Treatment: Controversial because of variable natural history. If renal func- tion deteriora tes, persistent heavy proteinuria (e.g., >8 g/d for 6 months) consider corticosteroids + ch lorambucil (Ponticelli regimen)/cyclophosph- amide; cyclosporine, rituximab, others. Clinic al features of nephrotic syndrome Symptoms Ask about acute or chronic infections, drugs, al lergies, systemic symptoms (SLE, malignancy). Signs: Periorbital/peripheral edema (anasarca ); HTN. Rarely, pleural effu- sions; ascites. Examine for signs associated with secondary c auses/hyper- coagulable state. Complications \212 e n i c i d e m l a n e R MPGN (10 \200\22340%) with loss Thromboembolism, especially membranous or of anticoagulant proteins, \206\221 of procoagulant proteins, \206\221 platelet (PLT) aggregation (deep ve in thrombosis [DVT], pulmonary embolism [PE], renal vein thrombosis; central nervous system [CNS] vessels) Hyperlipidemia AKI, overdiuresis, elderly with minimal change disease, rena l vein thrombosis \212 \206\221 Susceptibility pneumococcus) Accelerated atherosclerosis \212 \212 to infection, possibly from \206\223 Ig (peritonitis, \212 Tests Urine: Dipstick (hematuria, proteinuria), microscopy (oval fat bodies, RBCs, ca sts), culture/sensitivity, 24 h collection (protein excretion, creati- nine clearance) or s pot urine protein-to-creatinine ratio for approxima- tion, urine protein electrophoresis. B lood: Electrolytes, BUN, creatinine, LFT, ESR, CRP, cholesterol, serum electrophoresis, com plement (C3, C4), autoantibodies (ANA, anti-dsDNA), HEP B/C serology, VDRL/RPR. Imaging: C XR, renal ultrasound. Renal biopsy: Usually do in all adults unless suspect diabetic nephro pathy (and steroid-unresponsive children or if unusual features). Treatment \212 \212 \212 267 Monitor BUN, creatinine, electrolytes, BP, fluid balance, weight. Fluid restriction (1 \200 \2231.5 L/d), sodium-restriction (<88 mEq/d or 2 g/d) Diet: Target moderate protein intake and avoid excess, with lower end aim of < 0.8 g/kg/d protein. Diuretics, e.g., furosemide 4 0 \200\223400 mg/d in bid doses metolazone. Aim for loss of 1 kg/d . Occasionally, to pr omote diuresis, you may need very high doses of furosemide (e.g., up to 200 mg iv) Diuril (up to 500 mg iv) or metolazone. Treat HTN with ACE-inhibitors or ARBs; other proteinuric attenuating agents: \222 -blockers, nondihydropyridine calcium-channel blockers, aldos- te rone antagonists. Persistent nephrotic syndrome: Immunosuppressive medications as above; AC E-inhibitors or ARBs to reduce proteinuria. Hypercoagulable state: Prophylactic warfarin is advocated by some at high risk (membranous nephropathy with massive proteinuria >10 g/d); war- farin for thrombosis. Hyperlipidemia improves with resolution of nephrotic syndrome. I f unrespon- sive, treatment with an HMG-CoA reductase inhibitors + ACE-inhibitor/ ARB may r educe proteinuria further than ACE-inhibitor/ARB alone. \212 \212 \212 \212 \212 Renal vein thrombosis Clinical prevalence: 6 \200\2238% with membranous GN; 1 \200\2233% of those with other forms of GN. Radiologic prevalence: 10 \200\22340% of patients with membr anous GN; 10% other causes. Clinical features: Flank pain, hematuria, proteinuria, renal en largement, and deteriorating renal function. Usually asymptomatic and diagnosed incidentall y. 35% have coincident PE. IVC/bilateral renal vein thrombosis with AKI is reported. Diagnosis: Doppler ultrasound, renal angiography (venous phase), spiral ct, or MRI. Treatme nt: Anticoagulate with warfarin until non-nephrotic protei- nuria achieved. Thrombolytic tr eatment/mechanical thrombolysis for acute severe thrombosis. Acute kidney injury: Diagnosis Definition There are numerous definitions of AKI that includ e a change in urine output and change in creatinine. All the definitions reflect a signifi- cant deterioration in renal function occurring over hours or days. AKI may lead to hyperka lemia, acidosis, pulmonary edema, and uremia. Clinically, there may be nausea, vomiting, fa tigue, shortness of breath (crackles), chest pain (pericarditis), change in mental status ( asterixis), seizures, \206\223 urine vol- ume (oliguria <400 cc/d), or no symptoms or sign s. Biochemically, AKI is detected by rising creatinine. AKI may arise as an isolated proble m; more commonly, it occurs in the setting of circulatory disturbance (e.g., severe illness , sepsis, trauma, or surgery) or in the context of nephrotoxic drugs. Causes See various se ctions for details. AKI can be divided into three types Prerenal (renal hypoperfusion) is u sually reversible. Causes are volume deple- tion, renal vasoconstriction due to medications (NSAIDs, ACE-inhibitor/ ARB, calcineurin inhibitors, amphotericin, iodinated contrast dye) ; hypercal- cemia; sepsis; hepatorenal syndrome; decreased