Acute Renal Failure

Article Last Updated: Sep 21, 2007

AUTHOR AND EDITOR INFORMATION

Mahendra Agraharkar, MD, MBBS, FACP, President, Space City Associates of Nephrology; Medical Director, Acute Dialysis Unit and Chronic Home Dialysis Unit, Gambro Healthcare Reliant Dialysis Center
Mahendra Agraharkar is a member of the following medical societies: American College of Physicians, American Society of Nephrology, and National Kidney Foundation
Coauthor(s): Rajiv Gupta, MD, Assistant Professor, Department of Medicine, Texas A & M University Health Science Center; Consulting Staff, Veteran's Affairs Hospital, Temple, Texas; Aruna Agraharkar, MD FACP, Consulting Staff, Department of Gerontology, Space Center Clinic; Biruh T Workeneh, MD, Fellow in Nephrology, Stanford University School of Medicine
Editors: Laura L Mulloy, DO, FACP, Professor of Medicine, Chief, Section of Nephrology, Hypertension and Transplantation Medicine, Glover/Mealing Eminent Scholar Chair in Immunology, Medical College of Georgia; Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine; Eleanor Lederer, MD, Consulting Staff, Louisville VA Hospital; Professor of Medicine, Director of Nephrology Training Program, Kidney Disease Program, University of Louisville School of Medicine; Director, Metabolic Stone Clinic; Rebecca J Schmidt, DO, FACP, FASN, Clinical Associate Professor of Medicine, West Virginia School of Osteopathic Medicine; Professor of Medicine, Section Chief, Department of Medicine, Section of Nephrology, West Virginia University School of Medicine; Vecihi Batuman, MD, FACP, FASN, Chief, Medical Service, VA Medical Center, New Orleans, Professor of Medicine, Tulane University School of Medicine; Chief, Renal-Hypertension Section, Department of Medicine, Tulane University Medical Center, New Orleans Veterans Affairs Medical Center

INTRODUCTION

Background

Acute renal failure (ARF) or acute kidney injury (AKI), as it is now referred to in the literature, is defined as an abrupt or rapid decline in renal filtration function. This condition is usually marked by a rise in serum creatinine concentration or azotemia (a rise in blood urea nitrogen [BUN] concentration). However, immediately after a kidney injury, BUN or creatinine levels may be normal, and the only sign of a kidney injury may be decreased urine production. A rise in the creatinine level can result from medications (eg, cimetidine, trimethoprim) that inhibit the kidney’s tubular secretion. A rise in the BUN level can occur without renal injury, such as in GI or mucosal bleeding, steroid use, or protein loading, so a careful inventory must be taken before determining if a kidney injury is present.

Pathophysiology

AKI may occur in 3 clinical patterns, including the following: (1) as an adaptive response to severe volume depletion and hypotension, with structurally intact nephrons; (2) in response to cytotoxic, ischemic, or inflammatory insults to the kidney, with structural and functional damage; and (3) with obstruction to the passage of urine. Therefore, in general terms, AKI may be classified as prerenal, intrinsic, and postrenal. While these classifications are useful in establishing a differential diagnosis, many pathophysiologic features are shared among the different categories.

Patients who develop AKI can be oliguric or nonoliguric, have a rapid or slow rise in creatinine levels, and may have qualitative differences in urine solute concentrations and cellular content. The reason for this lack of a uniform clinical presentation is a reflection of the variable nature of the injury. Classifying AKI as oliguric or nonoliguric based on daily urine excretion has prognostic value. Oliguria is defined as a daily urine volume of less than 400 mL/d and has a worse prognosis, except in prerenal failure.  Anuria is defined as a urine output of less than 100 mL/d and, if abrupt in onset, is suggestive of bilateral obstruction or catastrophic injury to both kidneys.  Stratification of renal failure along these lines helps in decision-making (eg, timing of dialysis) and can be an important criterion for patient response to therapy.

Prerenal AKI

Prerenal AKI represents the most common form of kidney injury and often leads to intrinsic AKI if it is not promptly corrected. Volume loss from GI, renal, cutaneous (eg, burns), and internal or external hemorrhage can result in this syndrome. Prerenal AKI can also result from decreased renal perfusion in patients with heart failure or shock (eg, sepsis, anaphylaxis). Special classes of medications that can induce prerenal AKI in volume-depleted states are angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs), which are otherwise safely tolerated and beneficial in most patients with chronic kidney disease. Arteriolar vasoconstriction leading to prerenal AKI can occur in hypercalcemic states, with the use of radiocontrast agents, nonsteroidal anti-inflammatory drugs (NSAIDs), amphotereicin, calcineurin inhibitors, norepinephrine, and other pressor agents. The hepatorenal syndrome can also be considered a form of prerenal AKI because functional renal failure develops from diffuse vasoconstriction in vessels supplying the kidney.
Intrinsic AKI

Structural injury in the kidney is the hallmark of intrinsic AKI, and the most common form is acute tubular injury (ATN), either ischemic or cytotoxic.  Frank necrosis is not prominent in most human cases of ATN and tends to be patchy.  Less obvious injury includes loss of brush borders, flattening of the epithelium, detachment of cells, formation of intratubular casts, and dilatation of the lumen. Although these changes are observed predominantly in proximal tubules, injury to the distal nephron can also be demonstrated. The distal nephron may also be subjected to obstruction by desquamated cells and cellular debris. 
In contrast to necrosis, the principal site of apoptotic cell death is the distal nephron. During the initial phase of ischemic injury, loss of integrity of the actin cytoskeleton leads to flattening of the epithelium, with loss of the brush border, loss of focal cell contacts, and subsequent disengagement of the cell from the underlying substratum.

Many endogenous growth factors that participate in the process of regeneration have not been identified; however, administration of growth factors exogenously has been shown to ameliorate and hasten recovery from AKI.  Depletion of neutrophils and blockage of neutrophil adhesion reduce renal injury following ischemia, indicating that the inflammatory response is responsible, in part, for some features of ATN, especially in postischemic injury after transplant. 

Intrarenal vasoconstriction is the dominant mechanism for the reduced glomerular filtration rate (GFR) in patients with ATN. The mediators of this vasoconstriction are unknown, but tubular injury seems to be an important concomitant finding. Urine backflow and intratubular obstruction (from sloughed cells and debris) are causes of reduced net ultrafiltration. The importance of this mechanism is highlighted by the improvement in renal function that follows relief of such intratubular obstruction. In addition, when obstruction is prolonged, intrarenal vasoconstriction is prominent in part due to the tubuloglomerular feedback mechanism, which is thought to be mediated by adenosine and activated when there is proximal tubular damage and the macula densa is presented with increased chloride load.

Apart from the increase in basal renal vascular tone, the stressed renal microvasculature is more sensitive to potentially vasoconstrictive drugs and otherwise-tolerated changes in systemic blood pressure.  The vasculature of the injured kidney has an impaired vasodilatory response and loses its autoregulatory behavior. This latter phenomenon has important clinical relevance because the frequent reduction in systemic pressure during intermittent hemodialysis may provoke additional damage that can delay recovery from ATN. Often, injury results in atubular glomeruli, where the glomerular function is preserved, but the lack of tubular outflow precludes its function.

