InternalMed_Harrison

InternalMed_Harrison. A careful review of all medications is imperative in the evaluation of an individual with AKI. Not only are medications frequently a cause of AKI, but doses of administered medications must be adjusted for estimated GFR. Idiosyncratic reactions to a wide variety of medications can lead to allergic interstitial nephritis, which may be accompanied 1805 by fever, arthralgias, and a pruritic erythematous rash. The absence of systemic features of hypersensitivity, however, does not exclude the diagnosis of interstitial nephritis. AKI accompanied by palpable purpura, pulmonary hemorrhage, or sinusitis raises the possibility of systemic vasculitis with glomerulonephritis. Atheroembolic disease can be associated with livedo reticularis and other signs of emboli to the legs. A tense abdomen should prompt consideration of acute abdominal compartment syndrome, which requires measurement of bladder pressure. Signs of limb ischemia may be clues to the diagnosis of rhabdomyolysis.


InternalMed_Harrison

InternalMed_Harrison. Complete anuria early in the course of AKI is uncommon except in the following situations: complete urinary tract obstruction, renal artery occlusion, overwhelming septic shock, severe ischemia (often with cortical necrosis), or severe proliferative glomerulonephritis or vasculitis. A reduction in urine output (oliguria, defined as <400 mL/24 h) usually denotes more severe AKI (i.e., lower GFR) than when urine output is preserved. Oliguria is associated with worse clinical outcomes. Preserved urine output can be seen in nephrogenic diabetes insipidus characteristic of longstanding urinary tract obstruction, tubulointerstitial disease, or nephrotoxicity from cisplatin or aminoglycosides, among other causes. Red or brown urine may be seen with or without gross hematuria; if the color persists in the supernatant after centrifugation, then pigment nephropathy from rhabdomyolysis or hemolysis should be suspected.


InternalMed_Harrison

InternalMed_Harrison. The urinalysis and urine sediment examination are invaluable tools, but they require clinical correlation because of generally limited sensitivity and specificity (Fig. 334-6) (Chap. 62e). In the absence of preexisting proteinuria from CKD, AKI from ischemia or nephrotoxins leads to mild proteinuria (<1 g/d). Greater proteinuria in AKI suggests damage to the glomerular ultrafiltration barrier or excretion of myeloma light chains; the latter are not detected with conventional urine dipsticks (which detect albumin) and require the sulfosalicylic acid test or immunoelectrophoresis. Atheroemboli can cause a variable degree of proteinuria. Extremely heavy proteinuria (“nephrotic range,” >3.5 g/d) can occasionally be seen in glomerulonephritis, vasculitis, or interstitial nephritis (particularly from NSAIDs). AKI can also complicate cases of minimal change disease, a cause of the nephrotic syndrome (Chap. 332e). If the dipstick is positive for hemoglobin but few red blood cells are evident


InternalMed_Harrison

InternalMed_Harrison. from NSAIDs). AKI can also complicate cases of minimal change disease, a cause of the nephrotic syndrome (Chap. 332e). If the dipstick is positive for hemoglobin but few red blood cells are evident in the urine sediment, then rhabdomyolysis or hemolysis should be suspected.


InternalMed_Harrison

InternalMed_Harrison. Prerenal azotemia may present with hyaline casts or an unremarkable urine sediment exam. Postrenal AKI may also lead to an unremarkable sediment, but hematuria and pyuria may be seen depending on the cause of obstruction. AKI from ATN due to ischemic injury, sepsis, or certain nephrotoxins has characteristic urine sediment findings: pigmented “muddy brown” granular casts and tubular epithelial cell casts. These findings may be absent in more than 20% of cases, however. Glomerulonephritis may lead to dysmorphic red blood cells or red blood cell casts. Interstitial nephritis may lead to white blood cell casts. The urine sediment findings overlap somewhat in glomerulonephritis and interstitial nephritis, and a diagnosis is not always possible on the basis of the urine sediment alone. Urine eosinophils have a limited role in differential diagnosis; they can be seen in interstitial nephritis, pyelonephritis, cystitis, atheroembolic disease, or glomerulonephritis. Crystalluria may be


InternalMed_Harrison

InternalMed_Harrison. eosinophils have a limited role in differential diagnosis; they can be seen in interstitial nephritis, pyelonephritis, cystitis, atheroembolic disease, or glomerulonephritis. Crystalluria may be important diagnostically. The finding of oxalate crystals in AKI should prompt an evaluation for ethylene glycol toxicity. Abundant uric acid crystals may be seen in the tumor lysis syndrome.


InternalMed_Harrison

InternalMed_Harrison. Certain forms of AKI are associated with characteristic patterns in the rise and fall of SCr. Prerenal azotemia typically leads to modest rises in SCr that return to baseline with improvement in hemodynamic status. Contrast nephropathy leads to a rise in SCr within 24–48 h, peak within 3–5 days, and resolution within 5–7 days. In comparison, atheroembolic disease usually manifests with more subacute rises in 1806 taBLe 334-1 MajOr Causes, CLInICaL Features, anD DIagnOstIC stuDIes FOr prerenaL anD IntrInsIC aCute KIDney Injury Nephrotoxin-Associated AKI: Endogenous BUN/creatinine ratio above 20, FeNa <1%, hyaline casts in urine sediment, urine specific gravity >1.018, urine osmolality >500 mOsm/kg Positive culture from normally sterile body fluid; urine sediment often contains granular casts, renal tubular epithelial cell casts Urine sediment often contains granular casts, renal tubular epithelial cell casts. FeNa typically >1%.


InternalMed_Harrison

InternalMed_Harrison. Urine sediment often contains granular casts, renal tubular epithelial cell casts. FeNa typically >1%. Low FeNa, high specific gravity and osmolality may not be seen in the setting of CKD, diuretic use; BUN elevation out of proportion to creatinine may alternatively indicate upper GI bleed or increased catabolism. Response to restoration of hemodynamics is most diagnostic. FeNa may be low (<1%), particularly early in the course, but is usually >1% with osmolality <500 mOsm/kg toms, bone pain Nephrotoxin-Associated AKI: Exogenous Elevated myoglobin, creatine kinase; urine heme positive with few red blood cells Anemia, elevated LDH, low haptoglobin Hyperphosphatemia, hypocalcemia, hyperuricemia Other Causes of Intrinsic AKI Exposure to iodinated contrast Aminoglycoside antibiotics, cisplatin, tenofovir, zoledronate, ethylene glycol, aristolochic acid, and melamine (to name a few)


InternalMed_Harrison

InternalMed_Harrison. Other Causes of Intrinsic AKI Exposure to iodinated contrast Aminoglycoside antibiotics, cisplatin, tenofovir, zoledronate, ethylene glycol, aristolochic acid, and melamine (to name a few) Recent medication exposure; can have fever, rash, arthralgias Characteristic course is rise in SCr within 1–2 d, peak within 3–5 d, recovery within 7 d Urine sediment often contains granular casts, renal tubular epithelial cell casts. FeNa typically >1%. Eosinophilia, sterile pyuria; often nonoliguric FeNa may be low (<1%) Urine eosinophils have limited diagnostic accuracy; systemic signs of drug reaction often absent; kidney biopsy may be helpful Postrenal AKI Variable (Chap. 338) features include skin rash, arthralgias, sinusitis (AGBM disease), lung hemorrhage (AGBM, ANCA, lupus), recent skin infection or pharyngitis (poststreptococcal) Nondrug-related causes include tubulointerstitial nephritis-uveitis (TINU) syndrome, Legionella infection


InternalMed_Harrison

InternalMed_Harrison. Nondrug-related causes include tubulointerstitial nephritis-uveitis (TINU) syndrome, Legionella infection Neurologic abnormalities and/or AKI; recent diarrheal illness; use of calcineurin inhibitors; pregnancy or postpartum; spontaneous Recent manipulation of the aorta or other large vessels; may occur spontaneously or after anticoagulation; retinal plaques, palpable purpura, livedo reticularis, GI bleed History of kidney stones, prostate disease, obstructed bladder catheter, retroperitoneal or pelvic neoplasm ANA, ANCA, AGBM antibody, hepatitis serologies, cryoglobulins, blood culture, decreased complement levels, ASO titer (abnormalities of these tests depending on etiology) Eosinophilia, sterile pyuria; often nonoliguric Schistocytes on peripheral blood smear, elevated LDH, anemia, thrombocytopenia


InternalMed_Harrison

InternalMed_Harrison. Eosinophilia, sterile pyuria; often nonoliguric Schistocytes on peripheral blood smear, elevated LDH, anemia, thrombocytopenia Hypocomplementemia, eosinophiluria (variable), variable amounts of proteinuria “Typical HUS” refers to AKI with a diarrheal prodrome, often due to Shiga toxin released from Escherichia coli or other bacteria; “atypical HUS” is due to inherited or acquired complement dysregulation. “TTP-HUS” refers to sporadic cases in adults. Diagnosis may involve screening for ADAMTS13 activity, Shiga toxin–producing E. coli, genetic evaluation of complement regulatory proteins, and kidney biopsy. Imaging with computed tomography or ultrasound


InternalMed_Harrison

InternalMed_Harrison. Imaging with computed tomography or ultrasound Abbreviations: ACE-I, angiotensin-converting enzyme inhibitor-I; AGBM, antiglomerular basement membrane; AKI, acute kidney injury; ANA, antinuclear antibody; ANCA, antineutrophilic cytoplasmic antibody; ARB, angiotensin receptor blocker; ASO, antistreptolysin O; BUN, blood urea nitrogen; CKD, chronic kidney disease; FeNa, fractional excretion of sodium; GI, gastrointestinal; LDH, lactate dehydrogenase; NSAID, nonsteroidal anti-inflammatory drug; TTP/HUS, thrombotic thrombocytopenic purpura/hemolytic-uremic syndrome.


InternalMed_Harrison

InternalMed_Harrison. Acute Kidney InjuryUrinary sediment in AKI Normal or few RBC or WBC or hyaline casts Prerenal Postrenal Arterial thrombosis or embolism Preglomerular vasculitis HUS or TTP Scleroderma crisis RBCs RBC casts GN Vasculitis Malignant hypertension Thrombotic microangiopathy Interstitial nephritis GN Pyelonephritis Allograft rejection Malignant infiltration of the kidney ATN Tubulointerstitial nephritis Acute cellular allograft rejection Myoglobinuria Hemoglobinuria ATN GN Vasculitis Tubulo interstitial nephritis Allergic interstitial nephritis Atheroembolic disease Pyelonephritis Cystitis Glomerulo nephritis Acute uric acid nephropathy Calcium oxalate (ethylene glycol intoxication) Drugs or toxins (acyclovir, indinavir, sulfadiazine, amoxicillin) Abnormal WBCs WBC casts Renal tubular epithelial (RTE) cells RTE casts Pigmented casts Granular casts Eosinophiluria Crystalluria FIGuRE 334-6 Interpretation of urinary sediment findings in acute kidney injury (AKI). ATN, acute


InternalMed_Harrison

InternalMed_Harrison. tubular epithelial (RTE) cells RTE casts Pigmented casts Granular casts Eosinophiluria Crystalluria FIGuRE 334-6 Interpretation of urinary sediment findings in acute kidney injury (AKI). ATN, acute tubular necrosis; GN, glomerulonephri-tis; HUS, hemolytic-uremic syndrome; RBCs, red blood cells; RTE, renal tubular epithelial; TTP, thrombotic thrombocytopenic purpura; WBCs, white blood cells. (Adapted from L Yang, JV Bonventre: Diagnosis and clinical evaluation of acute kidney injury. In Comprehensive Nephrology, 4th ed. J Floege et al [eds]. Philadelphia, Elsevier, 2010.)