effective circulating volume due to hypoalbuminemia; decreased cardiac output due to cardiomyopathy, arrhythmia, or decreas ed ejection fraction; or decreased perfusion due to intra-abdominal HTN or abdominal compar tment syndrome. Intrinsic (intrarenal) Tubular: Ischemic ATN is associated with prolonged h ypoperfusion (shock), nephrotoxic ATN is associated with aminoglycosides, amphotericin B, i odi- nated contrast dye, prolonged NSAIDs, ACE-inhibitors, or rhabdomyolysis. Complete reco very of renal function usually occurs within days or weeks. Vascular : Renal artery/vein oc clusion, renal infarction, malignant HTN, atheroemboli. Glomerular: Acute glomerulonephriti s, small vessel vasculitis, hemolytic ure- mic syndrome \200\224TTP. Interstitial : Interst itial nephritis, tumor infiltration. Intratubular obstruction (uric acid from tumor lysis s yndrome, acyclovir, sulfonamides, indinavir). Postrenal: AKI is due to urinary obstruction from nephrolithiasis, \206\221 prostate, pelvic masses; dysfunctional bladder is a potenti ally treatable cause. Assessment 1. Is the kidney injury acute or chronic? Suspect chronic kidney disease if: History of chronic ill-health or signs of chronic kidney disease Previou sly abnormal blood tests (prior records, laboratory results) Small kidneys (<9 cm) on ultra sound 268 \212 \212 \212 The presence of anemia, Ca 2+ \206\223 , or PO 4 3 \200\223 \206\221 may not help to dis tinguish AKI from CKD, as these can occur subacutely, but their absence suggests AKI. Secon dary hyperparathyroidism is suggestive of CKD 2. Is there urinary tract obstruction? Obstru ction should always be considered as a cause of AKI because it is revers- ible, and prompt treatment is required to prevent permanent renal damage . Obstruction should be suspected i n patients with a single functioning kid- ney or in those with history of renal stones, anu ria, prostatism, or previous pelvic/retroperitoneal surgery. Examine for a palpable bladder , pelvic or abdominal masses, or an enlarged prostate. Remember having good urine output doesn \200\231t exclude some component of obstruction. Assess with post- void residu al or imaging studies. Focused history and physical \212History: Urinary changes in output , color. History of urinary tract infec- tions, nephrolithiasis, prior obstruction, hematur ia, proteinuria, previous episodes of AKI, medication exposure: NSAIDs, contrast, aminoglyc o- sides, ACE-inhibitors/arbs, or chemotherapy. Recent GI losses, fluid losses, blood loss. Other medical conditions including connective tissue disorders, autoimmune disorders, HTN. e n i c i d e m l a n e R \212Physical examination: Vital signs, orthostatics, assess jugular venous pres- sure (JVP ), check for bruits, evidence of volume overload, arrhythmias, skin lesions or rashes, join t abnormalities, stigmata of other chronic dis- ease (e.g., liver disease, jaundice, etc.), enlarged bladder, tense/distended abdomen. Tests Urine: Dipstick for leukocytes, nitrite, blood, protein, glucose, specific gravity. M icroscopy for RBC, WBC, crystals, cellular or granular casts. Culture and sensitivity . Che mistry : Sodium, urea nitrogen, creatinine, osmolality; protein (spot/24 h with urine creat inine measurement). UPEP: Beware K + \206\221 ; LFT. Blood tests : Electrolytes, BUN, CR, CBC; clotting; CPK; ESR; ABG; blood cultures. When glomerular disease is suspected, conside r complement levels (C3/C4), autoantibodies (ANA, ANCA, anti-dsDNA, anti-GBM, and aso. Susp ect myeloma \200\224serum electropho- resis. CXR : Pulmonary edema/hemorrhage? ECG : Signs of hyperkalemia? Renal ultrasound: Renal size or obstruction? Bladder pressure over 12 mm H g defines increased intra-abdominal pressure and may cause abdominal compartment syndrome. Distinguishing prerenal failure and ATN Prerenal ATN Urine Na (mmol/L) Urine osmolality (mosm/L) Urine/plasma urea Urine/plasma creatinine Fract ional Na excretion (%) BUN/Cr <20 >500 >8 >40 <1 >20 >40 <350 <3 <20 >2 <20 269 These indices are of limited clinical use as intermediate values are common, they may be in fluenced by diuretics and preexisting tubular disease, and \200\234typical \200\235 values do not predict renal prognosis. Fractional excretion of urea nitrogen FeUN (<35% prerenal vs. >50%) used for patients on diuretics. Both FeNa and FeUN are most accurate when patient s are oliguric. Acute kidney injury: Management Enlist nephrologist \200\231s help. While awaiting this, ma ke sure that urine micros- copy results are available. If shock is the cause, treatment may include volume resuscitation with crystalloids or blood products, pressors for blood press ure support, or inotropic support in setting of poor cardiac output. Ultrasound : Check for a palpable bladder, but absence of this sign does not rule