A physiologic hallmark of ATN is a failure to maximally dilute or concentrate urine (isosthenuria). This defect is not responsive to pharmacologic doses of vasopressin. The injured kidney fails to generate and maintain a high medullary solute gradient because the accumulation of solute in the medulla depends on normal distal nephron function. Failure to excrete concentrated urine, even in the presence of oliguria, is a helpful diagnostic clue to distinguish prerenal from intrinsic renal disease, in which urine osmolality is less than 300 mOsm/kg. In prerenal azotemia, urine osmolality is typically more than 500 mOsm/kg.
Glomerulonephritis can be a cause of AKI and usually falls into a class referred to as rapidly progressive glomerulonephritis (RPGN). The pathologic correlation of RPGN is the presence of glomerular crescents (glomerular injury) on biopsy; if more than 50% of glomeruli contain crescents, this usually results in a significant decline in renal function. Although comparatively rare, acute glomerulonephritides should be part of the diagnostic consideration in cases of AKI.
Postrenal AKI

Mechanical obstruction of the urinary collecting system, including the renal pelvis, ureters, bladder, or urethra, results in obstructive uropathy or postrenal AKI.

If the site of obstruction is unilateral, then a rise in the serum creatinine level may not be apparent due to contralateral renal function. Although the serum creatinine level may remain low with unilateral obstruction, a significant loss of GFR occurs, and patients with partial obstruction may develop progressive loss of GFR if the obstruction is not relieved. Causes of obstruction include stone disease; stricture; and intraluminal, extraluminal, or intramural tumors.

Bilateral obstruction is usually a result of prostate enlargement or tumors in men and urologic or gynecologic tumors in women.

Patients who develop anuria typically have obstruction at the level of the bladder or downstream to it.

Frequency

United States

Approximately 1% of patients admitted to hospitals have AKI at the time of admission, and the estimated incidence rate of AKI is 2-5% during hospitalization.  Approximately 95% of consultations with nephrologists are related to AKI.  Feest and colleagues calculated in their report that the appropriate nephrologist referral rate is approximately 70 cases per million population.¹

Mortality/Morbidity

The mortality rate estimates vary from 25-90%. The in-hospital mortality rate is 40-50%; in intensive care settings, the rate is 70-80%. Increments of 0.3 mg/dL in serum creatinine have important prognostic significance.

Race

No racial predilection is recognized.

 

CLINICAL

History

A detailed and accurate history is crucial to aid in diagnosing the type of AKI and in determining its subsequent treatment. A detailed history and a physical examination in combination with routine laboratory tests are useful in making a correct diagnosis (see Lab Studies).

• Distinguishing AKI from chronic renal failure is important, yet making the distinction can be difficult. A history of chronic symptoms of fatigue, weight loss, anorexia, nocturia, and pruritus all suggest chronic renal failure.
• Take note of the following findings during the physical examination:
• • Hypotension
  • Volume contraction
  • Congestive heart failure
  • Nephrotoxic drug ingestion
  • History of trauma or unaccustomed exertion
  • Blood loss or transfusions
  • Evidence of connective tissue disorders or autoimmune diseases
  • Exposure to toxic substances, such as ethyl alcohol or ethylene glycol
  • Exposure to mercury vapors, lead, cadmium, or other heavy metals, which can be encountered in welders and miners
• People with the following comorbid conditions are at a higher risk for developing AKI:
• • Hypertension
  • Congestive cardiac failure
  • Diabetes
  • Multiple myeloma
  • Chronic infection
  • Myeloproliferative disorder
• Urine output history can be useful. Oliguria generally favors AKI. Abrupt anuria suggests an acute obstruction, acute and severe glomerulonephritis, or an embolic event due to the renal artery occlusion. A gradually diminishing urine output may indicate a urethral stricture or bladder outlet obstruction due to prostate enlargement.
• Because of a decrease in functioning nephrons, even a trivial nephrotoxic insult may cause AKI to be superimposed on chronic renal insufficiency.

Physical

Obtaining a thorough physical examination is extremely important when collecting evidence about the etiology of AKI.

• Skin
• • Examination of the skin for petechiae, purpura, ecchymosis, and livedo reticularis provides clues to inflammatory and vascular causes of AK
  • Infectious diseases, thrombotic thrombocytopenic purpura (TTP), disseminated intravascular coagulation (DIC), and embolic phenomena can present with typical cutaneous changes.
• Eyes
• • Evidence of uveitis may indicate interstitial nephritis and necrotizing vasculitis.
  • Ocular palsy may indicate ethylene glycol poisoning or necrotizing vasculitis.
  • Findings suggestive of severe hypertension, atheroembolic disease, and endocarditis may be observed after a careful examination of the eyes.
• Cardiovascular system
• • The most important part of the physical examination is the assessment of cardiovascular and volume status.
  • The physical examination must include pulse rate and blood pressure recordings measured in both the supine position and the standing position; close inspection of the jugular venous pulse; careful examination of the heart, lungs, skin turgor, and mucous membranes; and assessment for the presence of peripheral edema.
  • Accurate daily records of fluid intake and urine output and daily measurements of patient weight are important.
  • Blood pressure recordings can be important diagnostic tools.
  • Hypovolemia leads to hypotension; however, hypotension may not necessarily indicate hypovolemia.
  • Severe congestive cardiac failure (CHF) may also cause hypotension. Although patients with CHF may have low blood pressure, volume expansion is present and effective renal perfusion is poor, which can result in AKI.
  • Severe hypertension with renal failure suggests renovascular disease, glomerulonephritis, vasculitis, or atheroembolic disease.
• Abdomen
• • Abdominal examination findings can be useful to help detect obstruction at the bladder outlet as the cause of renal failure, which may be due to cancer or an enlarged prostate.
  • The presence of an epigastric bruit suggests renal vascular hypertension.

Causes

The causes of AKI traditionally are divided into 3 main categories: prerenal, intrinsic, and postrenal. The 3 main categories are summarized below.

• Prerenal AKI
• • Volume depletion
  • • Renal losses (diuretics, polyuria)
    • GI losses (vomiting, diarrhea)
    • Cutaneous losses (burns, Stevens-Johnson syndrome)
    • Hemorrhage
    • Pancreatitis
  • Decreased cardiac output
  • • Heart failure
    • Pulmonary embolus
    • Acute myocardial infarction
    • Severe valvular disease
    • Abdominal compartment syndrome (tense ascites)
  • Systemic vasodilation
  • • Sepsis
    • Anaphylaxis
    • Anesthetics
    • Drug overdose
  • Afferent arteriolar vasoconstriction
  • • Hypercalcemia
    • Drugs (NSAIDs, amphotericin B, calcineurin inhibitors, norepinephrine, radiocontrast agents)
    • Hepatorenal syndrome
  • Efferent arteriolar vasodilation – ACEI or ARB
• Intrinsic AKI
• • Vascular (large and small vessel)
  • • Renal artery obstruction (thrombosis, emboli, dissection, vasculitis)
    • Renal vein obstruction (thrombosis)
    • Microangiopathy (TTP, hemolytic uremic syndrome [HUS], DIC, preeclampsia)
    • Malignant hypertension
    • Scleroderma renal crisis
    • Transplant rejection
    • Atheroembolic disease
  • Glomerular
  • • Anti–glomerular basement membrane (GBM) disease (Goodpasture syndrome)
    • Anti–neutrophil cytoplasmic antibody-associated glomerulonephritis (ANCA-associated GN) (Wegener granulomatosis, Churg-Strauss syndrome, microscopic polyangiitis)
    • Immune complex GN (lupus, postinfectious, cryoglobulinemia, primary membranoproliferative glomerulonephritis)
  • Tubular
  • • Ischemi
    • Cytotoxic
    • • Heme pigment (rhabdomyolysis, intravascular hemolysis)
      • Crystals (tumor lysis syndrome, seizures, ethylene glycol poisoning, megadose vitamin C, acyclovir, indinavir, methotrexate)
      • Drugs (aminoglycosides, lithium, amphotericin B, pentamidine, cisplatin, ifosfamide, radiocontrast agents)
  • Interstitial
  • • Drugs (penicillins, cephalosporins, NSAIDs, proton-pump inhibitors, allopurinol, rifampin, indinavir, mesalamine, sulfonamides)
    • Infection (pyelonephritis, viral nephritides)
    • Systemic disease (Sjogren syndrome, sarcoid, lupus, lymphoma, leukemia, tubulonephritis, uveitis)
• Postrenal AKI
• • Ureteric obstruction (stone disease, tumor, fibrosis, ligation during pelvic surgery)
  • Bladder neck obstruction (benign prostatic hypertrophy [BPH], cancer of the prostate [CA prostate or prostatic CA], neurogenic bladder, tricyclic antidepressants, ganglion blockers, bladder tumor, stone disease, hemorrhage/clot)
  • Urethral obstruction (strictures, tumor, phimosis)

