CHRONIC KIDNEY DISEASE

Background

(Ann Int Med 2015;162:ITC-1; JAMA 2015;313:837; Lancet 2012;379:165; NEJM 2014;371:58)

• Definition: ≥3 mo w/ GFR <60 mL/min/1.73 m2 or signs of kidney damage: Proteinuria/albuminuria, pathology on renal biopsy/imaging
  • Estimated GFR (eGFR): Measure of filtration of all glomeruli; used to classify CKD; ↓ w/ age; Preferred formula: CKD-EPI, but MDRD equation also commonly used; (JAMA 2012;307:1941); online calculator: kidney.org/professionals/kdoqi/gfr_calculator.cfm
  • Proteinuria: See “Proteinuria” section Nephrotic syndrome: Proteinuria >3.5 g/d, serum albumin <3.5 g/dL, edema, HLD, HTN
  • Glomerulonephritis: Hematuria (dysmorphic RBCs or RBC casts), subnephrotic proteinuria, often AKI, HTN, edema Medications that interfere w/ serum Cr assay: TMP-SMX, cimetidine, cefoxitin
• Pathophysiology: Diabetes mellitus (45%), HTN (27%), glomerulonephritis (10%), interstitial/obstruction (4%), polycystic kidney disease (PKD) (2%) (NEJM 2010;362:56)
  • Reversible causes: Hypovolemia, hypotension, nephrotoxic agents, urinary obstruction
• Epidemiology: Prevalence ~16.8% in US, by stage: 1: 1.8%, 2: 3.2%, 3: 7.7%, 4: 0.35%, ESRD: 2.4% (JAMA 2007;298:2038)
• Risk factors: More likely to suffer CV events/mortality with each stage of CKD than progress to ESRD (NEJM 2004;351:1296); severity of proteinuria assoc w/ worse outcomes independent of eGFR

CKD Staging (Kid Int 2013;3:19)
Stage	Description	GFR (mL/min/1.73 m2)	Actions
1	Nl or GFR	≥90	Dx/Rx underlying condition/ comorbidities, CVD risk reduction
2	Mild ↓ GFR	60–89	Est progression, CVD risk reduction

 

3a	Mod ↓ GFR	45–59	Eval & Rx complications
3b	Mod/sev ↓ GFR	30–44	Nephrology referral (if not yet done)
4	Sev ↓ GFR	15–29	Prepare for RRT, transplant referral
5	Kidney failure	<15 or dialysis	Dialysis if uremic
Albuminuria stage based on albuminuria (mg/d) or spot urine alb (mg) to Cr (mg) ratio (ACR): A1: nl or mildly ↑ (ACR <30); A2: mod ↑ [formerly microalbuminuria] (ACR 30–299); A3: or severely ↑ [formerly macroalbinuria] (ACR ≥300)

Evaluation

(AFP 2011;84:1138)

• History: Variety of presentations, from asx to edema, HTN, uremia (nausea, pericarditis, anorexia, neuropathy, altered MS), hematuria, flank pain, neuropathy; urine output
• Exam: Regular exam, emphasis on volume status and vascular system
• Workup: Urine microscopy/sediment, Chem-7, Ca, PO₄, PTH, lipids, serum albumin, CBC, urine protein:creatinine ratio (UPCR), SPEP; urine albumin:creatinine ratio (UACR); renal ultrasound; Consider: HbA1c, hepatitis serologies, HIV, RPR, based on clinical suspicion; Can usually defer to specialist: 24-h urine protein, ESR, CRP, C3, C4, ANA, anti-dsDNA, ANCA, anti-GBM, APLA₂R Ab, cryoglobulins, serum/urine immunofixation for amyloid, light chains, renal biopsy
  • Screening for CKD: Indicated in pts w/ CKD risk factors (HTN, DM, FHx CKD); ✓ serum Cr, UA, UACR; USPSTF found insufficient evidence to recommend screening asx adults (excluding those w/ HTN, DM2) (Ann Intern Med 2012;157:567)  Monitoring: Chem-7, CBC, Ca, PO₄, PTH, vit D, UACR, iron studies (q3–12mo based on CKD stage)

Management

(AFP 2012;86:749; Ann Int Med 2013;158:825; Kidney Int Sup 2013;3:5; NEJM 2010;362:56)

• Correct reversible causes: Dehydration, meds (diuretics, NSAIDs, ACEI/ARB), infection, urinary obstruction
• Lifestyle modification: Smoking cessation (see “Tobacco Use”), weight loss; mod exercise 30–60 min 4–7 d/wk, nutrition referral
• Nephrology referral: Early referral assoc w/ ↓ mortality (Am J Med 2007;120:1063). Refer if: eGFR <30, stage 4/5 CKD; DM w/ mod albuminuria (30–299 mg/d); any UACR ≥300 mg/g, ? etiology, rapidly ↓ GFR, complications of CKD requiring Rx (i.e., Epo, PO₄ binders, vit D), hyperkalemia, resistant HTN, recurrent nephrolithiasis, suspicion of hereditary CKD
• Slowing CKD progression:
  • BP control: Goal <130/80, <120/80 if tolerated (NEJM 2015;373:2103); start w/ ACEI (or ARB), then add diuretic, then CCB
  • ACEI or ARB: 1st-line/renoprotective in all CKD (NEJM 2004;351:1952); tolerate 25% ↑ in Cr and K <5.5; no benefit of ACEI + ARB combined and assoc w/ adverse outcomes (NEJM 2013;369:1892); 2nd-line agents include loop diuretics (if edema present) or diltiazem/verapamil (↓ proteinuria; antiproteinuric effect not seen w/ amlodipine)