InternalMed_Harrison

InternalMed_Harrison. SCr, although severe AKI with rapid increases in SCr can occur in this setting. With many of the epithelial cell toxins such as aminoglycoside antibiotics and cisplatin, the rise in SCr is characteristically delayed for 3–5 days to 2 weeks after initial exposure.


InternalMed_Harrison

InternalMed_Harrison. A complete blood count may provide diagnostic clues. Anemia is common in AKI and is usually multifactorial in origin. It is not related to an effect of AKI solely on production of red blood cells because this effect in isolation takes longer to manifest. Peripheral eosinophilia can accompany interstitial nephritis, atheroembolic disease, polyarteritis nodosa, and Churg-Strauss vasculitis. Severe anemia in the absence of bleeding may reflect hemolysis, multiple myeloma, or thrombotic microangiopathy (e.g., HUS or TTP). Other laboratory findings of thrombotic microangiopathy include thrombocytopenia, schistocytes on peripheral blood smear, elevated lactate dehydrogenase level, and low haptoglobin content. Evaluation of patients suspected of having TTP-HUS includes measurement of levels of the von Willebrand factor cleaving protease (ADAMTS13) and testing for Shiga toxin–producing Escherichia coli. “Atypical HUS” constitutes the majority of adult cases of HUS; genetic testing is


InternalMed_Harrison

InternalMed_Harrison. of the von Willebrand factor cleaving protease (ADAMTS13) and testing for Shiga toxin–producing Escherichia coli. “Atypical HUS” constitutes the majority of adult cases of HUS; genetic testing is important because it is estimated that 60–70% of atypical HUS patients have mutations in genes encoding proteins that regulate the alternative complement pathway.


InternalMed_Harrison

InternalMed_Harrison. AKI often leads to hyperkalemia, hyperphosphatemia, and hypocalcemia. Marked hyperphosphatemia with accompanying hypocalcemia, however, suggests rhabdomyolysis or the tumor lysis syndrome. Creatine phosphokinase levels and serum uric acid are elevated in rhabdomyolysis, while tumor lysis syndrome shows normal or marginally elevated creatine kinase and markedly elevated serum uric acid. The anion gap may be increased with any cause of uremia due to retention of anions such as phosphate, hippurate, sulfate, and urate. The co-occurrence of an increased anion gap and an osmolal gap may suggest ethylene glycol poisoning, which may also cause oxalate crystalluria. Low anion gap may provide a clue to the diagnosis of multiple myeloma due to the presence of unmeasured cationic proteins. Laboratory blood tests helpful for the diagnosis of glomerulonephritis and vasculitis include depressed complement levels and high titers of antinuclear antibodies (ANAs), antineutrophilic cytoplasmic


InternalMed_Harrison

InternalMed_Harrison. blood tests helpful for the diagnosis of glomerulonephritis and vasculitis include depressed complement levels and high titers of antinuclear antibodies (ANAs), antineutrophilic cytoplasmic antibodies (ANCAs), antiglomerular basement membrane (AGBM) antibodies, and cryoglobulins.


InternalMed_Harrison

InternalMed_Harrison. Several indices have been used to help differentiate prerenal azotemia from intrinsic AKI when the tubules are malfunctioning. The low tubular flow rate and increased renal medullary recycling of urea seen in prerenal azotemia may cause a disproportionate elevation of the BUN compared to creatinine. Other causes of disproportionate BUN elevation need to be kept in mind, however, including upper gastrointestinal bleeding, hyperalimentation, increased tissue catabolism, and glucocorticoid use.


InternalMed_Harrison

InternalMed_Harrison. The fractional excretion of sodium (FeNa) is the fraction of the filtered sodium load that is reabsorbed by the tubules, and is a measure of both the kidney’s ability to reabsorb sodium as well as endogenously and exogenously administered factors that affect tubular reabsorption. As such, it depends on sodium intake, effective intravascular volume, GFR, diuretic intake, and intact tubular reabsorptive mechanisms. With prerenal azotemia, the FeNa may be below 1%, suggesting avid tubular sodium reabsorption. In patients with CKD, a FeNa significantly above 1% can be present despite a superimposed prerenal state. The FeNa may also be above 1% despite hypovolemia due to treatment with diuretics. Low FeNa is often seen early in glomerulonephritis and other disorders and, hence, should not be taken as prima facie evidence of prerenal azotemia. Low FeNa is therefore suggestive, but not synonymous, with effective intravascular volume depletion, and should not be used as the sole guide for


InternalMed_Harrison

InternalMed_Harrison. taken as prima facie evidence of prerenal azotemia. Low FeNa is therefore suggestive, but not synonymous, with effective intravascular volume depletion, and should not be used as the sole guide for volume management. The response of urine output to crystalloid or colloid fluid administration may be both diagnostic and therapeutic in prerenal azotemia. In ischemic AKI, the FeNa is frequently above 1% because of tubular injury and resultant inability to reabsorb sodium. Several causes of ischemia-associated and nephrotoxin-associated AKI can present with FeNa below 1%, however, including sepsis (often early in the course), rhabdomyolysis, and contrast nephropathy.


InternalMed_Harrison

InternalMed_Harrison. The ability of the kidney to produce a concentrated urine is dependent upon many factors and reliant on good tubular function in multiple regions of the kidney. In the patient not taking diuretics and with good baseline kidney function, urine osmolality may be above 500 mOsm/kg in prerenal azotemia, consistent with an intact medullary gradient and elevated serum vasopressin levels causing water reabsorption resulting in concentrated urine. In elderly patients and those 1808 with CKD, however, baseline concentrating defects may exist, making urinary osmolality unreliable in many instances. Loss of concentrating ability is common in septic or ischemic AKI, resulting in urine osmolality below 350 mOsm/kg, but the finding is not specific.


InternalMed_Harrison

InternalMed_Harrison. Postrenal AKI should always be considered in the differential diagnosis of AKI because treatment is usually successful if instituted early. Simple bladder catheterization can rule out urethral obstruction. Imaging of the urinary tract with renal ultrasound or CT should be undertaken to investigate obstruction in individuals with AKI unless an alternate diagnosis is apparent. Findings of obstruction include dilation of the collecting system and hydroureteronephrosis. Obstruction can be present without radiologic abnormalities in the setting of volume depletion, retroperitoneal fibrosis, encasement with tumor, and also early in the course of obstruction. If a high clinical index of suspicion for obstruction persists despite normal imaging, antegrade or retrograde pyelography should be performed. Imaging may also provide additional helpful information about kidney size and echogenicity to assist in the distinction between acute versus CKD. In CKD, kidneys are usually smaller unless the


InternalMed_Harrison

InternalMed_Harrison. Imaging may also provide additional helpful information about kidney size and echogenicity to assist in the distinction between acute versus CKD. In CKD, kidneys are usually smaller unless the patient has diabetic nephropathy, HIV-associated nephropathy, or infiltrative diseases. Normal sized kidneys are expected in AKI. Enlarged kidneys in a patient with AKI suggests the possibility of acute interstitial nephritis. Vascular imaging may be useful if venous or arterial obstruction is suspected, but the risks of contrast administration should be kept in mind. MRI with gadolinium-based contrast agents should be avoided if possible in severe AKI due to the possibility of inducing nephrogenic system fibrosis, a rare but serious complication seen most commonly in patients with end-stage renal disease.


InternalMed_Harrison

InternalMed_Harrison. If the cause of AKI is not apparent based on the clinical context, physical examination, laboratory studies, and radiologic evaluation, kidney biopsy should be considered. The kidney biopsy can provide definitive diagnostic and prognostic information about acute kidney disease and CKD. The procedure is most often used in AKI when prerenal azotemia, postrenal AKI, and ischemic or nephrotoxic AKI have been deemed unlikely, and other possible diagnoses are being considered such as glomerulonephritis, vasculitis, interstitial nephritis, myeloma kidney, HUS and TTP, and allograft dysfunction. Kidney biopsy is associated with a risk of bleeding, which can be severe and organor life-threatening in patients with thrombocytopenia or coagulopathy.


InternalMed_Harrison

InternalMed_Harrison. BUN and creatinine are functional biomarkers of glomerular filtration rather than tissue injury biomarkers and, therefore, may be suboptimal for the diagnosis of actual parenchymal kidney damage. BUN and creatinine are also relatively slow to rise after kidney injury. Several novel kidney injury biomarkers have been investigated and show promise for earlier and accurate diagnosis of AKI. Kidney injury molecule-1 (KIM-1) is a type 1 transmembrane protein that is abundantly expressed in proximal tubular cells injured by ischemia or nephrotoxins such as cisplatin. KIM-1 is not expressed in appreciable quantities in the absence of tubular injury or in extrarenal tissues. KIM-1’s functional role may be to confer phagocytic properties to tubular cells, enabling them to clear debris from the tubular lumen after kidney injury. KIM-1 can be detected shortly after ischemic or nephrotoxic injury in the urine and, therefore, may be an easily tested biomarker in the clinical setting. Neutrophil


InternalMed_Harrison

InternalMed_Harrison. lumen after kidney injury. KIM-1 can be detected shortly after ischemic or nephrotoxic injury in the urine and, therefore, may be an easily tested biomarker in the clinical setting. Neutrophil gelatinase associated lipocalin (NGAL, also known as lipocalin-2 or siderocalin) is another novel biomarker of AKI. NGAL was first discovered as a protein in granules of human neutrophils. NGAL can bind to iron siderophore complexes and may have tissue-protective effects in the proximal tubule. NGAL is highly upregulated after inflammation and kidney injury and can be detected in the plasma and urine within 2 h of cardiopulmonary bypass–associated AKI. Other candidate biomarkers of AKI include interleukin (IL) 18, a proinflammatory cytokine of the IL-1 superfamily that may mediate ischemic proximal tubular injury, and L-type fatty acid binding protein, which is expressed in ischemic proximal tubule cells and may be renoprotective by binding free fatty acids and lipid peroxidation products. A


InternalMed_Harrison

InternalMed_Harrison. tubular injury, and L-type fatty acid binding protein, which is expressed in ischemic proximal tubule cells and may be renoprotective by binding free fatty acids and lipid peroxidation products. A number of other biomarkers are under investigation for early and accurate identification of AKI and for risk stratification to identify individuals at increased risk. The optimal use of novel AKI biomarkers in clinical settings is an area of ongoing investigation.


InternalMed_Harrison

InternalMed_Harrison. The kidney plays a central role in homeostatic control of volume status, blood pressure, plasma electrolyte composition, and acid-base balance, and for excretion of nitrogenous and other waste products. Complications associated with AKI are, therefore, protean, and depend on the severity of AKI and other associated conditions. Mild to moderate AKI may be entirely asymptomatic, particularly early in the course.