out obstruction. If it is palpable, insert a catheter. Stop nephrotoxic drugs (e.g., gentamicin, amphotericin B); any drug may be nephrotoxic. Per ipheral eosinophilia is suggestive of allergic interstitial nephritis (unreliable). Monitoring \212 Check pulse, BP, JVP, CVP (if available), and urine output frequently. Daily fluid balance + weight chart. If euvolemic, match input to losses (urine, vomit, diarrhea, drains) + 500 mL for insensible losses (more if T \206\221 ). Correct volume depletion with IV fluid ( colloid, saline, or blood [watch plasma \206\221 K + ]) as appropriate. If the patient is septic, take appropriate cultures and treat empirically with antibiotics. Remove or change any potential sources of sepsis (e.g., central lines). Recheck for any nephrotoxic medicati ons; adjust doses of renally excreted medications. NB: When the creatinine is continuing to rise, the effective GFR is 0 mL/min. Dose medications for GFR <10 mL/min. \212 \212 \212 \212Nutrition : Aim for calorie intake of 35 kcal/kg/d and protein intake 1 \200\2231.2 g/kg/d, although some recommend 0.8 g/dk/d if uremic but not on renal replacement therapy. If oral intake is poor, consider nasogastric nutri- tion early (parenteral if NGT impossibl e). Restrict dietary sodium intake if volume overloaded to <2 g/d, and if volume depleted, to 2 g/d. Oral potassium intake if hyperkalemic to <50 mEq/d. Phosphate restriction to 600 \200\223800 mg/d if hyperphosphatemic. Treat complications Hyperkalemia may cause arrhythmias or cardiac arrest. Electrocardiogram (ECG) changes: Peaked T waves; small or absent P wave; \206\221 P \200\223R interval; wid ened QRS complex; \200\234sine wave \200\235 pattern; asystole (ECG, p. 672). \212 Stabilize myocardium if severe hyperkalemia >7 or severe (loss of P waves, QRS widening). \212IV calcium (e.g., 10 mL 10% calcium gluconate IV over 1 min), repeat as ECG changes necessary until ECG improves. \212 Shift potassium into cells \212IV insulin + glucose (e.g., 10 U regular insulin + 50 mL of 50% glucose IV over 10 min). If not diabetic, consider continuous infusion of D5 to preven t hypoglycemia. Insulin stimulates the intracellular uptake of K + , lowering serum K + by 1 \200\2232 mmol/L over 30 \200\22360 min. \222 -agonists. 10 \200\22320 mg by albutero l nebulizer lowers potassium within 30 min; 8 times usual dose and may not work if used alo ne. Sodium bicarbonate in patient with severe metabolic acidosis to shift potassium in cell s, otherwise unlikely benefit. 270 \212 \212 \212 Remove potassium. Usually requires one of measures below: \212 Sodium polystyrene sulfonat e (Kayexalate) (e.g., 15 \200\22360 g bind K + in the gut. SE: Colonic necrosis of ileus (e .g., recent surgery). Diuretics if responsive Hemodialysis ( HD)/continuous renal replaceme nt therapy (crrt); see opposite ; latter much slower potassium removal rate is usually requ ired if anuric. CRRT will not remove potassium as quickly as HD. PO or PR) to \212 \212 Pulmonary edema (p. 754): \212 \212IV furosemide 200 mg IV as bolus, followed by continuo us drip if some High-flow oxygen by face mask response with bolus IV chlorothiazide Consider dysfunction If no response, Other measure s: Consider continuous positive airway pressure ventilation (CPAP) therapy. Venous vasodila tor (e.g., morphine 2.5 mg IV) IV nitrates \212 inotropes in congestive heart failure due to systolic \212 \212 \212 HD/CRRT is necessary. \212 \212 Bleeding: Impaired hemostasis due to uremic platelets may be compounded by the precipitatin g cause. In patients with AKI who are actively bleeding, give: \212 e n i c i d e m Fresh frozen plasma, cryoprecipitate, and platelets as needed, if there are clotting proble ms Blood transfusion to maintain Hb >10 g/dL and hematocrit >30% Desmopressin to increase r elease of von Willebrand factor and increase factor VIII activity, normalizing bleeding tim e \212 \212 l a n e R Prognosis for AKI Mortality depends on cause: Burns (80%), trauma/ surgery (60%), medical i llness (30%), obstetric/poisoning (10%), ICU setting requiring renal replacement therapy (5 0 \200\22380%). Indications for dialysis \212 Severe hyperkalemia (K \212 Refractory pulm onary edema \212 Severe or worsening metabolic acidosis (pH <7.2 or base excess < \200\223 10) \212 Uremic encephalopathy or other symptoms (nausea/vomiting) \212 Uremic pericardit is \212 Toxic ingestions (SALT: Salicylates, Alcohols, Lithium, Theophylline) Indications for CRRT CRRT may be preferable in an ICU setting when sudden shifts in volume removal or o smolarity are undesirable. Indications : Large obligate intake of fluids, ongoing electroly te abnormalities (rhabdomyolysis, tumor lysis syndrome), drug toxicities/poisoning (lithium , aspirin), elevated intracranial pressure, hemodynamic instability