Medicine SC067: Drug And The Kidney Flashcards
Kidneys physiology
- 25% of CO
- GFR + Renal tubular functions
- Other functions: Hormonal functions, Indirectly regulate blood vessels, lipids
- Susceptibility (Even more when there is CKD) to direct / indirect injury —> AKI —(if not reversed early)—> CKD
Drug use in patients with impaired renal function
Altered clearance +/- ↑ Susceptibility to adverse effects due to decreased renal function
—> Adjust dosage / frequency
Drugs and kidney:
1. Metabolised by kidney
2. Active metabolites excreted by kidney
Important principles in Drug prescription:
1. Avoid further nephrotoxic insult
2. Attention to correct dose / interval
3. Beware of SE that only occur in patients with impaired kidney function (that would not normally occur in normal patients)
- e.g. Ethambutol (retrobulbar neuritis), Acyclovir (CNS abnormalities), INAH, Quinolone, Imipenem
Reno-protection in patients with impaired renal function (CKD)
- Prevent additional insult to kidneys
- ***Optimal BP control
- ***Proteinuria reduction (via RAAS inhibition) (correlation between amount of proteinuria and rate of RFT deterioration)
- ACEI / ARB / Aldosterone antagonist / Renin inhibitor - ***SGLT2 inhibition (not only in diabetic but also non-diabetic kidney disease)
- No smoking (direct + indirect insult to kidneys)
- ***Vascular risk factors (accelerated vascular disease in CKD)
***Mechanisms of Drug-induced renal impairment
- Functional (i.e. **Haemodynamic)
- Impaired renal perfusion (e.g. **NSAID, ***ACEI (esp. in undiagnosed renal artery stenosis)) - Structural (i.e. **Renal parenchymal disease)
- **Immunological injury (Tubulointerstitial (more common) vs Glomerular)
- ***Direct toxicity to Tubular cells (Acute tubular necrosis (self notes))
NSAID:
- Inhibit COX —> Reduce PG —> Inhibit vasodilation —> esp. important in Hypoperfusion states (e.g. cardiac insufficiency, hypovolaemia, massive haemorrhage, nephrotic, cirrhosis)
RAAS blockage (ACEI, ARB, Aldosterone antagonist, Renin inhibitor):
- Inhibit vasoconstriction of efferent arteriole —> esp. important in renal artery stenosis, hypovolaemia, cirrhosis
- Caution
—> **Renal artery stenosis (exclude in patients with vascular risk factors)
—> **HyperK (may not need to stop drug —> have other measures to treat e.g. correct metabolic acidosis, diuretic)
—> ***Metabolic acidosis
Drug-induced Glomerular diseases
- Secondary membranous nephropathy (proteinuria / nephrotic syndrome range)
- Gold salts
- D-Penicillamine - Minimal change disease
- NSAID (can also cause Acute TIN)
(**Minimal change + **TIN —> think about NSAID)
D-Penicillamine
- Membranous nephropathy (85%)
- Immunological injury —> IgG deposition in subepithelium of GBM —> Podocyte injury
(- Anti-PLA2R much less common) - Mesangioproliferative
- Minimal change, Focal necrotising
- Resolve 6-8 months after withdrawal
- Sometimes resolve despite continue drug
- Rarely lupus-like syndrome, Goodpasture-like syndrome
Drug-induced Tubulointerstitial nephritis
- Most common type of drug-induced nephropathy
- Many drugs implicated
1. **Antibiotics (e.g. Methicillin, Rifampicin)
2. **NSAID
3. ***Immunotherapy
4. Many more - Many have other “allergic” features (e.g. Allopurinol —> skin manifestations, acute hepatitis)
- Not uncommon
Histology:
- Lymphocytes, Eosinophil (characteristic) infiltration
Effect:
- Acute kidney injury
- May lead to permanent damage
Management:
- Stop drug
- Immunosuppression (usually not necessary except in severe systemic response e.g. Drug-induced vasculitis, Immune CPI-associated AKI)
Immune CPI-associated AKI
Immune checkpoint inhibitors
- Monoclonal Ab targeting molecules on surface of T cells for treatment of solid organ / haematological malignancies
—> Increase T cell activity
