Medicines in Kidney + Transplant

Kidney disease signs

  • Fluid Overload: oedema and hypertension
  • Electrolyte imbalance: hyperkaelemia, hyperphosphatemia and hypocalcaemia.
  • Acid-base imbalance: acidosis
  • Impaired excretion: uraemia (N/V), gout and protein/blood excretion
  • Impaired hormonal function: anemia, hypocalcaemia and hyperthyroidism + impaired BP
  • Impaired drug excretion: toxicities.

Classification

Acute Renal Failure: rapid onset (with hours and days) + identifiable cause and potentially reversible.

  • Anything that can cause hypoperfusion (reduce blood supply to kidney), intrinsic damage (physical/immune damage to nephron) or kidney obstruction (kidney stones)

Chronic Renal Failure: develops over months to years, a progressive irreversible decline in kidney function.

  • Anything that speeds up permanent damage.

Diagnosis

  • History + Physical examination (family history, dysuria/infection, nocturia)
  • Urinalysis and culture of fresh urine
  • Renal imaging: ultrasound or flowscan
  • Renal Biopsy
  • Renal function tests: Serum creatinine, urea, GFR.

Assessment of renal function:

  • Serum Creatine: useful for quick view on long term trend but SeCr changes only seen when >50% of kidney function is gone.
  • GFR: cockroft-gault formula or MDRD, simple calculations but requires height, weight and sex.

End Stage Renal Disease (GFR <15mL/min)

Treatment options:

  • Peritoneal Dialysis
  • Transplant
  • Haemodialysis

Haemodialysis: removal of waste and solutes from the body by perfusing blood and dialysate across a semi-permeable membrane.

  • Takes 3-5 hours

Peritoneal dialysis: Instil dialysis fluid (glucose solution) into peritoneal cavity. Removal of waste product via osmotic diffusion into the glucose solution.

  • Potential infection (glucose environment perfect for bacterial growth)
  • Better than haemodialysis as it portable.

Causes of death: Cardiac (40%), Social factors (27%), infection, malignancy, vascular and others (33%)

Causes of ESRD: - High BP and Protein in kidneys causes damage

  • Glomerulonephritiis (30%): Immune reaction causing inflammation of the glomeruli allowing proteins to leak through into kidneys and nephrons.


  • Diabetic Nephropathy (30%): Albumin in urine causing damage. Good diabetic control reduces albumin in the urine


  • Hypertension: cause and sign of renal failure. Occurs due to compensatory mechanism to maintain GFR. Improving BP can improve outcome and progression targeting BP of 130/80


Diabetic Nephropathy:

  • Insulin (clearance is dependent in renal function)
  • Metformin (not recommended in GFR < 60mL/min)
  • Sulphonylureas: Gliclazide is safest (shorter t1/2 and no active metabolites)
  • DPP4i: sitagliptan (Januvia) is extensively cleared, use with caution.

Glomerulonephritis treatment:

  • Immunosuppressant (if immune reaction) - prednisolone, cyclophosphamide, cyclosporin.
  • Antiproteinuric therapy - ACEi/ARBs
  • Acid Suppression: PPI (due to high dose of steroids)
  • Antibacterial prophylaxis: Bactrim (during cytotoxic therapy) or Resprim
  • Statins: low albumin levels due to excretion - liver ramps up protein production which also ramps up lipid production.

Hypertension:

  • ACEi/ARB: careful of renal function, can reduce function but stables out
  • Beta-blockers and diuretics
  • CCBs (similar reduction in BP but less antiproteinuric properties, verapamil and ditiazem have similar effect)

Nephrolithiasis (Kidney Stones)

  • More than 90% due to calcium deposits and ammonium phosphate.
  • 3% Uric acid
  • 1 % Cystine

Treat with:

  • Increased fluid intake to increase solubility
  • More acidic to change solubility
  • Surgery to physically remove

Signs and Symptoms of CRF and Uraemia

GI Signs: Nausea and vomiting, Weight loss
Fatigue and Lethargy: Anaemia
Uraemic Pericarditis: inflammation of the pericaridum in the heart
Cardiac: Pulmonary Oedema, enlarged heart
Bones and Joints: Bone pain and gout
Neurological: Poor concentration and sleep
Skin: Itchy and eruptions

Ususally asymptomatic until GFR is less than 15. Symptoms occur when there's a build up of uraemic toxins.

