7/12/16

Disclosures

• I am site PI for the REPRISE study evaluating efficacy of ABIM CERTIFICATION tolvaptan in autosomal dominant polycystic kidney EXAM: NEPHROLOGY disease (Otsuka pharmaceuticals) JULY 2016

UCSF CME

Division of Nephrology Department of Medicine

Meyeon Park, MD MAS As s is tant Pr ofes s or

Roadmap for today

• Glomerular diseases (30 min) ------Scheduled 15 min break------• Common abnormalities (30 min) • Acid-base (45 min) • Acute kidney injury (20 min) GLOMERULAR DISEASES • Secondary hypertension (10 min)

1 7/12/16

Case Laboratory studies

A 74 yo man is evaluated for a 5-month history of sinusitis • Hemoglobin 11.5 g/dl and intermittent otitis media. He has lost 9 lbs (4.1 kg) • Leukocyte count 10.8x10^9 /L and has occasional joint pains. • 28 mg/dl Physical exam: Afebrile • 1.6 m/dl HEENT: crusting in right nares; opaque right tympanic • Albumin 3.8 g/dl membrane; bilateral maxillary sinus tenderness • C3 100 mg/dl CV: 2/6 systolic murmur • C4 32 mg/dl Lungs: rhonchi • Urinalysis: 18 dysmorphic erythrocytes and 1 erythrocyte Extremities: 2+ edema bilateral lower ext cast/hpf • CXR: nodule in RUL, hazy density in LLL

Case Question Case answer review A. Antinuclear antibody – lupus nephritis – wrong age / Which one of the following studies is most appropriate? sex – low complements A. Antinuclear antibody B. Anti-glomerular basement membrane antibody – wrong B. Anti-glomerular basement membrane antibody history; usually younger men; no respiratory C. Myeloperoxidase antineutrophil cytoplasmic antibody involvement D. Proteinase-3 antineutrophil cytoplasmic antibody C. Myeloperoxidase ANCA – can exist in granulomatous E. Anti-double-stranded DNA antibody polyangiitis (Wegener’s) but less specific D. Proteinase-3 ANCA – right answer – granulomatous polyangiitis E. Anti-double-stranded DNA antibody – lupus nephritis – wrong age / sex

2 7/12/16

Granulomatous polyangiitis (GPA) Glomerular diseases: ‘nephritic’

• Formerly known as Wegener’s granulomatosis • , tea-colored • Granulomatous inflammation involving respiratory tract • Hypertension (often acute) and necrotizing vasculitis affecting small to medium sized • +/- Edema vessels • +/- Rapid loss of GFR • Necrotizing glomerulonephritis is common • Active urine sediment • Dysmorphic red blood cells • Red cell casts

Glomerulonephritis: many ways to Vasculitis approach approach • Small vessel: microscopic polyangiitis, GPA, Churg- • Renal limited (mostly): IgA nephropathy, post-strep GN, Strauss, cryoglobulinemic, Henoch-Schonlein purpura– anti-GBM antibody disease inflammation / leukocyte infiltration; crescentic • Pulmonary-renal: Goodpasture’s syndrome, microscopic glomerulonephritis polyangiitis, Churg-Strauss, granulomatous polyangiitis • Renal-dermal: Henoch-Schonlein purpura; ANCA- • Medium-vessel: Kawasaki’s disease, polyarteritis nodosa associated vasculitis; cryoglobulinemia; systemic lupus – renal infarctions / renovascular hypertension erythematosus • Systemic: systemic lupus erythematosus; HUS/TTP • Large-vessel: giant cell arteritis, Takayasu’s arteritis- renal ischemia due to narrowed abdominal aorta / renal arteries • Rapidly progressive GN: 50% eGFR loss in <30 days

3 7/12/16

Immunologic approach Rapidly progressive glomerulonephritis Ser ologic analy s is • Immune complex mediated: Henoch-Schonlein purpura;

cryoglobulinemic vasculitis; lupus; serum sickness; Anti-neutrophil cytoplasmic Anti-GBM Immune c omplex rheumatoid; polyarteritis nodosa; infection-induced; viral autoantibodies (ANCA) autoantibodies disease markers (hep B/C), bacterial (strep); Goodpasture’s (anti-GBM Others antibodies) No extra- Systemic Pulmonary Asthma Lung Anti-DNA Anti-pathogen renal necrotizing necrotizing and hemorrhage autoabs abs Cryoglobulins/ disease HCV • ANCA mediated (non-immune-complex mediated): GPA, arteritis granulomas eosinophilia No lung MPA, Churg-Strauss hemorrhage IgA Renal Microscopic Granulo- Churg- Goodpasture's Lupus GN Post-strep Cryo- • Cell-mediated: allograft cellular vascular rejection; giant limited polyangiitis matosis Strauss syndrome GN globulinemic vasculitis GN / MPGN cell arteritis; Takayasu’s with syndrome Anti-GBM polyangitis GN

ANCA GN Anti-GBM GN Immune complex GN (‘pauci-immune’)

Immune complex GN Immune complex GN

• Post-streptococcal GN • SLE nephritis • Hematuria 2-3 weeks after pharyngitis or skin infection • Usually occurs within first 3 years of SLE diagnosis • Elevated ASO and anti-DNase B antibody • ANA, anti-dsDNA, anti-Smith antibodies • Low C3 / low-normal C4 • Immunosuppression: • No direct therapy available • Mycophenolate (CellCept) or cyclophosphamide • IgA nephropathy • Steroids (combined with above) • Synpharyngitic gross hematuria • Henoch-Schonlein Purpura (HSP) = Abdominal pain, diarrhea, often seen in kids, rarely in adults • Rx: steroids, fish oil(?), ACEi/ARB

4 7/12/16

Immune complex GN Anti-GBM antibody disease

• Membranoproliferative glomerulonephritis (MPGN) type I • Antibodies to noncollagenous portion of type IV collagen causes autoantigen response • Secondary to cryoglobulinem ia, neoplasms, or chronic infections (eg HCV) • Renal limited: Anti-GBM Disease (older women) • Cryoglobulin deposits in vessels -> mesangiocapillar y GN • Pulmonary renal syndrome (hemoptysis / pulmonary hemorrhage + RPGN): Goodpasture’s Syndrome (young Caucasian men) • Low complements; + C3 nephritic factor (autoantibody against C3 convertase of alternative complement activation pathway) • Anti-GBM titer, kidney biopsy • Cryos: arthralgias, purpura, livedo reticularis • Rx: Plasmapheres is, steroids, cyclophosphamide • Rx: Underlying HCV à interferon and ribavirin

ANCA Pauci-Immune GN /ANCA Vasculitis

• Antineutrophil Cytoplasmic Antibodies • Diagnosis: ANCA +, normal complements, no • ANCAs react with cytoplasmic antigens (PR3 and MPO) that are immunohistologic evidence for vascular immune complex present at surface of cytokine-stimulated leukocytes, causing localization on biopsy leukocytes to adhere to vessel walls, degranulate, and generate toxic oxygen metabolites • Microscopic polyangiitis (p-ANCA) • Specific for within granules of neutrophils and monocytes • Necrotizing vasculitis; no granulomas • Cytoplasmic (c-ANCA) versus perinuclear (p-ANCA) • Granulomatosis with polyangiitis (c-ANCA) • Cytoplasmic = PR3 (serine proteinase) = more common in GPA • Lung disease, upper airway disease, granulomas (Wegener) • Churg-Strauss Disease (p-ANCA or ANCA neg) • Perinuclear = myeloperoxidas e (MPO) = more common in MPA • Eosinophilia, asthma, sinus disease, peripheral neuropathy, (microscopic polyangiitis) granulomas • Treatment: Steroids, cyclophosphamide (+/- pheresis if hemoptysis, GPA)

