1. Principles of drug prescribing in patients with impaired kidney function 2. Renal complications associated with drugs — examples, prevention & management

Past papers frequently test: dose adjustment principles (especially DPP-4 inhibitors, tenofovir, aminoglycosides), mechanisms of NSAID/ACEI-induced AKI, drug-induced tubulointerstitial nephritis, calcineurin inhibitor toxicity, contrast nephropathy prevention, and the concept that one drug can injure the kidney through multiple mechanisms. The GC 043 slides are the primary examinable source. ^[1][2][3]

Two levers to adjust:

• Reduce the dose (keep the same interval) — useful for drugs with concentration-dependent toxicity
• Extend the interval (keep the same dose) — useful for drugs with time-dependent efficacy (e.g., aminoglycosides where you want high peak but low trough)

DPP-4 inhibitors — endogenous incretin → ↑ insulin & ↓ glucagon in a glucose-dependent manner → blood glucose control ^[1]

The glucose-dependent mechanism means DPP-4 inhibitors carry low hypoglycaemia risk — important in CKD where hypoglycaemia risk is already elevated (reduced renal gluconeogenesis, reduced insulin clearance).

Tenofovir — HBV, HIV treatment; renal & bone side-effects; pharmacokinetic interactions with other HIV drugs ^[1]

Why TAF is better than TDF for the kidney:

• TAF is a prodrug with higher intracellular concentration and lower plasma concentration vs TDF ^[1]
• Lower plasma levels = less drug exposure to renal tubular cells = better renal (and bone) safety profile ^[1]
• TDF causes proximal tubular toxicity → can manifest as Fanconi syndrome (hyperphosphaturia, hypophosphataemia, glycosuria, aminoaciduria, type 2 RTA) ^[7]
• TDF also causes bone mineral density loss via phosphate wasting

NSAID → inhibit cyclo-oxygenase → ↓ PG (prostaglandin) → loss of vasodilation ^[1]

First principles explanation:

• Under normal conditions, the afferent arteriole is kept dilated by prostaglandins (PGE2, PGI2). This maintains renal blood flow and GFR.
• In hypoperfusion states (cardiac failure, hypovolaemia, haemorrhage, nephrotic syndrome, cirrhosis), the kidneys become increasingly dependent on prostaglandin-mediated vasodilation to maintain adequate blood flow. The sympathetic nervous system and RAAS are already causing systemic vasoconstriction — prostaglandins are the kidney's "safety valve."
• NSAIDs block COX → ↓ prostaglandins → afferent arteriole constricts → dramatic fall in renal blood flow and GFR → AKI

Hypoperfusion states — cardiac insufficiency, hypovolaemia, massive haemorrhage, nephrotic, cirrhosis ^[1]

NSAID can cause: ^[1]

• Sodium & fluid retention
• Reduce renal blood flow and GFR
• Hyperkalemia
• Tubulointerstitial nephritis
• Minimal change nephrotic syndrome
• Papillary necrosis in diabetic patients

This is a perfect example of the lecture's key teaching point:

One drug can lead to kidney complications through different / multiple mechanisms ^[1]

NSAID-induced nephrotic syndrome + AKI: minimal change glomerulopathy + acute tubulointerstitial nephritis ^[1] T lymphocytes, eosinophils (40%), ? higher risk in elderly ^[1]

This is a unique combination: the patient presents with both nephrotic syndrome (massive proteinuria, hypoalbuminaemia, oedema) AND AKI. On biopsy, you see minimal change disease in the glomeruli AND interstitial nephritis simultaneously. The eosinophilic infiltrate (present in ~40% of cases) is a clue to drug-induced AIN. Elderly patients are at higher risk.

Angiotensin II → vasoconstriction of efferent arteriole ^[1] Conditions: renal artery stenosis, hypovolaemia, cirrhosis ^[1]

First principles:

• The glomerulus has an afferent arteriole (blood IN) and efferent arteriole (blood OUT).
• GFR depends on the pressure gradient across the glomerular capillary. Angiotensin II preferentially constricts the efferent arteriole → increases pressure within the glomerular capillary → maintains GFR even when systemic BP drops.
• ACEI/ARB blocks angiotensin II → efferent arteriole dilates → intraglomerular pressure drops → GFR falls.
• In normal people, this modest GFR drop (up to ~25%) is tolerable and even beneficial long-term (less hyperfiltration injury).
• But in renal artery stenosis, the kidney is already underperfused. The only thing maintaining GFR is efferent constriction by Ang II. Block it → GFR crashes → AKI.