InternalMed_Harrison

InternalMed_Harrison. Buildup of nitrogenous waste products, manifested as an elevated BUN concentration, is a hallmark of AKI. BUN itself poses little direct toxicity at levels below 100 mg/dL. At higher concentrations, mental status changes and bleeding complications can arise. Other toxins normally cleared by the kidney may be responsible for the symptom complex known as uremia. Few of the many possible uremic toxins have been definitively identified. The correlation of BUN and SCr concentrations with uremic symptoms is extremely variable, due in part to differences in urea and creatinine generation rates across individuals.


InternalMed_Harrison

InternalMed_Harrison. Expansion of extracellular fluid volume is a major complication of oliguric and anuric AKI, due to impaired salt and water excretion. The result can be weight gain, dependent edema, increased jugular venous pressure, and pulmonary edema; the latter can be life threatening. Pulmonary edema can also occur from volume overload and hemorrhage in pulmonary renal syndromes. AKI may also induce or exacerbate acute lung injury characterized by increased vascular permeability and inflammatory cell infiltration in lung parenchyma. Recovery from AKI can sometimes be accompanied by polyuria, which, if untreated, can lead to significant volume depletion. The polyuric phase of recovery may be due to an osmotic diuresis from retained urea and other waste products as well as delayed recovery of tubular reabsorptive functions.


InternalMed_Harrison

InternalMed_Harrison. Administration of excessive hypotonic crystalloid or isotonic dextrose solutions can result in hypoosmolality and hyponatremia, which, if severe, can cause neurologic abnormalities, including seizures. Abnormalities in plasma electrolyte composition can be mild or life threatening. Frequently the most concerning complication of AKI is hyperkalemia. Marked hyperkalemia is particularly common in rhabdomyolysis, hemolysis, and tumor lysis syndrome due to release of intracellular potassium from damaged cells. Potassium affects the cellular membrane potential of cardiac and neuromuscular tissues. Muscle weakness may be a symptom of hyperkalemia. The more serious complication of hyperkalemia is due to effects on cardiac conduction, leading to potentially fatal arrhythmias.


InternalMed_Harrison

InternalMed_Harrison. Metabolic acidosis, usually accompanied by an elevation in the anion gap, is common in AKI, and can further complicate acid-base and potassium balance in individuals with other causes of acidosis, including sepsis, diabetic ketoacidosis, or respiratory acidosis. AKI can lead to hyperphosphatemia, particularly in highly catabolic patients or those with AKI from rhabdomyolysis, hemolysis, and tumor lysis syndrome. Metastatic deposition of calcium phosphate can lead to hypocalcemia. AKI-associated hypocalcemia may also arise from derangements in the vitamin D–parathyroid hormone–fibroblast growth factor-23 axis. Hypocalcemia is often asymptomatic but can lead to perioral paresthesias, muscle cramps, seizures, carpopedal spasms, and prolongation of the QT interval on electrocardiography. Calcium levels should be corrected for the degree of hypoalbuminemia, if present, or ionized calcium levels should be followed. Mild, asymptomatic hypocalcemia does not require treatment.


InternalMed_Harrison

InternalMed_Harrison. Hematologic complications of AKI include anemia and bleeding, both of which are exacerbated by coexisting disease processes such as sepsis, liver disease, and disseminated intravascular coagulation. Direct hematologic effects from AKI-related uremia include decreased erythropoiesis and platelet dysfunction. Infections are a common precipitant of AKI and also a dreaded complication of AKI. Impaired host immunity has been described in end-stage renal disease and may be operative in severe AKI. The major cardiac complications of AKI are arrhythmias, pericarditis, and pericardial effusion. AKI is often a severely hypercatabolic state, and therefore, malnutrition is a major complication.


InternalMed_Harrison

InternalMed_Harrison. AKI is often a severely hypercatabolic state, and therefore, malnutrition is a major complication. The management of individuals with and at risk for AKI varies according to the underlying cause (Table 334-2). Common to all are several principles. Optimization of hemodynamics, correction of fluid and electrolyte imbalances, discontinuation of nephrotoxic medications, and dose adjustment of administered medications are all critical. Common causes of AKI such as sepsis and ischemic ATN do not yet have specific therapies once injury is established, but meticulous clinical attention is needed to support the patient until (if ) AKI resolves. The kidney possesses remarkable capacity to repair itself after even severe, dialysis-requiring AKI. However, many patients with AKI do not recover fully and may remain dialysis dependent. It has become increasingly apparent that AKI predisposes to accelerated progression of CKD, and CKD is an important risk factor for AKI.


InternalMed_Harrison

InternalMed_Harrison. Prerenal Azotemia Prevention and treatment of prerenal azotemia require optimization of renal perfusion. The composition of replacement fluids should be targeted to the type of fluid lost. Severe acute blood loss should be treated with packed red blood cells. Isotonic crystalloid and/or colloid should be used for less severe acute hemorrhage or plasma loss in the case of burns and pancreatitis. Crystalloid solutions are less expensive and probably equally efficacious as colloid solutions. Hydroxyethyl starch solutions increase the risk of severe AKI and are contraindicated. Crystalloid has been reported to be preferable to albumin in the setting of traumatic brain injury. Isotonic crystalloid (e.g., 0.9% saline) or colloid should be used for volume resuscitation in severe hypovolemia, whereas hypotonic crystalloids (e.g., 0.45% saline) suffice for less severe hypovolemia. Excessive chloride administration from 0.9% saline may lead to hyperchloremic metabolic acidosis and may impair


InternalMed_Harrison

InternalMed_Harrison. hypotonic crystalloids (e.g., 0.45% saline) suffice for less severe hypovolemia. Excessive chloride administration from 0.9% saline may lead to hyperchloremic metabolic acidosis and may impair GFR. Bicarbonate-containing solutions (e.g., dextrose water with 150 mEq sodium bicarbonate) should be used if metabolic acidosis is a concern.


InternalMed_Harrison

InternalMed_Harrison. Optimization of cardiac function in AKI may require use of inotropic agents, preloadand afterload-reducing agents, antiarrhythmic drugs, and mechanical aids such as an intraaortic balloon pump. Invasive hemodynamic monitoring to guide therapy may be necessary. Cirrhosis and Hepatorenal Syndrome Fluid management in individuals with cirrhosis, ascites, and AKI is challenging because of the frequent 1. Optimization of systemic and renal hemodynamics through volume resuscitation and judicious use of vasopressors 2. Elimination of nephrotoxic agents (e.g., ACE inhibitors, ARBs, NSAIDs, aminoglycosides) if possible 3. Initiation of renal replacement therapy when indicated 1. Nephrotoxin-specific a. Rhabdomyolysis: aggressive intravenous fluids; consider forced alkaline diuresis b. Tumor lysis syndrome: aggressive intravenous fluids and allopurinol or rasburicase 2. Volume overload a. b. c. 3. Hyponatremia a.


InternalMed_Harrison

InternalMed_Harrison. Tumor lysis syndrome: aggressive intravenous fluids and allopurinol or rasburicase 2. Volume overload a. b. c. 3. Hyponatremia a. Restriction of enteral free water intake, minimization of hypotonic intravenous solutions including those containing dextrose b. Hypertonic saline is rarely necessary in AKI. Vasopressin antagonists are generally not needed. 4. Hyperkalemia a. Restriction of dietary potassium intake b. Discontinuation of potassium-sparing diuretics, ACE inhibitors, ARBs, NSAIDs c. Loop diuretics to promote urinary potassium loss d. e. Insulin (10 units regular) and glucose (50 mL of 50% dextrose) to promote entry of potassium intracellularly f. Inhaled beta-agonist therapy to promote entry of potassium intracellularly g. Calcium gluconate or calcium chloride (1 g) to stabilize the myocardium 5. Metabolic acidosis a. Sodium bicarbonate (if pH <7.2 to keep serum bicarbonate >15 mmol/L) b. Administration of other bases, e.g., THAM c. 6. Hyperphosphatemia a.


InternalMed_Harrison

InternalMed_Harrison. Sodium bicarbonate (if pH <7.2 to keep serum bicarbonate >15 mmol/L) b. Administration of other bases, e.g., THAM c. 6. Hyperphosphatemia a. Restriction of dietary phosphate intake b. Phosphate binding agents (calcium acetate, sevelamer hydrochloride, aluminum hydroxide—taken with meals) 7. Hypocalcemia a. Calcium carbonate or calcium gluconate if symptomatic 8. Hypermagnesemia a. Discontinue Mg2+ containing antacids 9. Hyperuricemia a. Acute treatment is usually not required except in the setting of tumor lysis syndrome (see above) 10. Nutrition a. Sufficient protein and calorie intake (20–30 kcal/kg per day) to avoid negative nitrogen balance. Nutrition should be provided via the enteral route if possible. 11. Drug dosing a. Careful attention to dosages and frequency of administration of drugs, adjustment for degree of renal failure b. Note that serum creatinine concentration may overestimate renal function in the non–steady state characteristic of patients with AKI


InternalMed_Harrison

InternalMed_Harrison. Note that serum creatinine concentration may overestimate renal function in the non–steady state characteristic of patients with AKI Abbreviations: ACE, angiotensin-converting enzyme; ARBs, angiotensin receptor blocker; NSAIDs, nonsteroidal anti-inflammatory drug; THAM, tris (hydroxymethyl) aminomethane.


InternalMed_Harrison

InternalMed_Harrison. difficulty in ascertaining intravascular volume status. Administration of intravenous fluids as a volume challenge may be required diagnostically as well as therapeutically. Excessive volume administration may, however, result in worsening ascites and pulmonary compromise in 1810 the setting of hepatorenal syndrome or AKI due to superimposed spontaneous bacterial peritonitis. Peritonitis should be ruled out by culture of ascitic fluid. Albumin may prevent AKI in those treated with antibiotics for spontaneous bacterial peritonitis. The definitive treatment of the hepatorenal syndrome is orthotopic liver transplantation. Bridge therapies that have shown promise include terlipressin (a vasopressin analog), combination therapy with octreotide (a somatostatin analog) and midodrine (an α1-adrenergic agonist), and norepinephrine, in combination with intravenous albumin (25–50 g, maximum 100 g/d).


InternalMed_Harrison

InternalMed_Harrison. Intrinsic AKI Several agents have been tested and have failed to show benefit in the treatment of acute tubular injury. These include atrial natriuretic peptide, low-dose dopamine, endothelin antagonists, loop diuretics, calcium channel blockers, α-adrenergic receptor blockers, prostaglandin analogs, antioxidants, antibodies against leukocyte adhesion molecules, and insulin-like growth factor, among many others. Most studies have enrolled patients with severe and well-established AKI, and treatment may have been initiated too late. Novel kidney injury biomarkers may provide an opportunity to test agents earlier in the course of AKI.