with pres- sor requirem ents. Advantages: Less hemodynamic instability. Disadvantage: More expensive than HD and re quires ICU setting and elevated clotting. + >6.5 \200\2237 mmol/L) Chronic kidney disease Definitions Either GFR of <60 mL/min/1.73 m 2 body surface area or s truc- tural or urinary abnormalities (such as proteinuria) that have been present for the l ast 3 months. It is classified according to GFR into five categories: Stage 1 (kidney dam- age with normal GFR >90 mL/min), stage 2 (60 \200\22389 mL/min), stage 3 (30 \200\22359 mL/ min), stage 4 (15 \200\22329 mL/min), and stage 5 (<15 mL/min). ESRD is renal failure that would require treatment with either dialysis therapy or renal transplantation. Causes Almos t all causes of renal disease can progress to ESRD Common : Diabetes, HTN, chronic glomerul onephritis, polycystic kidney disease, tub- ulointerstitial disease, vasculitis, renal vasc ular disease, or amyloidosis. History Ask about urinary symptoms: Change in output, change in color, hematuria, foamy urine, nocturia, recurrent UTIs, voiding difficulties, previ- ou s episodes of AKI especially requiring dialysis. Other : HTN (duration, urgencies/emergenci es), diabetes, connective tissue disorders (vasculitis, rheumatoid arthritis, scleroderma), vascular disease, infections (HIV, hepati- tis, recurrent infections). General : Anorexia, weight loss, pruritus. Physical exam Elevated BP. Cardiovascular : cardiomegaly, pericardi tis, edema. Lungs : Pleural effusion/pulmonary edema. Skin: Pallor; jaundice, livedo reticu laris, malar rash, purpura, easy bruising; epistaxis; calcifications of skin, eye, calciphy laxis. Neuro : Proximal myopathy, peripheral neuropa- thy, myoclonus, asterixis, encephalop athy, seizures, coma. Workup Common tests : Complete metabolic panel (renal and hepatic pan el), intact PTH (assess for metabolic bone disease) urinalysis, urine microscopy, spot urin e protein/creatinine ratio. Further serologic testing (not 271 needed for everyone): ANA, complement levels, anti-GBM, ANCAs depen- dent on clinical prese ntation. Renal imaging : Renal ultrasound with Doppler to assess for kidney size (small-sca rring/progressive disease; normal or large-amyloidosis, HIV, DM, asymmetry) scarring-renova scular disease, or obstruction. Doppler or MRA for renovascular. CXR : Pulmonary infiltrate s, pulmonary vascular congestion. Renal biopsy : Definitive diagnosis, to help guide manage ment and prognosis. Not necessary in every patient. Treatment Refer early to a nephrologist , especially in cases of proteinuria or to assess for reversible conditions . Regardless of etiology, begin basic manage- ment to delay progression of CKD. HTN: Target blood pressure of <130/80 mm Hg; with proteinuria. ACE-inhibitor/ARB can slow the rate of loss of functio n even if BP is nor- mal if there is micro-albuminuria. Watch serum creatinine and potassiu m after start/increase of the ACE-inhibitor/ARB. Hyperlipidemia: This may contribute to renal damage and increases the risk of cardiovascula r disease. Target low-density lipoprotein (LDL) choles- terol of <100 mg/dL. Proteinuria: The degree of proteinuria and the inability to reduce the levels are significa nt factors in accelerated loss of renal function. Goal protei- nuria is <500 mg/d. Edema: Appropriate diuretic use (loop diuretics if GFR <35 mL/min and dosing several times daily). As renal function declines, diuretic doses may need to be increased for same effect . Sodium restriction to 2 g/d is impor- tant as well. Anemia: Caused by erythropoietin deficiency. If other causes are excluded and iron stores r eplete, consider erythropoietin to maintain Hb between 10 and 11 g/dL. Metabolic bone disease (osteodystrophy ): Manifested by hypocalcemia (due to vitamin D defi ciency), hyperphosphatemia (decreased excretion), hyper- parathyroidism (driven by hypocalc emia, hyperphosphatemia, and PTH resistance), vitamin D deficiency (decreased conversion to 1,25 OH vitamin D). Hyperphosphatemia : Management with phosphate restriction (1 g/d), pho sphate binders with meals (calcium carbonate and calcium acetate used in stages 3 \200\223 5, sevelamer carbonate and lanthanum carbonate used for stage 5) to prevent phosphate absor ption. Either 1,25 OH vitamin D or analog for management of secondary hyperparathyroidism. Target intact PTH stage V 150 \200\223300 pg/mL. Other guidelines allow for 150 \200\223600 pg/mL in patients on dialysis. In setting of hypercalcemia, calcimimetic can be used for t reatment of secondary hyperparathyroidism. Dietary advice: Individualized based on labs. Ma y need potassium restriction of 40 \200\22360 meq/d. Protein restriction of 0.8 g/kg/d for elevated urea levels, acidosis and proteinuria. Sodium restriction to 2 g/d and fluid restr iction to 1 \200\2231.5 L/d for volume overload. Acidosis : Treat with HCO 3 , supplements. Renal replacement therapy planning: Should start at stage IV CKD. Vascular access referral for arteriovenous fistula (AVF) creation if HD planned. If no suitable veins, AVG placemen t delayed until 6 wks prior to HD. Insert a Tenckhoff catheter 4 \200\2236 wks before antic ipating need to start peritoneal dialysis (PD). Refer for transplantation unless there is a contraindication. 