Renal Nutrition Suggestions
Factor	Goal/Rational
Sodium	<2 g/d. For BP and volume control
Potassium	<2 g/d if hyperK, to tolerate ACEI/ARB
Glucose	Low carb/sugar, if diabetic. See “Diabetes”
Phosphorus	Low PO4, ↑ PO4 assoc w/ increased mortality, vasc. calcification
Protein	0.6–0.8 g/kg/d. ↓↓ protein diet assoc w/ ↑ mortality (Cochrane 2009;8:CD001892)
Herbal Suppl.	Avoid and/or review with nephrologist before taking

• Vaccines: PSV23, PCV13, Influenza, HBV (see “Immunizations”)
• CV risk reduction: BP control, lipids at goal (Ann Int Med 2012;157:251)
• Renal replacement therapy: Includes hemodialysis (HD), peritoneal dialysis (PD), transplant

Renal Replacement Therapy Options
Modality	Pros	Cons
Transplant	Outcomes approach general population 1 y after transplant	Wait list, risks of surgery. Refer when eGFR <20
Hemodialysis	Common	Vascular complications; requires being at an HD center
Peritoneal dialysis	Preserves residual renal function; independence	Sterile technique; requires compliant, knowledgeable patient

• • Indications: Clinical decision; consider when eGFR 5–10 & sx of uremia/fluid overload (CJASN 2011;6:1222). No mortality benefit to early initiation of dialysis & no difference in CV events, infection, HD complications (IDEAL, NEJM 2010;363:609) Preparation for HD: For stage 4 CKD, avoid subclavian or PICC lines; AV fistulas take mo to mature; synthetic grafts mature in wks, but have thrombosis/infections
• Care after transplant checklist for PCPs: ✓ all medications for interaction w/ immunosuppressants; all fevers need broad w/u; avoid live vaccines; annual derm exam for ↑ risk of skin cancers; prompt w/u for change in SCr (Med Clin N Am 2016;100:435)
• Patient information: JAMA 2007;298:1244

Complications of CKD

(NEJM 2010;362:56;1312)

• Anemia: ↓ renal Epo production, ↓ iron absorption in CKD; goal Hgb 10–11 g/dL; correct iron deficiency before starting epoetin/ darbepoetin (NEJM 2009;361:2019)
• Bone disease: ↓ GFR → ↑ PO₄, ↓ Ca, ↓ calcitriol, ↑ FGF-23 → ↑ PTH → renal osteodys

1. 1. PO₄ binder (calcium acetate, sevelamer, lanthanum) if ↑ PO₄ å Ca (<8.4 mg/dL): Use calcium acetate (Phos Lo) or carbonate (Tums) Intermediate Ca (8.4–9.5): Calcium acetate/carbonate; if bone disease, vascular calcification, or ↓ PTH then sevelamer or lanthanum ↑ Ca (>9.5 mg/dL): Use sevelamer or lanthanum (non-Ca based); Sevelamer carbonate as effective as sevelamer HCl at reducing PO_4, yet has less of a lowering effect on HCO₃

• • ↑ ↑ PO₄: Use aluminum hydroxide short term (<4 wk) 2. 1,25-(OH) vit D (calcitriol, paricalcitol) if ↑ PTH (AJKD 2009;53:408) 3. Cinacalcet (parathyroid Ca-sensing receptor agonist) or parathyroidectomy if ↑↑ PTH despite above measures (CJASN 2016;11:161)
• Volume overload/edema: <2 g/d Na restriction + diuretics
• Metabolic acidosis: ↓ GFR → ↓ acid excretion → ↓ HCO₃ → osteopenia, ↑ PTH, ↑ inflammation, muscle wasting, progressive CKD; treat w/ sodium bicarbonate or citrate to HCO₃ goal of 23–29 mEq/L (J Am Soc Nephrol 2015;26:515; Kidney Int 2010;78:303); 1 tsp baking soda ≈ 6 tabs of Na-HCO₃ ≈ 50 mEq HCO₃; citrate contraindicated in pts on aluminum- containing medications, i.e., antacids, buffered aspirin, sucralfate, or some phosphate binders due to ↑ aluminum absorption → intoxication and osteomalacia
• Diabetic nephropathy: Occurs in both type 1 and 2 DM, most common cause of CKD worldwide (AJKD 2014;63:S3; JASN 2007;18:1353); tracks with other microvascular changes (retinopathy), occurs 10–15 y after Dx
  • Pathogenesis: Hyperfiltration, advanced glycation due to hyperglycemia, hypoxia/inflammation; degree of proteinuria predicts progression to ESRD
  • Treatment: Prevention of progression with ACEI/ARB and tight glycemic control Diabetic medications in CKD: Metformin can be safely used until eGFR <30 (risk of lactic acidosis); reduced dose sulfonyl urea are alternative (e.g., glipizide); SGTL2-I may have additional renal protective effects (NEJM 2016;375:323)

PROTEINURIA

Background

(AFP 2000;62:1333; 2009;80:1129; JABFM 2008;21:569)

• Normal physiology: Kidney filters 180 L ultrafiltrate/d with approx; 1 mg/dL albumin in Bowman space; majority of protein (albumin, low– molecular-weight protein) reabsorbed in the proximal convoluted tubule (PCT); healthy individuals secrete <150 mg/d of protein
• Nephrotic syndrome: >3.5 g/24 h proteinuria, hypoalbuminemia (<3 g/dL), and peripheral edema; may be accompanied by protein malnutrition, renal failure, hyperlipidemia, arterial/venous thromboses, atherosclerosis, urinary hormone loss

Etiologies of Proteinuria
Category	Description	Etiologies
Glomerular (can be >3 g/d)	Disruption of filtration barrier → lose albumin	Glomerulonephritis Nephrotic syndrome
Tubulointerstitial (usually <1–2 g/d)	↓ reabsorption of freely filtered proteins → lose globulins	ATN; AIN Fanconi syndrome

 