5 7/12/16

IgA and SLE: Chameleons Case

Both IgA Nephropathy and SLE can be… A 67 yo man with a h/o osteoarthritis, BPH, hyperlipidemia • Indolent or rapidly progressive is evaluated for new-onset joint pain in shoulders • Crescentic GN accompanied by lower extremity swelling. 3 months ago, • Nephritic and/or nephrotic baseline kidney function was normal. Meds include tamsulosin, simvastatin, naproxen. IgA Nephropathy Physical examination reveals BP 132/68. • More common in Asians and Hispanics HEENT: pale conjunctivae • Episodic macrohematuria Cardiac: S3 gallop SLE Pulmonary: decreased breath sounds at bases • More common in Asians, Hispanics, African-Americans Ext: 3+ LE edema • Up to 75% with SLE have renal disease; usually presents with

Case, continued Case Question

Labs Which of the following studies is most likely to confirm the • Hemoglobin 8.2 g/dl cause of this patient’s kidney failure? • Leukocyte count 8.1 x10^9/L • Platelets 132K/mcL A. ANCA antibodies • BUN 68 mg/dl, Creatinine 5.6 mg/dl B. Serum electrophoresis / urine protein • Na 131 / K 3.5 / Cl 110 / Bicarb 18 / Albumin 3 / Anion electrophoresis gap 3 C. Urine eosinophil measurement • Ca 10.5 / Phos 5.4 • UA: pH 5, SG 1.015, no blood, 2+ protein D. Hepatitis C antibody assay • Urine protein:creatinine ratio 5 mg/g E. Kidney ultrasonography

6 7/12/16

Case answer review Nephrotic disease: Amyloidosis

A. ANCA antibodies – no hematuria • Pathology B. Serum protein electrophoresis / urine protein • β pleated structure that forms 8-10 nm fibrils electrophoresis – right answer – amyloidosis, multiple • Congo Red stain has apple-green birefringence with polarized light myeloma – low (increase in unmeasured • Classification cations including immunoglobulins) • ~ 20 unique amyloidoses • AL (primary) amyloidosis C. Urine eosinophil measurement – wrong history; test no • myeloma and monoclonal gammopathies longer favored even in AIN • AA (secondary) amyloidosis D. Hepatitis C antibody assay – MPGN can be nephrotic • chronic infections, inflammatory states (inflammatory bowel disease, rheumatoid arthritis, familial Mediterranean fever) and associated with RPGN, but no hematuria E. Kidney ultrasonography – dx obstructive uropathy in older man with BPH, but more going on here

Nephrotic Disease: Amyloidosis Nephrotic Disease: Amyloidosis

• Clinical findings • Treatment • Large kidneys and massive proteinuria • AA Amyloidosis: Treat underlying infection or inflammation, • Multi-organ involvement colchicine for Familial Mediterranean Fever • Periorbital hemorrhage (raccoon sign), macroglossia • AL Amyloidosis: Treat underlying myeloma, melphalan, prednisone, • Cardiac deposits stem-cell transplant • GI involvement, hepatomegaly • Adjuvant therapy: ACEi/ARB, blood pressure control, diuretics, • Carpal tunnel syndrome, neuropathy /water restriction • Shoulder pad sign = amyloid deposits in deltoids • Cardiac and kidney disease are poor prognostic signs

7 7/12/16

Glomerular Disease: ‘nephrotic’ Nephrotic Diseases: DDx

• Proteinuria > 3 g/day • Focal Segmental Glomerulosclerosis (FSGS) • Dyslipidemia • More common in African-Americans, age < 40 y/o • Edema • Membranous Nephropathy (MN) • Tend to be Caucasian, age > 40 y/o • Hypoalbuminemia • Minimal Change Disease (MCD) • Lipiduria (oval fat bodies in urine, Maltese cross with polarized light) • Age <15 y/o, BUT 10% adults (second peak age 60-70) • Amyloidosis • Associated Feature: Hypercoagulability • Diabetic nephropathy Caveat: Many patients do not have all 5 features, i.e. • Others: SLE, IgA nephropathy, MPGN nephrotic-range proteinuria without nephrotic “syndrome”

Nephrotic Disease: Focal Segmental Nephrotic Disease: Glomerulosclerosis (FSGS) Membranous Nephropathy

• Primary • Idiopathic/Primary • Can be treated with steroids • Secondary • Can recur rapidly post-kidney transplant • Malignancy • Secondary • Typically solid (colon, lung, breast), also non-Hodgkin’s • HIV-associated nephropathy (HIVAN): from uncontrolled HIV; • 5-10% have malignancy, but <1-2% are occult almost exclusively in African-Americans • Chronic infections, HBV > HCV, syphilis • Chronic kidney disease, reduced mass, hyperfiltration • SLE (10-20% of lupus nephritis) and autoimmune/connectiv e tissue injury diseases • Morbid obesity • Drugs: NSAIDs, gold, penicillamine (think of this in pts with RA • Heroin, drugs (lithium, pamidronate) treated with these agents) • Sickle cell disease • Typically not steroid responsive

8 7/12/16

Nephrotic Disease: Nephrotic Disease: Membranous Nephropathy Minimal Change Disease (MCD)

• Clinical • Idiopathic/Primary • Second peak in 60-70 year old patients • Renal vein thrombosis and hypercoagulability • More steroid resistance/dependence and higher relapse rate in • Secondary prophylaxis with warfarin adults than in children • Malignancy and age-appropriat e cancer screening • Secondary • Prognosis: Mixed • Drugs • Third get better, third stay same, third get worse • NSAID-induced AIN with MCD, pyuria with proteinuria • Treatment: • Infections • Neoplasm, Hodgkins and others • Carefully selected patients with poor prognostic features (older age, • Allergy and toxins (bee stings, mercury, lead) men, chronic kidney disease, symptomatic proteinuria/nephr otic syndrome) • Rx: Steroids typically first-line • Immunosuppression: steroids AND (cyclophosphamide or chlorambucil)

Kidney Disease in Multiple Myeloma Diabetic Nephropathy

• Amyloidosis • Common cause of nephrotic-range proteinuria • Lambda > kappa light chains • Unusual cause of nephrotic syndrome • Light chain deposition disease • Early hyperfiltration phase usually with preserved creatinine and large kidneys • Kappa > lambda light chains • Diagnosis • Cast nephropathy • Usually clinical diagnosis without kidney biopsy • Hypercalcemia and vasoconstrictive AKI • Compatible clinical history • Hypercalcemia and nephrogenic DI with pre-renal AKI • Duration and severity of DM • Evidence of end-organ disease from DM (retinopathy, neuropathy) • No suspicious features for alternative diagnosis

9 7/12/16

DDx Enlarged Kidneys Adjuvant Rx in nephrotic syndrome

• Obstruction / hydronephrosis • Blood pressure control • Proteinuria suppression • Polycystic kidney disease • ACE inhibitors / ARB • Infiltrative disease (lymphoma) • Goal urine protein:creatinine ratio < 0.5 • Dietary protein restriction à controversial • Amyloidosis • Loop diuretics for edema • Diabetic nephropathy (early stage) • Sodium/fluid restriction • HIV-associated nephropathy • Primary prophylaxis with anticoagulation for hypercoagulability somewhat controversial