 

DIFFERENTIALS

Acute Tubular Necrosis

Azotemia
Chronic Renal Failure

Other Problems to be Considered

Obstructive uropathy
GI bleeding
Protein overloading
Steroid use

WORKUP

Lab Studies

• Several laboratory tests are useful for assessing the etiology of AKI, and the findings can aid in proper management. These tests include complete blood cell count, serum biochemistries, urine analysis with microscopy, and urine electrolytes.
• Blood urea nitrogen and serum creatinine
• • Although increased levels of BUN and creatinine are the hallmarks of renal failure, the rate of rise is dependent on the degree of renal insult as well as protein intake with respect to BUN.
  • The ratio of BUN to creatinine is an important finding because the ratio can exceed 20:1 in conditions in which enhanced reabsorption of urea is favored (eg, in volume contraction) and suggests prerenal AKI.
  • BUN may be elevated in patients with GI or mucosal bleeding, steroid treatment, or protein loading. 
  • Assuming no renal function, the rise in BUN over 24 hours can be roughly predicted using the following formula: 24-hour protein intake in milligrams X 0.16 divided by total body water in mg/dL added to the BUN value.
  • Assuming no renal function, the rise in creatinine can be predicted using the following formulas:
  • • For males: weight in kilograms X [28 – 0.2(age)] divided by total body water in mg/dL added to the creatinine value
    • For females: weight in kilograms X [23.8 – 0.17(age)] divided by total body water added to the creatinine value
  • As a general rule, if serum creatinine increases to more than 1.5 mg/dL/d, rhabdomyolysis must be ruled out.
• CBC, peripheral smear, and serology
• • These tests may be useful, and the peripheral smear results may show schistocytes in conditions such as HUS or TTP.
  • A finding of increased rouleaux formation suggests multiple myeloma, and the workup should be directed toward immunoelectrophoresis of serum and urine.
  • The presence of myoglobin or free hemoglobin, increased serum uric acid level, and other related findings may help further define the etiology of AKI.
  • Serologic tests for antinuclear antibody (ANA), ANCA, anti-GBM antibody, hepatitis, and antistreptolysin (ASO) and complement levels may help include and exclude glomerular disease. Although serologic tests can be informative, the costs can be prohibitive if not ordered judiciously.
• Urinalysis
• • Findings of granular muddy-brown casts are suggestive of tubular necrosis. The presence of tubular cells or tubular cell casts also supports the diagnosis of ATN.  Often, oxalate crystals are observed in cases of ATN.
  • Reddish brown or cola-colored urine suggests the presence of myoglobin or hemoglobin, especially in the setting of a positive dipstick for heme and no RBCs in the microscopic examination.
  • Dipstick assay findings may show the presence of significant proteinuria, which would suggest glomerular or interstitial disease.
  • The presence of RBCs in the urine is always pathologic. Eumorphic RBCs suggest bleeding along the collecting system. Dysmorphic RBCs or RBC casts indicate glomerular inflammation, suggesting glomerulonephritis is present. 
  • The presence of WBCs or WBC casts suggests pyelonephritis or acute interstitial nephritis. The presence of urine eosinophils is helpful in establishing a diagnosis but is not necessary for allergic interstitial nephritis to be present.
  • The presence of eosinophils, as visualized with Wright stain or Hansel stain, suggests interstitial nephritis but can be seen in urinary tract infections, glomerulonephritis, and atheroembolic disease.   
  • The presence of uric acid crystals may represent ATN associated with uric acid nephropathy.
  • Calcium oxalate crystals are usually present in cases of ethylene glycol poisoning.
• Urine electrolytes
• • Urine electrolyte findings also can serve as valuable indicators of functioning renal tubules.
  • The fractional excretion of sodium (FENa) is the commonly used indicator. However, the interpretation of results from patients in nonoliguric states, those with glomerulonephritis, and those receiving or ingesting diuretics can lead to an erroneous diagnosis. FENa can be a valuable test for helping to detect extreme renal avidity for sodium in conditions such as hepatorenal syndrome. The formula for calculating the FENa is as follows:

FENa = (U_Na/P_Na) / (U_Cr/P_Cr) X 100

• Calculating the FENa is useful in AKI only in the presence of oliguria.
• In patients with prerenal azotemia, the FENa is usually less than 1%. In ATN, the FENa is greater than 1%. Exceptions to this rule are ATN caused by radiocontrast nephropathy, severe burns, acute glomerulonephritis, and rhabdomyolysis.
• In the presence of liver disease, FENa can be less than 1% in the presence of ATN. On the other hand, because administration of diuretics may cause the FENa to be greater than 1%, these findings cannot be used as the sole indicators in AKI.
• In patients who are receiving diuretics, a fractional excretion of urea (FEUrea) can be obtained since urea transport is not affected by diuretics. The formula for calculating the FEUrea is as follows:

FEUrea = (U_urea/P_urea) / (U_Cr/P_Cr) X 100

• FEUrea of less than 35% is suggestive of a prerenal state.

Imaging Studies

• In some cases, renal imaging is useful, especially if the cause of renal failure is secondary to obstruction.
• Ultrasound
• • Renal ultrasonography is useful for evaluating existing renal disease and obstruction of the urinary collecting system.  The degree of hydronephrosis does not necessarily correlate with the degree of obstruction.  Mild hydronephrosis may be observed with complete obstruction if found early. 
  • Obtaining images of the kidneys can be technically difficult in patients who are obese or in those with abdominal distension due to ascites, gas, or retroperitoneal fluid collection.
  • Ultrasound scans or other imaging studies showing small kidneys suggest chronic renal failure.
• Doppler scans
• • Doppler scans are useful for detecting the presence and nature of renal blood flow.
  • Because renal blood flow is reduced in prerenal or intrarenal AKI, test findings are of little use in the diagnosis of AKI.
  • Doppler scans can be quite useful in the diagnosis of thromboembolic or renovascular disease.
  • Increased resistive indices can be observed in patients with hepatorenal syndrome.
• Nuclear scans
• • Radionuclide imaging with a technetium Tc 99m diethylenetriamine pentaacetic acid (DTPA), 99m Tc-DTPA iodine I 131–hippuran scan can be used to assess renal blood flow and tubular functions.       
  • Because of a marked delay in tubular excretion of radionuclide in both prerenal disease and intrarenal disease, the value of these scans is limited.
• Aortorenal angiography can be helpful in establishing the diagnosis of renal vascular diseases, including renal artery stenosis, renal atheroembolic disease, atherosclerosis with aortorenal occlusion, and in certain cases of necrotizing vasculitis (eg, polyarteritis nodosa).

Procedures

• Renal biopsy
• • A renal biopsy can be useful in establishing the diagnosis of intrarenal causes of AKI and can be justified if it will change management (eg, initiation of immunosuppressive medications). A renal biopsy may also be indicated when renal function does not return for a prolonged period and a prognosis is required to develop long-term management.
  • In as many as 40% of cases, renal biopsy results reveal an unexpected diagnosis.
  • Acute cellular or humoral rejection in a renal transplant can be definitively diagnosed only by performing a renal biopsy.