InternalMed_Harrison

InternalMed_Harrison. AKI due to acute glomerulonephritis or vasculitis may respond to immunosuppressive agents and/or plasmapheresis (Chap. 332e). Allergic interstitial nephritis due to medications requires discontinuation of the offending agent. Glucocorticoids have been used, but not tested in randomized trials, in cases where AKI persists or worsens despite discontinuation of the suspected medication. AKI due to scleroderma (scleroderma renal crisis) should be treated with ACE inhibitors. Idiopathic TTP-HUS is a medical emergency and should be treated promptly with plasma exchange. Pharmacologic blockade of complement activation may be effective in atypical HUS.


InternalMed_Harrison

InternalMed_Harrison. Early and aggressive volume repletion is mandatory in patients with rhabdomyolysis, who may initially require 10 L of fluid per day. Alkaline fluids (e.g., 75 mmol/L sodium bicarbonate added to 0.45% saline) may be beneficial in preventing tubular injury and cast formation, but carry the risk of worsening hypocalcemia. Diuretics may be used if fluid repletion is adequate but unsuccessful in achieving urinary flow rates of 200–300 mL/h. There is no specific therapy for established AKI in rhabdomyolysis, other than dialysis in severe cases or general supportive care to maintain fluid and electrolyte balance and tissue perfusion. Careful attention must be focused on calcium and phosphate status because of precipitation in damaged tissue and release when the tissue heals.


InternalMed_Harrison

InternalMed_Harrison. Postrenal AKI Prompt recognition and relief of urinary tract obstruction can forestall the development of permanent structural damage induced by urinary stasis. The site of obstruction defines the treatment approach. Transurethral or suprapubic bladder catheterization may be all that is needed initially for urethral strictures or functional bladder impairment. Ureteric obstruction may be treated by percutaneous nephrostomy tube placement or ureteral stent placement. Relief of obstruction is usually followed by an appropriate diuresis for several days. In rare cases, severe polyuria persists due to tubular dysfunction and may require continued administration of intravenous fluids and electrolytes for a period of time.


InternalMed_Harrison

InternalMed_Harrison. SuPPORTIVE MEASuRES Volume Management Hypervolemia in oliguric or anuric AKI may be life threatening due to acute pulmonary edema, especially because many patients have coexisting pulmonary disease, and AKI likely increases pulmonary vascular permeability. Fluid and sodium should be restricted, and diuretics may be used to increase the urinary flow rate. There is no evidence that increasing urine output itself improves the natural history of AKI, but diuretics may help to avoid the need for dialysis in some cases. In severe cases of volume overload, furosemide may be given as a bolus (200 mg) followed by an intravenous drip (10–40 mg/h), with or without a thiazide diuretic. In decompensated heart failure, stepped diuretic therapy was found to be superior to ultrafiltration in preserving renal function. Diuretic therapy should be stopped if there is no response. Dopamine in low doses may transiently increase salt and water excretion by the kidney in prerenal states, but clinical trials


InternalMed_Harrison

InternalMed_Harrison. function. Diuretic therapy should be stopped if there is no response. Dopamine in low doses may transiently increase salt and water excretion by the kidney in prerenal states, but clinical trials have failed to show any benefit in patients with intrinsic AKI. Because of the risk of arrhythmias and potential bowel ischemia, it has been argued that the risks of dopamine outweigh the benefits in the treatment or prevention of AKI.


InternalMed_Harrison

InternalMed_Harrison. Electrolyte and Acid-Base Abnormalities The treatment of dysnatremias and hyperkalemia is described in Chap. 63. Metabolic acidosis is generally not treated unless severe (pH <7.20 and serum bicarbonate <15 mmol/L). Acidosis can be treated with oral or intravenous sodium bicarbonate (Chap. 66), but overcorrection should be avoided because of the possibility of metabolic alkalosis, hypocalcemia, hypokalemia, and volume overload. Hyperphosphatemia is common in AKI and can usually be treated by limiting intestinal absorption of phosphate using phosphate binders (calcium carbonate, calcium acetate, lanthanum, sevelamer, or aluminum hydroxide). Hypocalcemia does not usually require therapy unless symptoms are present. Ionized calcium should be monitored rather than total calcium when hypoalbuminemia is present.


InternalMed_Harrison

InternalMed_Harrison. Malnutrition Protein energy wasting is common in AKI, particularly in the setting of multisystem organ failure. Inadequate nutrition may lead to starvation ketoacidosis and protein catabolism. Excessive nutrition may increase the generation of nitrogenous waste and lead to worsening azotemia. Total parenteral nutrition requires large volumes of fluid administration and may complicate efforts at volume control. According to the Kidney Disease Improving Global Outcomes (KDIGO) guidelines, patients with AKI should achieve a total energy intake of 20–30 kcal/kg per day. Protein intake should vary depending on the severity of AKI: 0.8–1.0 g/kg per day in noncatabolic AKI without the need for dialysis; 1.0–1.5 g/kg per day in patients on dialysis; and up to a maximum of 1.7 g/kg per day if hypercatabolic and receiving continuous renal replacement therapy. Trace elements and water-soluble vitamins should also be supplemented in AKI patients treated with dialysis and continuous renal


InternalMed_Harrison

InternalMed_Harrison. if hypercatabolic and receiving continuous renal replacement therapy. Trace elements and water-soluble vitamins should also be supplemented in AKI patients treated with dialysis and continuous renal replacement therapy.


InternalMed_Harrison

InternalMed_Harrison. Anemia The anemia seen in AKI is usually multifactorial and is not improved by erythropoiesis-stimulating agents, due to their delayed onset of action and the presence of bone marrow resistance in critically ill patients. Uremic bleeding may respond to desmopressin or estrogens, but may require dialysis for treatment in the case of longstanding or severe uremia. Gastrointestinal prophylaxis with proton pump inhibitors or histamine (H2) receptor blockers is required. Venous thromboembolism prophylaxis is important and should be tailored to the clinical setting; low-molecular-weight heparins and factor Xa inhibitors have unpredictable pharmacokinetics in severe AKI and should be avoided.


InternalMed_Harrison

InternalMed_Harrison. Dialysis Indications and Modalities (See also Chap. 336) Dialysis is indicated when medical management fails to control volume overload, hyperkalemia, or acidosis; in some toxic ingestions; and when there are severe complications of uremia (asterixis, pericardial rub or effusion, encephalopathy, uremic bleeding). The timing of dialysis is still a matter of debate. Late initiation of dialysis carries the risk of avoidable volume, electrolyte, and metabolic complications of AKI. On the other hand, initiating dialysis too early may unnecessarily expose individuals to intravenous lines and invasive procedures, with the attendant risks of infection, bleeding, procedural complications, and hypotension. The initiation of dialysis should not await the development of a life-threatening complication of renal failure. Many nephrologists initiate dialysis for AKI empirically when the BUN exceeds a certain value (e.g., 100 mg/dL) in patients without clinical signs of recovery of kidney function.


InternalMed_Harrison

InternalMed_Harrison. of renal failure. Many nephrologists initiate dialysis for AKI empirically when the BUN exceeds a certain value (e.g., 100 mg/dL) in patients without clinical signs of recovery of kidney function. The available modes for renal replacement therapy in AKI require either access to the peritoneal cavity (for peritoneal dialysis) or the large blood vessels (for hemodialysis, hemofiltration, and other hybrid procedures). Small solutes are removed across a semipermeable membrane down their concentration gradient (“diffusive” clearance) and/or along with the movement of plasma water (“convective” clearance). The choice of modality is often dictated by the immediate availability of technology and the expertise of medical staff. Peritoneal dialysis is performed through a temporary intraperitoneal catheter. It is rarely used in the United States for AKI in adults but has enjoyed widespread use internationally, particularly when hemodialysis technology is not available. Dialysate solution is


InternalMed_Harrison

InternalMed_Harrison. catheter. It is rarely used in the United States for AKI in adults but has enjoyed widespread use internationally, particularly when hemodialysis technology is not available. Dialysate solution is instilled into and removed from the peritoneal cavity at regular intervals in order to achieve diffusive and convective clearance of solutes across the peritoneal membrane; ultrafiltration of water is achieved by the presence of an osmotic gradient across the peritoneal membrane achieved by high concentrations of dextrose in the dialysate solution. Because of its continuous nature, it is often better tolerated than intermittent procedures like hemodialysis in hypotensive patients. Peritoneal dialysis may not be sufficient for hypercatabolic patients due to inherent limitations in dialysis efficacy.


InternalMed_Harrison

InternalMed_Harrison. Hemodialysis can be used intermittently or continuously and can be done through convective clearance, diffusive clearance, or a combination of the two. Vascular access is through the femoral, internal jugular, or subclavian veins. Hemodialysis is an intermittent procedure that removes solutes through diffusive and convective clearance. Hemodialysis is typically performed 3–4 h per day, three to four times per week, and is the most common form of renal replacement therapy for AKI. One of the major complications of hemodialysis is hypotension, particularly in the critically ill.


InternalMed_Harrison

InternalMed_Harrison. Continuous intravascular procedures were developed in the early 1980s to treat hemodynamically unstable patients without inducing the rapid shifts of volume, osmolarity, and electrolytes characteristic of intermittent hemodialysis. Continuous renal replacement therapy (CRRT) can be performed by convective clearance (continuous venovenous hemofiltration [CVVH]), in which large volumes of plasma water (and accompanying solutes) are forced across the semipermeable membrane by means of hydrostatic pressure; the plasma water is then replaced by a physiologic crystalloid solution. CRRT can also be performed by diffusive clearance (continuous venovenous hemodialysis [CVVHD]), a technology similar to hemodialysis except at lower blood flow and dialysate flow rates. A hybrid therapy combines both diffusive and convective clearance (continuous venovenous hemodiafiltration [CVVHDF]). To achieve some of the advantages of CRRT without the need for 24-h staffing of the procedure, some physicians


InternalMed_Harrison

InternalMed_Harrison. diffusive and convective clearance (continuous venovenous hemodiafiltration [CVVHDF]). To achieve some of the advantages of CRRT without the need for 24-h staffing of the procedure, some physicians favor slow low-efficiency dialysis (SLED) or extended daily dialysis (EDD). In this therapy, blood flow and dialysate flow are higher than in CVVHD, but the treatment time is reduced to 12 h or less.


InternalMed_Harrison

InternalMed_Harrison. The optimal dose of dialysis for AKI is not clear. Daily intermittent hemodialysis and high-dose CRRT do not confer a demonstrable survival or renal recovery advantage, but care should be taken to avoid undertreatment. Studies have failed to show that continuous therapies are superior to intermittent therapies. If available, CRRT is often preferred in patients with severe hemodynamic instability, cerebral edema, or significant volume overload.


InternalMed_Harrison

InternalMed_Harrison. The development of AKI is associated with a significantly increased risk of in-hospital and long-term mortality, longer length of stay, and increased costs. Prerenal azotemia, with the exception of the cardiorenal and hepatorenal syndromes, and postrenal azotemia carry a better prognosis than most cases of intrinsic AKI. The kidneys may recover even after severe, dialysis-requiring AKI. Survivors of an episode of AKI requiring temporary dialysis, however, are at extremely high risk for progressive CKD, and up to 10% may develop end-stage renal disease. Postdischarge care under the supervision of a nephrologist for aggressive secondary prevention of kidney disease is prudent. Patients with AKI are more likely to die prematurely after they leave the hospital even if their kidney function has recovered. Joanne M. Bargman, Karl Skorecki


InternalMed_Harrison

InternalMed_Harrison. Joanne M. Bargman, Karl Skorecki Chronic kidney disease (CKD) encompasses a spectrum of different pathophysiologic processes associated with abnormal kidney function and a progressive decline in glomerular filtration rate (GFR). Figure 335-1 provides a recently updated classification, in which stages of CKD are stratified by both estimated GFR and the degree of albuminuria, in order to predict risk of progression of CKD. Previously, CKD had been staged solely by the GFR. However, the risk of worsening of kidney function is closely linked to the amount of albuminuria, and so it has been incorporated into the classification.