Interstitial kidney disease

• Affect vascular / interstitial compartments of kidney with relative sparing of glomeruli • Often asymptomatic TUBULOINTERSTITIAL • May not have the fever, rash, and arthralgias of acute interstitial nephritis DISEASES • Minimal proteinuria/hematuria • Sterile pyuria • Urine sediment: +/- WBC, WBC casts

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Chronic tubulointerstitial diseases Interstitial kidney disease

• Toxic • Tubular abnormalities • Occupational exposures, lead and heavy metals • Urinary concentrating defects and nephrogenic diabetes insipidus • Medications: analgesics, lithium, cisplatin, calcineurin inhibitors à polyuria, nocturia • Traditional medicines: aristolochic acid nephropathy • Fanconi syndrome • Medical • Impaired tubular reabsorption: amino acids, , phosphate, • Metabolic: hyperCa, hypoK, oxalosis glucose in urine • • Immune disorders: SLE, Sjogren’s, sarcoidosis Glucosuria with normal serum glucose • Lymphoproliferative disease • Proximal (type 2) RTA/ from bicarbonate spilling • Hypertensive nephropathy • Distal (type 1) RTA/metabolic acidosis from inability to acidify urine • Atheroemboli • Genetic: Alport’s, cystinosis, medullary cystic kidney disease, polycystic kidney disease • Chronic urinary tract obstruction

44

NSAIDs and kidney disease

• AKI: Hemodynamic acute renal failure • vasodilate afferent arteriole • AKI: Acute interstitial nephritis +/- minimal change disease • Sterile pyuria with proteinuria • CKD: Analgesic nephropathy ELECTROLYTE ABNORMALITIES • Cumulative nephrotoxicity, high doses over years • Sometimes associated with papillary necrosis • CKD: Membranous nephropathy • Heavy proteinuria, nephrotic syndrome • Hypercoagulability

11 7/12/16

Case Case, continued

54 yo man was hospitalized for shortness of breath. Found Labs to have pleural effusion, dx’ed with metastatic small-cell • Glucose 114 mg/dl lung ca. Long h/o cigarette smoking. Now seen in follow- • BUN 10 mg/dl, Cr 0.6 mg/dl up a few weeks later. • Sodium 112 / K 3.2 / Cl 84 / Bicarb 21 / Phos 3.1 Medications include ACEI • Albumin 3.2 g/dl Exam: BP 126/84, pulse 84, afebrile, RR 18 • Serum Osm 243 mmol/kg Fatigued, cachectic, but alert/oriented • Urine Na 120 mmol/L CV reg • Urine K 24 mmol/L Lungs diminished breath sounds right base • Urine Osm 542 mmol/kg No edema

Case Question Case answer review

Which of the following is the most appropriate therapy at A. 3% saline via infusion pump – chronic hyponatremia – this time? do not want to correct aggressively; no symptoms B. Tolvaptan – right answer – need to increase free water A. 3% saline via infusion pump excretion B. Tolvaptan C. Fluid restriction < 1 L/day – insufficient due to electrolyte-free water C. Fluid restriction < 1 L/day D. Sodium chloride tablets, 2g three times daily – not D. Sodium chloride tablets, 2g three times daily getting at problem of water out of proportion to salt E. Hydrochlorothiazide E. Hydrochlorothiazide – impairs diluting capacity – can be a cause of hyponatremia

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Sodium: Key physiology Hyponatremia

• Think about water, not salt! • Serum Osmolality • Water and sodium balance are interrelated, but regulated • High: Translocational, mannitol and glucose by separate mechanisms • Normal: Pseudohyponatremia, triglycerides and paraproteinem ias • ADH regulates osmolality (water balance) • Low: Majority of hyponatremia cases • regulates sodium balance • Volume status can be confusing • Appropriate ADH release: normovolemic states of ADH excess due to non-osmotic stimulus: postop, pain, nausea • States of effective circulating volume depletion: heart failure, cirrhosis, diuretics • Inappropriate ADH release: SIADH, cortisol deficiency, hypothyroidism

Serum sodium < 135 meq/L Serum osmolality Serum osmolality <280 mosm/kg H2O >280 mosm/kg H2O Review case Urine osmolality Hyperglycemia <100 mosm/kg H2O >100 mosm/kg H2O Mannitol infusion Labs • Glucose 114 mg/dl Psychogenic polydipsia Water intoxication • BUN 10 mg/dl, Cr 0.6 mg/dl Reset osm ostat • Sodium 112 / K 3.2 / Cl 84 / Bicarb 21 / Phos 3.1 • Albumin 3.2 g/dl Volume depleted Normal volume Edematous • Serum Osm 243 mmol/kg • Urine Na 120 mmol/L / Urine K 24 mmol/L Urine sodium Urine sodium Heart failure <25 meq/L >25 meq/L Renal failure Cirrhosis • Urine Osm 542 mmol/kg Hypothyroidism Renal failure Adrenal insufficiency Pain/stress/trauma • Electrolyte-free water clearance: (UNa + UK) > (Serum Na + Serum K) Extrarenal Renal Postoperative fluid loss* fluid loss means free water is being RETAINED rather than excreted –only ADH antagonism will help Present Absent • Same concept as UOsm > SOsm but more accurate; UOsm that is not maximally dilute could still be inappropriate for the low POsm – does not Urine sodium >25 meq/L necessarily have to be greater than SOsm Syndrome of inappropriate ADH secretion

13 7/12/16

Case Laboratory studies

• CD4 cell count 87 / mcl • A 23 yo man with HIV infection comes for a follow-up after • Glucose 182 mg/dl being hospitalized with pneumocystis jiroveci pneumonia, • BUN 12 mg/dl which is being treated with trimethoprim-sulfamethoxazole • Cr 0.7 mg/dl and pred taper. • Sodium 111 mmol/L o • Exam: Temp 97.8 F, pulse 84, respirations 12, BP 110/60 • 3.6 mmol/L • Thin, in no apparent distress • Chloride 96 mmol/L • Cardiac exam normal • Bicarb 22 mmol/L • Albumin 3.3 g/dl • Lungs clear • Phos 2.6 mg/dl • No peripheral edema • Serum Osm 246 mOsm/kg H2O • Urine sodium 117 mmol/L • Urine potassium 24 mmol/L • Urine Osm 453 mosm/kg

Case Question Case answer review

• Which of the following is the most likely cause of this • A. Syndrome of inappropriate antidiuretic hormone patient’s hyponatremia? secretion – correct answer – hypotonic (hypoosmolal) hyponatremia with excess free water retention / abnormal • A. Syndrome of inappropriate antidiuretic hormone secretion free water excretion • B. Volume Depletion – history not suggestive; would have • B. Volume Depletion a lower urine sodium • C. Adrenal insufficiency • C. Adrenal insufficiency – common cause of • D. Pseudohyponatremia hyponatremia including in HIV but no evidence of • E. Psychogenic polydipsia. mineralocorticoid deficiency • D. Pseudohyponatremia – in pseudohyponatremia, osmolality is normal • E. Psychogenic polydipsia – would have very low urine Osm and low urine

14 7/12/16

Review laboratory studies SIADH: Syndrome of Inappropriate Antidiuretic Hormone • Serum Osm 246 mOsm/kg H2O • Common cause of hyponatremia • Urine sodium 117 mmol/L • Low serum osmolality • Urine potassium 24 mmol/L • Clinically euvolemic • Urine Osm 453 mosm/kg • DDx • CNS: head trauma, infection, CVA, tumors, others • Pulmonary: Small cell lung cancer, pneumonia, lung abscess, (Urine sodium + urine potassium) > (serum sodium + pneumothorax serum potassium) • Drugs: Chlorpropamide, tricyclic antidepressants, haloperidol, Urine Osm > Serum Osm SSRIs • Neoplasm • Pain, nausea

SIADH: Syndrome of Inappropriate Hyponatremia Antidiuretic Hormone • Treatment • Findings • Free water restriction; increase solute intake • Urine osms > Serum osms • Hypovolemic: Saline IVF, suppress ADH excretion • Urine Na > 20 mEq/L • Euvolemic: Free H2O restriction • Diagnosis of exclusion • Hypervolemic: Diuretics and/or dialysis • Rule-out hypothyroidism and adrenal insufficiency • Hypertonic Saline (3% NaCl) • Rarely indicated • Treatment more specific for SIADH • Risk of osmotic demyelination/pontine myelinolysis • Sodium tablets and water restriction • Used for severely symptomatic patients • Demeclocycline no longer used, nephrotoxic (induces nephrogenic • Infusion rate typically 0.5 to 1 mL/kg/hour diabetes insipidus) • Correction rate • receptor antagonists (vaptans) – liberalize fluid intake • Approximately 10-12 mEq/L per day if on vaptan!