Cautions with RAAS Blockade (ACEI / ARB / Aldosterone Antagonist / Renin Inhibitor): ^[1]

• Renal artery stenosis [patients with vascular risk factors]
• Hyperkalaemia
• Metabolic acidosis

Why hyperkalaemia? Aldosterone drives K+ secretion in the collecting duct. Block RAAS → ↓ aldosterone → ↓ K+ excretion → hyperK. This risk is compounded in CKD (already ↓ K+ excretion), DM (type 4 RTA), and with concurrent K-sparing drugs.

Why metabolic acidosis? Aldosterone also promotes H+ secretion in the collecting duct (via H+-ATPase). ↓ Aldosterone → ↓ H+ excretion → non-anion gap metabolic acidosis (type 4 RTA).

Why membranous? Gold and penicillamine cause immune complex deposition along the glomerular basement membrane (subepithelial deposits). This is "secondary" membranous because there is an identifiable cause (vs. primary/idiopathic membranous which involves anti-PLA2R antibodies).

Many drugs implicated: ^[1]

• Antibiotics (e.g. methicillin, rifampicin)
• NSAIDs, immunotherapy
• May have other 'allergic' features (e.g. allopurinol)
• Not uncommon

Classic triad of drug-induced AIN (though only present in ~30% of cases):

1. Fever
2. Rash
3. Eosinophilia ^[10]

These represent a systemic hypersensitivity reaction. The kidney shows interstitial oedema, inflammatory cell infiltration (lymphocytes, eosinophils, macrophages), and tubular damage.

AKI — may lead to permanent damage ^[1] Management — STOP the incriminated drug ^[1] ? Immunosuppression (usually not necessary, except in drug-induced vasculitis, immune CPI-associated AKI?) ^[1]

Key management principle: The most important step is drug withdrawal. Most cases recover. Steroids are controversial — generally reserved for:

• Cases not improving after drug withdrawal
• Drug-induced vasculitis (requires immunosuppression)
• Immune checkpoint inhibitor (CPI)-associated AIN (emerging indication) ^[1]

CPIs — monoclonal antibodies targeting molecules on the surface of T cells for treatment of solid organ or haematologic malignancies ^[1]

This is an increasingly tested topic as immunotherapy becomes more common.

Key data (Cortazar et al., Kidney Int 2016): ^[1]

• Onset: 21–245 days, one case 2 months after last CPI dose
• Urine WBC present in 8/13
• Peak Cr 3.6–7.3 mg/dL; 4 patients required HD
• Pathology: acute TIN 12/13, granulomatous 3/13, TMA 1/13
• 10 treated with steroid: 2 complete, 7 partial improvement
• 2 with AIN not given steroid did not improve

Clinical pearls:

• CPI nephrotoxicity can present weeks to months after the last dose — late onset!
• The predominant lesion is acute TIN (not glomerular)
• Steroids seem to help — unlike most drug-induced AIN where steroids are optional
• Extra-renal immune-related adverse events (irAEs) were present in 7/13 — look for colitis, hepatitis, thyroiditis, dermatitis as clues

Concentrated in kidneys → phospholipid brush border of proximal tubular epithelium → endocytosis → inhibit phospholipases → accumulation of lipids → modify enzyme activities → Na-K ATPase inhibition → reduce lysosomal membrane permeability and mitochondrial respiration ^[1]

Step-by-step mechanism:

1. Aminoglycosides (gentamicin, amikacin, tobramycin) are polycationic molecules that bind to megalin receptors on the proximal tubular brush border
2. They are internalized via endocytosis into lysosomes
3. Inside lysosomes, they inhibit phospholipases → phospholipid accumulation → formation of "myeloid bodies" (lamellar structures seen on EM)
4. They also impair mitochondrial respiration and Na-K ATPase activity
5. This leads to cellular energy failure and tubular cell necrosis
6. Clinically: non-oliguric AKI initially, preceded by polyuria and tubular dysfunction ^[1]

Pathology: rarefication then disappearance of brush border; enlarged lysosomes with myeloid bodies; mitochondrial swelling; tubular necrosis; regeneration ^[1]

