CPCJuly 8th, 2013

A 65 y/o female with uncontrolled hypertension and acute kidney injury

Melanie Braganza, MD, MPHHolly Rosencranz, MD

H&P

• 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

Past Medical History

• 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 surgical history

• Appendectomy• Hysterectomy• Pacemaker placement

Home medications

BenazeprilFurosemidePotassium chlorideCarvedilolAnastrozole (Arimidex)Fulvestrant (Faslodex)

Physical examination

• 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

Laboratory tests

• 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)

Urine analysis with microscopy

• 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 /ul 123 (H)• WBC Latest Range: 0-25 /ul 958 (H)• SQUAMOUS EPILatest Range: 0-30 /ul 19• HYALINE CASTS Latest Range: 0-5 /ul 0

Imaging

• 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.

CXR

Summary

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

Acute Kidney Injury (AKI)

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

AKI definition

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

Etiology of AKI CausesPre renal azotemia Poor fluid intake, fluid loss

(vomiting, diarrhea, hemorrhage), NSAIDS, ACEI and ARBS, evidence of volume depletion, heart failure, decreased effective circulatory volume (cirrhosis, heart failure)

Sepsis associated AKI Sepsis, sepsis syndrome, septic shock

Ischemia associated AKI Systemic hypotension, age, CKDNephrotoxin associated AKI (endogenous)

Rhabdomyolysis, hemolysis, tumor lysis syndrome, multiple myeloma, contrast nephropathy

Nephrotoxin associated AKI (exogenous)

Tubular injury from medications, interstitial nephritis

AKI

Etiology of AKI CausesGlomerulonephritis/ vasculitis Good Pasteur’s disease,

Microscopic polyangitis, granulomatous polyangitis

Non drug associated interstitial nephritis

Tubuluinterstitial nephritis uveitis syndrome, Legionella infection

Thrombotic microangiopathy TTP/HUSAtheroembolic disease Recent vascular procedures :

cardiac catheterizationPost Renal AKI Kidney stones, prostate

hypertrophy, obstructed bladder catheter

Urine sediment

Pre renal azotemia

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

Pathophysiology

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

Laboratory studies

BUN/Creatinine ratio >20

FeNa <1%

Hyaline casts in urine sediment

Urine specific gravity >1.018

Urine osmolality >500 mOsm/kg

Post renal AKI

Upper urinary tractExtrinsic

Upper urinary tract intrinsic

Lower urinary tract

Retroperitoneal space-lymph nodes, tumors

Nephrolithiasis Prostate- BPH, Carcinoma, infection

Pelvic or intraabdominal tumors

Strictures Bladder- calculi, neck obstruction, cancer, infection

Fibrosis Edema FunctionalUreteral ligation/surgical trauma

Debris, blood clots, sloughed papillae, fungal ball

Urethral – posteriors urethral valves, strictures, trauma

Granulomatous disease

malignancy

Hematoma

Post renal AKI

Accounts for less than 5% of AKIPain and oliguria are non specific findings

Intrinsic AKI

Acute Tubular Necrosis (ATN)

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

ATN

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

Laboratory findings

Muddy brown granular or tubular epithelial cell casts

FeNa >1%

UNa >20 mEq/L

Specific gravity ~ 1.010

Acute interstitial nephritis (AIN)

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

Nephrotoxic AKI

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 ATN -AKI

Intrinsic AKI

Glomerular injury

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.

Acute Nephritic syndrome

Ig A nephropathy

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

ANCA associated glomerulonephritis

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

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

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

Anti- GBM syndrome

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

Membranoproliferative GN

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

Thrombotic microangiopathy (TMA)

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

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

TTP

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

Thrombotic microangiopathy

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

TMA in cancer patients

Drugs Immunosuppressive Agents

Malignancy Hematopoietic cell transplantation

Mitomycin C Cyclosporin Gastric Ca Bone marrow transplant nephropathy

Cisplatin Tacrolimus Breast Ca Radiation nephropathy

Bleomycin Rapamycin Lung CaGemcitabine

Malignant hypertension

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

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

Renal vein thrombosis

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, antiphospholipid antibody syndrome, nephrotic syndrome, proteins C and S, antithrombin deficiency, factor V Leiden, disseminated malignancy, and oral contraceptives

Intrinsic AKI

Urine sediment

Extra information for diagnosis

Historyh/o chemotherapyh/o infections, feversOTC medication use

ExamPrevious BP readings, orthostats

Laboratory testsCBC with differential and RBC indicesHepatic function panel with bilirubinFractional excretion of sodium

Differential Diagnosis

1. Thrombotic thrombocytopenic purpura2. Malignant hypertension3. Renal vein thrombosis4. ANCA associated vasculitis5. ATN- nephrotoxins/ischemic

References

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