272 e n i c i d e m Figure 8.3 l a n e R Plot of reciprocal plasma creatinine (mcmol/L) against time in a patient with adult polycys tic disease. The letters represent life events: (a) work promotion, (b) arteriovenous fistu la, and (c) hemodialysis. Some patients with CKD lose renal function at a constant rate. Cr eatinine is produced at a fairly constant rate and rises on an exponential curve as renal f unction declines, so the reciprocal creatinine plot is a straight line, parallel to the fal l in GFR. This is used to monitor renal function and to predict need for dialysis, but ther e is much individual variation in progression so the plot has limited application. Rapid de cline in renal function greater than that expected may be due to infection, dehydra- tion, uncontrolled \206\221 BP, metabolic disturbance (e.g., Ca 2+ \206\221 ), obstruction, nep hrotoxins (e.g., drugs). Investigation and treatment at this point may delay ESRD. 273 Table 8.5 Prescribing in renal failure Never prescribe in renal failure before checking through Micromedex or the Physician \200 \231s Desk Reference for how a drug \200\231s dosing should be altered. In AKI, when the cr eatinine is rising, the effective GFR is 0 mL/min/1.73 m 2 . Renal replacement therapy The criterion for initiating dialysis in CKD patients is when GFR falls below 10 mL/min/1.73 m 2 BSA by using the four-variable MDRD formula, the creatinine clearance estimated by the Cockroft \200\223Gault formula (p. 250), or when patients devel op refractory volume overload, hyperkalemia, or ure- mic symptoms. Early preparation is vit al, including education about different dialysis modalities and transplantation options. Me dical preparation involves hepatitis B vaccination and creating an AVF if HD is the planned option. Choice of HD versus PD depends on medical, social, and psychological fac- tors. NB : Kidney function is only partially replaced by dialysis. Hemodialysis Solute transfer occu rs by diffusion and is based on con- centration gradients. Blood flows on one side of a sem ipermeable mem- brane countercurrent to the dialysate flow to maximize the concentration gr adient. Ultrafiltration describes fluid removed during any type of renal replacement therap y. Dialysis prescriptions can be written for a combina- tion of ultrafiltration with dialys is or for either procedure alone. In HD/ CRRT, negative pressure across the dialysis membra ne removes fluid from filtered blood. Complications : Dialysis dysequilibrium syndrome (rap id shift in osmolality), hypotension, arrhythmias, hemolysis, dialysis access compli- catio ns (poor flow, infection, thrombosis, prolonged bleeding, steal syn- drome), infection, vas cular access (poor flow, infection) Peritoneal dialysis PD fluid is introduced into the per itoneal cavity via a Tenckhoff catheter, and uremic solutes diffuse into it across the peri - toneal membrane. The peritoneal membrane functions as the dialyzer. Ultrafiltration may b e achieved by using osmotic agents (e.g., glucose) in the dialysis fluid of variable streng ths. Convection and diffusion both clear uremic toxins. PD clearance is significantly enhan ced by residual renal func- tion. Important to ask PD patients about reduced urine output i f uremic symptoms arise. This is a good option in patients with low ejection frac- tions or hypotension as it allows for slow fluid removal. Continuous ambulatory PD (CAPD): Patient performs manual exchanges of dialysate in which fluid is continuously dwelling in the patie nt except for filling and draining of dialysate. 2 \200\2233 L bags are exchanged usually f our times a day to produce, with ultrafiltration, a total dialysate of >10 L/d. Automated P D: Patient uses a cycler machine that automatically performs exchanges at night. Techniques include continuous cyclic peritoneal dialysis (CCPD), in which there is fluid left in the abdomen during the day, and night intermittent peritoneal dialysis (NIPD), in which the pat ient has no fluid in abdomen in the daytime. A manual exchange may have to be added to CCPD or NIPD patients if there is poor dialysis clearance. Problems : Peritonitis (60% staphylo cocci, 20% gram-negative organisms, <5% fungi), exit-site infection, catheter malfunction, loss of ultrafiltration , obesity, hyper- glycemia; rare, peritoneal-pleural leaks, hernias , back