15 7/12/16

Hypernatremia Hypernatremia

• Clinical • CNS symptoms: lethargy, weakness, irritability, altered mental Free water deficit = status, seizures, coma 0.5 x Wt (kg) x [(plasma Na – 140)/140] • usually protects against hypernatremia; impaired access to free water

• DDx • Free water deficit typically at least 2 L • Renal water loss: DM and glucosuria, diabetes insipidus (central or • Intravenous D5W vs. water NG/PO nephrogenic), post-obstructive or post-ATN diuresis • Extra-renal water loss: insensible losses, GI losses • If hypovolemic, resuscitate with NS first or • Excess Na+ retention: AKI simultaneously with free water • Correction rate: 12 mEq/L per 24 hours (approx)

Potassium Hyperkalemia: Work-up

• Primarily intracellular compartment (98%) • Transtubular Potassium Gradient (TTKG) • Shifts (from one compartment to another) versus absolute • TTKG = (UK/PK) / (Uosm/Posm) excess / deficiency of total body potassium • Normal range is 6-8 • TTKG < 6 à renal hyperkalemia • 90% of regulation in kidney (trivial amounts in sweat / GI tract) • TTKG > 10 à appropriate renal response • Daily excretion in urine 120-140 mEq/24 hours • Aldosterone is primarily responsible for activity of Na/K ATPase in collecting duct, which stimulates excretion of K+ • TTKG can assess aldosterone effect • Hyperkalemia generally asymptomatic • Symptoms of hypokalemia: Weakness, rhabdomyolysis, arrhythmias, cramps

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Hyperkalemia: Etiology EKG findings in hyperkalemia

• Loss of P waves, QRS widening, T wave peaking, • Dietary ingestion - salt substitutes, K supplementation Ventricular tach/ fib • Decreased excretion • Correlate poorly with severity of hyperkalemia • AKI/CKD • Decreased RAAS (ACEi/ARB, NSAIDs, heparin) • Hypoaldosteronis m (Addison’s disease) or lack of aldosterone effect (type 4 RTA) • Block tubular K handling (trimethoprim, pentamidine, amiloride, calcineurin inhibitors) • Extracellular K shift: metabolic acidosis, insulin deficiency, beta-blockers, tumor lysis, digoxin overdose, succinylcholine, hyperkalemic periodic paralysis

NEJM 2016;374:23

Hyperkalemia Treatment Hypokalemia: Etiology

• Stabilization of membrane = Fast • Low dietary intake – not really a problem on Western diet • gluconate IV • Increased excretion • Shift potassium = Fast • GI: diarrhea, vomiting (TTKG <2) • Beta-agonists (albuterol) • Kidney (TTKG >4): diuretics, hypomagnes emia, mineralocortic oid excess (primary aldosteronism, Cushing’s, European licorice, • Insulin/glucose hyperreninemia, syndrome of apparent mineralocortic oid excess), Bartter, Gitelman • NaHCO3 (may not work in ESRD) • Removal of potassium = Slow • Shift: alkalemia, increased insulin, increased beta-activity, • Diuretics, Dialysis periodic paralysis (classically with thyrotoxicosis) • Cation exchange resins (sodium polystyrene - avoid in peri-operative pts, ileus/SBO)

17 7/12/16

Phosphorus Calcium

• Excreted through kidneys, reabsorbed in proximal tubule • Intracellular levels are low – stored in bone • 5-20% of filtered load excreted, except in malnutrition • PTH regulates vitamin D, urinary Ca excretion and • Regulated by parathyroid hormone and (1,25 reabsorption vitD), which stimulates phosphate absorption in gut • Vitamin D regulates gut absorption • Hypophosphatemia: malnutrition, alcoholism • Hypocalcemia: vitamin D deficiency, hyperphos / renal • Hyperphosphatemia: renal failure failure, hypoparathyroidism • Hypercalcemia: hyperparathyroidism, malignancy, increased vitamin D (granulomatous production)

Case

68 year-old man with chronic kidney disease due to type 2 diabetes is evaluated in clinic for nausea, vomiting, and fatigue for the past several weeks. His symptoms started several days after a cardiac catheterization which ACID-BASE DISORDERS demonstrated two-vessel coronary artery disease. Physical examination is remarkable for bibasilar crackles, a regular cardiac rhythm, and 2+ peripheral edema.

18 7/12/16

Case Case Question

• Laboratory studies: Which of the following describes this patient’s acid-base • BUN 110 m g/ dL status? • Serum Cr 14.0 mg/dL A. No acid-base abnormality • Serum sodium 135 mEq/L • Serum potassium 5.5 mEq/L B. Metabolic acidosis and • 80 mEq/L C. Metabolic acidosis with respiratory compensation • Serum bicarbonate 23 mEq/L D. Metabolic acidosis and • Arterial blood gas (room air): pH 7.39 PCO2 39 mmHg PO2 72 mmHg Bicarbonate 23 mEq/L

Acid base disorders: systematic Acid base formulas – expected approach is key! compensation for primary metabolic • Identify Primary Disorder disturbance • Calculate the anion gap and learn the use of delta gap • Know 1 set of compensation methods and apply • • Finalize the acid base disturbance and generate a Metabolic Acidosis differential diagnosis for each problem identified • Winter’s formula – predicts pCO2 = (1.5 x HCO3-) + 8 +/- 2 • Metabolic Alkalosis • 0.6 mmHg rise in PCO2 per 1 meq/L elevation in plasma [HCO3-]

19 7/12/16

Expected compensation for primary Case respiratory disturbance 68 year-old man with chronic kidney disease due to type Acute Acute respiratory alkalosis 2 diabetes is evaluated in clinic for nausea, vomiting, and 1 meq/L increase in 2 meq/L decrease in plasma fatigue for the past several weeks. His symptoms started plasma [HCO3-] per 10 [HCO3-] per 10 mmHg several days after a cardiac catheterization which mmHg rise in PCO2 decrease in PCO2 demonstrated two-vessel coronary artery disease. Physical examination is remarkable for bibasilar crackles, a regular cardiac rhythm, and 2+ peripheral edema. Chronic respiratory acidosis Chronic respiratory alkalosis 3.5 meq/L elevation in 4 meq/L decrease in plasma [HCO3-] per 10 plasma [HCO3-] per 10 mmHg increase in PCO2 mmHg decrease in PCO2

Case: Laboratory studies Case: Laboratory studies

• BUN 110 mg/dL • Is there a secondary disorder? • Serum Cr 14.0 mg/dL • BUN 110 mg/dL • Serum sodium 135 mEq/L • Serum Cr 14.0 mg/dL • Serum potassium 5.5 mEq/L • Serum sodium 135 mEq/L • Serum chloride 80 mEq/L • Serum potassium 5.5 mEq/L • Serum bicarbonate 23 mEq/L • Serum chloride 80 mEq/L • Arterial blood gas (room air): • Serum bicarbonate 23 mEq/L pH 7.39 • Arterial blood gas (room air): PCO2 39 mmHg pH 7.39 PO2 72 mmHg PCO2 39 mmHg Bicarbonate 23 mEq/L PO2 72 mmHg • Primary disorder: difficult to tell from ABG! Bicarbonate 23 mEq/L

Calculate anion gap = 135-80-23 = 32: there is Calculate delta delta =32 – 12 = 20: there is a DEFINITELY an anion gap metabolic acidosis superimposed metabolic alkalosis!