TREATMENT

Medical Care

The mortality rate for patients in the intensive care unit (ICU) is higher in those who have AKI, especially when AKI is severe enough to require dialysis treatment. In addition, evidence suggests that the relative risk of death is 4.9 in patients in the ICU who have renal failure that is not severe enough to require dialysis. This reflects that the high mortality rate in patients with AKI who require dialysis may not be related to the dialysis procedure or accompanying comorbidities and that AKI alone may be an independent indicator of mortality.

• Aggressive treatment should begin at the earliest indication of renal dysfunction. A large proportion of the renal mass is damaged before any biochemical evidence of renal dysfunction is appreciated because the relationship between the GFR and the serum creatinine level is exponential, not linear. The rise of serum creatinine may not be evident before 50% of the GFR is lost.
• At this point, recognizing the presence of AKI and promptly initiating therapy aimed at minimizing the damage to the remaining functional renal mass are important considerations. This may also aid in reversing the renal damage that has already occurred. Reversing renal damage can be accomplished only by identifying the underlying cause and directing the appropriate therapy.
• Maintenance of volume homeostasis and correction of biochemical abnormalities remain the primary goals of treatment. Furosemide can be used to correct volume overload when the patients are still responsive to it. Furosemide plays no role in converting an oliguric AKI to a nonoliguric AKI or to increase urine output when a patient is not hypervolemic. However, the response to furosemide can be taken as a good prognostic sign. At this stage, the kidneys remain vulnerable to the toxic effects of various chemicals. All nephrotoxic agents (eg, radiocontrast agents, antibiotics with nephrotoxic potential, heavy metal preparations, cancer chemotherapeutic agents, NSAIDs) are either avoided or used with extreme caution. Similarly, all medications cleared by renal excretion should be avoided or their doses should be adjusted appropriately.
• Correcting acidosis with bicarbonate administration is important. It cannot be overstated that the current treatment of AKI is mainly supportive in nature and no therapeutic modalities to date have shown efficacy in treating the condition. Therapeutic agents, such as dopamine, fenoldopam, and mannitol, are not indicated in the management of AKI and may be harmful for the patient.
• Hyperkalemia, which can be life-threatening, should be treated by decreasing the intake of potassium, delaying the absorption of potassium, exchanging potassium across the gut lumen using potassium-binding resins, controlling intracellular shifts, and instituting dialysis, as outlined in Hyperkalemia.
• Correcting hematologic abnormalities (eg, anemia, platelet dysfunction) warrants appropriate measures, including transfusions and administration of desmopressin or estrogens.

Diet

• Dietary modulation is an important facet of the treatment of AKI. Diet and fluid restriction become crucial in the management of oliguric renal failure, wherein the kidneys do not adequately excrete either toxins or fluids.
• Because potassium and phosphorous are not excreted optimally in patients with AKI, blood levels of these electrolytes tend to be high. Frequent measurements are mandatory to achieve acceptable blood levels by modification of the diet or by intravenous supplementation.
• In the polyuric phase of AKI, potassium and phosphorous may be depleted and patients require dietary supplementation and intravenous fluids.
• Calculation of the nitrogen balance can be challenging, especially in the presence of volume contraction, hypercatabolic states, gastrointestinal bleeding, and diarrheal disease.

MEDICATION

Pharmacologic treatment of AKI has been attempted on an empiric basis, with varying success rates. Several promising experimental therapies in animal models are awaiting human trials. Experimental therapies include growth factors, vasoactive peptides, adhesion molecules, endothelin inhibitors, and bioartificial kidneys. Aminophylline has also been used experimentally for prophylaxis against renal failure.

A prophylactic strategy shown to decrease the incidence of contrast nephropathy is the IV administration of fluids. Although controversy exists regarding the ideal fluid, normal saline and isotonic NaHCO3 have proven to be effective. Normal saline solution of 1 mL/kg/h administered 12 hours before the procedure and then 12 hours after the procedure is recommended. In patients who are at high risk for volume overload, isotonic NaHCO3 solution should be administered before and after the procedure. It can be prepared by mixing 3 ampules of NaHCO3 in a liter of D5W and can be given at a rate of 3 mL/kg/h for 1 hour prior to the procedure; 1 mL/kg/h during the procedure; and for 6 hours afterward. Another prophylactic agent used with varying success is N-acetylcysteine at a dosage of 1200 mg PO q12h. This is administered to high-risk patients the day before a contrast study is performed and is continued the day of the procedure. Diuretics, NSAIDs, and possibly ACEIs should be withheld near the time of the procedure.

Drug Category: Diuretics

Although diuretics seem to have no effect on the outcome of established AKI, they appear useful in fluid homeostasis and are used extensively. The use of isotonic sodium chloride solution in conjunction with diuretics is debatable. The only therapeutic or preventive intervention that has an established beneficial effect in the management of AKI is administration of isotonic sodium chloride solution to keep the patient euvolemic or even hypervolemic.

Drug Name
Furosemide (Lasix)

Description
Increases excretion of water by interfering with chloride-binding cotransport system, which, in turn, inhibits sodium and chloride reabsorption in the thick ascending loop of Henle and the distal renal tubule. Potent and rapid-acting agent with peak action at 60 min and lasting 6-8 h.
In renal failure, higher doses must be used for greater diuretic effects. Doses as high as 600 mg/d may be needed under monitored conditions.
Frequently, IV doses are needed in AKI to maintain urine output. IV infusions are often helpful in ICU settings, in which larger doses are necessary. This method promotes a sustained natriuresis with reduced ototoxicity compared to conventional intermittent bolus dosing.

Adult Dose
20-40 mg PO qd initially

Pediatric Dose
Not established

Contraindications
Documented hypersensitivity; hepatic coma, anuria, and states of severe electrolyte depletion

Interactions
Metformin decreases concentrations; interferes with hypoglycemic effect of antidiabetic agents and antagonizes muscle-relaxing effect of tubocurarine; auditory toxicity appears to be increased with coadministration of aminoglycosides or ethacrynic acid; hearing loss of varying degrees may occur; anticoagulant activity of warfarin may be enhanced when taken concurrently; increased plasma lithium levels and toxicity are possible when taken concurrently

Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions
Perform frequent serum electrolyte, carbon dioxide, glucose, creatinine, uric acid, calcium, and BUN determinations during first few months of therapy and periodically thereafter; avoid using other nephrotoxic agents if possible

Drug Category: Vasodilators

Dopamine in small doses (eg, 1-5 mcg/kg/min) causes selective dilatation of the renal vasculature, enhancing renal perfusion. Dopamine also reduces sodium absorption, thereby decreasing the energy requirement of the damaged tubules. This enhances urine flow, which, in turn, helps prevent tubular cast obstruction. Most clinical studies have failed to establish this beneficial role of renal-dose dopamine infusion.

Drug Name
Dopamine (Intropin)

Description
Stimulates both adrenergic and dopaminergic receptors. Hemodynamic effect is dose-dependent. Lower doses predominantly stimulate dopaminergic receptors, which, in turn, produce renal and mesenteric vasodilation. Cardiac stimulation and renal vasodilation produced by higher doses.

Adult Dose
1-5 mcg/kg/min IV

Pediatric Dose
Administer as in adults

Contraindications
Documented hypersensitivity; pheochromocytoma or ventricular fibrillation

Interactions
Phenytoin, alpha-adrenergic and beta-adrenergic blockers, general anesthesia, and MAOIs increase and prolong effects

Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions
Caution in hypertension, CVA, coronary heart disease, and dysrhythmias; closely monitor urine flow, cardiac output, pulmonary wedge pressure, and blood pressure during infusion; before infusion, correct hypovolemia with either whole blood or plasma, as indicated; monitoring central venous pressure or left ventricular filling pressure may be helpful in detecting and treating hypovolemia

Drug Category: Calcium channel blockers

Effective in animal models but efficacy not proven in humans. Effects are believed to be mediated through vasodilation, and calcium channel blockers increasingly are used to enhance the function of transplanted kidneys.

