CT1 Flashcards
Introduction
- Chronic kidney disease (CKD) is a long-term condition characterised by a gradual loss in kidney function over time.
- The kidneys play vital roles in waste and excess fluid filtration, urine production, electrolyte balance regulation and blood pressure control.
- Early stages of the disease may cause symptoms, though sometimes this is not the case, making the disease hard to detect.
- Clinically the disease is categorised by:
o Kidney damage >3 months, as defined by structural or functional abnormalities of the kidney, with or without decreased GFP.
This may be pathological abnormalities or markers such as blood or urine abnormalities.
o Alternatively by GFR <60mL/min/1.73m2 for >3months, with or without kidney damage. - As the disease progresses, symptoms are common, such as fatigue, swelling, changed urination frequency and nausea.
- There are various risk factors associated with the condition.
- One big one is diabetes.
o High blood glucose associated with the disease is damaging to the small blood vessels of the kidneys as well as the glomeruli.
o Chronic ox and inflammatory stress associated with the condition can also impair kidney function. - Hypertension is another risk factor.
o Can also damage blood vessels and glomeruli.
o Furthermore, can cause structural changes in kidney tissue, such as blood vessel thickening and scarring. - CVD can also contribute, similar reasons, alongside atherosclerosis.
o Not to mention a strong association to diabetes and hypertension also. - Obesity, metabolic syndrome, age all linked.
- Others like Infection
o Can lead to acute kidney injury, Glomerulonephritis.
o Immune system activation. - Then nephrotoxins, a genetic component likely. Even some OTC drugs like NSAIDs.
Progression
There are 5 stages in the progression of kidney damage to ESRD.
- 1 - Abnormalities in imaging, or things like mild proteinuria.
o Might be slight reduction in GFR or could be normal.
- 2 - A reduction in GFR, indicative of mild to moderate kidney function impairment.
o Still minimal symptoms – detection challenging.
- 3 - Moderate reduction in GFR.
Moderate dysfunction.
3a (45-59ml/min/1.73m2) and 3b (30-44).
Symptoms: Fatigue, fluid retention, urination changes.
- 4 - Severe decrease in GFR (15-29 4a) (or below 15 4b).
o More severe symptoms.
- 5 = ESRD - GFR very low.
o Unable to remove waste.
o Life threatening without dialysis or transplantation.
ACE inhibs
- Angiotensin converting enzyme inhibitors.
- Exert their hemodynamic effect mainly by inhibiting the renin-angiotensin system, specifically by blocking angiotensisn 1 conversion to angiotensin 2.
- They also modulate sympathetic NS activity
- And increase prostaglandin synthesis.
- This causes vasodilation as well as mild natriuresis (or salt excretion) without affecting heart rate and contractility.
- Used for mild-moderate hypertension.
- Have some side effects including cough, hypotension, hyperkalemia, headache, dizziness, fatigue and nausea.
- This can affect compliance.
- Examples include Enalapril, which is a prodrug of an ace inhibitor, activated by hepatic biotransformation.
- Captopril is another, potent and competitive ACE inhibitor.
ARBs
- Angiotensin II receptor blockers.
- Will often be used if patient is experiencing coughing with ACE inhibitor.
- Eg. Losartan or ibersartan.
o Reversibly and competitively prevents angiotensin II binding to the AT1 receptor in tissues such as vascular smooth muscle.
o The active metabolite is a non competitive inhibitor.
o Losartans prevention of angiotensin II binding causes vasc smooth muscle relaxation, lowering BP.
o Some S/E: Dizziness, headache, hyperkalemia.
SGLT2 inhibitors
- Such as Canagliflozin.
- Sodium-glucose cotransporter 2 co transporter inhibitor.
- The receptor is found in the proximal tubules of the kidney, and reabsorbs filtered glucose from the renal tubular lumen.
- Inhibition leads to lower reabsorption of filtered glucose into the body.
- Also decreases the renal threshold for glucose, leading to increased urine glucose excretion.
- Side effects include bladder pain, bloating, painful urination.
DPP-4 inhibitors
- DPP-4 inhibitors, such as sitagliptin and saxagliptin.
- Sitagliptin is an oral dipeptidyl peptidase 4 inhibitor, and it’s mainly used in the management of T2D.
- Slows DPP-4 mediated inactivation of incretins like GLP-1 and GIP.
- Incretins are released throughout the day and are upregulated in response to meals, as part of glucose homeostasis.
- Reduced incretin inhibition results in increased insulin synthesis and decreased glucagon release – overall decrease in blood glucose, as demonstrated by reduced glycosylated hemoglobin.
- Can lead to anxiety, agitation and diarrhoea.
- Notably, some drugs in class require dose reduction in CKD patients as they have a predominantly renal excretion, but others like linagliptin are exempt.
Control of Blood Lipids
High levels of cholesterol and triglycerides have been associated with progression of KD.