—> Inadvertently have off-target effect
—> Acute TIN
Use of Steroid can return kidney function to normal
Drug Direct toxicity to Tubular cells
- Tubular cells are metabolically active cells
- Drugs that are concentrated in tubular cells can cause direct toxicity
- Antibiotics
- Aminoglycosides
- Cephalosporins (some)
- Quinolones - Lithium
- Cisplatin
- Methotrexate
- Nitrosoureas
- Adefovir, TDF (can cause Fanconi syndrome: group of tubular disorder) (vs TAF)
- Contrast media (removal other potential nephrotoxic factors e.g. hypovolaemia, other nephrotoxic drugs, good hydration)
- NSAID
Aminoglycoside
- Concentrated in kidneys
- Narrow therapeutic window
- Phospholipid brush border of proximal tubular epithelium
- Endocytosis
—> Inhibit Phospholipase
—> Accumulation of lipids
—> Modify enzyme activities, Na-K ATPase
—> Reduce lysosomal membrane permeability and mitochondrial respiration
Other effects:
- Nephrotoxicity
—> ARF (non-oliguric initially)
—> preceded by polyuria, tubular dysfunction
—> pathology: rarification then disappearance of brush border, enlarged lysosomes with myeloid bodies, mitochondrial swelling, tubular necrosis, regeneration
- Ototoxicity
Management:
- Clinical diagnosis is enough (no need biopsy)
- Check blood levels (available for certain aminoglycoside)
Risk factors for nephrotoxicity:
1. Dose + Duration of therapy (esp. worse if long duration of treatment e.g. endocarditis, abscess)
2. Hypovolaemia, Na depletion, K depletion (enhance susceptibility of nephrotoxic injury)
3. Other nephrotoxic agents
4. Pre-existing renal impairment
5. Clinical state (e.g. septicaemia)
Lithium
Effect:
1. ***Nephrogenic DI
- ∵ tubular toxicity —> impair concentrating ability of kidney
- ***CKD
- ∵ Chronic TIN (out of proportion to glomerulosclerosis, cysts, tubular dilatation)
- Histology: Inflammatory cell infiltration, Fibrosis, Renal tubular dilatation, Flattening of tubular cells - Acute lithium intoxication
- ***Hypothyroidism
- ***Hyperparathyroidism
Cisplatin
Effect:
1. Nephrotoxicity
2. Ototoxicity
3. GI
4. Myelosupression
Mechanism:
- ↑ Renal vascular resistance —> ↓ Renal plasma flow
- Dose >100 mg/m2 —> ↑ Risk of nephrotoxicity
- Tubular dysfunction may not correlate with ↓ CrCl
- Can be ***irreversible
Clinical features of nephrotoxicity:
1. **HypoMg (70-80%, may persist for months)
2. **HypoK
3. ***HypoCa
Histology:
- Focal ATN, distal and collecting tubule
- Dilatation of convoluted tubules
- Casts
Prevention:
- Hydration 200 mL/h during + 6 hours after Cisplatin
NSAID
Effect:
1. Na + fluid retention
2. Reduce renal blood flow + GFR
3. HyperK
4. TIN (acute + chronic)
5. Minimal change nephrotic syndrome
6. Papillary necrosis in DM patients + pyelonephritis (∵ impairment of perfusion of renal papilla)
NSAID-induced nephrotic syndrome + AKI
- **Minimal change GN
- **Acute TIN
- T lymphocyte + Eosinophils (40%)
- ?Higher risk in elderly
Calcineurin inhibitors (Cyclosporine / Tacrolimus)
Very wide pharmacokinetic + pharmacogenetics —> No fixed dose for every patient
Effect:
1. Acute nephrotoxicity
- Excessive drug exposure induces renal vasoconstriction —> ↓ Intra-renal blood flow —> Reversible if stop
- Enhanced by mTOR inhibitors
- Chronic nephrotoxicity
- Can be subtle initially
- Depends on susceptibility of patient (e.g. pre-existing CKD)
- Vasculopathy + Fibrosis (TGF-β) - Metabolic effects (~ ***Type 4 RTA ∵ inhibition on collecting tubule that transport K + H into luminal fluid —> retain K + H)
- Normal AG metabolic acidosis
- ↑ K
- ↑ Cl
- ↓ HCO3
- HT
- DM
Prevention:
1. Blood level monitoring
- Trough level (12 hours / 24 hours for long-acting after previous dose)
- C2 level (i.e. 2 hours after taking Cyclosporine)
Aristocholic acid nephropathy
Effect:
1. CKD
2. Uro-epithelial malignancies (can be multifocal)