Drug Name
Nifedipine (Adalat, Procardia)

Description
Relaxes smooth muscle and produces vasodilation, which, in turn, improves blood flow and oxygen delivery.

Adult Dose
10-30 mg IR cap PO tid; not to exceed 120-180 mg/d
30-60 mg SR tab PO qd; not to exceed 90-120 mg/d

Pediatric Dose
0.25-0.5 mg/kg/dose PO tid/qid prn

Contraindications
Documented hypersensitivity

Interactions
Caution with coadministration of any agent that can lower BP, including beta-blockers and opioids; H2 blockers (eg, cimetidine) may increase toxicity

Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions
May cause lower extremity edema; allergic hepatitis has occurred rarely

Drug Category: N-acetylcysteine

Used for prevention of contrast toxicity in susceptible individuals such as those with diabetes mellitus.

Drug Name
N-acetylcysteine (Mucosil, Mucomyst)

Description
May provide substrate for conjugation with toxic metabolites.

Adult Dose
For prevention of nephrotoxicity: 600 mg PO bid on day preceding and day of procedure

Pediatric Dose
Not established

Contraindications
Documented hypersensitivity

Interactions
None reported

Pregnancy
B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions
GI distress may occur

FOLLOW-UP

Further Outpatient Care

• Always keep in mind that renal recovery in most cases is not complete and the kidneys remain vulnerable to nephrotoxic effects of all therapeutic agents. Therefore, agents with nephrotoxic potential are best avoided.

Prognosis

• The prognosis of patients with AKI is directly related to the cause of renal failure and, to a great extent, to the duration of renal failure prior to therapeutic intervention. If AKI is defined by a sudden increment of serum creatinine of 0.5-1 mg/dL and is associated with a mild-to-moderate rise in creatinine, the prognosis tends to be worse. However, even if renal failure is mild, the mortality rate is 30-60%. If these patients need dialytic therapy, the mortality rate is 50-90%.
• • The mortality rate is 31% in patients with normal urine sediment test results and is 74% in patients with abnormal urine sediment test results.
  • If using Acute Physiology and Chronic Health Evaluation II (APACHE II) scores, the survival rate is nearly 0% among patients with AKI who have a score higher than 40 and is 40% in patients with APACHE II scores of 10-19.
  • Other prognostic factors include the following:
  • • Older age
    • Multiorgan failure (ie, the more organs that fail, the worse the prognosis)
    • Oliguria
    • Hypotension
    • Vasopressor support
    • Number of transfusions
    • Noncavitary surgery
• Prerenal azotemia due to volume contraction is treated with volume expansion; however, if left untreated for a prolonged duration, tubular necrosis may result and may not be reversible.
• Postrenal AKI, ie, urinary obstruction related renal failure, causes renal damage due to increased pressure proximal to the obstruction, which results in a thinning of the renal cortex. If left untreated for a long time, it may result in irreversible renal damage. Simple procedures such as catheter placement, lithotripsy, prostatectomy, stent placement, or percutaneous nephrostomy can help prevent permanent renal damage.
• Timely identification of pyelonephritis, proper treatment, and further prevention using prophylactic antibiotics may improve the prognosis, especially in females.
• • Early diagnosis of crescentic glomerulonephritis via renal biopsy and other appropriate tests may enhance early renal recovery because appropriate therapy can be initiated promptly and aggressively.
  • The number of crescents, the type of crescents (ie, cellular vs fibrous), and the serum creatinine level at the time of presentation may dictate prognosis for renal recovery in this subgroup of patients.

Patient Education

• Educating patients about the nephrotoxic potential of common therapeutic agents is always helpful. A good example is NSAIDs; most patients are unaware of their nephrotoxicity, and their universal availability makes them a constant concern.
• For excellent patient education resources, see eMedicine's Diabetes Center. Also, visit eMedicine's patient education article Acute Kidney Failure.

MISCELLANEOUS

Medical/Legal Pitfalls

• Although AKI potentially is a reversible condition, it can occur in patients with chronic renal failure. Every effort should be made to identify reversibility, even if improvement in renal function is marginal. The best way to identify reversibility is by tracking the rate of deterioration of renal function. If the rate of worsening renal function accelerates, the cause should be sought and treated.
• Renal recovery is usually observed within the first 2 weeks, and many nephrologists tend to diagnose patients with end-stage (ie, irreversible) renal failure 6-8 weeks after onset of AKI. It is always better to check these patients periodically because some patients may regain renal function much later.

Special Concerns

• Great controversy exists regarding the timing of dialysis. Dialysis, especially hemodialysis, may delay the recovery of patients with AKI. Most authorities prefer using biocompatible membrane dialyzers for hemodialysis. There seems to be no difference in outcome between the use of intermittent hemodialysis and continuous renal replacement therapy (CRRT), but this is currently under investigation. However, CCRT may have a role in patients who are hemodynamically unstable and who have had prolonged renal failure after a stroke or liver failure. Such patients may not tolerate the rapid shift of fluid and electrolytes caused during conventional hemodialysis. Although not frequently used, peritoneal dialysis can also technically be used in acute cases and probably is tolerated better hemodynamically than conventional hemodialysis.
• Indications for dialysis in patients with AKI are as follows:
• • Volume expansion that cannot be managed with diuretics
  • Hyperkalemia refractory to medical therapy
  • Correction of severe acid-base disturbances that are refractory to medical therapy
  • Severe azotemia (BUN >80-100)
  • Uremia

REFERENCES and more information:

http://www.emedicine.com/MED/topic1595.htm

Chronic Renal Failure

AUTHOR INFORMATION

Author: Mauro Verrelli, MD, FRCPC, FACP, Assistant Professor, Department of Medicine, Section of Nephrology, University of Manitoba, Winnipeg, Canada

Mauro Verrelli, MD, FRCPC, FACP, is a member of the following medical societies: American College of Physicians-American Society of Internal Medicine, American Society of Nephrology, Canadian Medical Association, and Royal College of Physicians and Surgeons of Canada

Editor(s): Laura L Mulloy, DO, FACP, Professor of Medicine, Chief, Section of Nephrology, Hypertension and Transplantation Medicine, Glover/Mealing Eminent Scholar Chair in Immunology, Medical College of Georgia; Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine; George R Aronoff, MD, Director, Professor, Departments of Internal Medicine and Pharmacology, Section of Nephrology, Kidney Disease Program, University of Louisville School of Medicine; Rebecca J Schmidt, DO, FACP, FASN, Clinical Associate Professor of Medicine, West Virginia School of Osteopathic Medicine; Professor of Medicine, Section Chief, Department of Medicine, Section of Nephrology, West Virginia University School of Medicine; and Vecihi Batuman, MD, FACP, FASN, Professor of Medicine, Chief, Section of Nephrology, Tulane University School of Medicine; Professor, Renal-Hypertension Section, Department of Medicine, Tulane University Medical Center and Veterans Affairs Medical Center

 

INTRODUCTION

Background: The Kidney Disease Outcomes Quality Initiative (K/DOQI) of the National Kidney Foundation (NKF) defines chronic kidney disease (CKD) as either kidney damage or a decreased kidney glomerular filtration rate (GFR) of <60 mL/min/1.73 m² for 3 or more months. Whatever the underlying etiology, the destruction of renal mass with irreversible sclerosis and loss of nephrons leads to a progressive decline in GFR. The different stages of CKD form a continuum in time; prior to February 2002, no uniform classification of the stages of CKD existed. At that time, K/DOQI published a classification of the stages of CKD, as follows:

• Stage 1: Kidney damage with normal or increased GFR (>90 mL/min/1.73 m²)
• Stage 2: Mild reduction in GFR (60-89 mL/min/1.73 m²)
• Stage 3: Moderate reduction in GFR (30-59 mL/min/1.73 m²)
• Stage 4: Severe reduction in GFR (15-29 mL/min/1.73 m²)
• Stage 5: Kidney failure (GFR <15 mL/min/1.73 m² or dialysis)

The K/DOQI definition and the classification of CKD allow better communication and intervention at the different stages.