InternalMed_Harrison

InternalMed_Harrison. The pathophysiologic processes, adaptations, clinical presentations, assessment, and therapeutic interventions associated with CKD will be the focus of this chapter. The dispiriting term end-stage renal disease represents a stage of CKD where the accumulation of toxins, fluid, and electrolytes normally excreted by the kidneys results in the uremic syndrome. This syndrome leads to death unless the toxins are removed by renal replacement therapy, using dialysis or kidney transplantation. These interventions are discussed in Chaps. 336 and 337. End-stage renal disease will be supplanted in this chapter by the term stage 5 CKD.


InternalMed_Harrison

InternalMed_Harrison. The pathophysiology of CKD involves two broad sets of mechanisms of damage: (1) initiating mechanisms specific to the underlying etiology (e.g., genetically determined abnormalities in kidney development or integrity, immune complex deposition and inflammation in certain types of glomerulonephritis, or toxin exposure in certain diseases of the renal tubules and interstitium) and (2) a set of progressive mechanisms, involving hyperfiltration and hypertrophy of the remaining viable nephrons, that are a common consequence following long-term reduction of renal mass, irrespective of underlying etiology (Chap. 333e). The responses to reduction in nephron number are mediated by vasoactive hormones, cytokines, and growth factors. Eventually, these short-term adaptations of hypertrophy and hyperfiltration become maladaptive as the increased pressure and flow within the nephron predisposes to distortion of glomerular architecture, abnormal podocyte function, and disruption of the filtration


InternalMed_Harrison

InternalMed_Harrison. become maladaptive as the increased pressure and flow within the nephron predisposes to distortion of glomerular architecture, abnormal podocyte function, and disruption of the filtration barrier leading to sclerosis and dropout of the remaining nephrons (Fig. 335-2). Increased intrarenal activity of the renin-angiotensin system (RAS) appears to contribute both to the initial adaptive hyperfiltration and to the subsequent maladaptive hypertrophy and sclerosis. This process explains why a reduction in renal mass from an isolated insult may lead to a progressive decline in renal function over many years (Fig. 335-3).


InternalMed_Harrison

InternalMed_Harrison. It is important to identify factors that increase the risk for CKD, even in individuals with normal GFR. Risk factors include small for gestation birth weight, childhood obesity, hypertension, diabetes mellitus, autoimmune disease, advanced age, African ancestry, a family history of kidney disease, a previous episode of acute kidney injury, and the presence of proteinuria, abnormal urinary sediment, or structural abnormalities of the urinary tract.


InternalMed_Harrison

InternalMed_Harrison. Many rare inherited forms of CKD follow a Mendelian inheritance pattern, often as part of a systemic syndrome, with the most common in this category being autosomal dominant polycystic kidney disease. In addition, recent research in the genetics of predisposition to common complex diseases (Chap. 82) has revealed DNA sequence variants at a number of genetic loci that are associated with common forms of CKD. A striking example is the finding of allelic versions of the APOL1 gene, of West African population ancestry, which contributes to the several-fold higher frequency of certain common etiologies of nondiabetic CKD (e.g., focal segmental glomerulosclerosis) observed among African and Hispanic Americans. The prevalence in West African populations seems to have arisen as an evolutionary adaptation conferring protection from tropical pathogens. As in other common diseases


InternalMed_Harrison

InternalMed_Harrison. FIGuRE 335-2 Left: Schema of the normal glomerular architecture. Right: Secondary glomerular changes associated with a reduction in nephron number, including enlargement of capillary lumens and focal adhesions, which are thought to occur consequent to compensatory hyperfiltration and hypertrophy in the remaining nephrons. (Modified from JR Ingelfinger: N Engl J Med 348:99, 2003.) FIGuRE 335-1 Kidney Disease Improving Global Outcome (KDIGO) classification of chronic kidney disease (CKD). Gradation of color from green to red corresponds to increasing risk and progression of CKD. GFR, glomerular filtration rate. (Reproduced with permission from Kidney Int Suppl 3:5-14, 2013.) with a heritable component, an environmental trigger (such as a viral pathogen) is required to transform genetic risk into disease.


InternalMed_Harrison

InternalMed_Harrison. Int Suppl 3:5-14, 2013.) with a heritable component, an environmental trigger (such as a viral pathogen) is required to transform genetic risk into disease. To stage CKD, it is necessary to estimate the GFR rather than relying on serum creatinine concentration (Table 335-1). Many laboratories now report an estimated GFR, or eGFR, using one of these equations.


InternalMed_Harrison

InternalMed_Harrison. The normal annual mean decline in GFR with age from the peak GFR (~120 mL/min per 1.73 m2) attained during the third decade of life is ~1 mL/min per year per 1.73 m2, reaching a mean value of 70 mL/min per 1.73 m2 at age 70. Although reduced GFR occurs with human aging, the lower GFR signifies a true loss of kidney function, with all of the implications that apply to the corresponding stage of CKD. The mean GFR is lower in women than in men. For example, a woman in her 80s with a normal serum creatinine may have a GFR of just 50 mL/min per 1.73 m2. Thus, even a mild elevation in serum creatinine concentration (e.g., 130 μmol/L [1.5 mg/dL]) often signifies a substantial reduction in GFR in most individuals.


InternalMed_Harrison

InternalMed_Harrison. FIGuRE 335-3 Left: Low-power photomicrograph of a normal kidney showing normal glomeruli and healthy tubulointerstitium without fibrosis. Right: Low-power photomicrograph of chronic kidney disease with sclerosis of many glomeruli and severe tubulointerstitial fibrosis (Masson trichrome, ×40 magnification). (Slides courtesy of the late Dr. Andrew Herzenberg.) The equations for estimating GFR are valid only if the patient is in steady state, that is, the serum creatinine is neither rising nor falling over days.


InternalMed_Harrison

InternalMed_Harrison. Measurement of albuminuria is also helpful for monitoring nephron injury and the response to therapy in many forms of CKD, especially chronic glomerular diseases. Although an accurate 24-h urine collection is the standard for measurement of albuminuria, the measurement of protein-to-creatinine ratio in a spot first-morning urine sample is often more practical to obtain and correlates well, but not perfectly, with 24-h urine collections. Microalbuminuria (Fig. 335-1, stage A2) refers to the excretion of amounts of albumin too small to detect by urinary dipstick or conventional measures of urine protein. It is a good screening test for early detection of renal disease, and may be a marker for the presence of microvascular disease in general. If a patient has a large amount of excreted albumin, there is no reason to test for microalbuminuria.


InternalMed_Harrison

InternalMed_Harrison. Stages 1 and 2 CKD are usually not associated with any symptoms arising from the decrement in GFR. If the decline in GFR progresses to stages 3 and 4, clinical and laboratory complications of CKD become reCOMMenDeD equatIOns FOr estIMatIOn OF gLOMeruLar FILtratIOn rate (gFr) usIng seruM CreatInIne COnCentratIOn (sCr), age, sex, raCe, anD BODy WeIght 1. Equation from the Modification of Diet in Renal Disease study Estimated GFR (mL/min per 1.73 m2) = 1.86 × (SCr) −1.154 × (age)−0.203 Multiply by 0.742 for women Multiply by 1.21 for African ancestry 2. CKD-EPI equation GFR = 141 × min(SCr/κ, 1)α × max(SCr/κ, 1)–1.209 × 0.993Age Multiply by 1.018 for women Multiply by 1.159 for African ancestry where SCr is serum creatinine in mg/dL, κ is 0.7 for females and 0.9 for males, α is –0.329 for females and –0.411 for males, min indicates the minimum of SCr/κ or 1, and max indicates the maximum of SCr/κ or 1. Abbreviation: CKD-EPI, Chronic Kidney Disease Epidemiology Collaboration.


InternalMed_Harrison

InternalMed_Harrison. more prominent. Virtually all organ systems are affected, but the most 1813 evident complications include anemia and associated easy fatigability; decreased appetite with progressive malnutrition; abnormalities in calcium, phosphorus, and mineral-regulating hormones, such as 1,25(OH)2D3 (calcitriol), parathyroid hormone (PTH), and fibroblast growth factor 23 (FGF-23); and abnormalities in sodium, potassium, water, and acid-base homeostasis. Many patients, especially the elderly, will have eGFR values compatible with stage 2 or 3 CKD. However, the majority of these patients will show no further deterioration of renal function. The primary care physician is advised to recheck kidney function, and if it is stable and not associated with proteinuria, the patient can usually be managed in this setting. However, if there is evidence of decline of GFR, uncontrolled hypertension, or proteinuria, referral to a nephrologist is appropriate. If the patient progresses to stage 5 CKD, toxins


InternalMed_Harrison

InternalMed_Harrison. this setting. However, if there is evidence of decline of GFR, uncontrolled hypertension, or proteinuria, referral to a nephrologist is appropriate. If the patient progresses to stage 5 CKD, toxins accumulate such that patients usually experience a marked disturbance in their activities of daily living, well-being, nutritional status, and water and electrolyte homeostasis, eventuating in the uremic syndrome.


InternalMed_Harrison

InternalMed_Harrison. It has been estimated from population survey data that at least 6% of the adult population in the United States has CKD at stages 1 and 2. An additional 4.5% of the U.S. population is estimated to have stages 3 and 4 CKD. Table 335-2 lists the five most frequent categories of causes of CKD, cumulatively accounting for greater than 90% of the CKD disease burden worldwide. The relative contribution of each category varies among different geographic regions. The most frequent cause of CKD in North America and Europe is diabetic nephropathy, most often secondary to type 2 diabetes mellitus. Patients with newly diagnosed CKD often also present with hypertension. When no overt evidence for a primary glomerular or tubulointerstitial kidney disease process is present, CKD is often attributed to hypertension. However, it is now appreciated that such individuals can be considered in two categories. The first includes patients with a silent primary glomerulopathy, such as focal segmental


InternalMed_Harrison

InternalMed_Harrison. to hypertension. However, it is now appreciated that such individuals can be considered in two categories. The first includes patients with a silent primary glomerulopathy, such as focal segmental glomerulosclerosis, without the overt nephrotic or nephritic manifestations of glomerular disease (Chap. 338). The second includes patients in whom progressive nephrosclerosis and hypertension is the renal correlate of a systemic vascular disease, often also involving largeand small-vessel cardiac and cerebral pathology. This latter combination is especially common in the elderly, in whom chronic renal ischemia as a cause of CKD may be underdiagnosed. The increasing incidence of CKD in the elderly has been ascribed, in part, to decreased mortality rate from the cardiac and cerebral complications of atherosclerotic vascular disease, enabling a greater segment of the population to eventually manifest the renal component of generalized vascular disease. Nevertheless, it should be appreciated


InternalMed_Harrison

InternalMed_Harrison. of atherosclerotic vascular disease, enabling a greater segment of the population to eventually manifest the renal component of generalized vascular disease. Nevertheless, it should be appreciated that the vast majority of such patients with early stages of CKD will succumb to the cardiovascular and cerebrovascular consequences of the vascular disease before they can progress to the most advanced stages of CKD. Indeed, even a minor decrement in GFR or the presence of albuminuria is now recognized as a major risk factor for cardiovascular disease.


