Drug induced nephritis

transcript

Acute Renal Failure and Drug-Induced Nephrotoxicity

Case Presentation

Joseph O. Oweta Intern Pharmacist ( MNRRH)Karen Ng, BScPharm, ACPR, UBC PharmD Candidate

April 4, 2013

Case: NJ

• ID: NJ, 12 yo female; ~40 kg• PC: Fever, hematuria, facial swelling x 2 wks (worse

in morning)• HPI: – Unwell since 3 wks ago, high grade persistent fever– Taken to clinic, diagnosed with malaria– Self referral to Naguru hospital after vomiting 6-7x/d– At Naguru hospital, treated for bronchopneumonia and

malaria frequency of vomiting reduced– Decreased urine output

Case: NJ

• NKDA• Meds PTA: – Ceftriaxone 1 g IV x 2– Gentamicin 2 doses– Hydrocortisone – Cefixime– Atemisinin/lumefantrines– Salbutamol– Paracetamol

Case: NJ

• PMHx:– SVD– Birth weight ¬5 kg; delivered in clinic– Breastfed for 5 months then started on soft feeds.

Has been feeding well– Immunizations UTD– Normal growth and development– P3 pupil, last born of 6 children, elder siblings alive

and well

Case: Physical ExamVitals T 35.8oC, HR 88, BP 110/75, RR 35

HEENT Facial swelling since 2 weeks ago; severe in the morning, reduces throughout day

CNS Fully conscious, no focal neurological deficits

CVS S1, S2 normal; no added sounds

Resp No distress, bronchovesicular breath sounds

GI Soft, liver 3 cm below costal margin, no splenomegaly, no renal angle tendernessLower abdo pain: severe, persistentPoor appetite, no diarrhea, previous vomiting

GU Hematuria, ?reduced urine output, normal frequency (5x/day), no dysuria

Case: Labs (Mar 20, 2013)

• CBC: WBC 9.97 Neut 6.57, Hgb 5.8 g/dL, Plt 624– RBC 2.29, HCT 17.3%, MCV 75.5 fL, MCH 25.3 pg, MCHC 33.5 g/dL,

RDW-CV 16.4%– Severe anemia, thrombocytosis

• Liver: Alb 36.6, ALT 5.3, AST 21.5, Bili: 2.3, GGT: 26.8, Total protein 74.3

• Amylase: 69.9• Renal: SCr 1711 umol/L, Cl: 89.8, K: 7.57, Na: 127.5, BUN: 51.2

mmol/L• ASO ver. 2 (specific proteins) : 279.30 IU/mL (ref: 0.00-200.00)

– Mar 25• No MPS

Case: Laboratory SummaryMar 20, 2013 Mar 25, 2013

CRE 1711 394

Na 127.5 133

K 7.57 4.07

Hb 5.8 8.2

Case: diagnostics

• Abdo U/S (Mar 19, 2013)– Kidneys: increased echogenicity with scarring of renal

cortex– Bladder normal– Uterus normal– Liver/spleen normal– Bowel loops normal– U/S scan findings suggestive of renal parenchymal disease

• Urinalysis– Normal colour

Case: Diagnosis

• Diagnosis: – Acute glomerular nephritis– R/O nephrotic syndrome– Severe anaemia secondary to haematuria?– UTI??

Case: Treatment

• Admit to acute care unit• Transfused x 1• Abx– Ceftriaxone 1 g IV q24h (Mar 20- 25)– Prednisolone 10 mg po bid x 1 wk (Mar 20-26) – Ampicillin 500 mg IV q6h (Mar 25-

• Paracetamol 500 mg po tds x 3d) • Folic acid 10 mg po daily x 1 month• Multivitamins 10 mg po daily x 1 wk

Case: NJ

Summary:7 yo female with 3 weeks hx of vomiting 2 wks of body swelling starting with facial swelling that resolves with increasing hours of day, 10 days lower abdo pain with hematuria, presenting with acute renal injury

Case:Questions to Consider

• What is the etiology of NJ’s acute renal failure? What are possible drug causes?

• How should NJ’s acute renal failure be managed?

• Considering possible drug causes, which are the most likely in NJ’s case?

Objectives

1. Define acute kidney injury (AKI).2. Understand the stages of AKI based on RIFLE classification

systems.3. Be familiar with the three pathophysiological categories of

AKI and some of the etiologies behind the three major categories.

