CPC July 8 th , 2013 A 65 y/o female with uncontrolled hypertension and acute kidney injury

1. CPCJuly 8th, 2013A 65 y/o female with uncontrolled hypertension and acute kidney injury Melanie Braganza, MD, MPH Holly Rosencranz, MD

2. 65 Y/O F • Worsening shortness of breath with orthopnea and paroxysmal nocturnal dyspnea for 1 week • Non-specific fatigue for several weeks • Nausea and vomiting • Decreasing urine output • Severe neck pain with tingling and numbness in 2nd and 3rd fingers of right hand H&P

3. Breast cancer, ER/PR positive stage 4 with metastatic disease to cervical spine, received radiotherapy and was on anastrazole Aug 2012 • Recent addition of Fulvestrant for newly noted cervical spine disease • Recurrent pleural effusions, non-malignant • Pericardial effusion with tamponade s/p emergent pericardiocentesis in Nov 2012 • HTN Past Medical History

4. Appendectomy • Hysterectomy • Pacemaker placement Past surgical history

5. Benazepril • Furosemide • Potassium chloride • Carvedilol • Anastrozole (Arimidex) • Fulvestrant (Faslodex) Home medications

6. Vitals: BP: 239/124 mmHg, HR: 114/min, O2: 99% -100% on 2 L nasal cannula, T 36.6 C/ 97.9 F • General: alert • ENT: unremarkable, no icterus • Resp: crackles to middle of chest bilaterally, wheezes in upper lobes • CV: JVP to jaw, no murmur, RRR, S3, 2 +pitting edema • Abdomen: no organomegaly • Neurological: alert/oriented, normal strength, tone, reflexes and coordination • Skin: no petechiae, no bruising Physical examination

7. CBC: WBC: 8.99 (4-11) • Hgb: 11.6 (3/2013)-> 10.1 (4/1/2013)-> 8.1 (4/18/2013) • Platelets: 100-130 (3/2013) -> 80(4/18/2013) • RDW=17.3 • Calcium 7.7 (8.5-10.1) • Phos 2.8 (2.5-4.9) • Glucose 85 • Na 143 • K 4.6 (3.5-5.1) • CL 106 (98-107) • CO2 29 (21-32) • LDH 660 (84-246) • Haptoglobin 14.1 (30-200) • Creatinine 0.77 (3/2013)->1.82 (4/1/2013)->4.69 ( 4/18/2013) Laboratory tests

8. COLOR Latest Range: COLORLESS-YEL. LT YELLOW • APPEARANCE Latest Range: CLEAR HAZY (A) • SP. GRAVITY Latest Range: 1.003-1.033 1.010 • PH Latest Range: 5.0-8.0 6.0 • PROTEIN Latest Range: NEGATIVE mg/dl 100 (A) • GLUCOSE Latest Range: NEGATIVE mg/dl NEGATIVE • KETONE Latest Range: NEGATIVE mg/dl TRACE • BILIRUBIN Latest Range: NEGATIVE NEGATIVE • BLOOD Latest Range: NEGATIVE MODERATE (A) • NITRITE Latest Range: NEGATIVE NEGATIVE • UROBILINOGEN Latest Range: <2.0 mg/dl NORMAL • LEUKOCYTE ESTERASE Latest Range: LARGE (A) • RBC Latest Range: 0-20 /ul123 (H) • WBC Latest Range: 0-25 /ul958 (H) • SQUAMOUS EPI Latest Range: 0-30 /ul 19 • HYALINE CASTS Latest Range: 0-5 /ul 0 Urine analysis with microscopy

9. CT Brain : IMPRESSION: Minimal cerebral atrophy. Moderate chronic small vessel ischemic change. Otherwise negative with no evidence of acute finding. • CXR: Bibasilar atelectasis and pleural fluid. Pleural fluid is increased in the left base compared with 11/20/13. Decreased right base pleural fluid. Left anterior chest with CCD with lead tips in right atrium and right ventricle. No other change. Imaging

10. CXR

11. 65 y/o female with metastatic breast cancer with hypertensive crisis, new onset renal failure, anemia, thrombocytopenia • Volume overload with elevated JVD and chest X ray picture suggestive of vascular congestion • UA with proteinuria, hematuria and pyuria Summary

12. The RIFLE criteria consists of various graded levels of kidney injury based upon percent rise in serum creatinine, urine output and outcome measures. • Risk: 1.5-fold increase in the serum creatinine or GFR decrease by 25 percent or urine output <0.5 mL/kg per hour for six hours • Injury: Twofold increase in the serum creatinine or GFR decrease by 50 percent or urine output <0.5 mL/kg per hour for 12 hours • Failure: Threefold increase in the serum creatinine or GFR decrease by 75 percent or urine output of <0.5 mL/kg per hour for 24 hours, or anuria for 12 hours • Loss: Complete loss of kidney function (eg, need for renal replacement therapy) for more than four weeks • ESRD: Complete loss of kidney function (eg, need for renal replacement therapy) for more than three months Acute Kidney Injury (AKI)

