Diseases of renal system

Question 1

Cancers of the GI tract

Answer 1

• Cancer identifiers: evasion of apoptosis, self-sufficiency in growth signals, insensitivity to anti-growth signals, metastasis, and sustained angiogenesis
• Adenocarcinoma = occurs at gastroesophageal junction (most reflux and Barrett’s), squamous carcinomas = in top third of of oesophagus predominantly
• Barrett’s metaplasia = huge risk factor in terms of adenocarcinoma but conversion of Barrett’s to adenocarcinoma is relatively low as it is underpinned by many different molecular + genetic aberrations
• Heliobacter pylori = protective in developing in oesophageal adenocarcinoma → drives hypochlorhydria, however infection is most important risk factor as infection → reduced acid secretion but infection in antrum → hypergastrinemia and duodenal ulcers
• Triple therapy treatment: antibiotics amoxicillin, clarithromycin, and proton pump inhibitor
• Mechanisms of helicobacter pylori: flagella for motility, urease allows conversion of stomach acid to HCO3- (allows for neutral local environment), lipopolysaccharides adhere to host cells that drives inflammation, exotoxins drive gastric mucosa injury

Question 2

Hereditary diffuse type gastric carcinoma

Answer 2

• Direct effect of transmembrane protein E cadherin and germline mutation, adherens junctions are made of E cadherins forming ‘zipper-like’ structures, E cadherin functions as ‘glue’ between epithelial cells → formation of tight bond (binding = Ca2+-dependent), E cadherin is also linked to actin cytoskeleton via cytoplasmic proteins
• Mutations of E cadherin → cell no loner bind tightly to one another, become disorganised → invade underlying tissue or break away from initial tumour and metastasise (no cell adhesion)
• Reduced cadherin = worse effects than preserved E cadherin (E cadherin = prognostic marker for determining survival, decreases chance of invasion)
• E cadherin repression caused by: epigenetic event, promoter hypermethylation, and epithelial mesenchymal transition (EMT) regulators
• EMT regulators (snail and slug) = suppress E cadherin by binding through various E boxes in promoter → induces mesenchymal protein
• Snail and slug = regulators of epithelial mesenchymal transition, convert epithelial linages to more mesenchymal/fibroblastic phenotype
• Inverse relationship between EMT regulators and E cadherin (no snail lines have preserved E cadherin)

Question 3

Colorectal cancer risk factors

Answer 3

1. Meat/fish: increases in red meat consumption but white meat decreases risk
2. Fibre: high fibre → lower risk
3. Obesity: associated with increased risk, high levels of physical activity to reduce risk
4. Alcohol increases risk, long-term regular use of aspirin reduces risk (similar for other NSAIDs)
   - Colorectal cancer can be divided into sporadic and familial
   - Familiar adenomatous polyposis coli (FAP): multiple benign adenomatous polyps in colon at early stage, caused by APC gene on chromosome 5q21 (germline mutation)
   - Germline mutation in tumour suppressor APC: APC = regulating levels of protein (β-catenin), regulation of β-catenin required as it enters nucleus to switch on different oncogenes by binding 2 transcription factors of Tcf/Lef family
   - Absence of mutation: APC binds to protein partners that regulate levels of β-catenin , binding partner GSK β is a kinase (phosphorylates β-catenin so marked for degradation by ubiquitin proteosome)
   - In FAP with APC mutation, functional destruction cannot be formed, β-catenin not phosphorylated → accumulation → uncontrolled cell growth
   - Sporadic cancers: APC mutation is early event but inadequate to form full tumour
   - 2 alleles need to be abrogated to drive tumourgenesis

Question 4

Failure of homeostasis

Answer 4

• If salt/water homeostasis fails → inability to concentrate urine so loss of diurnal rhythm of urine excretion
• Inability to excrete water load → oedema and Na retention causing hypertension and CNS dysfunction
• K homeostasis failure → enormous functional reserve to excrete K → severe hyperkalaemia, alterations in membrane excitability and cardiac arrhythmias
• Acid/base homeostasis failure → H+ excretion failure, increase in H+ → increase in CO2 so lungs need to remove CO2 to maintain pH
• Inability to excrete H+ means respiratory functions increases → development of systemic acidosis causing: breathlessness, physiological systems start to fail, incorrect pH so enzymes denature, drives hyperkalaemia
• Vitamin D failure → Ca2+ not absorbed from gut, risk of hypocalcaemia → muscle spasms, bone fragility and cardiac rhythm problems
• No erythropoietin production → anaemia, consequences: impaired cognition, transfusion requirement, iron overload, and increased risk of left ventricular hypertrophy (increased cardiovascular disease for patient with CKD)
• No excretion of metabolic waste → accumulation of toxic waste so creatine rises, retention of nitrogenous waste, urate, and phosphate
• Drugs needs to be excreted by kidneys but metabolism of drugs is impaired by renal failure, affected drugs: insulin, opiates, antibiotics, sedatives, and digoxin → increased toxicity risk

Question 5

Renal replacement therapy

Answer 5

• Used for acute or chronic kidney disease, in cases of patient unable to maintain H2O, electrolyte or acid/base homeostasis, or inability to excrete metabolic waste products
• Therapy includes: peritoneal dialysis, haemodialysis, or transplantation (requires palliative care)
• Dialysis replaces: water, electrolyte, acid/base homeostasis, and can excrete metabolic waste products, whereas transplantation replaces all kidney functions
• Dialysis = extracorporeal therapy where fluid/solutes are removed or added to blood, works by separating patient’s blood and dialysis fluid with semipermeable membrane
• Peritoneal dialysis: removes waste products, filters blood through cleansing fluid that flow through catheter into part of abdomen (peritoneum), acts as filter, after set period. fluid with filtered waste flow out of abdomen and is discarded
• Haemodialysis: blood circulates outside of body, through machine with special filters, then out of patient, into catheter (inserted into veins), filter removes waste then returns blood to patient through different catheter (works as artificial kidney)
• Transplantation: patient will have CDK for years prior to transplant, will need immunosuppressants (steroids, calcineurin inhibitors. azathioprine, and mycophenolate)
• Kidneys come from: cadaveric donor (brain-stem dead donor), non-heart beating donors (need to be assessed within 30 minutes of death and need to presume consent), or from living donors (must ensure assess donor carefully - most likely source to increase available organs)
• Transplant immunology = organ is transfect between non-genetically identical individuals, rejection is driven by allogenic response (mechanisms to discriminate self from non-self)
• Those likely to have transplant: everyone with CDK, absolute contraindication with high peri-operative mortality, poor life expectancy, and active malignancy (age is not absolute contraindication and relative contraindication includes coronary or cerebrovascular disease/ recurrent disease)