Pathophysiology: Approximately 1 million nephrons are present in each kidney, each contributing to the total GFR. Regardless of the etiology of renal injury, with progressive destruction of nephrons, the kidney has an innate ability to maintain GFR by hyperfiltration and compensatory hypertrophy of the remaining healthy nephrons. This nephron adaptability allows for continued normal clearance of plasma solutes such that substances such as urea and creatinine start to show significant increases in plasma levels only after total GFR has decreased to 50%, when the renal reserve has been exhausted. The plasma creatinine value will double with a 50% reduction in GFR. A rise in plasma creatinine from a baseline value of 0.6 mg/dL to 1.2 mg/dL in a patient, although still within the reference range, actually represents a loss of 50% of functioning nephron mass.

The residual nephron hyperfiltration and hypertrophy, although beneficial for the reasons noted, has been hypothesized to represent a major cause of progressive renal dysfunction. This is believed to occur because of increased glomerular capillary pressure, which damages the capillaries and leads initially to focal and segmental glomerulosclerosis and eventually to global glomerulosclerosis. This hypothesis has been based on studies of five-sixths nephrectomized rats, which develop these lesions that are identical to those observed in humans with CKD.

Factors other than the underlying disease process and glomerular hypertension that may cause progressive renal injury include the following:

• Systemic hypertension
• Acute insults from nephrotoxins or decreased perfusion
• Proteinuria
• Increased renal ammoniagenesis with interstitial injury
• Hyperlipidemia
• Hyperphosphatemia with calcium phosphate deposition
• Decreased levels of nitrous oxide

Frequency:

• In the US: The US Renal Data System (USRDS) has shown a dramatic increase in patients with CKD who require chronic dialysis or transplantation. In 1999, there were 340,000 such patients, but, by 2010, this number is projected to reach 651,000. CKD, particularly at the stage requiring renal replacement therapy (dialysis or transplantation), is already a major burden to health care resources, and this will only worsen in time.

  Because of the nonuniform definition of kidney disease prior to February 2002, among other factors, most patients with earlier CKD stages have not been recognized or adequately treated. The Third National Health and Examination Survey (NHANES III) estimated that the prevalence of CKD in adults in the United States was 11% (19.2 million): 3.3% (5.9 million) had stage 1, 3.0% (5.3 million) had stage 2, 4.3% (7.6 million) had stage 3, 0.2% (400,000) had stage 4, and 0.2% (300,000) had stage 5.

• Internationally: The incidence rates of end-stage renal disease (ESRD) have increased steadily internationally since 1989. The United States has the highest incident rate of ESRD, followed by Japan. Japan has the highest prevalence per million population, with the United States taking second place.

Mortality/Morbidity: CKD is a major cause of morbidity and mortality, particularly at the later stages. Although the diabetic population is at highest risk, in the United States, the general hemodialysis and peritoneal dialysis populations have 2.0 hospital admissions per patient per year; patients who have a renal transplant have an average of 1.0 hospital admissions per year. The 5-year survival rate for a patient undergoing chronic dialysis in the United States is approximately 35%. This is approximately 25% in patients with diabetes. The most common cause of death in the dialysis population is cardiovascular disease.

Race:

• CKD affects all races, but, in the United States, a significantly higher incidence of ESRD exists in blacks as compared to whites; the incident rate for blacks is nearly 4 times that for whites.

Sex:

• In NHANES III, the distribution of estimated GFRs for the CKD stages was similar in both sexes. Nonetheless, the USRDS 2004 Annual Data Report reveals that the incident rate of ESRD cases is higher for males with 409 per million population in 2002 compared to 276 for females.

Age: CKD is found in persons of all ages. Nonetheless, in the United States, the highest incidence rate of ESRD occurs in patients older than 65 years. Besides diabetes mellitus and hypertension, age is an independent major predictor of CKD. Of the US population older than 65 years without diabetes mellitus or hypertension, 11% had CKD stage 3 or worse according to the NHANES III. The geriatric population is the most rapidly growing kidney failure (CKD stage 5) population in the United States.

Note that after age 30 years progressive physiological glomerulosclerosis occurs, with GFR (and creatinine clearance [CrCl) falling linearly at a rate of approximately 8 cc/min/1.73 m²/y from a maximal GFR of 140 cc/min/1.73 m². Aging also results in concomitant progressive physiological decrease in muscle mass such that daily urinary creatinine excretion also decreases; this combination of factors results in constant serum creatinine values over time in a given individual, despite a decrease in CrCl (and GFR).

Therefore, a serum creatinine value of 0.8 mg/dL in a 70-kg, 25-year-old man versus one who is 80 years old represents a CrCl of 140 cc/min and 73 cc/min, respectively. What can appear as only mild renal impairment in an 80-year-old, 70-kg man with a pathologically elevated serum creatinine of 2.0 mg/dL actually represents severe renal impairment when the CrCl is calculated to be 29 cc/min. Therefore, a CrCl must be calculated simply by using the Cockcroft-Gault formula (see

Other Tests) in elderly people so that appropriate drug dosing adjustments can be made and nephrotoxins can be avoided in patients who have more extensive CKD than would be suggested by the serum creatinine alone.

CLINICAL

History: Patients with CKD stage 3 or lower (GFR >30 mL/min) generally are asymptomatic and do not experience clinically evident disturbances in water or electrolyte balance or endocrine/metabolic derangements. Generally, these disturbances clinically manifest with CKD stages 4 and 5 (GFR <30 mL/min). Uremic manifestations in patients with CKD stage 5 are believed to be primarily secondary to an accumulation of toxins, the identity of which is generally not known.

• Hyperkalemia usually develops when GFR falls to less than 20-25 mL/min because of the decreased ability of the kidneys to excrete potassium. It can be observed sooner in patients who ingest a potassium-rich diet or if serum aldosterone levels are low, such as in type IV renal tubular acidosis commonly observed in people with diabetes and commonly observed with use of angiotensin-converting enzyme (ACE) inhibitors or nonsteroidal anti-inflammatory drugs (NSAIDs). Hyperkalemia in CKD can be aggravated by an extracellular shift of potassium, such as that occurs in the setting of acidemia or from lack of insulin.

• Metabolic acidosis often is mixed, non–anion gap and anion gap, the latter observed generally with CKD stage 5 but with the anion gap generally not higher than 20 mEq/L. In CKD, the kidneys are unable to produce enough ammonia in the proximal tubules to excrete the endogenous acid into the urine in the form of ammonium. In CKD stage 5, accumulation of phosphates, sulphates, and other organic anions are the cause of the small anion gap.

• Extracellular volume expansion and total-body volume overload results from failure of sodium and free water excretion. This generally becomes clinically manifest when GFR falls to less than 10-15 mL/min, when compensatory mechanisms have become exhausted. Patients present with peripheral and, not uncommonly, pulmonary edema and hypertension. At a higher GFR, excess sodium and water intake could result in a similar picture if the ingested amounts of sodium and water exceed the available potential for compensatory excretion.