20 7/12/16

Case: Mixed diosrder Normal Ketoacidosis Ketoacidosis plus vomiting • How do we know there is a superimposed metabolic alkalosis? AG • BUN 110 mg/dL ----AG------AG---- - HCO3 - - • Serum creatinine 14.0 mg/dL HCO3 HCO3 - • Serum sodium 135 mEq/L HCO3 • Serum potassium 5.5 mEq/L • Serum chloride 80 mEq/L • Serum bicarbonate 23 mEq/L + 20 = 43 = higher than Na+ Na+ Na+ normal serum bicarb of 24 = metabolic alkalosis – change in bicarb exceeded by change in anion gap – see diagram Cl- Cl- Cl- • Arterial blood gas (room air): pH 7.39 PCO2 39 mmHg PO2 72 mmHg Bicarbonate 23 mEq/L

Case: Laboratory studies Case Question

• Is there a third disorder? Which of the following describes this patient’s acid-base • BUN 110 mg/dL • Serum Cr 14.0 mg/dL status? • Serum sodium 135 mEq/L A. No acid-base abnormality – not true although the ABG • Serum potassium 5.5 mEq/L is deceiving! • Serum chloride 80 mEq/L • Serum bicarbonate 23 mEq/L B. Metabolic acidosis and respiratory alkalosis • Arterial blood gas (room air): C. Metabolic acidosis with respiratory compensation – pH 7.39 examples on subsequent slides PCO2 39 mmHg PO2 72 mmHg D. Metabolic acidosis and metabolic alkalosis Bicarbonate 23 mEq/L

Calculate expected respiratory compensation. Winter’s Correct answer is D. Metabolic (gap) acidosis from DKA / formula predicts pCO2 should be 43 +/- 2. pCO2 of 39 close renal failure plus metabolic alkalosis from vomiting. enough to predicted pCO2 of 43 +/- 2. No third disorder.

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Example: metabolic acidosis and Example: metabolic gap acidosis with respiratory alkalosis (choice B) respiratory compensation (choice C)

• Na 140 K 5.0 Cl 105 HCO3 15 • Na 140 K 4.5 Cl 105 HCO3- 12 • pH 7.4 pCO2 25 • pCO2 26 pH 7.29 • AG 140-105-15 = 20 • AG = 140-105-12 = 23 • Predicted pCO2 = 22.5+ 8 +/- 2 = 30.5 +/- 2 • Predicted pCO2 = 18 + 8 +/- 2 = 26 +/-2 • 25 is less than 30 = superimposed respiratory alkalosis (mild)

• What if pH were 7.5, pCO2 20? • More severe superimposed respiratory alkalosis

Metabolic disturbances Anion gap metabolic acidosis

1) Metabolic acidosis • Increased Anion Gap 2) Metabolic alkalosis • MUDPILES (methanol, uremia, DKA, paraldehyde, isoniazid, lactic 3) Gap metabolic acidosis acidosis, ethylene glycol, salicylate) 4) Gap metabolic acidosis AND nongap metabolic • AG > 20 implies metabolic acidosis regardless of serum acidosis (!!!) ß2 completely different disorders bicarbonate or pH 5) Gap metabolic acidosis AND metabolic alkalosis

Serum Anion Gap = Na – Cl – HCO3 Normal AG < 12

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Aside: DDx Decreased Anion Gap Case

• Extra Positive (+) charges • A 56 yo man with h/o alcoholism is found lying on the • Immunoglobulins (myeloma) street with impaired consciousness. On arrival at ED, he • Lithium is unresponsive and is intubated. • Potassium • Exam: Temp 97oF, pulse 70, BP 126/80 • Magnesium • Funduscopic exam: no papilledema • Calcium • Cardiac, pulmonary, abdominal exams normal. No • Decreased Negative (-) charges edema. • Albumin

• Corrected AG – add 2.5 to the AG for every 1 g/dL drop in albumin

Laboratory studies Case Question

• Glucose 86 mg/dl Which of the following is the most appropriate treatment for • Blood urea nitrogen 45 mg/dl this patient? • Creatinine 2.8 mg/dl A. Fomepizole and hemodialysis • Sodium 138 mmol/L B. Bicarbonate supplementation • Potassium 5.4 mmol/L C. Ethanol drip • Chloride 94 mmol/L D. Hemodialysis • Bicarb 14 mmol/L E. Fomepizole and ethanol drip • 316 mosm/kg H2O

• ABG pH 7.28 / pCO2 29 / PO2 108 • UA calcium oxalate crystals

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Case answer review Osmolar Gap A. Fomepizole and hemodialysis – correct answer – Os molar Gap = ethylene glycol poisoning – block metabolism with Measured Osms – Estimated Osms fomepizole and remove / treat severe acidosis with dialysis B. Bicarbonate supplementation – could be a temporizing Estimated osms = measure, but is inadequate on its own 2Na + BUN/2.8 + glucose/18 + EtOH/4.6 C. Ethanol drip – ethanol can also be used but more toxic – sometimes fomepizole is not available Normal Osmolar Gap < 10 D. Hemodialysis – on its own insufficient because does not block ethylene glycol metabolism E. Fomepizole and ethanol drip – do not use both concurrently because fomepizole prolongs ethanol half-life

Osmolar Gap Metabolic acidosis: Non-anion gap

Major conditions with increased osmolar gap • Normal gap (non-gap) metabolic acidosis • Same as for Anion gap (MUDPILES) • Also called hyperchloremic metabolic acidosis • Conditions = uremia, DKA, alcoholic ketoacidosis, lactic acidosis • PLUS ingestions = methanol, paraldehyde, formaldehyde, ethylene • Primary decrease in serum bicarb with increase in glycol serum chloride • Normal AG, no metabolic acidosis • GI: Diarrhea with bicarbonate loss • Exogenous = isopropanol, diethyl ether, mannitol • Negative urine anion gap • Artifact = hyperproteinemia, hypertriglyceridem ia (artificial lowering of serum sodium concentration) • Renal: (RTA) • Positive urine anion gap (think, “if it’s the kidney, it’s positive!”)