pain, hyperlipidemia. It may be difficult to achieve adequate clearance in larger pa tients who have lost residual renal function. Complications in ESRD patients Cardiovascular disease (e.g., coronary heart disease, congestive heart failure, sudden cardiac death, cer ebrovascu- lar disease is \206\221 \206\221 in dialysis patients and a major cause of mort ality). HTN persists in 25 \200\22330% of patients on HD. Some is related to large fluid ga ins. Timing of antihypertensive doses in HD patients may need to be altered to allow for fl uid removal during the dialysis sessions. Anemia is com- monly treated with erythropoiesis- stimulating agents and oral or IV iron supplements if deficient. Bleeding tendency is due t o platelet dysfunction. Acute bleeding is treated with desmopressin and transfusion, as nec essary. 274 CKD: Mineral bone disorders are treated with phosphate binders (calcium acetate, calcium ca rbonate, sevelamer, or lanthanum) for hyperphos- phatemia. Secondary hyperparathyroidism wi th goal IPTH 150 to 300 \200\223600 pg/mL is treated with 1,25 dihydroxy vitamin D (calcitr iol) PO or IV, parical- citol (Zemplar) IV or PO (Hectorol) IV or PO, or cinacalcet (Sensip ar) PO. Calcitriol and, to a lesser extent, analogs paricalcitol and doxercalciferol may \206\221 serum calcium and phosphate. Cinacalcet reduces serum calcium and phosphate. Infec tions are caused by nonsterility with exchanges during PD or vascular access procedures wit h HD. \222 2 -microglobulin amyloidosis may cause carpal tunnel syndrome, arthralgia, and fractures. Acquired renal cystic disease is seen in patients with long-standing CKD (>90% i ncidence if on dialysis >5 yrs), and there may be renal malignancy in 4 \200\22310%. Malign ancy is more common in dialysis patients; some tumors are related to the cause of renal fai lure (e.g., urothelial tumors in analgesic nephropathy). Aluminum toxicity due to the use o f aluminum-based phosphate binders is now rare (bone disease, dementia, anemia). e n i c i d e m l a n e R Renal transplantation Table 8.6 Renal transplantation This is the treatment of choice for ESRD. Each patient requires careful medical assessment and consideration of the advantages and disadvan- tages of dialysis vs transplantation. Ass essment Note the following: Preexisting cardiovascular disease; Screening for diseases that would cause severe disease while patient is immunocompromised and would require treatment or prophylaxis: CMV, VZV, EBV, HBV, Hep C, or TB. ABO blood group and human leukocyte antig en (HLA) tissue typing is required. \212 Urological assessment is made, where indicated. C ontraindications Active infection; recently treated cancer (<2 yrs); severe vascular diseas e, pulmonary disease with FEV 1 <1, severe heart disease; HIV patients are being enrolled f or transplantation. Types of graft Living related donor (LRD) grafts offer the advantages o f an optimally timed surgical procedure, HLA haplotype matching, and improved graft surviva l. Living unrelated donation is an option that is becoming commonplace. Deceased donor allo grafts are obtained from a brainstem-dead donor and should ideally be transplanted within 2 4 \200\22336 h. Grafts are inserted into an iliac fossa. Immunosuppressants Prednisone + ta crolimus /cyclosporine (calcineu- rin inhibitors) + mycophenolate mofetil/azathioprine (ant iproliferative agents) . Doses are slowly reduced over the first year. Common side effects with immunosuppressants (prednisone-hyperglycemia, osteopo- rosis; calcineurin inhibitors, HTN, hyperkalemia, nephrotoxicity; and antiproliferative agents, leukopenia, viral prolifer ation). Others : Sirolimus is an option for calcineurin inhibitor nephrotoxicity (CIN)(risk of pneu- monitis, proteinuria, poor wound healing); anti-T-cell antibodies and antithymocy te globulin (polyclonal Ab)/OKT3 (monoclonal AB0, and anti-IL-2 Ab)are used for induction t herapy or treatment of rejection. Complications immediate postsurgery Bleeding thrombosis o f renal vasculature, infection, urinary leaks, oliguria. Later complications : complication s. 275 Infections, rejection, malignancy, medication (Continued) Table 8.6 (Continued) Acute rejection (<3 \200\2236 months postop): This is characterized by rising serum creatin ine fever and graft pain. Graft biopsy in acute cellular rejection shows an immune cell infiltrate and tubular damage. Treatment : IV high-dose corticosteroids for 3 \200\2235 d f ollowed by PO. Cases with vascu- lar component or resistant cases require antithymocyte glo bulin (ATG) ( SE : Fevers, chills, anaphylaxis) or monoclonal OKT3 ( SE : First-dose reacti on, pulmonary edema, thrombotic microangiopathy, lymphopro- liferative disease) antibody . Antibody-mediated rejection : Plasma cell infil- trate with + CD4 