IE 3: DIKD

What is the most common manifestation in Drug induced kidney injury?

• Decline in glomerular filtration rate (GFR) which results in rise of Scr and BUN

Initial diagnosis of DIKD is delayed because what?

• Bc it is based on detection of elevated Scr and BUN for which there is a temporal relationship between kidney injury and exposure to nephrotoxic drug

What causes hemodynamically mediated kidney injury? How do we prevent this?

• ACEI and ARBs

• NSAIDs and Selective COX2 inhibitors

• Calcineurin inhibitors (Tacro and Cyclosporine)

How do ACEI cause kidney injury?

• ACEI inhibit synthesis of angiotensin II which dilate the efferent arteriole → reduce outflow resistance and decrease GFR

How do NSAIDs cause kidney injury?

• Constrict the AFFERENT ARTERIOLE → decrease GFR

Instead of NSAIDs and COX-2 inhibitors, what can you use?

• AVOID indomethacin (potent)

• Use APAP, nonacetylates salicylates, aspirin, and even nabumetone when anti inflammation needed

• Tramadol (nonnarcotic analgesic) can be useful but do not provide anti-inflammatory activity

How do calcineurin inhibitors cause kidney injury?

• Afferent vasoconstriction with reduced GFR

Aminoglycoside associated ATN is due to accumulation of high drug concentrations within what?

• Within proximal tubular epithelial cells and subsequent generation of reactive oxygen species that produce mitochondrial injury → cellular apoptosis

What causes acute tubular necrosis in aminoglycosides?

• Number of cationic groups (-NH2)

  • Neomycin, gentamycin, tobramycin, amikacin

  • The number of cationic groups on the drug appears to correlate to nephrotoxicity → Neomycin is most toxic because it has the most NH2 groups

How does radiographic contrast media cause nephrotoxicity? What are risk factors?

• Renal ischemia results from systemic hypotension and nephrptoxiity and simultaneous acute vasoconstriction caused by disruption of normal prostaglandin synthesis

• Cellular toxicity is also related to duration of tubular cell exposure to contrast

  • Risk factors: GFR <60, concurrent use of NSAIDs, ACEI, aminoglycosides

How does Cisplatin cause nephrotoxicity?

• Tubular cell injury and death via necrosis and/or apoptosis

  • Accumulation in proximal tubular epithelial cells

If you have cisplatin nephrotoxicity, what can you do for prevention?

• Dose reduction and decreased frequency of administration

• Use of hypertonic saline (3% saline) to reduce tubular cisplatin uptake

• Amifostine, an organic thiophosphate that is converted to active metabolite can reduce the Cisplatin nephrotoxicity

What is the pathogenesis of amphotericin B neprhotoxicity?

• Direct tubular epithelial cell toxicity → interaction of amphotericin B with ergosterol in cell membrane → necrosis of proximal tubular cells

• Exacerbated by ischemic injury which is result of reduction in renal blood flow and GFR bc vasoconstriction

What is characteristic of glomerular disease?

• Proteinuria, particularly nephritic range PROTEINURIA (urine protein greater than 3.5 g/day per 1.73 m²) with or without a decline in the GFR is hallmark

In tubulointerstitial disease, what drug can cause chronic interstitial nephritis?

• Lithium

What is the pathogenesis of lithium?

• Lithium induced nephrogenic diabetes insipidus: lithium reduces the kidney’s ability to concentrate urine → lithium down regulates aquaprin 2 water channel expression

For tubulointersititial disease, what is the pathogenesis of aristolochic acid?

• Aristolochic acid is metabolized to mutagenic compounds called aristolactam 1 and II → from aristolochic acid DNA adducts in humans → DNA damage and apotosis

In tubulointersititial disease, what is papillary necrosis?

• Necrosis of renal papillae → collecting ducts enter renal pelvis which leads to progressive kidney disease

In Obstructive nephropathy, what is intratubular obstruction? (Direct)

• Direct means precipitation of the drug itself

  • Acyclovir, Foscarnet complexation with CALCIUM ION

  • Indinavir, Sulfadiazine, methotrexate may precipitate in acidic urine

In Obstructive nephropathy, what is intratubular obstruction? (Indirect)

• Antineoplastic drugs: intratubular precipitation of uric acid crystals

• HMG-CoA reductase inhibitors or statins: intratubular precipitation of myoglobin (drug induced rhabdo)

• Warfarin: RBCs

What is the pathogenesis in nephrocalcinosis for obstructive neprhopathy?

• extensive tubulointerstitial precipitation and deposition of calcium phosphate crystals leading to marked tubular calcification. associated with hypercalcemia and hypercalciuria