Risk factors for aminoglycoside nephrotoxicity [note narrow therapeutic window]: ^[1]

• Dose & duration of therapy
• Na depletion, hypovolaemia, K depletion
• Other nephrotoxic agents
• Pre-existing renal impairment
• Clinical state e.g. septicaemia

Clinical approach to safe aminoglycoside use:

• Use once-daily (extended-interval) dosing — achieves high peaks (bactericidal) with prolonged low troughs (less tubular uptake)
• Monitor trough levels (pre-dose) — trough > 2 μg/mL for gentamicin = nephrotoxic
• Ensure euvolaemia — dehydration concentrates the drug in tubules
• Limit duration — shortest effective course
• Avoid concurrent nephrotoxins (NSAIDs, contrast, vancomycin)

Lithium nephrotoxicity: ^[1]

• Nephrogenic diabetes insipidus
• CKD — chronic tubulointerstitial nephropathy (out of proportion to glomerulosclerosis, cysts and tubular dilatation)
• Acute lithium intoxication
• [Lithium could also lead to hypothyroidism and hyperparathyroidism]

Nephrogenic Diabetes Insipidus (NDI):

• Lithium enters collecting duct principal cells via ENaC channels
• It accumulates and interferes with aquaporin-2 (AQP2) trafficking — AQP2 channels cannot be inserted into the apical membrane in response to ADH
• Result: the collecting duct cannot respond to ADH → water cannot be reabsorbed → dilute polyuria (up to 3–12 L/day) with polydipsia
• This is the most common renal effect of lithium (~40% of long-term users)
• Usually reversible if caught early, but may become permanent with prolonged use

Quiz from lecture: "What is nephrogenic diabetes insipidus and how does it manifest?" ^[1]

• Answer: NDI is the kidney's inability to concentrate urine despite adequate/elevated ADH levels. It manifests as polyuria (large volumes of dilute urine, low urine osmolality) and polydipsia (compensatory water intake). Distinguished from central DI by the water deprivation test — in NDI, urine does NOT concentrate after desmopressin (DDAVP) administration.

Lithium-associated CKD: Chronic tubulointerstitial nephropathy with a characteristic pattern — tubular atrophy, interstitial fibrosis, cysts, and tubular dilatation, with relatively preserved glomeruli (out of proportion to glomerulosclerosis). ^[1]

Cisplatin: nephrotoxicity, ototoxicity, GI, myelosuppression ^[1]

• Dose > 100 mg/m² → ↑ risk of nephrotoxicity
• ↑ renal vascular resistance → ↓ renal plasma flow
• Tubular dysfunction may not correlate with ↓ CrCl

Pathology: focal ATN, distal & collecting tubular damage, dilatation of convoluted tubules, casts. Can be irreversible. ^[1]

Electrolyte consequences: ^[1]

• Hypo Mg — 70–80%, may persist for months
• Hypo Ca
• Hypo K

Mechanism: Cisplatin is a platinum-based chemotherapy agent that is concentrated in renal tubular cells (especially proximal and distal tubules). It causes:

• Direct DNA damage in tubular cells
• Mitochondrial dysfunction
• Oxidative stress
• Inflammation and apoptosis

Why hypomagnesaemia? Cisplatin damages the thick ascending limb of the Loop of Henle and distal convoluted tubule where Mg²⁺ is reabsorbed via TRPM6 channels. This magnesium wasting can persist for months after cisplatin discontinuation.

Prevention: hydration 200 mL/h during and for 6 hours after cisplatin ^[1]

This aggressive IV hydration dilutes cisplatin in the tubular lumen, reduces contact time with tubular epithelium, and maintains renal blood flow.

Acute nephrotoxicity — reduced intra-renal blood flow, enhanced by mTOR inhibitors ^[1] Chronic nephrotoxicity — vasculopathy and fibrosis (TGF-beta) ^[1] Blood level monitoring ^[1] Modulatory effect on podocytes ^[1]

Metabolic effects: ^[1]

• ↑ K (hyperkalaemia)
• ↓ Cl (but actually often ↑ Cl with metabolic acidosis)
• ↓ Bicarbonate (metabolic acidosis)

Why hyperkalaemia? Calcineurin inhibitors suppress renin secretion and reduce aldosterone levels (similar to type 4 RTA). They also directly inhibit potassium secretion in the collecting duct via Na-K-2Cl cotransporter and ROMK channel effects.