Overflow	↑ production of freely filtered proteins	Multiple myeloma Myoglobinuria
Isolated	By def’n: asx, normal renal fxn, sed, & imaging, no h/o renal disease	Functional (fever, exercise, CHF) Orthostatic (only when upright) Idiopathic (transient or persistent)

(ANOTHER TABLE MISSING)

Differential Diagnosis of Glomerular Proteinuria

1° glomerulopathy: Minimal change disease, membranous nephropathy, focal segmental glomerulosclerosis, membranoproliferative glomerulonephritis, IgA nephropathy, fibrillary, immunotactoid, mesangial proliferative GN, transplant rejection

2° glomerulopathy: DM, SLE, amyloid (AL from light chains or AA 2/2 inflammation), cryoglobulinemia, infection (HIV, HBV, HCV, poststreptococcal, syphilis, malaria, endocarditis), GI/lung cancer, lymphoma, small vessel vasculitis (ANCA) or anti-GBM dz

Medications associated w/ proteinuria: NSAIDs, heroin, lithium

Evaluation

(AFP 2005;71:1153; JABFM 2008;21:569)

• History: Foamy or cola-colored urine; Δ in UOP; fatigue, edema, wt Δ, swelling; PMHx: DM, CHF, autoimmune disease, recent infxn; Meds: (NSAIDs); FHx: Alport syndrome
• Exam: BP, wt, periorbital or dependent edema, ascites
• Workup: See Evaluation section of “Chronic Kidney Disease”
  • Urinalysis (“Dipstick”): Measures albumin concentration via colorimetric reaction; false ⊖ if nonalbumin proteinuria, false ⊕ if urine pH >7.5, SG >1.015, hematuria, mucus, semen, leukocytes, recent IV contrast. 1+ → ~30 mg; 2+ → 100 mg; 3+ → 300 mg; 4+ → >1–2 g Urine microscopy (“sediment”): May help to distinguish glomerular vs. other proteinuria (i.e., presence of RBCs, WBCs, eosinophils, casts) Spot UPCR or UACR: Acceptable for screening (vs. 24-h collection; proteinuria underestimated in muscular pts & overestimated in cachectic pts); generally, ratio is equiv to grams of protein excreted in urine/d (AFP 2000;62:1333) Orthostatic proteinuria: Have pt void before going to sleep at night & ✓ UPCR in sample after awakening (<0.2 g/g suggests orthostasis); uncommon in pts >30 y

Management

(AFP 2009;80:1129; Kid Int Sup 2012;2:143; NEJM 2013;368:10)

• General principles: Varies by etiology; treat underlying disease & factors that predict CKD progression (see Management section of “Chronic Kidney Disease”)
• ACEI or ARB: ↓ proteinuria → slow nonimmunologic progression of renal disease
• 1° glomerular dis: Steroids ± cytotoxic therapy; cancer screening if membranous neph
• Secondary causes: Treat underlying disease
• Watch for malnutrition (protein loss), thrombosis (in ~25%, esp. renal vein, no consensus re: ppx anticoagulation), infxn (esp. encaps. organisms b/c loss of Ig)
• Edema: Dietary Na restriction (2 g/d) & diuretics
• When to refer to nephrology: see Management section of “Chronic Kidney Disease”
• Information for patients: JAMA 2010;303:470

Proteinuria in Pregnancy

(Int J Gynaecol Obstet 2002;77:67)

• Pathophysiology: In normal pregnancy, urinary protein excretion increases due to ↑ GFR and ↑ permeability of the GBM; normal up to 250 mg/d in third trimester
• Abnormal level of proteinuria: >300 mg/d anytime during gestation based on 24-h urine collection (correlates with 1+ on urine dipstick) Onset prior to 20-wk gestation: Suggestive of pre- existing renal disease Onset after 20-wk gestation: Must exclude preeclampsia
• Figure 14-1. Proteinuria evaluation

HEMATURIA

Background

(AFP 2006;73:1748; BMJ 2009;338:a3021; JAMA 2015;314:1865; NEJM 2003;348:2330)

• Gross hematuria: Red or brown urine (~1 mL blood/L urine enough to change urine color); 25% of pts will have urologic CA, 34% other urologic disease
• Asymptomatic microscopic hematuria (AMH): ≥3 RBCs/HPF on consecutive UA (clean catch, fresh void, midstream w/o menstruation); ⊕ dipstick should be followed by microscopy since to rule out false ⊕; AMH found in 9–18% of adults; 1–10% of these will have urologic CA, 8–10% will have no cause identified (but 1–3% of this group will later be diagnosed with malignancy) (Cleveland Clin J Med 2008;75:227)

• Figure 14-2. Differential diagnosis of hematuria

Evaluation

(AFP 2008;78:347; 2013;88:747; Ann Int Med 2016;164:488; JAMA 2016;315:2726; NEJM 2003;348:2330; Urology 2001;57:604)