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Urine anion gap Case

• Unmeasured anions + measured anions = unmeasured • A 22 yo woman with a history of Sjogren’s syndrome cations + measured cations presents with a 1 week history of progressive weakness • Rearrange equation: • Unmeasured anions-unmeasured cations = urine AG = • Physical Exam: Diffuse muscle weakness, normal DTRs measured cations - measured anions Urine Anion Gap = Na + K – Cl Normal UAG in acidosis is negative (because unmeasured cation term is LARGE from ammonium – which is the normal renal response to acidosis) RTA = Urine K is high = UAG becomes positive Diarrhea = GI losses of bicarb -> low urine bicarb (lower unmeasured anions) = negative UAG = “neGUTive”

Case Case Question

• Laboratory studies: Which of the following describes this patient’s acid-base • BUN 20 mg/dL • Serum Cr 0.7 mg/dL status? • Serum sodium 140 mEq/L A. No acid-base abnormality • Serum potassium 2.2 mEq/L B. Metabolic acidosis and respiratory acidosis • Serum chloride 120 mEq/L • Serum bicarbonate 12 mEq/L C. Metabolic acidosis with respiratory compensation • Arterial blood gas (room air): D. Metabolic acidosis and metabolic alkalosis pH 7.1 PCO2 40 mmHg PO2 72 mmHg • Urine pH 6.5 • Urine Na 95 K 32 Cl 90 (UAG = 37)

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Case Case answer review

• Laboratory studies: Which of the following describes this patient’s acid-base • BUN 20 mg/dL • Serum Cr 0.7 mg/dL status? • Serum sodium 140 mEq/L A. No acid-base abnormality • Serum potassium 2.2 mEq/L B. Metabolic acidosis and respiratory acidosis – right • Serum chloride 120 mEq/L • Serum bicarbonate 12 mEq/L answer – metabolic acidosis from type I RTA, • Arterial blood gas (room air): respiratory acidosis from poor muscle function pH 7.1 C. Metabolic acidosis with respiratory compensation PCO2 40 mmHg PO2 72 mmHg D. Metabolic acidosis and metabolic alkalosis • Urine pH 6.5 • Urine Na 95 K 32 Cl 90 (UAG = 37) Calculate anion gap. 140-120-12 = 8. No anion gap. Calculate predicted respiratory compensation. 18+8+/-2 = 26 +/-2

Renal tubular acidosis – non gap met acid Non-gap Metabolic Acidosis: Type 1 Type 2 Type 4 Stepwise Analysis Distal Proximal • Examine serum K Defect ↓ distal ↓proximal HCO3 Aldosterone • If high, then type 4 RTA acidification reabsorption deficiency or resistance • If normal, then type 1 or type 2 • Urine pH Urine pH > 5.3 > 5.3 early Usually < 5.3 • If urine pH > 5.5, then Type 1 (Distal) < 5.3 late • If urine pH < 5.0, then Type 2 (Proximal) Plasma K Low or normal, Low or normal High • If type 2 Proximal RTA can be high • Confirm with evidence of proximal tubular dysfunction Dose of Low High Low • Glucosuria, low-grade proteinuria, phosphaturia bicarbonate

Complications Nephrocalcinos is Rickets or None osteomalacia Nephrolithias is

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Case Case, continued

A 22 year-old woman comes to the emergency room with Labs Urine paresthesias and generalized weakness. • Sodium 138 mEq/L pH 6.0 • Potassium 2.4 mEq/L Na 16 mEq/L • Chloride 90 mEq/L K 20 mEq/L She has no significant medical history and does not take • Bicarbonate 36 mEq/L Cl < 5 mEq/L any medications. • BUN 14 mg/dL • Creatinine 1.0 mg/dL Her blood pressure is 120/72 and physical exam is • Magnesium 1.9 mg/dL unremarkable. • Calcium 9.0 mg/dL

Case Question Case - review

Which of the following is the most likely diagnosis? Labs Urine A. Surreptitious vomiting • Sodium 138 mEq/L pH 6.0 • Potassium 2.4 mEq/L Na 16 mEq/L B. Surreptitious active diuretic use • Chloride 90 mEq/L K 20 mEq/L C. Gitelman syndrome • Bicarbonate 36 mEq/L Cl < 5 mEq/L D. Bartter syndrome • BUN 14 mg/dL E. Liddle syndrome • Creatinine 1.0 mg/dL • Magnesium 1.9 mg/dL • Calcium 9.0 mg/dL

Calculate anion gap. 138-90-36 = 12. No anion gap. Calculate urine anion gap. 16+20-5 = 31. Positive UAG.

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Case answer review Pathogenesis of Metabolic Alkalosis A. Surreptitious vomiting – right answer – extracellular volume depletion – chloride retention by kidney - lots of • Generation, then maintenance urine bicarb (high unmeasured anion makes UAG pos • Generation: net gain of bicarb versus net loss of hydrogen – remember “neGUTive” is only in met ACIDOSIS) • Exogenous HCO3- loads: acute alkali administration, B. Surreptitious active diuretic use – would expect higher Milk-alkali syndrome, pica urine chloride • ECV contraction with high and high aldo C. Gitelman syndrome – autosomal recessive – mimics • GI losses: vomiting, gastric aspiration thiazide diuretics - hypocalciuria • Renal origin: diuretics (thiazide / loop) • Posthypercapnia D. Bartter syndrome – autosomal recessive, mimics loop • Hypokalemia diuretics • Bartter, Gitelman E. Liddle syndrome – autosomal dominant gain of function • ECV expansion with hypermineralocorticoidism of epithelial sodium channel – associated with elevated • High renin: RAS BP, hypokalemic metabolic alkalosis, low renin, low • Low renin: primary aldosteronism aldo – low urine chloride but history not supportive

Maintenance of Metabolic Alkalosis Urine Chloride in Metabolic Alkalosis

Reduced renal bicarbonate excretion due to: • Vomiting and long term diuretic use • Depleted body chloride stores • Kidneys will conserve/reabsorb chloride • Effective circulating volume depletion • Urine Cl < 15 mEq/L • Reduction in the filtered load of HCO3 • Urine Cl will be elevated with ACTIVE diuretic use • Secondary aldosteronism (paradoxical aciduria) • Primary aldosteronism • Chloride depletion • • Vomiting and diuretics Volume expanded • Urine Cl > 20 mEq/L • Hypokalemia • Intracellular shifting of potassium and hydrogen ions

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Example: post-hypercapnic metabolic Saline and Alkalosis alkalosis • Saline Responsive = Low urine Cl < 15 • Na 140 K 5 Cl 100 HCO3 31 (AG 9) • Vomiting or nasogastric suction • pCO2 55 pH 7.37 • Diuretics • Post-hypercapnic alkalosis • pH is low, pCO2 is HIGH = respiratory acidosis • Low dietary chloride intake • Saline Unresponsive = High urine Cl > 20 • Calculate expected metabolic compensation • Mineralocorticoid excess • Delta pCO2 = 15 • Severe hypokalemia • Divide 15 by 10, then multiply by 3.5 (for chronic • Edematous disorders, e.g. CHF compensation since pH relatively normal) • Bartter / Gitelman • Expected serum HCO3 = 24 + 5.25 = 29.25

• If you intubated this person, serum bicarb would remain elevated until volume status corrects

Example Acid base formulas

• Na 140 K 3.5 Cl 92 HCO3 34 AG 12 • Metabolic Acidosis • pCO2 55 pH 7.41 • Winters formula pCO2 =(1.5 x HCO3-) + 8 +/- 2 • If you don’t like Winter’s formula: expected pCO2 is [HCO3-] + 15 • Metabolic Alkalosis • pCO2 high = respiratory acidosis • 0.6 mmHg rise in PCO2 per 1 meq/L elevation in plasma [HCO3-] • Predicted bicarb 30 (24 + 1.5 * 3.5) • pCO2 = 0.7 [HCO3-] + 20 +/- 5 • Actual bicarb higher = concomitant metabolic alkalosis (which explains pH > 7.4)

• OR start with metabolic alkalosis • Predicted pCO2 = 0.7*34 = 23.8 + 20 = 43.8 +/-5 • Actual pCO2 higher = concomitant respiratory acidosis

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Acid base formulas Acid base formulas

