonary hypertension.
  – Indicate that Groups 1, 3, 4, and 5 are characterized by hypertension in the pre-capillary vessels.
  – Groups 2 and 5 are associated with post-capillary hypertension, but both may also progress to mixed hypertension with pre-capillary involvement.

Diagnostic Tests

When pulmonary hypertension is suspected, we can perform a variety of tests to determine its presence, severity, and cause.

• Initial tests may yield the following findings:
  – Chest radiographs may show enlarged pulmonary arteries and peripheral pruning.
  – Contrast chest CT may indicate thrombi in thromboembolic PH or show signs of PH due to left heart failure, interstitial lung disease, or other chronic lung diseases;
  – Echocardiography, ECG, and Cardiac MRI can show us abnormal cardiac structure and/or function that can indicate PH severity or cause; for example, abnormalities in the right ventricle can indicate that PH has progressed to right heart failure, or abnormalities in the left heart may indicate that PH is due to left heart disease.
  –  Other tests, such as spirometry or arterial blood gas tests, can tell us about lung function and gas diffusion.
• The definitive test for pulmonary hypertension is right heart catheterization, which measures the pressure in the right ventricle and pulmonary arteries.

Treatments

• Treat underlying causes, when known (for example, treating chronic lung diseases or left heart failure).
• Many patients can benefit from symptomatic treatment with oxygen supplementation, diuretics, digoxin, anti-coagulants, and exercise therapy.
• And, vasodilators may be helpful for patients in Group 1(Pulmonary Arterial Hypertension).
  – Key examples of medications used to treat PAH include epoprostenol, nitric oxide, endothelin receptor antagonists, and calcium channel blockers.