• History: Transient vs. persistent hematuria, fevers, pain, medications, trauma, pyuria, dysuria; blood clots; lower urinary tract symptoms (Chap X); recent URI (postinfectious glomerulonephritis/IgA nephropathy) or sexual activity; personal/family history of renal disease, malignancy, bleeding disorders; occupational exposures, travel Hx
  • Medications & food associated w/ red urine: Rifampin, phenazopyridine, iron sorbitol, nitrofurantoin, chloroquine; rarely beets, blackberry, rhubarb, food coloring Medications → hematuria: Aminoglycosides, amitriptyline, analgesics, anticonvulsants, ASA, diuretics, OCPs, penicillins (extended spectrum), warfarin OD (AFP 2006;73:1748)
• Workup: UA, UCx, microscopic urine evaluation (to confirm positive urine dipstick), serum Cr; 24-h urine protein may be estimated by multiplying random urine protein:Cr ratio (mg/mmol) by 10 (BMJ 2009;338:a3021); pts w/ microscopic hematuria & evidence of a UTI should have a repeat UA 6 wk later to confirm resolution of hematuria
  • Urine cytology: Cannot r/o bladder Ca (Se 40–76%), but ⊕ cytology diagnostic of urothelial Ca; NOT recommended as part of routine eval of AMH, but may be useful if workup otherwise ⊖ (Cancer 1987;60:1423) CT “hematuria protocol”: initial test of choice for gross hematuria or AMH w/o infection or glomerular bleeding; MRI urography or U/S are alternative in pregnant pts Cystoscopy: Gold standard for gross hematuria w/o glomerular disease or infection; indicated in all pts who pass urine blood clots, AMH w/o glomerular disease, infection, or other known cause of hematuria, & pts w/ malignancy risk factor (above)
• Exam: Urethral exam, pelvic exam in ♀, DRE to assess for BPH in men; ✓ BP

Figure 14-3. Hematuria workup algorithm

• Nephrology referral if: Suspect glomerular hematuria (RBC casts, dysmorphic urine RBC, absence of clots), ↑ Cr, eGFR <60, new HTN, >300 mg/g UPCR (see “Proteinuria”)
• Urology referral if: Urinary blood clots, unexplained AMH, malignancy risk factor
• Pts on anticoagulation: Same eval as if not anticoagulated (Arch Intern Med 1994;154:649)
• Insufficient evidence for bladder CA screening per USPSTF (Ann Intern Med 2011;155:246)
• Follow-up for AMH: In pts with negative workup but malignancy risk factors, check annual UA; If ⊖ for 2 consecutive y, then annual UAs may be discontinued
• Patient information: AFP 2005;71:135; 2006;73:1759

NEPRHOLITHIASIS

Background

(J Urol 2005;173:848; NEJM 1992;327:1141; 2010;363:954; 2012;367:50)

• Epidemiology: Affects 10–12% of US adults (7% of ♀, 13% of ♂)
• Risk factors: ⊕ FHx, sedentary/immobilized, IBD, UTI w/ urease ⊕ organism (i.e., Proteus), CKD, bone disease, hyperparathyroidism, CAD, HTN, DM2, chronic diarrhea, gout, pregnancy, RTA
  • Prior stone: ↑ risk of recurrence: 50–60%/5 y, 50–75%/10 y
• Pathophysiology: Supersat; urine w/ stone-forming salts + predisposing metabolic factors
  • Staghorn calculi: Form in renal pelvis & branch to fill renal calyces

Stone Types and Characteristics (J Clin Endocrinol Metab 2012;97:1847)
Stone Composition	Common Causes	Urine Findings
Ca Oxalate > phosphate (80%)	Dehydration, diet (↑ animal protein & salt), IBD, CKD, RTA, hyperparathyroidism, sarcoidosis, obesity, gastric bypass	↑ Ca, ↑ oxalate (Ca-Ox), ↓ pH (Ca-PO4), ↓ citrate
Uric acid (5–10%) (Pure uric acid stones are radiolucent on x-ray)	Dehydration, diet (high animal protein), gout, neoplastic disease w/ chemo, TLS, obesity, myeloproliferative d/o	↓ pH, ↑ uric acid
Struvite (Mg-ammonium phosphate)	Urease-splitting UTIs (Proteus, Klebsiella) → staghorn stones; indwelling catheters	↑ pH, ↑ NH3, bacteria
Cystine	Autosomal recessive d/o → cystinuria	↓ pH

Evaluation

(AFP 2011;84:1234; 2013;87:441; JAMA 2005;293:1107)

• History: Pain ranging from mild to acute colic ± nausea; sharp flank or abdominal pain ± radiation to groin/penis depending on location of stone; microscopic or gross hematuria (80% of pts); irritative sx (frequency, urgency, dysuria) occur with distal ureteral stones or UTI; fluid intake, diet (salt, animal protein, spinach/nuts [↑ oxalate]); pts may be asymptomatic and the stone may be an incidental finding on CT done for other reasons
  • Medications: Vitamin C (metabolized to oxalate), triamterene, protease inhibitors (Indinavir), furosemide (↑ calcium excretion), sulfadiazine, acyclovir
• Exam: Flank tenderness, fever, hemodynamic instability (S/Sx of pyelonephritis/urosepsis)
  • Clinical pearl: Pts w/acute abdomen lie still, pts w/renal colic writhe in pain
• Workup: UA (⊕RBCs, ⊕WBCs), UCx, CBC, Chem-7; Noncontrast low dose CT scan (gold standard; 97% sens, 96% spec; AJR 2008;191:396) or KUB + U/S (~60% sens, ~90% spec) to identify stone (Eur Urol 2002;41:351)
  • Urine strainer: Strain all urine & save passed stone for analysis 24-h urine (×2): >6 wk after acute setting, measure Ca, PO₄, oxalate, citrate, Na, Cr, pH, K, volume; monitor response to lifestyle mod/meds to prevent recurrence
• Prognosis: Diet, medical Rx prevent recurrence in 75% of pts, ↓ new stones in 98%; 68% of stones ≤5 mm pass in 40 d; ↓ passage w/ ↑ size or location in UV junction
  • Asymptomatic stones: ~50% risk of developing sx over next 5 y (J Urol 1992;147:319)

Treatment

(AFP 2011;84:1234; Ann Intern Med 2013;158:535; J Urol 2007;178:2418; NEJM 2004;350:684)