Respiratory Acidosis Respiratory Alkalosis • Acute: • Acute: • 1 meq/L increase in plasma [HCO3-] per 10 mmHg rise in PCO2 • 2 meq/L decrease in plasma [HCO3-] per 10 mmHg decrease in • ∆[H+] = 0.8 ∆PCO2 PCO2 • Chronic: • ∆ [H+] = 0.8 ∆PCO2 • 3.5 meq/L elevation in plasma [HCO3-] per 10 mmHg increase in • Chronic: PCO2 • 4 meq/L decrease in plasma [HCO3-] per 10 mmHg decrease in • ∆[H+] = 0.3 ∆PCO2 PCO2 • ∆ [H+] = 0.4 ∆PCO2

Case

A 57-yr-old man is admitted after a motor vehicle accident. He has sustained multiple fractures and blunt chest and abdominal trauma. A left hemothorax is treated with a chest tube, an abdominal lavage reveals only minimal blood, and ACUTE KIDNEY INJURY a noncontrast computed tomography (CT) scan of the abdomen is negative. He is volume-resuscitated with approximately 15 L of crystalloid. Twenty-four hours after admission, he is noted to have marked abdominal distension and low urine output.

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Case Case

Physical Exam: Labs: Tm 37.2 BP 135/86 HR 86 RR 16 UOP 100 cc/12h • Na 135 CVP 18 Bladder pressure 28 • K 5.8 Intubated, sedated • Cl 103 Decreased breath sounds at bases • HCO3 24 Regular heart sounds, no m/r/g • BUN 46 Abdomen distended and firm, hypoactive BS • Cr 2.3 • Imaging: Small retroperitoneal hematoma, normal sized kidneys without hydronephrosis, marked ascites.

Case Question Case answer review

Which of the following would be the most appropriate next A. Abdominal decompression - correct answer - step? Intraabdominal hypertension (IAH) is defined as a sustained intraabdominal pressure >12 mmHg. A. Abdominal decompression Abdominal compartment syndrome (ACS) is defined as B. Fluid resuscitation a sustained intraabdominal pressure>20 mmHg that is C. Placement of bilateral ureteral stents associated with new organ dysfunction D. Initiation of renal replacement therapy B. Fluid resuscitation – correct answer for AKI from hypovolemia / some cases of pre-renal azotemia C. Placement of bilateral ureteral stents – sometimes indicated for obstruction D. Initiation of renal replacement therapy – indicated for emergencies including acidosis, electrolyte abnormalities, ingestions, volume overload, and uremia

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Acute Renal Failure / Acute Kidney Fractional Excretion of Sodium (FeNa) Injury • Percent of filtered sodium that is excreted in the urine • Pre-Renal = Decreased kidney perfusion • FeNa = (U * P )/(P * U ) * 100 • Intra-Renal = Intrinsic kidney injury Na Cr Na cr • <1% consistent with pre-renal state • Post-Renal = Obstruction • Only useful when patient is oliguric (< 400 cc urine output/24 hours) • Confounded by use of diuretics

Pre-Renal: Pre-Renal: Kidney Hypoperfusion Kidney Hypoperfusion

• Dehydration, overdiuresis, hypovolemia • Diagnosis • Abdominal compartment syndrome: Typically occurs after massive • +/- Oliguria volume resuscitation • High BUN:Creatinine ratio > 20 • Hemorrhage • Bland urine sediment, normal kidney US • Hemodynamic effect: ACE/ARB and NSAIDs • Low FENa < 1% and low urine Na < 10 mEq/L • Heart failure • High specific gravity, high urine osmolality • Rapid renal recovery with resuscitation • Cardiorenal syndrome • Therapy: Restore renal perfusion • Cirrhosis/End-stage liver disease • Hepatorenal syndrome • Prognosis: Good, often rapid renal recovery • Exceptions: Cardiorenal and hepatorenal syndromes

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Pre-renal: Post-Renal: Obstruction Hepatorenal Syndrome • Urinary tract obstruction • Severe end-stage liver disease patients • Renal pelvis, ureters, bladder, prostate, urethra • Intense renal vasoconstriction • Congenital and acquired lesions, BPH • Diagnosis of exclusion • Neurogenic bladder, medication effects • Oliguria • Nephrolithiasis • Low urine sodium < 10 mEq/L, low FENa < 1% • Malignancy • Hyponatremia • GI cancers • Prostate cancers • Bland urine sediment • Uterine, cervical, ovarian cancers • Normal US (no hydronephros is) • Lymphadenopathy • No other identifiable cause • • Lack of response to volume expansion Retroperitoneal fibrosis • Treatment • Splanchnic vasoconstrictors (terlipressin, ornipressin), midodrine, octreotide; TIPS controversial; liver transplant

Post-Renal: Obstruction Intra-Renal: Acute Tubular Necrosis (ATN) • Clinical • Etiology • Oliguric or non-oliguric • Ischemic = hypotension, sepsis, shock, hemorrhage • Can have type 4 RTA, metabolic acidosis • Toxic • Foley does not definitively rule out obstructive nephropathy • Exogenous: intravascular radiocontrast, aminoglycosides, amphotericin, • Hydronephros is, although negative ultrasound does not rule out cisplatin, oxalate (ethylene glycol/anti-freeze ingestion) obstructive nephropathy • Endogenous: rhabdomyolysis (), hemolysis (hemoglobin), tumor lysis (urate) • Therapy • Diagnosis • Correct obstruction; can see post-obstructive diuresis from urinary • Muddy brown/pigmented casts in urine sediment concentrating defect • Elevated FENa > 1-2% • Urology consultation • High urine Na > 20 mEq/L • Interventional radiology consultation: nephrostomy tubes

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Intra-Renal: Intra-Renal: Acute Tubular Necrosis (ATN) Radiocontrast Nephropathy

• Prognosis • Etiology • Mortality: 40-70% in ICU if dialysis-requir ing AKI • Iodine-based radiocontrast • Slower recovery • Intravenous or intraarterial injection • Therapy • CT, angiography, cardiac catheterization • Supportive care • Risk factors • Dialysis as needed • Pre-existing chronic kidney disease • Fluid and electrolyte management • Proteinuria • Medication dosing adjustment for GFR • Age • No proven therapies • Diabetes mellitus • No benefit: mannitol, furosemide, dopamine, ANP, thyroxine • Multiple myeloma • Dehydration

Intra-Renal: Intra-Renal: Radiocontrast Nephropathy Radiocontrast Nephropathy

• Presentation • Prevention • Rise in creatinine 24-48 hours post-exposure • Avoid radiocontrast (US, nuclear medicine) • Patient with risk factors • Minimize dose of radiocontrast • Low FENa < 1% • Use iso-osmolar or hypo-osmolar contrast (as opposed to hyperosmolar contrast) • Bland sediment (mild forms with vasoconstriction) or muddy brown casts of ATN (severe forms with toxic injury) • IVF: Isotonic sodium bicarbonate vs. normal saline • Prognosis • N-Acetylcysteine (KDIGO yes, AHA no) • Mild cases resolve within 2-5 days, likely vasoconstriction mediated • Hold diuretics peri-contrast, avoid hypovolemia ARF • No clear benefit of post-contrast dialysis • Severe cases resolve slowly over days to weeks, require dialysis, • Many meta-analyses and may be irreversible due to toxin-induced ATN • Brar, CJASN 2009 • Kshirsagar, JASN 2004