InternalMed_Harrison

InternalMed_Harrison. Although serum urea and creatinine concentrations are used to measure the excretory capacity of the kidneys, accumulation of these two molecules themselves does not account for the many symptoms and signs that characterize the uremic syndrome in advanced renal failure. disease and primary glomerular disease with associated hypertension) aRelative contribution of each category varies with geographic region and race.


InternalMed_Harrison

InternalMed_Harrison. 1814 Hundreds of toxins that accumulate in renal failure have been implicated in the uremic syndrome. These include water-soluble, hydrophobic, protein-bound, charged, and uncharged compounds. Additional categories of nitrogenous excretory products include guanidino compounds, urates and hippurates, products of nucleic acid metabolism, polyamines, myoinositol, phenols, benzoates, and indoles. It is thus evident that the serum concentrations of urea and creatinine should be viewed as being readily measured, but incomplete, surrogate markers for these compounds, and monitoring the levels of urea and creatinine in the patient with impaired kidney function represents a vast oversimplification of the uremic state. The uremic syndrome and the disease state associated with advanced renal impairment involve more than renal excretory failure. A host of metabolic and endocrine functions normally performed by the kidneys is also impaired or suppressed, and this results in anemia, malnutrition,


InternalMed_Harrison

InternalMed_Harrison. involve more than renal excretory failure. A host of metabolic and endocrine functions normally performed by the kidneys is also impaired or suppressed, and this results in anemia, malnutrition, and abnormal metabolism of carbohydrates, fats, and proteins. Furthermore, plasma levels of many hormones, including PTH, FGF23, insulin, glucagon, steroid hormones including vitamin D and sex hormones, and prolactin, change with CKD as a result of reduced excretion, decreased degradation, or abnormal regulation. Finally, CKD is associated with worsening systemic inflammation. Elevated levels of C-reactive protein are detected along with other acute-phase reactants, whereas levels of so-called negative acute-phase reactants, such as albumin and fetuin, decline with progressive reduction in GFR. Thus, the inflammation associated with CKD is important in the malnutrition-inflammation-atherosclerosis/calcification syndrome, which contributes in turn to the acceleration of vascular disease and


InternalMed_Harrison

InternalMed_Harrison. Thus, the inflammation associated with CKD is important in the malnutrition-inflammation-atherosclerosis/calcification syndrome, which contributes in turn to the acceleration of vascular disease and comorbidity associated with advanced kidney disease. In summary, the pathophysiology of the uremic syndrome can be divided into manifestations in three spheres of dysfunction: (1) those consequent to the accumulation of toxins that normally undergo renal excretion, including products of protein metabolism; (2) those consequent to the loss of other kidney functions, such as fluid and electrolyte homeostasis and hormone regulation; and (3) progressive systemic inflammation and its vascular and nutritional consequences.


InternalMed_Harrison

InternalMed_Harrison. Uremia leads to disturbances in the function of virtually every organ system. Chronic dialysis can reduce the incidence and severity of many of these disturbances, so that the overt and florid manifestations of uremia have largely disappeared in the modern health setting. However, even optimal dialysis therapy is not completely effective as renal replacement therapy, because some disturbances resulting from impaired kidney function fail to respond to dialysis.


InternalMed_Harrison

InternalMed_Harrison. FLuID, ELECTROLYTE, AND ACID-BASE DISORDERS Sodium and Water Homeostasis In most patients with stable CKD, the total-body content of sodium and water is modestly increased, although this may not be apparent on clinical examination. With normal renal function, the tubular reabsorption of filtered sodium and water is adjusted so that urinary excretion matches intake. Many forms of kidney disease (e.g., glomerulonephritis) disrupt this balance such that dietary intake of sodium exceeds its urinary excretion, leading to sodium retention and attendant extracellular fluid volume (ECFV) expansion. This expansion may contribute to hypertension, which itself can accelerate the nephron injury. As long as water intake does not exceed the capacity for water clearance, the ECFV expansion will be isotonic and the patient will have a normal plasma sodium concentration (Chap. 333e). Hyponatremia is not commonly seen in CKD patients but, when present, often responds to water restriction. The patient


InternalMed_Harrison

InternalMed_Harrison. and the patient will have a normal plasma sodium concentration (Chap. 333e). Hyponatremia is not commonly seen in CKD patients but, when present, often responds to water restriction. The patient with ECFV expansion (peripheral edema, sometimes hypertension poorly responsive to therapy) should be counseled regarding salt restriction. Thiazide diuretics have limited utility in stages 3–5 CKD, such that administration of loop diuretics, including furosemide, bumetanide, or torsemide, may also be needed. Resistance to loop diuretics in CKD often mandates use of higher doses than those used in patients with more normal kidney function. The combination of loop diuretics with metolazone, which inhibits the sodium chloride co-transporter of the distal convoluted tubule, can promote renal salt excretion. Diuretic resistance with intractable edema and hypertension in advanced CKD may serve as an indication to initiate dialysis.


InternalMed_Harrison

InternalMed_Harrison. In addition to problems with salt and water excretion, some patients with CKD may instead have impaired renal conservation of sodium and water. When an extrarenal cause for fluid loss, such as gastrointestinal (GI) loss, is present, these patients may be prone to ECFV depletion because of the inability of the failing kidney to reclaim filtered sodium adequately. Furthermore, depletion of ECFV, whether due to GI losses or overzealous diuretic therapy, can further compromise kidney function through underperfusion, or a “prerenal” basis, leading to acute-on-chronic kidney failure. In this setting, cautious volume repletion with normal saline may return the ECFV to normal and restore renal function to baseline without having to intervene with dialysis.


InternalMed_Harrison

InternalMed_Harrison. Potassium Homeostasis In CKD, the decline in GFR is not necessarily accompanied by a parallel decline in urinary potassium excretion, which is predominantly mediated by aldosterone-dependent secretion in the distal nephron. Another defense against potassium retention in these patients is augmented potassium excretion in the GI tract. Notwithstanding these two homeostatic responses, hyperkalemia may be precipitated in certain settings. These include increased dietary potassium intake, protein catabolism, hemolysis, hemorrhage, transfusion of stored red blood cells, and metabolic acidosis. In addition, a host of medications can inhibit renal potassium excretion and lead to hyperkalemia. The most important medications in this respect include the RAS inhibitors and spironolactone and other potassium-sparing diuretics such as amiloride, eplerenone, and triamterene.


InternalMed_Harrison

InternalMed_Harrison. Certain causes of CKD can be associated with earlier and more severe disruption of potassium-secretory mechanisms in the distal nephron, out of proportion to the decline in GFR. These include conditions associated with hyporeninemic hypoaldosteronism, such as diabetes, and renal diseases that preferentially affect the distal nephron, such as obstructive uropathy and sickle cell nephropathy. Hypokalemia is not common in CKD and usually reflects markedly reduced dietary potassium intake, especially in association with excessive diuretic therapy or concurrent GI losses. The use of potassium supplements and potassium-sparing diuretics may be risky in patients with impaired renal function, and should be constantly reevaluated as GFR declines.


InternalMed_Harrison

InternalMed_Harrison. Metabolic Acidosis Metabolic acidosis is a common disturbance in advanced CKD. The majority of patients can still acidify the urine, but they produce less ammonia and, therefore, cannot excrete the normal quantity of protons in combination with this urinary buffer. Hyperkalemia, if present, further depresses ammonia production. The combination of hyperkalemia and hyperchloremic metabolic acidosis is often present, even at earlier stages of CKD (stages 1–3), in patients with diabetic nephropathy or in those with predominant tubulointerstitial disease or obstructive uropathy; this is a non-anion-gap metabolic acidosis.


InternalMed_Harrison

InternalMed_Harrison. With worsening renal function, the total urinary net daily acid excretion is usually limited to 30–40 mmol, and the anions of retained organic acids can then lead to an anion-gap metabolic acidosis. Thus, the non-anion-gap metabolic acidosis that can be seen in earlier stages of CKD may be complicated by the addition of an anion-gap metabolic acidosis as CKD progresses. In most patients, the metabolic acidosis is mild; the pH is rarely <7.35 and can usually be corrected with oral sodium bicarbonate supplementation. Animal and human studies have suggested that even modest degrees of metabolic acidosis may be associated with the development of protein catabolism. Alkali supplementation may attenuate the catabolic state and possibly slow CKD progression and accordingly is recommended when the serum bicarbonate concentration falls below 20–23 mmol/L. The concomitant sodium load mandates careful attention to volume status and the need for diuretic agents.


InternalMed_Harrison

InternalMed_Harrison. treatMent Fluid, electrolyte, And Acid-BAse disorders


InternalMed_Harrison

InternalMed_Harrison. Dietary salt restriction and the use of loop diuretics, occasionally in combination with metolazone, may be needed to maintain euvolemia. In contrast, overzealous salt restriction or diuretic use can lead to ECFV depletion and precipitate a further decline in GFR. The rare patient with salt-losing nephropathy may require a sodium-rich diet or salt supplementation. Water restriction is indicated only if there is a problem with hyponatremia. Intractable ECFV expansion, despite dietary salt restriction and diuretic therapy, may be an indication to start renal replacement therapy. Hyperkalemia often responds to dietary restriction of potassium, the use of kaliuretic diuretics, and avoidance of both potassium supplements (including occult sources, such as dietary salt substitutes) and potassium-retaining medications (especially angiotensin-converting enzyme [ACE] inhibitors or angiotensin receptor blockers [ARBs]). Kaliuretic diuretics promote urinary potassium excretion, whereas


InternalMed_Harrison

InternalMed_Harrison. potassium-retaining medications (especially angiotensin-converting enzyme [ACE] inhibitors or angiotensin receptor blockers [ARBs]). Kaliuretic diuretics promote urinary potassium excretion, whereas potassium-binding resins, such as calcium resonium or sodium polystyrene, can promote potassium loss through the GI tract and may reduce the incidence of hyperkalemia. Intractable hyperkalemia is an indication (although uncommon) to consider institution of dialysis in a CKD patient. The renal tubular acidosis and subsequent anion-gap metabolic acidosis in progressive CKD will respond to alkali supplementation, typically with sodium bicarbonate. Recent studies suggest that this replacement should be considered when the serum bicarbonate concentration falls below 20–23 mmol/L to avoid the protein catabolic state seen with even mild degrees of metabolic acidosis and to slow the progression of CKD.