4. State the 3 types of intrinsic acute renal failure and the related drug causes

5. Describe the mechanisms of drug-induced nephrotoxicities specifically relating to acute renal failure

6. Identify patients at risk for renal injury and strategies for prevention.

Acute Kidney Injury (AKI)

• Abrupt and sustained decrease in renal function resulting in retention of nitrogenous (urea and creatinine) and non-nitrogenous waste products

The Kidney is Vulnerable

• Responsible for excretion of many drugs• Routinely exposed to high concentrations of

drugs and metabolites• Nephrotoxins can accumulate– Kidney is highly vascular– Reabsorption of glomerular filtrate increases

intraluminal nephrotoxin concentrations

KDIGO Definition of AKI

KDIGO = Kidney Disease: Improving Global Outcomes

• An increase in serum creatinine of ≥ 0.3 mg/dL ≥26.5 μmol/L (0.3 mg/dL ) within 48 hours

• An increase in serum creation of ≥1.5 times baseline, which is known or presumed to have occurred within the prior 7 days

• Urine volume <0.5 mL/kg per hour x > 6 hours

Kidney Int Suppl 2012; 2:8

RIFLE Classification of AKI Severity

Can you classify NJ’s AKI based on RIFLE staging systems? What

information do you need?

• Missing information:– Urine output– Serial/repeat SCr

What are the four drug-related renal syndromes?

• Drugs can cause four major renal syndromes:1. Acute renal failure2. Nephrotic syndrome3. Renal tubular dysfunction with renal potassium

wasting and acidosis4. Chronic renal failure

Etiology of Acute Renal Failure

• Pre-renal causes• Intrinsic causes• Post-renal causes

Etiology of Acute Renal FailurePre-renal •Underperfusion of otherwise normal kidney

•Quickly reversible with appropriate therapy•Continued renal hypoperfusion can progress to intrinsic renal failure

Intrinsic •Disease of the renal parenchyma•Most often caused by renal hypoperfusion or ischemia, endogenous and exogenous nephrotoxic substances

Post-renal •Obstructions within urinary tract (e.g. blood clots, stones)•Extrinsic obstructions (e.g. tumors, retroperitoneal fibrosis)

http://www.clevelandclinicmeded.com/medicalpubs/diseasemanagement/nephrology/acute-kidney-injury/

Evaluation of Etiology of AKI• Findings that suggest prerenal causes:

– Volume depletion or shock states– Congestive heart failure– Severe liver disease or other edematous states

• Findings that suggest intrinsic renal disease– Exposure to nephrotoxic drugs or hypotension– Recent radiographic procedures with contrast

• Findings that suggest postrenal causes– Palpable bladder or hydronephrotic kidneys– Enlarged prostate– Abnormal pelvic examination– Large residual bladder urine volume– History of renal calculi

Evaluation of AKIPatients at Risk

Pre-renal AKI •Patients with compromised renal blood flow• Bilateral renal artery stenosis

•Patients with decreased effective circulatory volume• Cirrhosis• Nephrotic syndrome• Heart failure

Intrinsic AKI •Exposure to nephrotoxic drugs (see intrinsic AKI slides)Post-renal AKI

•Severe volume depletion•Underlying renal insufficiency•Bolus drug administration•Metabolic disorders (e.g. metabolic acidosis or alkalosis)

Drug Causes of AKIPre-renal AKI •Drugs may reduce volume or pressure or both of

blood delivered to kidney•Diuretics, radiocontrast media, cyclosporine, tacrolimus, NSAIDs, interleukin-2, ACEI

Intrinsic AKI •(see intrinsic AKI slides)

Post-renal AKI

•Crystal formation: acyclovir, sulfonamides, methotrexate, indinavir, triamterene, vitamin C in large doses

Urinary Findings of AKIPre-renal AKI •Low urine volume and sodium excretion

•High osmolality•Urine sediment usually without casts, RBC, WBC, protein

Intrinsic AKI •(see intrinsic AKI slides)

Post-renal AKI

•Urine sediment may contain RBC, WBC, crystals

What are the possible causes of NJ’s AKI?

• Prerenal: decreased fluid intake?• Intrinsic:– Allergic reaction to antibiotic– Nephrotoxic antibiotics

• Postrenal: ultrasound did not demonstrate obstruction

Prerenal/ Volume Responsive AKI

• Etiology:– Renal losses– GI losses– Fluid sequestration, inadequate perfusion pressures

• Capillary leak (sepsis)• Hypoalbuminemic states

– CHF– Cirrhosis, splanchnic vasodilation, hypoalbuminemia

– Impaired renal autoregulation• ACEI/ARBs• Contrast, calcineurin inhibitor, ampho B, vasopressors (osmotic

vasoconstriction off AA)• NSAIDs• Vascular disease exacerbation

Prerenal/ Volume Responsive AKI

• Diagnostics– Pre-renal urine biochemistry• Hyaline casts or granular casts, bland sediment• Increased osmolality > 500• Decreased sodium• Decreased fractional excretion of sodium, urea, uric

acid, lithium• SCr:BUN < 12.4 signals pre-renal

What are the 3 types of intrinsic ARF?