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Gadolinium based MRI agents – a Intra-Renal: word of caution Rhabdomyolysis • Nephrogenic systemic fibrosis • Etiology • Syndrome associated with MRI-based gadolinium administration • Patients with both acute renal failure/kidney injury and chronic • Crush injury, muscle trauma/ischemia/inflamm ation kidney disease (especially) are at risk • Prolonged immobilization: coma, ethanol, earthquake victims • Studies to ascertain incidence are ongoing • Fevers/rigors, seizures • Rarer than radiocontrast nephropathy, but can be debilitating and • Toxic injury: statins, cocaine, reverse transcriptase inhibitors fatal • Metabolic: Hypokalemia, hypophosphatem ia • Post-contrast hemodialysis is recommended • Genetic: McArdle disease • Recent reviews • Perazella Clin Journal Amer Soci Neph 2009

Intra-Renal: Intra-Renal: Rhabdomyolysis Acute Interstitial Nephritis (AIN) • Diagnosis • Etiology • High serum uric acid, phosphate, potassium • Medications = antibiotics (beta lactams), NSAIDs, diuretics, PPIs, others • Hypocalcemia • Infections = bacterial, fungal, viral, others • Elevated serum CK (along with AST/ALT) • Immune disorders = SLE, Sjogren’s, sarcoidosis • Dipstick heme+ from • Presentation • UA negative for RBCs • Fever (27%), drug rash (15%), eosinophilia (23%) • Urine sediment with ATN, muddy brown casts • Minority of patients have complete triad (10%) • Treatment • Arthralgias • Aggressive and early hydration • NSAID-AIN may have proteinuria from concomitant minimal • Alkalinization of urine vs. NS hydration alone? change disease • AIN is often occult, should be suspected if no other apparent • Stop offending medications etiology of AKI or if new medication started – time frame very variable

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Intra-Renal: Intra-Renal: Acute Interstitial Nephritis (AIN) Atheroembolic Disease • Diagnosis • Etiology • Sterile pyuria, WBC casts, eosinophilia • Spontaneous/idiopathic • Clinical diagnosis; kidneys improve after stopping offending drug • Anticoagulation (which may be a chronic medication or one tolerated safely in the • Instrumentation: aortic surgery/cross-clamping, CABG, past) angiography, cardiac catheterization • Kidney biopsy • Presentation • Skin biopsy (leukocytoclastic vasculitis) • Stuttering, inexorable rise in serum creatinine • Therapy • Livedo reticularis, stigmata of embolism • Stop offending drugs • Triad: precipitating event, subacute/acute AKI, skin findings • Treat underlying infection • Non-specific urine sediment • Consider oral steroids (e.g., prednisone 60 mg PO daily), lack of • Often occult, should be considered if no obvious etiology large randomized controlled trials showing efficacy

Intra-Renal: Intra-Renal: Atheroembolic Disease Thrombotic Microangiopathy • Diagnosis • Can be associated with and dysmorphic • Often clinical diagnosis, embolic skin findings hematuria • Low complements C3 and C4 • Spectrum: renal-limited to thrombotic thrombocytopenic • Eosinophilia and eosinophilur ia purpura (fever, microangiopathic hemolytic anemia, • Retinal embolization (Hollenhorst plaques) • Skin biopsy, kidney biopsy thrombocytopenia, renal failure, neurologic manifestations) • Therapy • Supportive. Stop anticoagulation? • Causes: drugs, diarrheal syndromes, antiphospholipid • Prognosis antibodies, lupus, HIV, hematopoietic stem cell • Poor, generally irreversible transplantation • Heavy burden of cardiovascular disease • Associated with scleroderma renal crisis, malignant hypertension, calcineurin inhibitors

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Common Etiologies of Kidney Injury in HIV-infected Patients

Pre-renal Renal Obstruction (P E , FE NA) (U/S, RBC, Crystals) dehydration Sulfadiazine NSAID HUS Acyclovir Indinavir Red cell casts and/or Acute Tubular Necrosis Glomerular lesion Acute Interstitial Nephritis Muddy brown casts à ATN (RTC, Gran. casts) (P roteinuria, +/-RBC) (Pyuria, WBC casts) dysmorphic RBCs à GN Hypotension/Sepsis HIVAN Trimethoprim- Aminoglycosides HIVIC Sulfamethoxazole Pentamadine NSAID (proteinuria) Acyclovir Rifampin Foscarnet Amphotericin B HIV may be coincident with: Tenofovir HBV: Membranous > MPGN White cell casts à HCV: MPGN, cryoglobulinemia AIN, pyelonephritis > Membranous

Diagnostics in AKI Diagnostics in AKI

• BUN:Creatinine Ratio • 24 Hour Urine for CrCl and Proteinuria • BUN:Cr > 20 pre-renal • Not helpful if serum creatinine not stable • Many causes of azotemia/elevat ed BUN (steroids, hypercatabolic • Estimate proteinuria with spot urine protein:creatinine states, total parenteral nutrition) • Predictive formulas (CrCl, eGFR) should not be used if Cr • Overused is not at steady state! • Renal Ultrasound • Serologies and Kidney Biopsy • Never wrong to R/O obstruction • Usually not necessary with careful history, physical, and urine • Safe, fast, and cheap sediment exam • Small kidneys suggest element of chronic kidney disease (AKI on • Serologies are low yield: ANA, ANCA, anti-GBM, ASO, CKD vs. CKD) cryoglobulins, HIV, HCV, HBV • Biopsy will often find occult atheroembolic disease or AIN

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Case

• 68 yo lady with h/o poorly controlled hypertension is evaluated for primary aldosteronism.

SECONDARY • Blood pressure is 176/105 mmHg • CV exam S3 gallop HYPERTENSION • Lungs clear • 0.06 ng/ml • 24 hour urine aldosterone 18 mcg per day • Adrenal CT scan reveals 1.5 cm solitary nodule in left adrenal gland. Right adrenal gland appears normal to slightly enlarged.

Case Question Case answer review A. Laparoscopic left adrenalectomy – Conn’s syndrome = Which of the following is the most appropriate next step in aldosterone-producing adenoma – cure rate from this patient’s management? resection only in 50-60% because of smaller functioning A. Laparoscopic left adrenalectomy nodules B. Adrenal vein sampling for aldosterone and cortisol B. Adrenal vein sampling for aldosterone and cortisol- C. Renal arteriography correct answer – document unilateral secretion of aldosterone and suppression from contralateral gland, D. Dexamethasone suppression test esp if age >40; cortisol shows that sample obtained from adrenal vein (rather than IVC) C. Renal arteriography – treatment will be aldosterone blockade – even in renal artery stenosis, med mgt favored over intervention D. Dexamethasone suppression test – diagnose glucocorticoid-remediable hyperaldosteronism

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Renovascular hypertension Renal Artery Stenosis

• Clinical Features • Atherosclerosis - #1 cause • Secondary HTN • Men and women, age > 50 • Flash pulmonary edema • Proximal/ostial lesions • Kidney size asymmetry > 1.5 cm • Complete occlusion and renal atrophy are common • AKI after initiation of ACE inhibitor/ARB • Medical management • Diagnosis • Fibromuscular Dysplasia • CTA, MRA, conventional angiography • Women, younger, 15-40 • Ultrasound: highly operator/institution dependent • Mid-vessel disease, can affect multiple vessels • String of beads appearance on angiography • Complete occlusion and renal atrophy are rare • Often reversible with angioplasty

References

• Primer on Kidney Diseases, 5th Edition • American College of Physicians Medical Knowledge Self- Assessment Program, Nephrology section

• THANK YOU FOR YOUR ATTENTION

Classic “string of beads” – medial fibroplasia Lesions occur in mid to distal vessel (Atherosclerotic disease – more proximal - closer to origin)

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