General Treatment Measures (Ann Int Med 2014;161:659)
Hydration	Increase fluid intake (>2.5 L/d) for goal UOP >2 L/d
Pain control	NSAIDs 1st line (unless preg, CKD, GI bleed, age >65 or otherwise contradind), then narcotics, APAP
Ureteral relaxation	α-Blocker (tamsulosin) > CCB
Indications for urgent urology/ED referral	AKI, >10 mm size (unlikely to pass on own); refractory pain, N/V; concurrent UTI; obstruction (esp. single or kidney transplant); staghorn; occupation (pilot, truck driver)
Surgical options	Extracorporeal shockwave lithotripsy (noninvasive), percutaneous nephrolithotomy (for large/cystine stones, staghorn), ureteroscopy (best for mid-distal ureteral stones)

 

Stone Specific Management
Calcium	↓ Na diet, ↓ animal protein, ↑ dietary calcium (will ↓ oxalate absorption) though unclear role of Ca supplements. HCTZ or chlorthalidone to ↓ urinary Ca excretion
Uric acid	Urine alkalinization (K-citrate or K-bicarbonate), allopurinol
Struvite	Antibiotics to treat UTI
Cystine	Urine alkalinization, penicillamine, tiopronin

• Medications for prevention (prescribed based on 24-h urine studies):
  • Potassium citrate: Alkalinizes urine as citrate is metabolized to bicarbonate; useful for calcium or uric acid stone formers, staghorn calculi prevention, cystine stones, urine pH <6, RTA, or if urine citrate is low; 10 mEq PO TID and titrate to urine pH 6.1–7.0; follow serum K; potassium bicarbonate may also be used Thiazide diuretics: HCTZ or chlorthalidone ↓ urinary Ca excretion, useful in ↑↑ Ca Allopurinol: Hyperuricemia & recurrent stones despite ↑ fluids & urine alkalinization Tiopronin: For patients w/ cystine stones; penicillamine also may be helpful; measurement of urine cystine assists in titration of dose Calcium supplements: If urine oxalate is high
• Patient information: AFP 2006;74:99; 2011;84:1243; JAMA 2012;307:2557

URINARY INCONTINENCE

Background

(JAMA 2004;291:996; 2010;303:2172; NEJM 2010;363:1156)

• Definitions: Hesitancy: Difficulty initiating urination; Urgency: Sudden urge to urinate
  • Functional incontinence: Physical or cognitive inability to toilet (or reach toilet) Continuous urinary incontinence: Continuous loss of urine usually d/t fistula Overactive bladder (OAB): Sx of urgency, frequency, nocturia ± urge incontinence Overflow incontinence: Incomplete bladder emptying or overdistension → dribbling Stress urinary incontinence (SUI): Incontinence due to ↑ abdominal pressure (i.e., cough, exertion) with decreased outlet resistance Urge urinary incontinence (UUI): Urgency + involuntary urination due to bladder overactivity/irritation Mixed urinary incontinence (MUI): UUI + SUI; common in ♀; tx of SUI alone may not help UUI and can make worse
• Epidemiology: 15–30% of pts >65 y
• Risk factors: Age, female gender, cognitive impairment, obesity, ↑ parity, prostate disease/surgery, ↓ mobility
• Pathophysiology: Not a normal part of aging; multifactorial in the elderly: ↓ bladder sensation/contractility, ↓ cognition, ↓ mobility/dexterity, detrusor overactivity, ↑ nocturia, comorbid disease (CHF, DM), medications, ↑ postvoid residual
  • Reversible causes: DIAPERS: Delirium, Infection, urethral/vaginal Atrophy, Pharmaceuticals, EtOH/Excess glucose (DM), Restricted mobility, Stool impaction
• Consequences: Falls, UTI, candida infections, cellulitis, pressure ulcers, sleep deprivation, isolation, depression

Evaluation

(AFP 2013;87:543; JAMA 2008;299:1446)

• History: Pts >65 y should be questioned about voiding habits, since many will not volunteer h/o incontinence; triggers (i.e., cough, laugh, exercise); frequency, severity (# pads per day), urgency, dysuria, interference w/ daily activities/sleep, degree of bother; bowel & sexual function, hematuria, meds, fluid & caffeine consumption, voiding diary, access to bathrooms; Obstetric/Urologic/Neurologic hx or hx of pelvic surgeries
• Exam: Mobility; pelvic/genital exam (assess for pain, prolapse, voluntary control of pelvic floor muscles, S/Sx inflammation/infection); consider DRE for masses/prostate size/fecal impaction; check for pressure ulcers; volume status
• Workup: UA, consider Chem-7, UCx, UCytology, HbA1c, & B₁₂ based on clinical suspicion; bladder U/S for sudden-onset UUI w/ neg UA to r/o bladder pathology (diverticulum, mass, etc.)
  • Cough stress test (SUI): Pt coughs w/ full bladder checked for urine leakage Postvoid residual (PVR): Remaining urine in bladder measured by catheter or U/S after pt attempts to urinate; PVR >200 mL suggests obstruction or bladder weakness

Treatment

(AFP 2005;71:315; 2006;74:2061; 2013;87:634; JAMA 2004;291:986; NEJM 2004;350:786) See also “BPH and Lower Urinary Tract Symptoms”

• Pt education: Nl urinary tract fxn, benefits/risks tx, discuss goals of tx
• Behavior modification: 1st-line tx for all forms of incontinence; frequent voiding while awake (q2h), prompted voiding in pts w/ dementia; bladder training (relaxation & deep breathing w/ sense of urgency to delay need to void), Kegels, pelvic floor physical therapy; wt loss (NEJM 2009;360:481), ↓ caffeine/EtOH, ↓ fluid intake (esp at night), smoking cessation; pads & protective garments; treat constipation & coughing; pessaries of prolapse
• Medications (if behavioral tx ineffective/partially effective)
  • OAB/UUI/MUI:

Antimuscarinics: Effects seen at 1 wk, max at 3 mo; pts should try medication for 4–8 wk before switching (can adjust dose), but most stop due to side effects (dry mouth, constipation, blurry vision, HA, dizziness, confusion); caution in elderly due to confusion, esp if dementia on cholinesterase inhibitors; Contraindications: urinary/gastric retention, intestinal obstruction, uncontrolled narrow-angle glaucoma, myasthenius gravis β₃ agonists: may be better tolerated/can be combined with antimuscarinics; caution if HTN

SUI: Usually d/t intrinsic sphincter deficiency (♂/♀) or urethral hypermobility (♀) ∴ unlikely to respond to antimuscarinics/β₃ agonists; tx primarily surgical

• If behavioral tx/medications insufficient: Re-assess (UA/UCx, post void residual, bladder diary, other diagnostic tests)
• Referral to specialist (urogynecology/urology): Painful sx, fistulas, hematuria w/o UTI, neuro conditions/sx, persistent sx despite behavioral tx/medication, h/o pelvic surgery/XRT, pelvic organ prolapse, recurrent infections Further testing: Cystoscopy, urodynamic testing, OAB/UUI surgical tx: Intradetrusor onabotulinumtoxinA injection, peripheral tibial nerve stimulation (PTNS), sacral neuromodulation SUI surgical tx: Periurethral bulking agents, perineal/bladder/urethral slings, artificial urinary sphincter; will not improve/may worsen urge incontinence if mixed; surgery contraindicated in ♀ who wish to have future children

Medical Therapy for Incontinence
Antimuscarinics (Starting dose → Maximum dose)
Solifenacin 5 mg→10 mg QD	More effective than tolterodine in urge incontinence (Eur Urol 2005;48:464)
Oxybutynin IR: 2.5 mg BID/TID→20 mg/d ER: 5 mg QD→30 mg QD TD: 1 patch q3d Gel: 1 mL QD	Less anticholinergic sx w/ ER & TD compared to IR; IR & ER are generic
Tolterodine IR: 1–2 mg BI ER: 2–4 mg QD	Better tolerated than oxybutynin & equally effective; may be combined w/ tamsulosin for urge incontinence in ♂ (JAMA 2006;296:2319); may cause dementia-like sx/hallucinations (NEJM 2003;349:2274) & ↑ INR in pts on warfarin
Fesoterodine 4 mg QD→8 mg QD	Useful in overactive bladder (Urology 2010;75:62) & more effective than tolterodine; nonhepatically metabolized, s/e constipation
Trospium IR: 20 mg BID ER: 60 mg QD	Renally cleared; ∴ fewer medication interactions & avoid in CKD; take on empty stomach; does not enter CNS (∴ may be better in elderly)
Darifenacin 7.5→15 mg QD	Useful in overactive bladder (Int J Clin Pract 2006;60:119); provides more “warning time” for urination
β3 Agonists
Mirabegron 25 mg → 50 mg QD	↓ Freq & incontinence in OAB/urge incontinence; s/e include HTN, UTI, constipation, abdominal pain (Int Urogynecol J 2012;23:1345); may interact w/ metoprolol
Other
Topical estrogen 0.01% 2–4 g/d × 7 d, then ↓ to 1–2 g/d × 7 d, then 1 g 3×/wk	Improves sx of incontinence in ♀, available in vaginal crm, ring, or tablets (Cochrane Database Syst Rev 2009:CD001405); oral estrogen ↑ incontinence

• Patient information: NAFC.org; simonfoundation.org; JAMA 2003;290:426; 2010;303:2208; www.urologyhealth.org/urologic- conditions/urinary-incontinence

SODIUM DISORDERS

Background

(AFP 2015;91:299; Am J Med 2013;126:256; NEJM 2015;372:55)

• Definition: Na = 1° extracellular osm; disorders of serum Na are generally due to d/o of total body H₂O (regulated by thirst response & ADH), not total body Na content
• Urine osm: 50 mOsm/L (no ADH) to 1200 mOsm/L (max ADH) (NEJM 1960;262:1306)
• Key principle: Hyper-or hypo-osmolality → rapid water shifts → Ds in brain cell volume → DMS, seizures
• Epidemiology: In pts >55 y, hyponatremia found in 7.7%, hypernatremia in 3.4%
• General approach: (1) acute vs. chronic (>48 h); (2) sx severity; (3) risk for neuro complications (alcoholism, malnourished, cirrhosis, older females on thiazides, hypoK); if chronic or asx, correct ≤6–8 mEq/d

---

HYPONATREMIA

(Ann Int Med 2015;163:ITC1-19; JASN 2012;23:1140; NEJM 2015;372:55)

 Evaluation

(NEJM 2000;342:158; JAMA 2015;313:1260; Nephrol Dial Transplant 2014;29S2:11)

• History: Fluid intake (including alcohol), diet, fluid losses (GI, diuretics/urine output), PMHx (cirrhosis, CKD, CHF), changes in cognition
• Exam: Volume status, orthostatic BP, axillary sweat
• Workup: Chem-7 & other tests (below)
  • Plasma osmolality: Confirms hypotonic “true” hyponatremia; excludes rare cases of pseudohyponatremia (↑↑ TGs, paraproteinemia) & hypertonic (↑↑ glucose) hypoNa Urine osmolality: Surrogate for ADH; U_osm >100 mOsm/L in an euvolemic pt w/o other pathologies is suggestive of SIADH
  • Urine Na: Surrogate for volume status; U_Na <20 → volume depletion; U_Na >40 → suggests euvolemia; U_Na unreliable if diuretic use, aldo def, metabolic alkalosis, polydipsia TSH & ACTH stimulation: To exclude endocrinopathy

