(9/21) Thambi Lecture: Drug-Induced Renal Disease Identifying Drug-Induced AKI [Drug-Induced] to be shorted to DI

- Sx: Decreased urination, hypervolemia (edema), N, Loss of appetite, Malaise, Confusion, SCr may lag behind renal damage by 1-2 days

Preventing DI AKI - Avoid nephrotoxic drugs in patients with risk factors for

AKI - Risk factors: Existing renal insufficiency, on other

nephrotoxic meds, intravascular volume depletion (dehydration, HF, Cirrhosis, Loop Diuretics), The elderly

Condition: Pseudo DI Renal Disease: Increased SCr due to competitive inhibition of creatinine secretion @proximal - Drugs: Trimethoprim (from Bactrim), Dronaedrone, Cimetidine [Create ‘false’ increase]

Condition: DI Renal Disease - PRE-RENAL: Similar to Pre-Renal AKI, DI involves reduced blood renal blood flow

o Cause: Loop Diuretics- Very common! § Will decrease Intravascular Volume, Decrease renal blood flow, decreased filtration, will result in

Increased SCr and AKI § Often occurs by inadvertent potent drug interactions – Loop + Thiazide

o Cause: ACE-I and ARBs § These drugs cause efferent renal artery vasodilation. Usually this all has little effect § Concurrent Renal Artery Stenosis: Stenosis involves decreased blood flow to the kidneys. The

RAAS system will act to compensate by causing efferent vasoconstriction. However, if using ACE-I/ARB to induce vasodilation, pressure will decrease again, and secretion will be unable to occur through the podocytes

§ à Bilateral Renal Artery Stenosis is a contraindication to ACE-I and ARB use o Cause: NSAIDs- occurs quickly, within days

§ NSAIDs block prostaglandin mediated vasodilation à Thus cause afferent vasoconstriction, which will reduce intraglomerular pressureà Decreasing filtration à Increasing SCr/AKI

§ Contraindication: NSAID + ACE-I/ARB, will cause double trouble o Cause: Cyclosporine and Tacrolimus- The sad irony for transplant patients

§ These drugs cause afferent vasoconstriction, potentially causing chronic ischemia of the tubulointerstitial compartment. This is dose-related, may reduce dose instead of d/c

- INTRINSIC: Involves multiple types, Glomerular Disease, ATN, Intratubular Obstruction, AIN o Glomerular Disease: Drug-induced autoimmune disease – drug allergy, very rare. It will cause

proteinuria and damage the glomerulus. Excess proteinuria à edema § Drugs: NSAIDs, Lithium, Quinolones, Bisphosphonates

o Acute Tubular Necrosis (ATN): Aminoglycosides (AG) are the classic cause. IV antibiotic used for gram(-) bacteria, with a rate 10-60%. Want to give as low a dose as possible. AG will accumulate in the lysosomes of the proximal tubule, burst them, releasing chemicals which can cause “autodigestion”. Since most of the action is in proximal tubule, which does 65% of the Na reabsorption, this can be bad.

§ Drugs: Aminoglycosides, Radiographic contrast media, cisplatin/carboplatin, amphotericin B § Prevention of ATN from Contrast Media: Pretreat with volume expansion (NS), or Ator 80mg. § With Carboplatin/Cisplatin, hallmark finding = hypomagnesemia, use IV hydration to maintain

urine output at 3-4L/day. § Amphotericin B = “Ampho-terrible”. Binds to ergosterol of membrane, causing necrosis in the

proximal tubule, resulting in a non-oliguric AKI. Also associated with rigors. • May choose to do Lipid formulations with long infusion time (avoids rigors)

o Intratubular Obstruction: Caused by precipitation of drug crystals in distal tubule. § Risk factors: Low urine volume (higher [drug]), Low urinary pH § Drugs: Acyclovir, Foscarnet, Methotrexate, Indinavir § Statin-Induced Rhabdomyolysis: Ocurs in 1/1000, leading to muscle cell injury/death

• Sx: Muscle pain (50%), Weakness, Red/Brown urine (heme), Elevated Creatine Kinase • Tx: Aggressive fluid resuscitation with NS and Alkalinization of Urine via Na-Bicarb

o Acute Interstitial Nephritis (AIN): Inflammation of the Kidney interstitium, allergic reaction.