13. The AKIN (Acute Kidney Injury Network) criteria are a modification of the RIFLE criteria and include both diagnostic and staging system. • Stage 1. Increase in serum creatinine 0.3 mg/dl or 1.5 to 2 fold increase from baseline or urine output less than 0.5 mL/kg per hour for more than 6 hours • Stage 2. Increase in serum creatinine >2-3 folds from baseline or urine output less than 0.5 mL/kg per hour for more than 12 hours • Stage 3. Increase in serum creatinine >3 fold from baseline or serum creatinine of 4.0 mg/dl with an acute rise of at least 0.5 mg/dl or urine output less than 0.3 mL/kg per hour for 24 hours or anuria for 12 hours. AKI definition

14. AKI

15. AKI

16. Urine sediment

17. Accounts for 40-55% of all cases of acute renal injury • Volume responsive- Hemorrhage (traumatic, gastrointestinal, surgical), gastrointestinal losses (vomiting, diarrhea, nasogastric suction), renal losses (overdiuresis, diabetes insipidus), and third spacing (pancreatitis, hypoalbuminemia) • Volume unresponsive - Cardiogenic shock, septic shock, cirrhosis, hypoalbuminemia, and anaphylaxis all decrease effective arterial circulating volume, independent of total body volume status, and result in reduced kidney blood flow Pre renal azotemia

18. Hypoperfusion activates baroreceptors and activates a cascade of neural and humoral responses • Increase in antidiuretic hormone and renal adrenergic activity • Increase in angiotensin II activity which causes afferent arteriolar constriction that reduces renal plasma flow, GFR, and the filtration fraction, and markedly augments proximal tubular sodium reabsorption in an effort to restore plasma volume • Severe and untreated hypoperfusion predisposes the kidney to ischemic acute tubular necrosis (ATN) and nephrotoxic AKI Pathophysiology

19. BUN/Creatinine ratio >20 • FeNa <1% • Hyaline casts in urine sediment • Urine specific gravity >1.018 • Urine osmolality >500 mOsm/kg Laboratory studies

20. Post renal AKI

21. Accounts for less than 5% of AKI • Pain and oliguria are non specific findings Post renal AKI

22. Intrinsic AKI

23. Ischemic insult causes proximal tubule cell injury and dysfunction • Profound drop in GFR through afferent arteriolar vasoconstriction • Mediated by tubular glomerular feedback and proximal tubular obstruction • Sloughed tubule cells, brush border vesicle remnants and cellular debris in combination with Tamm-Horsfall glycoprotein form the classical muddy brown granular casts Acute Tubular Necrosis (ATN)

24. Regeneration can occur after removal of the insult • Minimally injured cells will repair themselves without dedifferentiation • Severely injured cells will undergo dedifferentiation with proliferation of viable cells which spread across the denuded basement membrane and convert back into normal tubular cells ATN

25. Muddy brown granular or tubular epithelial cell casts • FeNa >1% • UNa >20 mEq/L • Specific gravity ~ 1.010 Laboratory findings

26. Systemic allergic response • Leukemia, lymphoma, sarcoidosis, bacterial infections, viral infections • Rash, fever, eosinophilia, pyuria with eosinophiluria (in NSAID related AIN lymphocytes predominate) • Inflammatory infiltrates in interstitium in deep cortex and outer medulla with edema Acute interstitial nephritis (AIN)

27. The kidneys are vulnerable to toxicity due to their high blood flow, and they are the major route for metabolizing and eliminating drugs and toxins • Concentration of drugs within the tubular lumen and the interstitium leads to higher exposure rates Nephrotoxic AKI

28. Nephrotoxic ATN -AKI

29. Intrinsic AKI

30. The nephrotic syndrome is defined by the relatively acute onset of edema, nephrotic range proteinuria (defined as greater than 3.5 g/d per 1.73 m2 of body surface area), hypoalbuminemia, hyperlipidemia, and lipiduria, all of which occur with minimal impairment of the glomerular filtration rate (GFR). • The acute nephritic syndrome in its full-blown form is characterized by edema; hypertension; azotemia with the variable presence of oliguria; and a ‘‘nephritic’’ urinary sediment marked by the presence of erythrocytes (red blood cells [RBCs]), leukocytes (white blood cells [WBCs]), cellular casts (especially RBC casts), and mild to moderate proteinuria. Glomerular injury

31. Acute Nephritic syndrome

32. All age groups might be affected though more common in children and young adults and occurs more often in boys and men • Characteristic presentation for IgAN is recurrent episodes of macroscopic hematuria (usually brown in color without blood clots) that may be associated with flank pain and typically coincide with or closely follow an upper respiratory tract infection Ig A nephropathy

33. Granulomatous polyangiitis and microscopic polyangiitis • Systemic small-vessel vasculitides that typically affect multiple organ systems and are associated with nonspecific features of inflammation, such as fever, malaise,myalgia, arthralgia, and weight loss, with a peak age of onset in the seventh and eighth decades ANCA associated glomerulonephritis