staining, plasmapheresis IVIG. Chronic allograft nephropathy (>3 months): Presents with a gradual rise in serum c reatinine and proteinuria. Graft biopsy shows vascular changes, glomerular changes, fibrosi s, and tubular atrophy. It is not responsive to increased immunosuppression. Calcineurin in hibitor nephrotoxicity: Afferent arteriole vasoconstriction causes reduced renal blood flow and GFR. There is also chronic tubular atrophy and fibrosis. Infection: Typically common c ommunity infections or those related to \206\223 t-cell immunity ( \201 immunosuppression ); e.g., skin infections (fungi, warts, hsv, zoster) and opportunistic (TB, fungi, P. jirov eci pneumonia, CMV), others (BK virus). Malignancy: Immunosuppression causes increased risk of neoplasia infection with viruses of malignant potential (EBV, HBV, HHV-8). Typical t umors are squamous cancers, lymphoma (EBV-related), and anogenital cancers. Atheromatous va scular disease: This is more common in transplant patients than in the general population a nd is a leading cause of death. HTN: This occurs in >50% of transplant patients and may be due to diseased native kidneys, immunosuppressive drugs, or dysfunction in the graft. Manag ement is along standard lines (p. 132). Use of ACE-inhibitor/ ARB is not contraindicated un less known renal artery stenosis of trans- plant kidney. Diabetes: Estimated incidence 24% at 3 yrs post transplant. Corticosteroids and calcineurin inhibitors are factors. Prognosis 1-yr graft survival: HLA identical 95%; 1 mismatch 90 \200\22395%; complete mismatch 75 \200\22380%. Average half-life of cadaveric grafts is 8 yrs; 20 yrs for HLA-identical livin g related donor grafts. Risk of neoplasia is elevated 5 \227 from immunosuppression (e.g., skin cancers, lymphomas). 276 Interstitial nephritis and nephrotoxins Interstitial nephritis is an important cause of bot h acute and chronic renal failure. Acute interstitial nephritis (AIN): Typical cause: Aller gic reac- tion to antibiotics: Penicillins/cephalosporins, furosemide (sulfonamides), NSAID s, allopurinol, rifampin; infection (staphylococci, streptococci, Brucella , Leptospira ); systemic disease (sarcoidosis, Sj gren \200\231s syndrome); or no obvious cause. Clinica l features: Fever, arthralgias, rash (especially if drug-related), eosinophilia, eosinophil uria, AKI or CKD, rarely an associ- ated uveitis (tubulointerstitial nephritis uveitis synd rome or TINU). Except for AKI or CKD, other features may be absent. Diagnosis: Biopsy shows mononuclear cell infiltration of the renal interstitium and tubules with eosinophils in dr ug-induced causes. Systemic features of fever, rash, and eosinophilia or eosinophiluria are rarely present wit h NSAIDs, + in 33 \200\22350% of non \200\223penicillin drug induced causes. Treatment: AK I (p. 269); corticosteroids may be used with systemic disease, but use in drug-induced caus es is controversial. Nevertheless, many neph- rologists will attempt its use. CKD: None. Pr ognosis: Favorable in AIN if due to drug or systematic disease. Chronic interstitial nephri tis may be a slowly evolving form of the acute disease or caused by analgesic nephropathy ( below), sickle-cell disease, or chronic pyelonephritis/reflux nephropathy with secondary FS GS . NB: Urine may have few WBC/HPF since this has been chronic. Analgesic nephropathy is a ssociated with the prolonged, heavy ingestion of compound antipyretic analgesics. The incid ence of analgesic nephropa- thy has fallen since the withdrawal of phenacetin. Use of aceta minophen has been associated, but controversial. Signs: Urinary abnormalities (pro- teinuri a, hematuria, sterile pyuria); renal colic/obstruction from sloughed papilla; secondary UTI or pyelonephritis from obstruction; chronic kidney disease; HTN. Diagnosis is based on a h istory of excess analgesic use and demonstrating the characteristic renal lesion. Tests : C T scan reveals papil- lary calcifications, \206\221 renal size, \200\234bumpy \200\235 co ntours. IVP shows cortical scar- ring/clubbed calyces; demonstrates papillary necrosis. Bio psy shows chronic interstitial nephritis or capillary sclerosis. Treatment: Stop analgesics , anti- biotics for infection, drainage for obstruction, dialysis or transplantation for ES RD. Urate nephropathy Acute crystal nephropathy may occur when insoluble purines deposit wi thin the tubules causing blockage or inflammation of the tubules. It is caused by gross uri c acid overproduction (e.g., treatment of myeloid tumors) or by inherited diseases (e.g., L esch \200\223Nyhan syndrome). Diagnosis is by elevated serum uric acid levels of 15 \200 \22320 and urine uric acid/ urine creatinine >1. Treatment : Allopurinol, uricase (rasburic ase) to \206\223 uric acid, good fluid intake, alkalinize urine, HD or CRRT if \206\221 