• Normochromic normocytic anemia principally develops from decreased renal synthesis of erythropoietin, the hormone responsible for bone marrow stimulation for red blood cell (RBC) production. It becomes more severe as GFR progressively decreases with the availability of less viable renal mass. No reticulocyte response occurs. RBC survival is decreased, and tendency of bleeding is increased from the uremia-induced platelet dysfunction.

• Secondary hyperparathyroidism develops because of hypocalcemia, decreased renal synthesis of 1,25-dihydroxycholecalciferol (1,25-dihydroxyvitamin D, or calcitriol), and hyperphosphatemia.

• Calcium and calcitriol are primary feedback inhibitors; hyperphosphatemia is a stimulus to parathyroid hormone (PTH) synthesis and secretion.

• Phosphate retention begins in early CKD; when GFR falls, less phosphate is filtered and excreted, but serum levels do not rise initially because of increased PTH secretion, which increases renal excretion. As GFR falls toward CKD stages 4 and 5, hyperphosphatemia develops from the inability of the kidneys to excrete the excess dietary intake. Hyperphosphatemia suppresses the renal hydroxylation of inactive 25-hydroxyvitamin D to calcitriol, so serum calcitriol levels are low when the GFR is less than 30 mL/min.

• Hypocalcemia develops primarily from decreased intestinal calcium absorption because of low plasma calcitriol levels and possibly from calcium binding to elevated serum levels of phosphate.

• Low serum calcitriol levels, hypocalcemia, and hyperphosphatemia have all been demonstrated to independently trigger PTH synthesis and secretion. As these stimuli persist in CKD, particularly in the more advanced stages, PTH secretion becomes maladaptive and the parathyroid glands, which initially hypertrophy, become hyperplastic. The persistently elevated PTH levels exacerbate hyperphosphatemia from bone resorption of phosphate.

• If serum levels of PTH remain elevated, a high–bone turnover lesion, known as osteitis fibrosa, develops. This is one of several bone lesions, which as a group are commonly known as renal osteodystrophy. These lesions develop in patients with severe CKD and are common in those with ESRD. Osteomalacia and adynamic bone disease are the 2 other lesions observed. The former, observed primarily from aluminum accumulation, is markedly less common than the latter, whose etiology is unclear. Adynamic bone disease represents the predominant bone lesion in patients on chronic peritoneal dialysis and is increasing in frequency. Dialysis-related amyloidosis from beta2-microglobulin accumulation in patients who have required chronic dialysis for at least 8-10 years is another form of bone disease that manifests with cysts at the ends of long bones.

• Other manifestations of uremia in ESRD, many of which are more likely in patients who are inadequately dialyzed, include the following:

• Pericarditis - Can complicate with cardiac tamponade, possibly resulting in death

• Encephalopathy - Can progress to coma and death

• Peripheral neuropathy

• Restless leg syndrome

• GI symptoms - Anorexia, nausea, vomiting, diarrhea

• Skin manifestations - Dry skin, pruritus, ecchymosis

• Fatigue, increased somnolence, failure to thrive

• Malnutrition

• Erectile dysfunction, decreased libido, amenorrhea
• Platelet dysfunction with tendency to bleeding

Physical: The physical examination often is not very helpful but may reveal findings characteristic of the condition underlying CKD (eg, lupus, severe arteriosclerosis, hypertension) or complications of CKD (eg, anemia, bleeding diathesis, pericarditis).

Causes:

• Vascular disease - Renal artery stenosis, cytoplasmic pattern antineutrophil cytoplasmic antibody (C-ANCA)–positive and perinuclear pattern antineutrophil cytoplasmic antibody (P-ANCA)–positive vasculitides, antineutrophil cytoplasmic antibody (ANCA)–negative vasculitides, atheroemboli, hypertensive nephrosclerosis, renal vein thrombosis

• Primary glomerular disease - Membranous nephropathy, immunoglobulin A (IgA) nephropathy, focal and segmental glomerulosclerosis (FSGS), minimal change disease, membranoproliferative glomerulonephritis, rapidly progressive (crescentic) glomerulonephritis

• Secondary glomerular disease - Diabetes mellitus, systemic lupus erythematosus, rheumatoid arthritis, mixed connective tissue disease, scleroderma, Goodpasture syndrome, Wegener granulomatosis, mixed cryoglobulinemia, postinfectious glomerulonephritis, endocarditis, hepatitis B and C, syphilis, human immunodeficiency virus (HIV), parasitic infection, heroin use, gold, penicillamine, amyloidosis, light chain deposition disease, neoplasia, thrombotic thrombocytopenic purpura (TTP), hemolytic-uremic syndrome (HUS), Henoch-Schönlein purpura, Alport syndrome, reflux nephropathy

• Tubulointerstitial disease - Drugs (eg, sulfa, allopurinol), infection (viral, bacterial, parasitic), Sjögren syndrome, chronic hypokalemia, chronic hypercalcemia, sarcoidosis, multiple myeloma cast nephropathy, heavy metals, radiation nephritis, polycystic kidneys, cystinosis

• Urinary tract obstruction - Urolithiasis, benign prostatic hypertrophy, tumors, retroperitoneal fibrosis, urethral stricture, neurogenic bladder

 

DIFFERENTIALS

Acute Renal Failure

WORKUP

Lab Studies:

• Elevated serum urea and creatinine

• Hyperkalemia, low serum bicarbonate, hypocalcemia, hyperphosphatemia, hyponatremia (in ESRD with free-water excess)

• Hypoalbuminemia in patients who are nephrotic and/or malnourished

• Normochromic normocytic anemia - Other underlying causes of anemia should be ruled out.

• Urinalysis - Dipstick proteinuria may suggest glomerular or a tubulointerstitial problem.

• Urine sediment finding of RBCs, RBC casts, suggests proliferative glomerulonephritis. Pyuria or/and WBC casts are suggestive of interstitial nephritis (particularly if eosinophiluria is present) or urinary tract infection.

• Spot urine collection for total protein-to-creatinine ratio allows reliable approximation (extrapolation) of total 24-hour urinary protein excretion. A value of greater than 2.0 g is considered to be within glomerular range, and a value greater than 3.0-3.5 g is within the nephrotic range; less than 2.0 is characteristic of tubulointerstitial problems.

• Twenty-four–hour urine collection for total protein and CrCl

• Serum and urine protein electrophoresis to screen for a monoclonal protein possibly representing multiple myeloma

• Antinuclear antibodies (ANA), double-stranded DNA antibody levels to screen for systemic lupus erythematosus

• Serum complement levels - May be depressed with some glomerulonephritides

• C-ANCA and P-ANCA levels - Helpful if positive in diagnosis of Wegener granulomatosis and polyarteritis nodosa or microscopic polyangiitis, respectively

• Anti–glomerular basement membrane (anti-GBM) antibodies - Highly suggestive of underlying Goodpasture syndrome

• Hepatitis B and C, HIV, Venereal Disease Research Laboratory (VDRL) serology - Conditions associated with some glomerulonephritides

Imaging Studies:

• Plain abdominal x-ray - Particularly useful to look for radio-opaque stones or nephrocalcinosis

• Intravenous pyelogram - Not commonly used because of potential for intravenous contrast renal toxicity; often used to diagnose renal stones

• Renal ultrasound - Small echogenic kidneys are observed in advanced renal failure. Kidneys usually are normal in size in advanced diabetic nephropathy, where affected kidneys initially are enlarged from hyperfiltration. Structural abnormalities, such as polycystic kidneys, also may be observed. This is a useful test to screen for hydronephrosis, which may not be observed in early obstruction, or involvement of the retroperitoneum with fibrosis, tumor, or diffuse adenopathy. Retrograde pyelogram may be indicated if a high index of clinical suspicion for obstruction exists despite a negative study finding.