Figure 14-4. Approach to Hyponatremia

Common Outpatient Causes and Management of Euvolemic Hyponatremia
Cause	Management
Medications (SIADH)	Discontinue offending agent. Includes thiazide diuretics (see below), SSRIs, opiates, NSAIDs, MDMA (“ecstasy,” causes free water cravings)
Poor solute intake	“Tea & toast” diet or “beer potomania”; insufficient Na/osm intake relative to fluid intake. Rx: dietary consult, alcohol counseling, “beer nuts”
1° polydipsia	Associated with thought disorders like schizophrenia. Rx: ψ referral, aggressive water restriction
CNS insult	Includes tumor, ICH, pain. Requires specialist/neurology input
Malignancy	Small cell lung, pancreas, lymphoma, leukemia. Rx: oncology referral

Thiazide-Induced Hyponatremia

(Am J Med 2011;124:1064; Chest 1993;103:601)

• Epidemiology: Affects up to 30% of pts on long-term thiazide Rx
• Pathophysiology: Manifests within first 1–2 wk of Rx w/ acute illness, & w/Δ in dose → ✓ Na 1 wk after starting & w/Δ in clinical status; can be euvolemic to mildly hypovolemic
• Risk factors: Elderly & low BMI (QJM 2003;96:911); alcoholics; avoid in pts w/ hx ↓ Na

Hypovolemic Hyponatremia

• Extrarenal loss (U_Na <20): Diarrhea, vomiting, poor solute intake
• Renal losses (U_Na >40): Diuretics (esp thiazides), osmotic diuresis, aldo deficiency

Euvolemic Hyponatremia

• SIADH: Inappropriate release of ADH w/ nl or mildly ↑ EAV → euvolemic hyponatremia; dx of exclusion; normal saline worsens ↓ Na if Osm_IVF < Osm_urine due to free water retention
• Adrenal insufficiency: ↓ cortisol → hyperkalemia (due to ↓ aldosterone) + hyponatremia due to co-secretion of ADH with CRH from hypothalamus
• Primary polydipsia (U_osm <100; U_Na often <20 b/c of dilution): H₂O consumption >> kidney excretory capacity (12 L/d) in psychiatric dz (schizophrenia) and hypothalamic dz
• Poor solute intake (U_osm <100): Solute intake insufficient to excrete daily water load; seen w/ “tea and toast” diet or “beer potomania”

Hypervolemic Hyponatremia

• Pathophysiology: CHF, cirrhosis, nephrotic syndrome (U_Na <20; U_osm >100): ↓ EAV → ↑ ADH → ↓ Na; in advanced CKD (U_Na >40) there is a ↓ ability to excrete free water

Treatment

(BMJ 2007;334:473)

• ED referral if: Sx (AMS, seizure, coma), Na <120, hypovolemia suspected and severe vomiting/diarrhea, concern that correction will be >6–8 mEq/d (risk of osmotic demyelination/central pontine myelinolysis) Hypovolemic: Give fluids, stop diuretics & treat underlying cause SIADH: Treat underlying cause & stop offending medications
  • Fluid restriction: Goal of <800 mL/d (adherence difficult) Defer to specialist: Salt tabs, demeclocycline, V2 antagonists (tolvaptan)
• Hypervolemic: Treat underlying disease (e.g., ACEI in CHF); loop diuretics impair medullary gradient → ↑ free water loss; fluid restriction if symptomatic or severe

---

HYPERNATREMIA

(Crit Care 2013;17:206; NEJM 2015;372:55)

 Evaluation

(NEJM 2000;342:1493)

• History: Must have both lack of access to free H₂O AND loss of hypotonic fluid
• Exam: Volume status, orthostatic BP, axillary sweat
• Workup: Generally can be diagnosed from Chem-7 and history
  • Urine osmolarity: Should be >700 due to max ADH effect U_osm >700 → extrarenal H₂O loss; U_osm <700 → renal H₂O loss

Common Outpatient Causes and Management of Hypernatremia
Cause	Management
Insensible loss in nurs home resident	Often due to fever/infection. May warrant evaluation for elder abuse/neglect
GI loss (vomiting, diarrhea)	Requires lack of access to free H2O. May warrant evaluation for elder abuse/neglect
Medications (causing nephrogenic DI)	Includes lithium, demeclocycline, cidofovir, foscarnet, didanosine. Discontinue offending agent, refer to specialist. Li-related DI occurs in 40% long-term users, can be irreversible (Nat Rev Nephro 2009;5:27)
HyperCa, HypoK	Correct metabolic abnormalities.

Treatment

(J Clin Endocrinol Metab 2012;97:3426)

• General principles: Determine barrier to H₂O access (i.e., AMS, hypodipsia, dependence on others); scheduled drinking totaling ≥1 L/d if impaired access to H₂O; treat underlying cause & stop offending drugs; evaluate for elder abuse/neglect if appropriate
• Central DI: Refer to endocrine for eval (H₂O deprivation test) & possible Rx: desmopressin
• Nephrogenic DI: Refer to nephrology; consider d/c Li or amiloride if related to Li (CJASN 2008;3:1324)

Potassium Content in Foods Recommended RDA for K is 4700 mg/d (~120 mEq). Low K diet is 2500 mg/d (~60 mEq)
High (>400 mg/serving)	Tomato, tomato sauce, potato, sweet potato, French fries, banana, broccoli, cantaloupe, orange juice, apricot, beets
Mod. (200–400 mg/serving)	Strawberries, almond, chocolate, milk, canned soup, prunes, figs, whole grains
Low (<200 mg/serving)	Turkey, tuna, raisins, apple, rice, white grains (including pasta), cucumber, coffee, onion, cranberry juice, grapes, most berries

• Patient information: https://www.kidney.org/atoz/content/potassium Web search for “potassium” and food item yields K content in mg or mEq (39 mg = 1 mEq)

---

HYPOKALEMIA

(AFP 2015;92:487; NEJM 2015;373:60) 