u ric acid levels and poor renal function (especially in cases of ongoing uric acid productio n; e.g., tumor lysis syn- drome). Chronic urate nephropathy typically affects middle-aged m en with gout. May be secondary to lead exposure. Diagnosis : X-ray fluorescence or \206 \221 urine lead levels after EDTA. Histologically, there is interstitial fibro- sis with as sociated vascular changes; crystals are rarely found. Treatment : Allopurinol ( \206\223 d ose in renal impairment); if lead nephropathy, can attempt EDTA to chelate lead with modera te CKD. Hypercalcemic nephropathy is caused by malignancy (most common), hyperparathyroidis m, multiple myeloma, sarcoidosis, vitamin D intoxica- tion. Clinical features: Nephrogenic diabetes insipidus (polyuria, polydipsia, dehydration, uremia), symptoms of hypercalcemia ( nausea, vomiting, con- stipation, lethargy, weakness, confusion, coma), pancreatitis. Inves tigations: Creatinine \206\221 , Ca 2+ \206\221 (1,25 OH vitamin D, intact PTH, PTH-relat ed peptide, SPEP if clinical suspicion), proteinuria, hematuria, pyuria, hypercalciuria. AX R may show renal calculi/nephrocalcinosis. Treatment : IV fluids (3 \200\2236 L 0.9% saline /24 h); loop diuretics; IV bisphosphonates (p. 307). Steroids may be useful in sarcoidosis. Radiation nephritis Acute radiation nephritis (within 1 yr of radiotherapy) Signs: Hematur ia, proteinuria, BP \206\221 , anemia. Chronic radiation nephritis may occur after acute r adiation nephritis or present with HTN, proteinuria, ane- mia, or end-stage renal failure ( ESRD 2 \200\2235 yrs after exposure to radiation). Treatment : Control BP, renal replacemen t therapy for ESRD. Prevention : Exclusion or shielding of renal areas during radiotherapy. e n i c i d e m l a n e R 277 Nephrotoxins Many agents may be toxic to the kidneys and cause ARF (see Table 8.7). Table 8.7 Nephrotoxins Exogenous nephrotoxins include: \212 \212 Analgesics: NSAIDs/cox-2 inhibitors Antimicrobials: ATN : Aminoglycosides, amphotericin, pe ntamidine. AIN (potentially all): Penicillins, cephalosporins, sulfonamides. Tubular obstru ction : Acyclovir, indinavir. RTA : Proximal \200\224tenofovir; distal \200\224am- photeric in; both \200\224ifosfamide. Chemotherapeutic agents: Cisplatin. obstruction : Methotrexate . ACE-inhibitors and angiotensin II receptor antagonists (ARBs) may cause glomerular hemody namic changes. Iodinated contrast agents: Especially in diabetic nephropathy, older patient s: CKD, AKI (myeloma) Organic solvents: Ethylene glycol, hippurate (glue sniffing: Acidosis ) Insecticides, herbicides, Amanita mushrooms, snake venom; all rare Immunosuppressants: Cy closporine, tacrolimus \212 ATN : Mitomycin C-TTP. Tubular \212 \212 \212 \212 \212 Endogenous nephrotoxins include: \212 Pigments (myoglobin, hemoglobin) C rystal deposition/precipitation (urate, phosphate) \212 \212 Tumors (immunoglobulin light chains) Aminoglycosides (e.g., gentamicin, amikacin) are well-recognized nephro- toxins. T he typical clinical picture is of nonoliguric renal failure 1 \200\2232 wks into therapy. T he risk of nephrotoxicity is increased in old age, lowered renal perfusion, preexisting CKD , high dosage or prolonged treatment, and coad- ministration of other nephrotoxic drugs. Th ese circumstances are common in severely ill patients. Recovery may be full, delayed, or in complete. Myoglobin from muscle injury or necrosis (rhabdomyolysis). Causes: Trauma, ischem ia, immobility, excessive exercise, seizures, myositis, meta- bolic (K + \206\223 , \206 \221 phosphate), medications (fibrates, statins), toxins (alcohol, ecstasy, snake bite, car bon monoxide), malignant hyperpyrexia, neuro- leptic malignant syndrome, inherited muscle d isorders. Clinical features: These may be absent or nonspecific (muscle pain, swelling, or tenderness). Tests: Dark brown urine is +ve for blood on dipstick but without RBCs on micro scopy. Blood tests : \206\221 BUN; \206\221 creatinine; \206\221 K + ; \206\223 Ca 2+ ; \206\223 PO 4 3 \200\223 . \206\221 ck; \206\221 ldh; \206\221 urate. Treatment: Large volumes of IV fluids, urinary alkalinization with IV bicarbonate has been used. Hemodialys is/CRRT may be required. 278 Renal vascular diseases/secondary hypertension HTN may be a cause or consequence of renal d isease. Essential HTN : Investigations (p. 132). Treatment (p. 134). Accelerated (malignant ) HTN may cause ARF. Treatment (p. 134). Pregnancy-induced HTN with proteinuria (preeclamps ia): Edema + proteinuria glomerular endotheliosis/oblitera- tion + deposition of fibrin and platelets. May see: Hemolysis, elevated liver enzymes, low platelet counts (HELLP). See Table 8.8. Renal diseases causing HTN Diabetic nephropathy, acute glomerulone- phritis, ch ronic interstitial nephritis, polycystic kidneys, CKD, renovascular