InternalMed_Harrison

InternalMed_Harrison. The principal complications of abnormalities of calcium and phosphate metabolism in CKD occur in the skeleton and the vascular bed, with occasional severe involvement of extraosseous soft tissues. It is likely that disorders of bone turnover and disorders of vascular and soft tissue calcification are related to each other (Fig. 335-3). Bone Manifestations of CKD The major disorders of bone disease can be classified into those associated with high bone turnover with increased PTH levels (including osteitis fibrosa cystica, the classic lesion of secondary hyperparathyroidism) and low bone turnover with low or normal PTH levels (adynamic bone disease and osteomalacia).


InternalMed_Harrison

InternalMed_Harrison. The pathophysiology of secondary hyperparathyroidism and the consequent high-turnover bone disease is related to abnormal mineral metabolism through the following events: (1) declining GFR leads to reduced excretion of phosphate and, thus, phosphate retention; (2) the retained phosphate stimulates increased synthesis of both FGF-23 by osteocytes and PTH and stimulates growth of parathyroid gland mass; and (3) decreased levels of ionized calcium, resulting from suppression of calcitriol production by FGF-23 and by the failing kidney, as well as phosphate retention, also stimulate PTH production. Low calcitriol levels contribute to hyperparathyroidism, both by leading to hypocalcemia and also by a direct effect on PTH gene transcription. These changes start to occur when the GFR falls below 60 mL/min.


InternalMed_Harrison

InternalMed_Harrison. FGF-23 is part of a family of phosphatonins that promotes renal phosphate excretion. Recent studies have shown that levels of this hormone, secreted by osteocytes, increase early in the course of CKD, even before phosphate retention and hyperphosphatemia. FGF-23 may defend normal serum phosphorus in at least three ways: (1) increased renal phosphate excretion; (2) stimulation of PTH, which also increases renal phosphate excretion; and (3) suppression of the formation of 1,25(OH)2D3, leading to diminished phosphorus absorption from the GI tract. Interestingly, high levels of FGF-23 are also an independent risk factor for left ventricular hypertrophy and mortality in CKD, dialysis, and renal transplant patients. Moreover, elevated levels of FGF-23 may indicate the need for therapeutic intervention (e.g., phosphate restriction), even when serum phosphate levels are within the normal range.


InternalMed_Harrison

InternalMed_Harrison. FIGuRE 335-4 Tumoral calcinosis. This patient was on hemodialysis for many years and was nonadherent to dietary phosphorus restric-tion or the use of phosphate binders. He was chronically severely hyperphosphatemic. He developed an enlarging painful mass on his arm that was extensively calcified. Hyperparathyroidism stimulates bone turnover and leads to osteitis fibrosa cystica. Bone histology shows abnormal osteoid, bone and bone marrow fibrosis, and in advanced stages, the formation of bone cysts, sometimes with hemorrhagic elements so that they appear brown in color, hence the term brown tumor. Clinical manifestations of severe hyperparathyroidism include bone pain and fragility, brown tumors, compression syndromes, and erythropoietin resistance in part related to the bone marrow fibrosis. Furthermore, PTH itself is considered a uremic toxin, and high levels are associated with muscle weakness, fibrosis of cardiac muscle, and nonspecific constitutional symptoms.


InternalMed_Harrison

InternalMed_Harrison. Low-turnover bone disease can be grouped into two categories— adynamic bone disease and osteomalacia. Adynamic bone disease is increasing in prevalence, especially among diabetics and the elderly. It is characterized by reduced bone volume and mineralization and may result from excessive suppression of PTH production, chronic inflammation, or both. Suppression of PTH can result from the use of vitamin D preparations or from excessive calcium exposure in the form of calcium-containing phosphate binders or high-calcium dialysis solutions. Complications of adynamic bone disease include an increased incidence of fracture and bone pain and an association with increased vascular and cardiac calcification. Occasionally the calcium will precipitate in the soft tissues into large concretions termed “tumoral calcinosis” (Fig. 335-4).


InternalMed_Harrison

InternalMed_Harrison. Calcium, Phosphorus, and the Cardiovascular System Recent epidemiologic evidence has shown a strong association between hyperphosphatemia and increased cardiovascular mortality rate in patients with stage 5 CKD and even in patients with earlier stages of CKD. Hyperphosphatemia and hypercalcemia are associated with increased vascular calcification, but it is unclear whether the excessive mortality rate is mediated by this mechanism. Studies using computed tomography (CT) and electron-beam CT scanning show that CKD patients have calcification of the media in coronary arteries and even heart valves that appear to be orders of magnitude greater than that in patients without renal disease. The magnitude of the calcification is proportional to age and hyperphosphatemia and is also associated with low PTH levels and low bone turnover. It is possible that in patients with advanced kidney disease, ingested calcium cannot be deposited in bones with low turnover and, therefore, is deposited at


InternalMed_Harrison

InternalMed_Harrison. low PTH levels and low bone turnover. It is possible that in patients with advanced kidney disease, ingested calcium cannot be deposited in bones with low turnover and, therefore, is deposited at extraosseous sites, such as the vascular bed and soft tissues. It is interesting in this regard that there is also an association between osteoporosis and vascular calcification in the general population. Finally, hyperphosphatemia can induce a change in gene expression in vascular cells to an osteoblast-like profile, leading to vascular calcification and even ossification.


InternalMed_Harrison

InternalMed_Harrison. FIGuRE 335-5 Calciphylaxis. This peritoneal dialysis patient was on chronic warfarin therapy for atrial fibrillation. She noticed a small painful nodule on the abdomen that was followed by progressive skin necrosis and ulceration of the anterior abdominal wall. She was treated with hyperbaric oxygen, intravenous thiosulfate, and discon-tinuation of warfarin, with slow resolution of the ulceration.


InternalMed_Harrison

InternalMed_Harrison. Other Complications of Abnormal Mineral Metabolism Calciphylaxis (calcific uremic arteriolopathy) is a devastating condition seen almost exclusively in patients with advanced CKD. It is heralded by livedo reticularis and advances to patches of ischemic necrosis, especially on the legs, thighs, abdomen, and breasts (Fig. 335-5). Pathologically, there is evidence of vascular occlusion in association with extensive vascular and soft tissue calcification. It appears that this condition is increasing in incidence. Originally it was ascribed to severe abnormalities in calcium and phosphorus control in dialysis patients, usually associated with advanced hyperparathyroidism. However, more recently, calciphylaxis has been seen with increasing frequency in the absence of severe hyperparathyroidism. Other etiologies have been suggested, including the increased use of oral calcium as a phosphate binder. Warfarin is commonly used in hemodialysis patients, and one of the effects of warfarin therapy


InternalMed_Harrison

InternalMed_Harrison. Other etiologies have been suggested, including the increased use of oral calcium as a phosphate binder. Warfarin is commonly used in hemodialysis patients, and one of the effects of warfarin therapy is to decrease the vitamin K– dependent regeneration of matrix GLA protein. This latter protein is important in preventing vascular calcification. Thus, warfarin treatment is considered a risk factor for calciphylaxis, and if a patient develops this syndrome, this medication should be discontinued and replaced with alternative forms of anticoagulation.


InternalMed_Harrison

InternalMed_Harrison. Calcitriol exerts a direct suppressive effect on PTH secretion and also indirectly suppresses PTH secretion by raising the concentration of ionized calcium. However, calcitriol therapy may result in hypercalcemia and/or hyperphosphatemia through increased GI absorption of these minerals. Certain analogues of calcitriol are available (e.g., paricalcitol) that suppress PTH secretion with less attendant hypercalcemia. Recognition of the role of the extracellular calcium-sensing receptor has led to the development of calcimimetic agents that enhance the sensitivity of the parathyroid cell to the suppressive effect of calcium. This class of drug, which includes cinacalcet, produces a dose-dependent reduction in PTH and plasma calcium concentration in some patients.


InternalMed_Harrison

InternalMed_Harrison. Current National Kidney Foundation Kidney Disease Outcomes Quality Initiative guidelines recommend a target PTH level between 150 and 300 pg/mL, recognizing that very low PTH levels are associated with adynamic bone disease and possible consequences of fracture and ectopic calcification. Cardiovascular disease is the leading cause of morbidity and mortality in patients at every stage of CKD. The incremental risk of cardiovascular disease in those with CKD compared to the ageand sex-matched general population ranges from 10-to 200-fold, depending on the stage of CKD. Between 30 and 45% of patients reaching stage 5 CKD already have advanced cardiovascular complications. As a result, most patients with CKD succumb to cardiovascular disease (Fig. 335-6) before ever reaching stage 5 CKD. Thus, the focus of patient care in earlier CKD stages should be directed to prevention of cardiovascular complications.


InternalMed_Harrison

InternalMed_Harrison. Ischemic Vascular Disease The presence of any stage of CKD is a major risk factor for ischemic cardiovascular disease, including occlusive coronary, cerebrovascular, and peripheral vascular disease. The increased prevalence of vascular disease in CKD patients derives from both traditional (“classic”) and nontraditional (CKD-related) risk factors. Traditional risk factors include hypertension, hypervolemia, dyslipidemia, sympathetic overactivity, and hyperhomocysteinemia. The CKD-related risk factors comprise anemia, hyperphosphatemia, hyperparathyroidism, increased FGF-23, sleep apnea, and generalized inflammation. The inflammatory state associated with a reduction in kidney function is reflected in increased circulating acute-phase reactants, such as inflammatory cytokines and C-reactive protein, with a corresponding fall in the “negative acute-phase reactants,” such as serum albumin and fetuin. The inflammatory state appears to accelerate vascular occlusive disease, and low levels


InternalMed_Harrison

InternalMed_Harrison. protein, with a corresponding fall in the “negative acute-phase reactants,” such as serum albumin and fetuin. The inflammatory state appears to accelerate vascular occlusive disease, and low levels of fetuin may permit more rapid vascular calcification, especially in the face of hyperphosphatemia. Other abnormalities seen in CKD may augment


InternalMed_Harrison

InternalMed_Harrison. The optimal management of secondary hyperparathyroidism and osteitis fibrosa is prevention. Once the parathyroid gland mass is very large, it is difficult to control the disease. Careful attention should be paid to the plasma phosphate concentration in CKD patients, who should be counseled on a low-phosphate diet as well as the appropriate use of phosphate-binding agents. These Medicare Cohort, 1998–99, % are agents that are taken with meals and complex the dietary phos-0 phate to limit its GI absorption. Examples of phosphate binders are calcium acetate and calcium carbonate. A major side effect of calcium-based phosphate binders is calcium accumulation and hypercalcemia, especially in patients with low-turnover bone disease.


InternalMed_Harrison

InternalMed_Harrison. Sevelamer and lanthanum are non-calcium-containing polymers FIGuRE 335-6 U.S. Renal Data System showing increased likelihood that also function as phosphate binders; they do not predispose of dying rather than starting dialysis or reaching stage 5 chronic kidney CKD patients to hypercalcemia and may attenuate calcium deposi-disease (CKD).


InternalMed_Harrison

InternalMed_Harrison. 1 , Death; 2 , ESRD; 3 , event-free. DM; diabetes mellitus. tion in the vascular bed. (Adapted from RN Foley et al: J Am Soc Nephrol 16:489-495, 2005.) myocardial ischemia, including left ventricular hypertrophy and microvascular disease. In addition, hemodialysis, with its attendant episodes of hypotension and hypovolemia, may further aggravate coronary ischemia and repeatedly stun the myocardium. Interestingly, however, the largest increment in cardiovascular mortality rate in dialysis patients is not necessarily directly associated with documented acute myocardial infarction but, instead, presents with congestive heart failure and all of its manifestations and sudden death.


