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Home , Acute tubular necrosis, Azotemia, Basic metabolic panel, Hydronephrosis

Acute Injury

Jade M Teakell, MD, PhD, FASN Assistant Professor Division of Renal Diseases and Hypertension Outline

• Scope • Definition • Tools to diagnose • Etiology • Treatments Why is this important?

• AKI occurs in 10-20% hospitalized patients – 40-60% ICU patients

• 5% of ICU patients with AKI require renal replacement therapy (50% mortality).

• AKI is associated with an increased risk for de novo CKD, CKD progression, and in some cases death. Definition

2004 2007 KDIGO Definition of AKI 2012

• Increase in SCr by ≥0.3mg/dL within 48 hours • Increase in SCr to ≥1.5x baseline, known or presumed to have occurred within prior 7 days • Urine volume <0.5mL/kg/h for 6 hours Stage Serum Creatinine Urine Output

1 1.5–1.9 x baseline <0.5mL/kg/h for 6-12h OR >0.3 mg/dL increase 2 2.0–2.9 x baseline <0.5mL/kg/h for >12h

3 3.0 x baseline <0.3mL/kg/h for >24h OR >4.0 mg/dL increase OR OR Initiation of RRT Anuria for >12h Limitations of

• Low Sensitivity – cellular injury that does not affect GFR • Low Specificity – creatinine can increase/decrease without change in GFR • Delayed – rise is seen 2-3 days after drop in GFR • Fluid therapy – may dilute serum creatinine delaying diagnosis • Inter-laboratory Variation Work-up

• • Urinalysis with micro • Fractional excretion of (and/or ) • Urine to creatinine ratio (UPC)* • Autoimmune and infectious • Renal ultrasound • Urinalysis – Cells

Isomorphic RBCs Dysmorphic RBCs

WBC

Renal Tubular Epithelial Cells (RTE) Squamous Epithelial Cells WBCs Urinalysis - Casts

Granular RBC

RTE WBC Fractional Excretion of Na/Urea 푼푵풂 풙 푺푪풓 푼푼푵풙 푺푪풓 푭푬푵풂 = 풙 ퟏퟎퟎ% 푭푬푼풓풆풂 = 풙 ퟏퟎퟎ% 푺푵풂 풙 푼푪풓 푩푼푵 풙 푼푪풓 • FENa < 1% suggests • FEUN < 35% suggests prerenal disease, prerenal disease where reabsorption of almost all of the • FEUN can be more filtered Na is an accurate than the appropriate response FENa in patients to decreased renal receiving diuretics perfusion. when the FENa is higher than expected • FENa > 2% percent for clinical prerenal usually indicates ATN disease Fractional Excretion of Na - Limitations

• The FENa criterion of less than 1% to diagnose prerenal disease applies only to patients with a marked reduction in GFR and oliguria • Single measurements of SCr may not provide an accurate estimate of the GFR. • There are other causes of AKI other than prerenal disease in which the FENa can be less than 1%. • The FENa may be above 1% when prerenal disease occurs in patients with CKD or any cause of sodium wasting, such as diuretic therapy. Renal Ultrasound

• Low yield in patients without risk factors or clinical concern for obstruction • Risk Factors - history of , recurrent urinary tract infections, a diagnosis consistent with obstruction, non-black race. – AND absence of: exposure to nephrotoxins, congestive failure, or prerenal AKI • RUS in AKI – 10-15% with hydronephrosis, but only 3-5% requiring intervention. Risk Factors for AKI Etiologies

Acute Tubular Necrosis

Acute Interstitial Prerenal

AKI Intrinsic Acute GN

Acute Vascular Postrenal Syndromes

Intratubular Obstruction Etiologies

Acute Tubular Necrosis

Acute Interstitial Prerenal Nephritis

AKI Intrinsic Acute GN

Acute Vascular Postrenal Syndromes

Intratubular Obstruction Prerenal AKI

Congestive Liver Failure

Volume Sepsis Depletion

Incr Vasoconstriction Renal Decr Vasodilation •↑ Angiotensin II •↓ Prostaglandins •↑ Adrenergic stim. Hypo- •↓ Nitric Oxide •↑ Vasopressin perfusion Volume Depletion