1. Acute tubular necrosis (ATN)2. Acute intrinsic nephritis (AIN)3. Thrombotic microangiopathy

Differentiation Between ATN and AIN

Intrinsic AKIMechanisms of Injury

Acute Tubular Necrosis

•Direct tubular toxicity•Deranged cellular energy production•Free radical injury•Heme tubular toxicity•Abnormal phospholipid metabolism•Intracellular calcium toxicity•Usual sites of injury: early or late segments of proximal tubule

Acute Allergic Interstitial Nephritis

Aminoglycosides ATN– Gradual increase SCr after 5-10 days– Tubular epithelial cell damage leading to obstruction of

tubular lumen– Non-oliguria >500 mL/day; granular casts in urine– Risk factors:

• Combination with other nephrotoxic drugs• Total cumulative dose; trough levels >2 mg/L• Repeated courses of A/G • Prolonged therapy >10 days• Dehydration

– Management: reversible if D/C drug, adequate hydration, monitor levels

Ampho B ATN– Direct tubular epithelial cell damage; binds to cell wall

resulting in increased tubular permeability and necrosis– Increased SCr, BUN, decreased Mg, K (urine wasting)-

monitor q1-2d – Distal RTA, polyuria (nephrogenic DI)– Risk factors:

• Combo with other nephrotoxic drugs• Total cumulative dose; daily dose > 0.5 mg/kg/day• Dehydration

– Management: reversible if D/C drug, hydration (1L NS daily)– All lipid-based preps decrease occurrence of nephrotoxicity

Radiographic Contrast Media ATN– Onset within 12-24 hr, SCr peaks 2-5 days after

exposure, recovery usually after 4-10 d– Direct tubular necrosis, renal ischemia– Typically non-oliguric– Urinalysis: hyaline and granular casts, low FENa– Risk factors: DM, CKD, prestudy dehydration– Management: low-osmolality nonionic contrast

agents, smallest dose, hydration

• Clinical presentation:– Systemic manifestations of hypersensitivity

reaction (e.g. fever, rash, arthralgias)– Onset after drug exposure:• 1st exposure: as long as several weeks• 2nd exposure: 3-5 days• As short as 1 day after rifampin• As long as 18 months with NSAIDS

Acute Allergic Interstitial NephritisImplicated Drugs:

• Penicillins• Cephalosporins• Cocaine• Sulfonamides• NSAIDs • Diuretics• Lithium• Phenytoin• Valproic acid

• Amphotericin B• Streptokinase• 5-aminosalicylates• Allopurinol• Rifampin• Some Chinese herbs

• Urinary Findings:– Urinalysis:

• WBC, RBC, white cell casts• Fractional excretion of sodium often >1%• Protein excretion usually mild• Eosinophilia or eosinophiluria present >75% of cases

• Diagnosis:– Diagnosis confirmed only by kidney biopsy– Biopsy indicated only if renal failure progresses or

persists despite stopping the offending drug

Acute Allergic Interstitial NephritisTreatment

• Stop the offending drug• Steroid therapy if renal failure persists– Prednisone 1-2 mg/kg/day PO x 4-6 weeks

• Cyclophosphamide if recovery not seen after trial of prednisone

Thrombotic Microangiography

• Clinical presentation:– Fever, hemolytic anemia, thrombocytopenia, renal

dysfunction, CNS abnormalities, TTP– Pathologic hallmark: hyaline thrombi in microvasculature of

many organs• Changes in kidney:

– Afferent arterioles– Glomerular thrombosis– Thickening of glomerular capillary wall

• Drugs implicated:– Cyclosporin, tacrolimus, chemotherapeutic agents, ticlopidine,

clopidogrel, estrogen-containing contraceptives, quinine, cocaine

Post-Renal Nephropathy

• Rhabdomyolysis– Intratubular precipitation of myoglobulin– Prevention: hold statin while on clarithro/erythro or itraconazole

• Drug-induced crystalluria– Drug insoluble in urine crystallizes in distal tubule– Risk factors:

• Decreased circulating volume• Renal dysfunction• Acid or alkaline urine pH

– Prevention:• Dose adjustment for renal failure• Volume expansion to enhance urinary output• Urinary alkalinization (for weak acids)

Post-Renal Nepropathy

• Implicated Drugs:• Methotrexate

– Weak acid- precipitates in acidic urine (pH < 7)– Precipitation of MTX and its metabolites in renal tubules– High dose MTX (12-15 g/m2)– Prevention:

» Diuresis- U/O 100-200 mL/h x 24h post-high dose MTX» Urinary alkalinization (sodium bicarb 25-59 mEq/L

hydration fluid)

• Implicated Drugs:• Acyclovir

– Weak acid and weak base– Intratubular precipitation of acyclovir in dehydrated oliguric

patients– Needle-shaped crystals– Risks/Prevention

» IV- too fast infusion rate- infuse over 1 h» High dose > 500 mg/m2

» Dehydration- IV NS» Pre-existing renal failure- adjust dose» Other nephrotoxins

• Implicated Drugs:• Indinavir

– Weak base- precipitates in alkaline urine– Crystal nephropathy, dysuria, urinary freq, rectangular cystals– Risk/Prevention:

» Severe volume depletion» Recipitation prevented by consumption of ~2L fluid/d

• Implicated Drugs:• Sulphonamides

– Weak acid- precipitates in acidic urine– Higher doses– More common with sulfadiazine– Risk/prevention:

» Volume depletion- maintain good fluid intake» Renal dysfunction- adjust dose» Urinary alkalinization (treatment)

Back to the case…

What are NJ’s drug therapy problems associated with AKI?

• NJ’s acute renal failure may be secondary to drug-induced nephrotoxicity and requires reassessment of drug therapy.

• NJ requires assessment of drug therapy to optimize hemodynamics and other strategies to prevent further renal injury and promote resolution of AKI.

What are the General Goals of Therapy for AKI?

1. Survive the insult2. Prevent further damage/insult3. Prevent/treat complications4. Regain life-sustaining renal function5. Minimize adverse effects of drug therapy

What are your specific goals of therapy?

• Hemodynamics optimization– Maintain MAP > 60– Establish and maintain euvolemia

• Appropriate antibiotic and antifungal therapy to treat sepsis (treating the underlying cause)

• Discontinue nephrotoxic agents• Avoid further insults• Electrolyte management• Allow renal function to recover

Principles of Therapy

• Prevention of AKI• Optimization of hemodynamic status– Appropriate fluid therapy– Vasopressors/ inotropes

• Treatment of underlying medical condition: sepsis, hemorrhage

• Discontinuation nephrotoxic medications• Adjust medication dosing

What is the pharmacotherapeutic plan?

• Optimize hemodynamics and maintain renal perfusion– Reassess fluid status

• If fluid overloaded, minimize fluid intake through IVs (Concentrate meds, meds in NS)

• Cautious trial of furosemide once hemodynamically stable and off norepinephrine

• Discontinue use of antibiotics NJ has been recently exposed to

• Discontinue/avoid nephrotoxic agents• Adjust medication doses for decreased GFR• If on opioids, consider switching morphine to

hydromorphone or fentanyl

A Look Back At How NJ Was TreatedDo You Agree?

• Transfused x 1 unit PRBC• Abx– Ceftriaxone 1 g IV q24h (~25 mg/kg/d) (Mar 20- 25)– Prednisolone 10 mg po bid x 1 wk (~0.5 mg/kg/d)

(Mar 20-26) – Ampicillin 500 mg IV q6h (~50 mg/kg/d) (Mar 25-

• Paracetamol 500 mg po tds x 3d) • Folic acid 5 mg po daily x 1 month• Multivitamins 10 mg po daily x 1 wk

Case (update)

• Mar 26: able to pass urine, volumes increased to 1L/day, non bloody

• Mar 30: Normal urine output, afebrile, mild pallor, no oedema

• No vomitting, no fever, no swelling • Discharged Mar 30, 2013; for follow up in

renal clinic in 7 days

Drug-Inducted NephrotoxicityKey Points

• Pretreatment hydration can reduce nephrotoxic potential of many drugs

• Renal injury can present as acute renal failure, nephrotic syndrome, renal tubular dysfunction, or chronic renal failure

• Early diagnosis is key

• Be aware of nephrotoxic potential of medications

• Be vigilant to exclude drugs as possible causes of renal disease

• Manage renal failure (replace fluid volume, adjust drug doses, steroid trials in AIN, avoid repeat exposures)

Drug induced nephritis

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