InternalMed_Harrison

InternalMed_Harrison. Cardiac troponin levels are frequently elevated in CKD without evidence of acute ischemia. The elevation complicates the diagnosis of acute myocardial infarction in this population. Serial measurements may be needed, and if the level is unchanged, it is possible that there is no acute myocardial ischemia. Therefore, the trend in levels over the hours after presentation may be more informative than a single, elevated level. Interestingly, consistently elevated levels are an independent prognostic factor for adverse cardiovascular events in this population.


InternalMed_Harrison

InternalMed_Harrison. Heart Failure Abnormal cardiac function secondary to myocardial ischemia, left ventricular hypertrophy, and frank cardiomyopathy, in combination with the salt and water retention that can be seen with CKD, often results in heart failure or even pulmonary edema. Heart failure can be a consequence of diastolic or systolic dysfunction, or both. A form of “low-pressure” pulmonary edema can also occur in advanced CKD, manifesting as shortness of breath and a “bat wing” distribution of alveolar edema fluid on the chest x-ray. This finding can occur even in the absence of ECFV overload and is associated with normal or mildly elevated pulmonary capillary wedge pressure. This process has been ascribed to increased permeability of alveolar capillary membranes as a manifestation of the uremic state, and it responds to dialysis. Other CKD-related risk factors, including anemia and sleep apnea, may contribute to the risk of heart failure.


InternalMed_Harrison

InternalMed_Harrison. Hypertension and Left Ventricular Hypertrophy Hypertension is one of the most common complications of CKD. It usually develops early during the course of CKD and is associated with adverse outcomes, including the development of ventricular hypertrophy and a more rapid loss of renal function. Many studies have shown a relationship between the level of blood pressure and the rate of progression of diabetic and nondiabetic kidney disease. Left ventricular hypertrophy and dilated cardiomyopathy are among the strongest risk factors for cardiovascular morbidity and mortality in patients with CKD and are thought to be related primarily, but not exclusively, to prolonged hypertension and ECFV overload. In addition, anemia and the placement of an arteriovenous fistula for hemodialysis can generate a high cardiac output state and consequent heart failure.


InternalMed_Harrison

InternalMed_Harrison. The absence of hypertension may signify poor left ventricular function. Indeed, in epidemiologic studies of dialysis patients, low blood pressure actually carries a worse prognosis than does high blood pressure. This mechanism, in part, accounts for the “reverse causation” seen in dialysis patients, wherein the presence of traditional risk factors, such as hypertension, hyperlipidemia, and obesity, appear to portend a better prognosis. Importantly, these observations derive from cross-sectional studies of late-stage CKD patients and should not be interpreted to discourage appropriate management of these risk factors in CKD patients, especially at early stages. In contrast to the general population, it is possible that in late-stage CKD, low blood pressure, reduced body mass index, and hypolipidemia indicate the presence of an advanced malnutrition-inflammation state, with poor prognosis.


InternalMed_Harrison

InternalMed_Harrison. The use of exogenous erythropoiesis-stimulating agents can increase blood pressure and the requirement for antihypertensive drugs. Chronic ECFV overload is also a contributor to hypertension, and improvement in blood pressure can often be seen with the use of dietary sodium restriction, diuretics, and fluid removal with dialysis. Nevertheless, because of activation of the RAS and other disturbances in the balance of vasoconstrictors and vasodilators, some patients remain hypertensive despite careful attention to ECFV status.


InternalMed_Harrison

InternalMed_Harrison. The overarching goal of hypertension therapy in CKD is to prevent the extrarenal complications of high blood pressure, such as cardiovascular disease and stroke. Although a clear-cut generalizable benefit in slowing progression of CKD remains as yet unproven, the benefit for cardiac and neurologic health is compelling. In all patients with CKD, blood pressure should be controlled to levels recommended by national guideline panels. In CKD patients with diabetes or proteinuria >1 g per 24 h, blood pressure should be reduced to 130/80 mmHg, if achievable without prohibitive adverse effects. Salt restriction should be the first line of therapy. When volume management alone is not sufficient, the choice of antihypertensive agent is similar to that in the general population. ACE inhibitors and ARBs appear to slow the rate of decline of kidney function in a manner that extends beyond reduction of systemic arterial pressure and that involves correction of the intraglomerular hyperfiltration


InternalMed_Harrison

InternalMed_Harrison. ARBs appear to slow the rate of decline of kidney function in a manner that extends beyond reduction of systemic arterial pressure and that involves correction of the intraglomerular hyperfiltration and hypertension involved in progression of CKD described above. Occasionally, introduction of ACE inhibitors and ARBs can actually precipitate an episode of acute kidney injury, especially when used in combination in patients with ischemic renovascular disease. The use of ACE inhibitors and ARBs may also be complicated by the development of hyperkalemia. Often the concomitant use of a kaliuretic diuretic, such as metolazone, can improve potassium excretion in addition to improving blood pressure control. Potassium-sparing diuretics should be used with caution or avoided altogether in most patients.


InternalMed_Harrison

InternalMed_Harrison. There are many strategies available to treat the traditional and nontraditional risk factors in CKD patients. Although these have proved effective in the general population, there is little evidence for their benefit in patients with advanced CKD, especially those on dialysis. Certainly hypertension, elevated serum levels of homocysteine, and dyslipidemia promote atherosclerotic disease and are treatable complications of CKD. Renal disease complicated by nephrotic syndrome is associated with a very atherogenic lipid profile and hypercoagulability, which increases the risk of occlusive vascular disease. Because diabetes mellitus and hypertension are the two most frequent causes of advanced CKD, it is not surprising that cardiovascular disease is the most frequent cause of death in dialysis patients. The role of “inflammation” may be quantitatively more important in patients with kidney disease, and the treatment of more traditional risk factors may result in only modest success.


InternalMed_Harrison

InternalMed_Harrison. patients. The role of “inflammation” may be quantitatively more important in patients with kidney disease, and the treatment of more traditional risk factors may result in only modest success. However, modulation of traditional risk factors may be the only weapon in the therapeutic armamentarium for these patients until the nature of inflammation in CKD and its treatment are better understood.


InternalMed_Harrison

InternalMed_Harrison. Lifestyle changes, including regular exercise, should be advocated. Hyperlipidemia in patients with CKD should be managed according to national guidelines. If dietary measures are not sufficient, preferred lipid-lowering medications, such as statins, should be used. Again, the use of these agents has not been of proven benefit for patients with advanced CKD. Pericardial Disease Chest pain with respiratory accentuation, accompanied by a friction rub, is diagnostic of pericarditis. Classic electrocardiographic abnormalities include PR-interval depression and diffuse ST-segment elevation. Pericarditis can be accompanied by pericardial effusion that is seen on echocardiography and can rarely lead to tamponade. However, the pericardial effusion can be asymptomatic, and pericarditis can be seen without significant effusion.


InternalMed_Harrison

InternalMed_Harrison. Pericarditis is observed in advanced uremia, and with the advent of timely initiation of dialysis, is not as common as it once was. It is now more often observed in underdialyzed, nonadherent patients than in those starting dialysis. intolerance, the patient may have to undergo IV iron infusion. For patients on hemodialysis, IV iron can be administered during dialy


InternalMed_Harrison

InternalMed_Harrison. intolerance, the patient may have to undergo IV iron infusion. For patients on hemodialysis, IV iron can be administered during dialy Uremic pericarditis is an absolute indication for the urgent initiation of dialysis or for intensification of the dialysis prescription in those already receiving dialysis. Because of the propensity to hemorrhage in pericardial fluid, hemodialysis should be performed without heparin. A pericardial drainage procedure should be considered in patients with recurrent pericardial effusion, especially with echocardiographic signs of impending tamponade. Nonuremic causes of pericarditis and effusion include viral, malignant, tuberculous, and autoimmune etiologies. It may also be seen after myocardial infarction and as a complication of treatment with the antihypertensive drug minoxidil.


InternalMed_Harrison

InternalMed_Harrison. HEMATOLOGIC ABNORMALITIES Anemia A normocytic, normochromic anemia is observed as early as stage 3 CKD and is almost universal by stage 4. The primary cause in patients with CKD is insufficient production of erythropoietin (EPO) by the diseased kidneys. Additional factors are reviewed in Table 335-3.


InternalMed_Harrison

InternalMed_Harrison. The anemia of CKD is associated with a number of adverse pathophysiologic consequences, including decreased tissue oxygen delivery and utilization, increased cardiac output, ventricular dilation, and ventricular hypertrophy. Clinical manifestations include fatigue and diminished exercise tolerance, angina, heart failure, decreased cognition and mental acuity, and impaired host defense against infection. In addition, anemia may play a role in growth restriction in children with CKD. Although many studies in CKD patients have found that anemia and resistance to exogenous erythropoietic-stimulating agents (ESA) are associated with a poor prognosis, the relative contribution to a poor outcome of the low hematocrit itself, versus inflammation as a cause of the anemia and ESA resistance, remains unclear.


InternalMed_Harrison

InternalMed_Harrison. The availability of recombinant human ESA has been one of the most significant advances in the care of renal patients since the introduction of dialysis and renal transplantation. The routine use of these recombinant hormones has obviated the need for regular blood transfusions in severely anemic CKD patients, thus dramatically reducing the incidence of transfusion-associated infections and iron overload. Frequent blood transfusions in dialysis patients also lead to the development of alloantibodies that can sensitize the patient to donor kidney antigens and make renal transplantation more problematic.


InternalMed_Harrison

InternalMed_Harrison. Adequate bone marrow iron stores should be available before treatment with ESA is initiated. Iron supplementation is usually essential to ensure an optimal response to ESA in patients with CKD because the demand for iron by the marrow frequently exceeds the amount of iron that is immediately available for erythropoiesis (measured by percent transferrin saturation), as well as the amount in iron stores (measured by serum ferritin). For the CKD patient not yet on dialysis or the patient treated with peritoneal dialysis, oral iron supplementation should be attempted. If there is GI


InternalMed_Harrison

InternalMed_Harrison. Relative deficiency of erythropoietin Diminished red blood cell survival Bleeding diathesis Iron deficiency Hyperparathyroidism/bone marrow fibrosis Chronic inflammation Folate or vitamin B12 deficiency Hemoglobinopathy Comorbid conditions: hypo-/hyperthyroidism, pregnancy, HIV-associated disease, autoimmune disease, immunosuppressive drugs sis, keeping in mind that iron therapy can increase the susceptibility to bacterial infections. In addition to iron, an adequate supply of other major substrates and cofactors for red cell production must be ensured, including vitamin B12 and folate. Anemia resistant to recommended doses of ESA in the face of adequate iron stores may be due to some combination of the following: acute or chronic inflammation, inadequate dialysis, severe hyperparathyroidism, chronic blood loss or hemolysis, chronic infection, or malignancy. Blood transfusions increase the risk of hepatitis, iron overload, and transplant sensitization; they should be avoided unless