§ May have other causes, but drug-induced 75% of the time. Methicillin is the famous cause § Drugs: ANY DRUG, but often Bactrim, beta lactams, Vanco, NSAIDs, Allopurinol, PPI § Hallmark Sx: Urine WBC casts § Tx: D/c offending drug, if no improvement in 3-7days, give Prednisone (corticosteroids) 40-60mg

qday until SCr is normal, then taper for 2-3 months. - POST-RENAL/Obstructive: DI Kidney stones

o Drugs: Triamterene (0.4%), Sulfadiazine (up to 30%) – poorly soluble (9/25) Drambarean Lecture: CKD I Review on Kidney Anatomy

- Cortex: The outer layer, comprises all the glomeruli, much of the proximal and distal tubules - Medulla: Inner layer with Loops of Henle and collecting tubules. 7-9 cone-shaped regions called pyramids that

extend into the renal pelvis at tips, which are important for urine concentration - Podocytes: They maintain the glomerular filtration barrier (integrity+selectivity), dysfunction may result in CKD

One function of the Kidney we have not discussed is its production and excretion of enzymes/hormones. This includes Renin, Erythropoietin, and 1,25-dihydroxyvitamin D3 Glomerular Filtration Rate (GFR): There may be substantial kidney damage before there is a decrease in GFR or SCr(d)

- Adjusted for body surface area, Normal Adults are 120ml/min (F) and 130ml/min (M) - To assess GFR, use a freely filterable substance, which is neither absorbed nor secreted by renal tubules

o Best examples: Inulin, Iothalamate, Iohexol - Often, however, we use CrCl, which is the end product of muscle catabolism, and its clearance is 15-20% higher

than actual GFR, thus it overestimates. Creatinine production relates directly to muscle mass. - Factors of SCr: Age, gender, diet, race, body habitus, meds - Cockcroft-Gault (CG): Most commonly used but least accurate, uses Age, SCr, Weight (*0.85 if female)

Chronic Kidney Disease (CKD) – A pretty expensive disease! High out-of-pocket costs for patients - Dx: Decrease in GFR (<60ml/min) and other abnormal functions of Kidney for more than 3 months

o Albumiuria >30mg/day, Hematuria (RBC casts), Electrolyte abnormalities - Epidemiology: 10% of US adults have CKD, Hispanics, AA, Native Americans are at higher risk.

o ESRD, 75% mortality rate within 5 years of initating dialysis - Sx: Edema, Decreased Urine output, Anemia, Abdominal Distention, Foamy urine, Fatigue, weakness, SOB,

Mental confusion, N/V, itching (phosphates), Cold intolerance, hypoglycemia, loss of appetite, HL o Electrolyte imbalance: K down, Na up, P up, Ca down, Uric Acid up o Patients begin to complain of symptoms when GFR is ~10-15ml/min – CKD stage 5

- Risk Factors: DM (#1), HT (#2), Proteinuria, AKI, Immunological disorders, Obesity, Smoking, AA, male, old, metabolic acidosis, hyperphosphatemia, HL, obstruction, hyperuricemia, Nephrotoxins (especially overuse), pregnancy, low birth weight

o When the glomerulus is damaged, larger molecules like albumin will be able to pass through and spill - Cause: DM: Damage will be done directly through hemodynamic modifications and inflammatory processes

o Hemodynamic Modification: RAAS activation, Vasoconstriction of efferent, Podocyte destruction o Inflammation: TNF-a and IL1,6,18

- Cause: Proteinuria: Upon podocyte destruction, diminished filtration barrier will allow proteins to leak out o à Overwhelms the proximal tubule to reabsorb [Microalbuminuria 30-300mg/day, Macro >300] o Dx: Spot test, early morning is recommended – correlates best to 24 hours collection.

§ If total P:Cr ratio >200mg/g à Damage § Nephrotic Syndrome: Urine Albumin >2200mg/day or urine protein excretion >3000mg/day

o Tx: Treat with ACE-I or ARB! They are renoprotective! Give even if normotensive. These will inhibit the vasoconstriction of the efferent arteriole. Usage with aldosterone antagonists may help, but increase K

§ 2nd line: Non-dihydropyridine CCB § It is important to reduce Na intake as well

- Cause: Hypertension: Will result from failure of primary protection via autoregulatory processes o Eventually, changes in extrarenal and renal vasculature involve breakdown of elastic fibers in arterial

circulation. à Nephrosclerosis: Narrowing of pre-glomerular arteries à decreased glomerular blood flow