• Isotonic Fluid Volume Deficit – Serum Na level remains wnl • Decreased Cardiac Output – Decreased pressure, decreased organ/tissue perfusion • Compensation – Neural – baro/chemoreceptors -> ↑SNS, ↑RR – Hormonal – renin (RAAS), epi/norepi, ADH Volume Depletion

• Extra-Renal Losses – Blood loss, third-spaced fluids, NPO, AMS – GI – vomiting, diarrhea, – Skin – excessive sweating, extensive burns, fever

• Renal Losses – Intrinsic – salt-wasting, DI, diuretic phase of AKI – Extrinsic – excess diuretics, osmotic Impaired Autoregulation can lead to “normotensive” prerenal AKI

Abuelo 2007 NEJM Congestive Heart Failure Advanced Liver Failure

Peripheral and splanchnic vasodilatation with inadequate increase in cardiac output

Activation of RAAS, SNS, Vasopressin

Renal Vasoconstriction Salt/Water Retention

SBP Ascites / Hemorrhage Infection Over Diuresis Large vol para HRS Prerenal AKI Treatment

• Correction of volume depletion (crystalloids) • Discontinuation or Dose Adjustment – NSAIDS – RAAS inhibitors – CNIs • Mgmt of “Effective” Volume Depletion – Diuresis in CHF – Improving MAP in HRS treatment – Antibiotics in Sepsis • Recongnize and Treat Abd Compartment Syndrome Etiologies

Acute Tubular Necrosis

Acute Interstitial Prerenal Nephritis

AKI Intrinsic Acute GN

Acute Vascular Postrenal Syndromes

Intratubular Obstruction Intrinsic Renal

Tubules Vasculature Apoptosis Vasoconstriction Necrosis Focal Mitochondrial Vasodilation dysfunction Thrombosis Back-leak Coagulation Detachment Inflammation Obstruction Intermittent flow

Microenvironment Innate immunity Systemic factors Adaptive immunity Proinflammatory Cellular dysfunction cytokines Paracrine factors Antiinflammatory Autocrine factors cytokines Acute Tubular Necrosis

Abuelo 2007 NEJM Acute Tubular Necrosis

• Ischemic – Prolonged prerenal – , – Cardiopulmonary arrest – Cardiopulmonary bypass • Septic – Cytokine mediated inflammation – Endothelial stress/injury • Nephrotoxic – Abx (aminoglycosides, vancomycin, amphotericin) – Chemotherapy (cisplatin, mtx) – Contrast? Sepsis-related AKI/ATN

Mechanisms

• Pro-Inflammatory state

• Cytokine-mediated Cell Injury

• Systemic Vasodilation

• Impaired Microcirculation

Schrier 2004 NEJM Toxins

There is no role for pre- or post-HD for prevention of CIN Acute Interstitial Nephritis

• Lymphocytic infiltration of the interstitium – Drugs (Abx, PPIs, NSAIDs, furosemide, etc) – Infection – Malignancy – Systemic Diseases (SLE, Sjogren’s, TINU, etc) • Classic Triad (rare) – fever + rash + eosinophilia • , WBC Casts • Role of glucocorticoids is uncertain (no RTCs) Urine Eos? Glomerulopathies

• Nephritic (proliferative) pattern is an active urine microscopy with RBC casts and/or dysmorphic red cells and a variable degree of albuminuria. • Nephrotic (non-proliferative) pattern is proteinuria, usually in the nephrotic range (>3.5 g per 24 hours), and an inactive urine microscopy with very few cells or casts* Glomerulopathies