- Promote inflammation, oxidative stress and fibrosis.
- Statins, which inhibit HMG-CoA-reductase, involve in cholesterol synthesis are commonly used for this purpose.
- Atorvastatin is the preferred initial high intensity statin.
- It is clinically and cost effective for the primary and secondary prevention of CKD.
- Atorvastatin is a competitive inhibitor of the enzyme HMG-CoA reductase, which catalyses the conversion of HMG-CoA to mevalonate, an early rate limiting step in cholesterol biosynthesis.
- Atovastatin acts primarily in the liver, where decreased hepatic cholesterol concentrations stimulate the upregulation of hepatic low-density lipoprotein receptors, which increase hepatic LDL uptake.
- Decrease inflammatory and oxidative stress which also has a positive effect of cardiovascular health.
- High dosages of this drug can be harmful to the liver, but not in the doses used.
- Some side effects ensue – nausea, headaches, GI, cold like symptoms.
Endothelian receptor agonists. (Endotheliin antagonists) (Novel)
- Binding of endothelin to the endothelin type A receptor leads to vasoconstriction, sodium retention and podocyte dysfunction.
- Ultimately leading to glomerular damage, proteinuria and renal function loss.
- Binding to endothelin type B receptor causes vasodilation and sodium excretion.
- Thus, specific blockade of the ETa receptor has been investigated as a promising target in managing CKD.
- Additionally, endothelin seems to promote renal fibrosis and mediates the secretion of proinflammatory cytokines and growth factors such as TGFb.
- This contributes to interstitial remodelling and scarring.
- Tubular cell exposure to albumin causes increased endothelin-1 production.
- One such drug is Avosetan.
- Significantly reduced proteinuria in patients with T2D and nephropathy.
- Phase 3 trial – ASCEND – terminated – excess of congestive heart failure and mortality.
- Failure of lack of specific investigator guidelines to prevent or treat sodium and fluid retention.
- Post hoc analysis showed rise in body weight.
- More specific for ETa- sitaxsentan and atrasentan.
- Theoretically reduce risk of retention adverse effects.
- Sitaxsentan reduced BP and moderately proteinuria.
- Favourable effects on pulse wave velocity, uric acid and ADMA – all positive.
- Further trials but in 2011 Pfizer voluntarily withdrew market owing to safety concerns based on trial and post market data.
Antiinflammatory Agents
The risk factors that cause CKD involve a pathophysiological mechanism in which low grade inflammation plays an important role.
Additionally, risk factors such as chronic infection and diabetes have an inflammatory component.
Inflammation also leads to an upregulation in harmful ROS production.
Hence, anti-inflammatory therapies are a logical treatment.
- Bardoxolone is an antioxidative and anti-inflammatory drug which activates the nuclear-factor-erythroid-2-related factor (Nrf-2)-Keap1 pathway.
- Nrf2 regulates the induction of various antioxidant genes.
- Treatment with the drug has been shown to (84) result in significantly increased eGFR in patients with CKD. And increased urine albumin-creatinine ratio.
- This improvement was sustained at 52-week follow up.
- Promising results- lead to BEACON phase 3 trial.
- Recommended early termination – excess mortality because of early onset fluid overload.
- Proof of principal of effects.
Another one?
TGFB
TGF-B
TGFB is a theoretical key mediator for renal fibrosis and hence targeting it could be a promising future therapeutic strategy for CKD.
Pirferone
- Initially designed for the treatment of pulmonary fibrosis.
- Inhibits Smad3 phosphorylation, profibrotic mediator synthesis, TGFB1 expression subsequent fibroblast differentiation and proliferation.
- Shown success in rat model of chronic cyclosporin nephrotoxicity.
o Reduced fibrosis and prevented loss of GF barrier (Al-bayati et al., 2002)
- However, In trial for diabetic nephropathy showed no improvement in eGFR (Sharma et al., 2011)
- Currently recruiting for phase 2 trials.
In UCD, the crean group has recently modelled fibrosis in kidney organoids, using TGFB.
Then inhibited EZH2 – the catalytic subunit of polycomb repressive complex 2 using GSK-343. PRC2 is involved in epigenetic modifications which has been linked to kidney fibrosis. The ultimate goal of this type of therapy is to target epigenetic modifications, to prevent fibrosis. Or in instances where changes have already occurred, reprogram cells to pluripotency, in vivo, which has been shown to have effects in other diseases, like age related blindness, albeit in a mouse model. Nonetheless, this highlights an exciting novel strategy which I’ve found really interesting to learn about.
Artificial Kindeys
The kidney project is aiming to create a bioartificial kidney.
- Kidney cells, housed in an implantable bioreactor, have been shown survive inside the body of a pig, and mimic several important renal functions (Kim et al., 2023).
- Lasts up to 7 days in a pig without immune suppression or therapeutic systemic anticoagulation.