  • There is not official GFR

Renal Anaemia

Reduced RBC production: Reduced EPO production in the kidney causing iron and folate deficiency.
Increased RBC loss: RBC fragility and acute blood loss.

Treatment: Treat underlying cause first.

  • Erythropoietin (ESAs) - Stimulates production of RBC. Erythropoietin Beta has less injection pain.
    • Check other potential causes such as bleeding before use
  • Iron Supplement - IV is preferred, quick effect and no absorption limit and GIT upset.
  • Vitamin B, C and Folate - due to overall reduced intake of food
  • Transfusion in serious cases - rapidly correct Hb but increases risk of antibody formation , increasing risk of kidney rejection
    • Immunosuppression cover in transfusions: Cyclsporins, azathioprine or mycophenolate

Aim to correct haemoglobin and not restore to baseline/normal range to prevent overshooting and minimise rapid Hb rise.

CKD Mineral and Bone Disorder

  • Hyperphosphatemia and PTH build up

Renal failure reduces conversion of vitamin D into active form, thus reducing calcium absorption and increasing PTH levels.

  • Increased PTH causes breakdown of bone to maintain calcium levels in the blood.
  • Thus renal osteodystrophy occurs

High phosphate levels can cause extraskeletal calcification. Calcium and Phosphate complex in the blood causes vascular calcification, hardening the blood vessels = increasing CVD risk and complications.


  • Build up of phosphate also increases PTH to reduce phosphate absorption, but that also increases calcium reabsorption from the bone.
  • Treatment
  • Phosphate management: Restriction in phosphate intake from diet and provide adequate dialysis to flush phosphate out.

  • Phosphate binders with meals


    • calcium carbonate (cheap and accessible)
    • aluminium phosphate binders (potent but expensive and potential aluminium build up toxicity)
    • renagel (low potentcy and expensive but works)
    • lanthanum (rare earth element = expensive, high potency and not absorbed)
    • velphoro (well tolerated but some mild diarrhoea and dark stools)

  • Vitamin D/analogs: to reduce phosphate levels due of vitamin D deficiency


    • given active form of vitamin D (calcitriol)

  • Calcium supplement and calcimimetics (cinacalcet)

  • Parathyroidectomy

Calciphylaxis: Soft tissue calcification cuasing pain and requires amputation.

  • Treatment: oxygen tank
    • Administer sodium thiosulphate to reverse precipitation
    • Stopping warfarin to prevent worsening, due to warfarin promoting calcium deposition leading to calciphylaxis

Hyperkalemia

  • Treatment:
    • Modify diet to reduce K intake
    • Modify drugs (ACEi/ARBs and spironolactone)
    • Binding resin (Resonium 15-30g oral)
    • IV Insulin + Dextrose (shift glucose to shift K),
    • Salbutamol (shifts K intracellularly)
    • Dialysis (physical filtering)

Acid Base Imbalance

  • Body produces 1mmol/kig of metabolic acid daily and buffered by kidney's by producing bicarbonate.
    - Imbalance treatment = Sodibic (Sodium bicarbonate 840mg) 1-2 sachets tds OR add to dialysis filtrate

Bleeding and Anticoagulation

  • CKD patients have higher risk of bleeding.
  • LMWH accumulate in CKD thus use with care
  • Standard Heparin, Warfarin and Antiplatelets are dosed as normal initially.

Gout and Hyperuricemia

  • Renal Impairment builds up uric acid = increase potential for gout attacks
  • Allopurinol 100-200mg daily recommended due to active metabolite uses renal clearance.
  • Probenecid - for gout and hyperuricemia may require higher doses to get into kidney.
  • Caution with colchine (renally cleared) and Avoid NSAIDs

Restless Leg Syndrome

Distrubs sleep
Treatment: BZD (Clonazepam 0.5mg nocte) or Levo/carbidopa (100/25mg nocte)

Oedema and fluid overload

Reduced urine output and low albumin levels

  • Treatment
    • Loop diuretics (Frusemide)

GI Problems

  • Commonly experience anorexia, nausea, vomiting and constipation
  • Treatment
    • Dialysis
    • Antacids
    • PPIs
    • Coloxyl Senna or Sorbitol

Transplantation

Immune response to the antigens on the donated organ triggers T and B cell response. Matching blood type, HLA and cross-matching essential in minimising major rejection.