Why blood level monitoring? These drugs have a narrow therapeutic window — too little = rejection (in transplant), too much = nephrotoxicity. Trough levels are measured routinely. ^[1][12]

Quiz from lecture: "Which of the following are potential side-effects of calcineurin inhibitors?" ^[1]

• A. Hypertension — YES (afferent vasoconstriction, Na retention)
• B. Hyperglycaemia — YES (tacrolimus > cyclosporin; ↓ insulin secretion)
• C. Hyperkalaemia — YES
• D. Metabolic acidosis — YES
• E. Nephrotoxicity — YES
• Answer: ALL of the above ^[1]

Toxicity to renal tubular cells → ↓ renal function / abnormal urine ^[1]

Susceptibility / Risk Factors: ^[1]

• Hypovolaemia, renal insufficiency, DM, dose, myeloma, other nephrotoxic agents, elderly

Prevention: ^[1]

• Patient selection
• Hydration
• ? N-acetyl cysteine
• ? Sodium bicarbonate
• Choose the imaging modality wisely

Contrast-induced nephropathy (CIN) / Contrast-associated AKI:

• Definition: Rise in serum creatinine ≥ 25% or ≥ 44 μmol/L within 48–72 hours of contrast administration
• Mechanism: Direct tubular cell toxicity + renal vasoconstriction (medullary ischaemia)
• Usually self-limiting (creatinine peaks at 3–5 days, returns to baseline by 7–14 days)
• But can cause permanent damage in high-risk patients

Prevention strategy:

• Hydration is the most important measure — IV 0.9% NaCl before, during, and after procedure
• N-acetyl cysteine: evidence is weak/mixed, but still used in some protocols (low cost, low risk)
• Sodium bicarbonate: alkalinizes tubular fluid, may reduce free radical injury; evidence also mixed
• Minimize contrast volume; use iso-osmolar or low-osmolar contrast agents
• Choose wisely: if ultrasound or MRI can answer the clinical question, avoid contrast CT

Expansion and fibrosis of dermis → thickened and hardened skin and internal organs ^[1] MRI with gadolinium in patients with moderate/severe renal failure (esp GFR < 30 mL/min) ^[1] ? Low risk with group 2 gadolinium ^[1]

Why does this happen? Gadolinium-based contrast agents (GBCAs) used in MRI are normally cleared by the kidneys. In severe CKD, gadolinium stays in the body longer → free gadolinium dissociates from its chelate → deposits in tissues → triggers a fibrotic response similar to systemic sclerosis.

Risk stratification: Group 1 agents (e.g., gadodiamide, gadopentetate) have the highest risk. Group 2 agents (e.g., gadobutrol, gadoterate) have very low/negligible risk and are preferred in CKD. Avoid GBCAs entirely if GFR < 15 unless absolutely essential.

Inhibit osteoclast-mediated bone resorption e.g. metastatic bone disease, osteoporosis ^[1] 40–60% bound to bone, remainder excreted unchanged through kidney (both glomerular filtration and active tubular secretion) ^[1] Tubular toxicity with ↓ renal function may occur with IV high-dose ^[1] Collapsing FSGS associated with IV high-dose ^[1]

Key points:

• Oral bisphosphonates (alendronate, risedronate) — generally safe in mild-moderate CKD
• IV bisphosphonates (zoledronic acid, pamidronate) at high doses for malignancy — risk of ATN or collapsing FSGS
• Contraindicated when eGFR < 30 mL/min ^[13]
• Important to check renal function before administering IV bisphosphonates

CKD + uro-epithelial malignancies ^[1]

This is the classic example of herbal/traditional medicine nephrotoxicity:

• Aristolochic acid is found in certain Chinese herbal medicines (e.g., Aristolochia species, guang fang ji)
• Causes chronic tubulointerstitial nephritis → progressive CKD
• Also a potent carcinogen → increased risk of upper urinary tract transitional cell carcinoma
• First described as "Chinese herb nephropathy" / "Balkan endemic nephropathy"
• Irreversible — no specific treatment once established
• Must screen for uro-epithelial malignancy in affected patients