Causes of Hypokalemia (Ann Int Med 2009;150:619)
General Mechanism		Specific Etiologies
Pseudohypokalemia		CML, CLL (WBC >105/µL → leukocyte uptake → falsely ↓ K)
Intracellular shift (most common)		↑ Insulin (including hyperalimentation), β2-agonists, caffeine, thyrotoxicosis, familial periodic paralysis, increased hematopoiesis (esp AML, megaloblastic anemia), alkalemia
GI loss		(↓ UK): Diarrhea, laxative abuse. Vomiting manifests as renal loss due to 2° hyperaldosteronism
Renal loss		(↑ UK): Divided into normo/hypotensive (diuretic, ↓ Mg, Bartter’s or Gitelman’s [rare]) and hypertensive (1° or 2° hyperaldosteronism). ↑ Aldosterone activity (primary hyperaldosteronism, renovascular disease, Cushing’s, licorice, chewing tobacco) Metabolic acidosis (proximal and some distal RTAs) Hypomagnesemia (alcoholism, prolonged PPI)
Medications and substances		Diuretics (thiazides (10–40% of treated pts)), laxatives, penicillins (especially in high doses), β2-agonists, insulin, theophylline, chemotherapy, alcohol, caffeine, cola (>3 L/d)
UK	Metabolic Acidosis		Metabolic Alkalosis
↑	DKA, type 1 (distal) or type 2 (proximal) renal tubular acidosis		Mineralocorticoid excess, renovascular dz, diuretic use (after diuretic has worn off)
↓	Lower GI loss		Vomiting, diuretic use, laxative abuse

Evaluation

(AJKD 2005;45:233)

• History: Medication and diet review (including OTCs & wt loss agents), PMHx (esp eating d/o, alcohol intake), FHx, GI fluid loss; sx rare unless K <3 mEq/L, include muscle weakness, cramping, constipation, fasciculations, tetany
• Workup: Repeat K if reported as hemolyzed or suspect lab artifact; ✓ Mg, CK, plasma renin:aldosterone (if HTN present), U_K, U_Cr. 24 h U_K > 30 mEq or U_K:U_Cr >13 mEq/g (1.5 mEq/mmol) creatinine suggests renal loss.
  • ECG changes: May be normal; ↑QT, T wave flattening, U waves, ectopy, AVB, VF

Management

• Remove offending agents
• K supplementation: May also need to replete Mg, ↓↓ Mg (<1.2 mEq) hard to replete orally
  • K-rich foods: See above
  • Liquid/powder potassium: Inexpensive, rapid, many pts dislike taste Slow-release K: Wax/microencapsulated formulation; more expensive K-sparing diuretics: Spironolactone, eplerenone
• When to refer: To ED if K <2.5 mEq/L, esp if pre-existing CV disease or ECG changes; To nephrology if persistent low K despite repletion; concurrent hypertension (suggests hyperaldosteronism state, see “Hypertension”)

---

HYPERKALEMIA

(JAMA 2015;314:2405; NEJM 2015;373:60)

 Evaluation

(Am J Med 2009;122:215)

• History: Medication and diet review, PMHx (esp DM, CKD, cirrhosis, CHF), FHx; sx rare unless K >6.5–7 mEq/L, include muscle weakness, nausea, paresthesias
• Workup: Repeat K, especially if reported as hemolyzed or suspect lab artifact, Chem-7. Hyponatremia and hyperkalemia are suggestive of adrenal insufficiency
  • ECG: Can be normal; If K >6 mEq/L, can have peaked T waves, ↑ PR, ↑ QRS, loss of P wave, sine wave, VF, cardiac arrest

Causes of Hyperkalemia
General Mechanism	Specific Etiologies
Pseudohyperkalemia	Gross hemolysis of sample, massive ↑ WBC or PLT, exercise (i.e., fist pumping during blood draw), clotted blood specimen.
Extracellular shift (most common)	Acidemia/metabolic acidosis, ↓ insulin (esp. diabetic w/ CKD), massive necrosis (rhabdo, tumor lysis, hemolysis, ischemic bowel), periodic paralysis, hyperglycemia, ↑ serum osmolarity
Decreased renal secretion	Advanced CKD (GFR <15), CHF/cirrhosis, tubulointerstitial dz (DM, sickle cell, SLE, amyloid), hypoaldosteronism, Addison disease, congenital adrenal hyperplasia, type IV renal tubular acidosis, adrenal insufficiency (in association w/ ↓ Na.
Medications and substances	NSAIDs, ACEIs/ARBs (occurs in ~10% of pts), K-sparing diuretics, β-blockers, TMP-SMX, digoxin, heparin, pentamidine, calcineurin inhibitors, transfusions, CsA.

• Most common outpatient causes: CKD with dietary indiscretion (esp in DM), meds including ACEI/ARB, K-sparing diuretics, NSAIDs, TMP- SMX

Management

• Dietary counseling: Nutrition referral, see “Potassium Content in Foods” above
• Medication review: In advanced CHF, survival benefit of ACEI/ARB & aldosterone antagonists → K ≤5.5 acceptable (Expert Opin Pharmacother 2011;12:2329); if K ↑ >5.5 on ACEI/ARB/aldosterone antagonist, ↓ dose or implement measures below; If on combination, d/c 1 & recheck K; Avoid NSAIDs, COX-2 inhibitors, other meds which ↑ K
• Diuretics: Thiazides (GFR >30) or loop (GFR <30)
• Correct metabolic acidosis: Na bicarbonate in pts w/ CKD
• K-binding resins (Kayexalate, Patiromer, Na zirconium): Binds K in GI tract (NEJM 2015;372:211; 222); s/e include N/V, constipation, diarrhea, ? rare bowel necrosis w/ Kayexalate (AJKD 2012;60:409)
• When to refer to ED: Any K >6.5; acute K >6; K >5.5 w/ sx; unable to make safe outpt plan