Immunosuppressant Therapy

Calcineurin Inhibitor: prevents NFAT translation thus prevent T-cell proliferation

  • Cyclosporin - used in very low/low risk transplant
    • Side effects: nephrotoxicity, aesthetic changes (hair growth), HTN and hyperlipidaemia
  • Tacrolimus - used in moderate to high risk transplant
    • Nephrotoxicity, HTN, Diabetes, Hyperlipidaemia

Antiproliferative agents: inhibits proliferation by blocking or disruptiing DNA base chains

  • Azathioprine - replaced with mycophenoate but used if cost is an issue for patient.
    • Side effects: skin photosensitivty, haematological reduction
  • Mycophenoate - IMPDH inhibitor selective of T and B cells, better ADRs than Azathiopurine and used in low to high risk patients.
    • Side effects: GI and Haemto effects

Steroids: to reduce inflammation and use its immunosuppresant side effect

  • Prednisolone - used in all approach of transplant
    • Switch from CNI in 4 months for very low risk patients
    • Fast taper for low risk patients
    • Slow taper for moderate to high risk.

Anti-body Induction: Anti-IL2 antibodies to prevent T-cell proliferation. Used in high risk patient to prevent rejection not treat.

  • Basiliximab - Dose given 2hr before surgery and 4 days post-op.
    • Effect lasts for 4-6 weeks used in low to moderate risk.
  • Anti-thymocyte globulin - used in high risk.

mTOR inhibitors: blocks the signals after IL-2 activation

  • Sirolimus - once daily for long term maintenance
  • Everolimus - BD dosing
    • switch from CNI in 4-6 months for very low to moderate risk and 12 months for high risk
      Less malignancy vs CNI and doesn't increase BP.
  • Side effects: delayed wound healing, hyperlipidaemia and haematological effects

Acute Rejection

Methylprednisolone: Short IV course (1g IV daily for 3 days) to help swelling and inflammation

Polyclonal antibodies: ATG, antibodies against T-cells. Will feel trash for first few days.

General immunosuppressed side effects

Infection: increase risk and reduced ability to fight infection.

  • Most common in weeks/months of therapy with UTIs, wounds and respiratory being most common.

Malignanacy: All cancers but prostate and breast increased risk.

  • Sun cancers can be prevented with sunscreen.

Drug Interactions and TDM

P-GP and 3A4 alterations

  • Especially for mTOR inhibitors due to low bioavailability
    • Changes to 3A4 = many folds of increases or decreases in drug concentration

TDM

  • Most fit the criteria for TDM
    • Narrow TPI
    • Poor relationship with dose and blood concentration
    • potential DDIs
  • Generally AUC is used for TDM

Compliance

  • Important as body never forgets and will attack new kidney as foreign object
  • Cost may drive non-compliance = may switch to generic BUT don't switch if stable already.
  • Missed doses = take within 6-8 hours of missed dose, or skip until next dose.

Monitoring for Cytomegalovirus Disease (CMV)

  • Normally suppresed by immune system
  • With immune compromised = nasty infection
    Treatment: Valcyte (prodrug to ganciclovir) for 3-6 months prophylaxis

Dosing in Renal Impairment

Assess degree of kidney damage and impairment

  • Assess stability: any big changes in GFR and serum creatinine
  • Clearance mechanism of the drug
    • any active metabolites (may need to reduce parent drug)
    • non active and non toxic metabolites may not require dose change
    • If Fe is low = no dose change
    • If Fe is high = dose change
  • Wide TI = No change
  • Narrow TI = dose change
  • Avoiding nephotoxic drugs if possible
    • PPIs and NSAIDs = Idiosyncratic reactions
    • Antivirals and Statins induced myopathy = block urine flow
  • Drugs aggravate metabolic changes
    • Hyperkalemia: ACEi/ARBs, K sparring diuretics and Eplerenone
    • Catabloic effects: Tetracycline
    • Sodium retention, fluid retention and anaemia
  • Changing doses
    • Dose method: reduce dose size with same intervals
    • Interval method: reduce intervals with same dose
    • Combination method: reduce dose size and increase intervals
    • 1 - Fe(1- % renal function) = % dose reduction
    • Changes must be practical

  • Pain relief:


    • Avoid NSAIDs
    • Avoid Morphine and pethidine
    • Use oxycodone or fentanyl

  • Diuretics


    • Avoid thiazides (less effective in low GFR)
  • Avoid K sparring diuretics
  • Use frusemide (loop diuretics)