Oral sodium phosphate bowel purgatives + dehydration → acute/chronic renal failure ^[1] Intra-tubular calcium phosphate precipitation ^[1] Avoid in high-risk patients — use alternatives e.g. polyethylene glycol ^[1]

Clinical scenario: Patient undergoing colonoscopy preparation with oral sodium phosphate (e.g., Fleet Phospho-soda). In patients with CKD, elderly, or dehydrated patients:

• Massive phosphate load → hyperphosphataemia → severe hypocalcaemia (life-threatening)
• Calcium-phosphate product rises → precipitates within renal tubules → acute phosphate nephropathy → may cause permanent CKD
• Prevention: Use polyethylene glycol-based preparations (e.g., GoLYTELY, Klean-Prep) instead — they are osmotic laxatives without phosphate load

• Drug-induced kidney disease can be classified temporally: Acute (< 7 days), Subacute (7–90 days), Chronic (> 90 days) ^[9]
• Manifestations include: vasoconstriction, glomerular disease, tubular toxicity, tubulointerstitial nephritis, nephrolithiasis, crystalluria — "drugs can affect every single step of the pathway" ^[9]

• Kidneys receive normalized blood flow of 3,333 mL/min/kg — highest of any organ
• Understanding clearance: renal clearance = GFR × free fraction for drugs cleared by filtration; add tubular secretion for drugs like penicillins

• Drug-induced AIN is an important cause of intrinsic renal AKI
• Biopsy findings: interstitial oedema, lymphocytic/eosinophilic infiltrate, tubulitis

• Elderly patients have reduced GFR (age-related decline), making them more susceptible to drug accumulation and nephrotoxicity
• NSAIDs and aminoglycosides appear on Beers Criteria for potentially inappropriate medications in the elderly

• Post-transplant patients require calcineurin inhibitors — understanding acute vs chronic CNI nephrotoxicity is essential for transplant medicine

1. "A 65-year-old man with CKD stage 3b (eGFR 35) and T2DM. Which DPP-4 inhibitor can be prescribed at full dose without renal adjustment?"

   • Answer: Linagliptin — hepatobiliary elimination, no renal dose adjustment needed ^[1]

2. "Which of the following is NOT a risk factor for aminoglycoside nephrotoxicity?" (List: hypovolaemia, hyperkalaemia, pre-existing CKD, concurrent NSAIDs, high dose)

   • Trap: Hyperkalaemia is a consequence of aminoglycoside toxicity, not a risk factor for it ^[1]

3. "A patient on long-term lithium presents with polyuria and polydipsia. Serum Na 148, urine osmolality 180 mOsm/kg. After DDAVP, urine osmolality remains 200 mOsm/kg. Diagnosis?"

   • Answer: Nephrogenic diabetes insipidus — urine fails to concentrate after DDAVP because the collecting duct cannot respond to ADH ^[1]

4. "List 4 renal complications of NSAIDs and explain the mechanism for each." (4 marks)

   • ↓ RBF/GFR: COX inhibition → ↓ PG-mediated afferent vasodilation
   • AIN: T-cell mediated hypersensitivity
   • MCD: altered T-cell function → podocyte injury
   • Papillary necrosis: medullary ischaemia (chronic PG inhibition)

5. "A 72-year-old woman with eGFR 25 is prescribed oral sodium phosphate for colonoscopy preparation. What complication may occur and how would you prevent it?" (3 marks)

   • Acute phosphate nephropathy: hyperphosphataemia → intra-tubular CaPO₄ precipitation → AKI/CKD
   • Prevention: use polyethylene glycol-based preparation instead; ensure adequate hydration

6. "Compare TDF and TAF in terms of renal safety." (3 marks)

   • TAF is a prodrug with higher intracellular and lower plasma concentration
   • Lower plasma levels = less tubular exposure = better renal safety profile
   • TDF causes proximal tubular toxicity (Fanconi syndrome); TAF has much lower risk

7. Patient on ipilimumab develops rising creatinine 3 months after starting treatment. Urine shows WBCs. Biopsy: acute TIN with granulomatous features.
   • Diagnosis: Immune checkpoint inhibitor-associated AKI
   • Management: Corticosteroids (steroids shown to improve outcomes); hold/discontinue CPI
   • Key: onset can be delayed (weeks to months after last dose) ^[1]