34. The renal features of ANCA-associated vasculitis are oliguria, hematuria, and proteinuria with RBC casts • Serum creatinine may or may not be elevated on initial presentation but generally increases rapidly over days to weeks without treatment ANCA associated glomerulonephritis

35. Diffuse pulmonary infiltrates on chest radiographs and a microcytic anemia are suggestive of concurrent alveolar hemorrhage • Antibodies directed against proteinase 3 are usually associated with c-ANCA and with GP, whereas antibodies against myeloperoxidase, generally seen in MPA and renal-limited disease, give a p-ANCA pattern ANCA associated glomerulonephritis

36. The disease has two peaks of occurrence, the first in younger men and the second in elderly women, but it can occur at any age and in either sex • Extra renal findings- pulmonary hemorrhage, arthralgias, fevers, chills, hepatosplenomegaly • Renal presentation is a typical nephritic syndrome Anti- GBM syndrome

37. Idiopathic type 1 MPGN is most often seen in adolescents and young adults as a renal-limited disorder presenting with severe proteinuria or nephrotic syndrome and accompanying nephritic features, particularly hematuria and RBC casts • Azotemia and hypertension may be present • The clinical presentation is similar in adults; however, the disease is usually secondary to a chronic or subacute infectious process, systemic autoimmune disorder, or lymphoma Membranoproliferative GN

38. Thrombotic microangiopathy (TMA) in the form of Hemolytic uremic syndrome (HUS) and Thrombotic thrombocytopenic purpura (TTP) is a disease of multiple etiologies manifesting as non-immune hemolytic anemia, thrombocytopenia, varying degrees of encephalopathy, and renal failure due to platelet thrombi in the microcirculation of the kidneys Thrombotic microangiopathy (TMA)

39. HUS develops in children with hemorrhagic colitis from infection by verotoxin-producing Escherichia coli associated with ingestion of undercooked meat • Idiopathic TTP is usually seen in adult women with encephalopathy as the predominant clinical feature • Both arise from endothelial cell dysfunction and cause a similar clinical and laboratory picture Thrombotic microangiopathy

40. TTP classically manifests with the pentad of thrombocytopenia, microangiopathic hemolytic anemia, fever, neurologic dysfunction, and renal dysfunction • Thrombocytopenia is diagnostic; most patients present with values below 60,000/μL TTP

41. Laboratory findings include elevated indirect bilirubin and lactate dehydrogenase levels, depressed serum haptoglobin values, and schizocytes on peripheral blood smear • The characteristic renal lesion consists of vessel wall thickening in capillaries and arterioles, with swelling and detachment of endothelial cells from the basement membranes and accumulation of subendothelial fluffy material Thrombotic microangiopathy

42. TMA in cancer patients

43. Rapidly progressive BP elevations with target organ injury including retinal hemorrhages, encephalopathy, and declining kidney function • If untreated, patients with target organ injury including papilledema and declining kidney function suffered mortality rates in excess of 50% over 6–12 months, hence the designation “malignant” Malignant hypertension

44. Renal abnormalities typically include rising serum creatinine and occasionally hematuria and proteinuria • Biochemical findings may include evidence of hemolysis (anemia, schistocytes, and reticulocytosis) and changes associated with kidney failure Malignant hypertension

45. Renal vein thrombosis (RVT) presents with flank pain, tenderness, hematuria, rapid decline in renal function, and proteinuria • Homocystinuria, endovascular intervention, surgery, dehydration, compression and kinking of the renal veins from retroperitoneal processes such as retroperitoneal fibrosis and abdominal neoplasms, antiphospholipidantibody syndrome, nephrotic syndrome, proteins C and S, antithrombin deficiency, factor V Leiden, disseminated malignancy, and oral contraceptives Renal vein thrombosis

46. Intrinsic AKI

47. Urine sediment

48. History • h/o chemotherapy • h/o infections, fevers • OTC medication use Exam • Previous BP readings, orthostats Laboratory tests • CBC with differential and RBC indices • Hepatic function panel with bilirubin • Fractional excretion of sodium Extra information for diagnosis

49. Thrombotic thrombocytopenic purpura • Malignant hypertension • Renal vein thrombosis • ANCA associated vasculitis • ATN- nephrotoxins/ischemic Differential Diagnosis

50. Taal: Brenner and Rector’s the kidney; 9th Ed. 2011-Saunders, an imprint of Elseviers, accessed through MD consult • Harrison’s online: Harrison’s principles of Internal Medicine, 18 Ed. Dan L. Longo, Anthony S. Fauci, Dennis L. Kasper, Stephen L. Hauser, J. Larry Jameson, Joseph Loscalzo, Eds. Accessed through Access Medicine • Beck, L.H., Salant, D.J. (2008) Glomerular and tubulointerstitial diseases. Primary Care Clinical Office Practice. Vol. 35: 265–296 References