General Pathogenic Mechanisms

Endothelial Immune Structural GBM Antibody- Complement Injury / Complex- Podocyte Injury Abnormalities Mediated Dysregulation Thrombosis Mediated

Thin Basement HUS Anti-GBM MPGN Membranous MCD Membrane

Alports TTP ANCA Vasculitis Atypical HUS Lupus Nephritis FSGS

C3 IgAN Glomerulopathy Acute Vascular Syndromes

• Thrombotic Microangiopathy (TMA) – Hemolytic Uremic Syndrome (HUS) • Diarrhea, Shiga/Vero Toxin associated • Supportive Care, if indicated – Thrombotic Thrombocytopenic Purpura (TTP) • ADAMS13 Deficiency (autoimmune or hereditary) • Autoimmunue - Supportive care, PLEX, adjuvant steroids/rituximab, rare splenectomy – Atypical HUS (aHUS) • Complement dysregulation (hereditary or acquired) • Supportive care, PLEX, immunosuppression, Eculizumab Intra Tubular Obstruction

• Protein – Myeloma light chain cast nephropathy

• Crystals – Uric acid – Oxalate – Medications Etiologies

Acute Tubular Necrosis

Acute Interstitial Prerenal Nephritis

AKI Intrinsic Acute GN

Acute Vascular Postrenal Syndromes

Intratubular Obstruction Post-Renal AKI

• Obstruction within the kidney leading to dilatation of individual calyces or caliectasis – stones, transitional cell carcinoma, blood clots, and sloughed papillae • Obstruction at or distal to the leading to pelviectasis, hypdronephrosis/ – stones, malignancy, external compression, blood clots, infection (fungus ball), bladder dysfunction A. Stone in renal pelvis B. Caliectasis C. Lymphatomatous infiltration

Urinary Tract Obstruction

Symptoms Lab Findings • Pain • Elevated creatinine • Change in UOP • Hyperkalemia / RTA • Hypertension • /pyuria • Hematuria Treatment = Relieve the pressure! • Percutaneous (PCN) • Ureteral / Lithotripsy • Foley / Suprapubic Catheter Natural History AKI Natural History AKI

AKI Risk Factors Outcomes Age Disease Modifiers Cardiovascular Race / Ethnicity Severity of AKI events Genetic Factors Duration of AKI Kidney Events Mellitus No. of Episodes ESRD Hypertension Stage of CKD Disability Metabolic syndrome Proteinuria Diminished QOL Death CKD References

• KDIGO Clinical Practice Guideline for Acute Kidney Injury • Cerdá J, et al. “Epidemiology of acute kidney injury.” CJASN. 2008; 3(3): 881-6. • Wang HE, et al. “Acute kidney injury and mortality in hospitalized patients.” AJN. 2012; 35(4): 349- 55. • Parazella MA, et al. “Diagnostic Value of Urine Microscopy for Differential Diagnosis of Acute Kidney Injury in Hospitalized Patients.” CJASN. 2008; 3(6): 1615–1619. • Carvounis CP, et al. “Significance of the fractional excretion of urea in the differential diagnosis of acute renal failure.” KI. 2002; 62(6): 2223-9. • Podoll AS, et al. “Clinical utility of gray scale renal ultrasound in acute kidney injury.” BMC Nephrol. 2013; 14: 188. • Abuelo JG, et al. “Normotensive ischemic acute renal failure.” NEJM. 2007; 357(8): 797-805. • Schrier RW, et al. “Acute Renal Failure and Sepsis.” NEJM. 2004; 351(2): 159-169. • Muriithi AK, et al. “Utility of urine eosinophils in the diagnosis of acute interstitial nephritis.” CJASN. 2013; (11): 1857-62. • McGrogan A, et al. “The incidence of primary worldwide: a systematic review of the literature.” NDT. 2011; 26(2): 414-30. • Chawla LS, et al. “Acute kidney injury and chronic as interconnected syndromes.” NEJM. 2014; 371(1): 58-66.