• Renal radionuclide scan - Useful to screen for renal artery stenosis when performed with captopril administration but is unreliable for GFR of less than 30 cc/min; also quantitates differential renal contribution to total GFR

• CT scan - CT scan is useful to better define renal masses and cysts usually noted on ultrasound. Also, it is the most sensitive test for identifying renal stones. IV contrast-enhanced CT scans should be avoided in patients with renal impairment to avoid acute renal failure; this risk significantly increases in patients with moderate-to-severe CKD. Dehydration also markedly increases this risk.

• MRI is very useful in patients who require a CT scan but who cannot receive intravenous contrast. It is reliable in the diagnosis of renal vein thrombosis, as are CT scan and renal venography. Magnetic resonance angiography also is becoming more useful for diagnosis of renal artery stenosis, although renal arteriography remains the criterion standard.

• Voiding cystourethrogram (VCUG) - Criterion standard for diagnosis of vesicoureteral reflux

Other Tests:

• The Cockcroft-Gault formula for estimating CrCl should be used routinely as a simple means to provide a reliable approximation of residual renal function in all patients with CKD. The formulas are as follows:

• CrCl (male) = ([140-age] X weight in kg)/(serum creatinine X 72)

• CrCl (female) = CrCl (male) X 0.85

• Alternatively, the Modification of Diet in Renal Disease (MDRD) Study equation could be used to calculate GFR. This equation does not require a patient's weight (Levey, 1999).

Procedures:

• Percutaneous renal biopsy currently is performed most often with ultrasound guidance and the use of a mechanical gun. It generally is indicated when renal impairment and/or proteinuria approaching the nephrotic range are present and the diagnosis is unclear after appropriate other workup. It is not indicated in the setting of small echogenic kidneys on ultrasound because these are severely scarred and represent chronic irreversible injury. The most common complication of this procedure is bleeding, which can be life threatening in a minority of occurrences.

• Surgical open renal biopsy can be considered when the risk of renal bleeding is felt to be great, occasionally with solitary kidneys, or when percutaneous biopsy is technically difficult to perform.

Histologic Findings: Renal histology in CKD reveals findings compatible with the underlying primary renal diagnosis and, generally, findings of segmental and globally sclerosed glomeruli and tubulointerstitial atrophy, often with tubulointerstitial mononuclear infiltrates.

TREATMENT

Medical Care: Medical care of the patients with CKD should focus on the following:

• Delaying or halting progression of CKD

• Treatment of the underlying condition if possible
• Aggressive blood pressure control to target values per current guidelines
• Use of ACE inhibitors as tolerated, with close monitoring for renal deterioration and for hyperkalemia (avoid in advanced renal failure, bilateral renal artery stenosis [RAS], RAS in a solitary kidney)
• Aggressive glycemic control per the American Diabetes Association (ADA) recommendations; target HbA1C <7.0%
• Protein restriction - Controversial
• Treatment of hyperlipidemia to target levels per current guidelines
• Avoidance of nephrotoxins - IV radiocontrast, nonsteroidal anti-inflammatory agents, aminoglycosides

• Treating pathologic manifestations of CKD, including the following:

• Anemia with erythropoietin
• Hyperphosphatemia with dietary phosphate binders and dietary phosphate restriction
• Hypocalcemia with calcium supplements +/- calcitriol
• Hyperparathyroidism with calcitriol or vitamin D analogs
• Volume overload with loop diuretics or ultrafiltration
• Metabolic acidosis with oral alkali supplementation
• Uremic manifestations with chronic renal replacement therapy (hemodialysis, peritoneal dialysis, or renal transplantation): Indications include severe metabolic acidosis, hyperkalemia, pericarditis, encephalopathy, intractable volume overload, failure to thrive and malnutrition, peripheral neuropathy, intractable gastrointestinal symptoms, and GFR less than 10 mL/min.
• Cardiovascular complications

• Timely planning for chronic renal replacement therapy

• Early education regarding natural disease progression, different dialytic modalities, renal transplantation, patient option to refuse or discontinue chronic dialysis
• Timely placement of permanent vascular access (arrange for surgical creation of primary arteriovenous fistula, if possible, and preferably at least 6 months in advance of anticipated date of dialysis)
• Timely elective peritoneal dialysis catheter insertion
• Timely referral for renal transplantation

Consultations:

• Early nephrology referral (decreases morbidity and mortality)

• Renal dietitian

• Vascular surgery for permanent vascular access

• General surgery for peritoneal catheter placement

• Referral to renal transplant center

Diet:

• Protein restriction early in CKD as a means to delay a decline in GFR is controversial; however, as the patient approaches CKD stage 5, this is recommended to delay the onset of uremic symptoms. Patients with CKD who already are predisposed to becoming malnourished are at higher risk for malnutrition with overly aggressive protein restriction. Malnutrition is a well-established predictor of increased morbidity and mortality in the ESRD population and must be avoided if possible.

• Phosphate restriction starting early in CKD

• Potassium restriction

• Sodium and water restriction as needed to avoid volume overload

 

MEDICATION

Drug Category: Phosphate-lowering agents -- Hyperphosphatemia is treated with dietary phosphate binders and dietary phosphate restriction. Hypocalcemia is treated with calcium supplements and possibly calcitriol. Hyperparathyroidism is treated with calcitriol or vitamin D analogs.

Drug Name
Calcium acetate (Calphron, PhosLo) -- For treatment of hyperphosphatemia in CKD. Combines with dietary phosphorus to form insoluble calcium phosphate, which is excreted in feces.

Adult Dose
1334 mg PO with each meal; increase to bring serum phosphate value to 6 mg/dL as long as hypercalcemia does not develop; may require as much as 2668 mg

Pediatric Dose
Not established

Contraindications
Hypercalcemia; hypophosphatemia; renal calculi

Interactions
May increase effect of quinidine; may decrease effects of tetracyclines, atenolol, salicylates, iron salts, and fluoroquinolones; IV administration antagonizes effects of verapamil; large intakes of dietary fiber may decrease calcium absorption and levels

Pregnancy
C - Safety for use during pregnancy has not been established.

Precautions
Hypercalcemia or hypercalcuria may occur when therapeutic amounts are administered

Drug Name
Calcium carbonate (Caltrate, Oystercal) -- For treatment of hyperphosphatemia or as a calcium supplement in CKD. Successfully normalizes phosphate concentrations in patients with CKD. Combines with dietary phosphate to form insoluble calcium phosphate, which is excreted in feces. Marketed in a variety of dosage forms and is relatively inexpensive.

Adult Dose
1-2 g PO divided bid/qid; with meals as a phosphorous binder; between meals as a calcium supplement

Pediatric Dose
45-65 mg/kg/d PO divided qid

Contraindications
Renal calculi; hypercalcemia; hypophosphatemia; digitalis toxicity

Interactions
May decrease effects of tetracyclines, atenolol, salicylates, iron salts, and fluoroquinolones; IV administration antagonizes effects of verapamil; large intakes of dietary fiber may decrease calcium absorption and levels

Pregnancy
C - Safety for use during pregnancy has not been established.

Precautions
Hypercalcemia or hypercalcuria may occur when therapeutic amounts are administered

Drug Name
Calcitriol (Rocaltrol, Calcijex) -- Used to suppress parathyroid production and secretion in secondary hyperparathyroidism and for treatment of hypocalcemia in CKD by increasing intestinal calcium absorption.

Adult Dose
0.25 mcg PO qd/qod
0.5 mcg IV qd 3 times per wk
Increase at 4- to 8-wk intervals by 0.25-mcg/d to achieve target PTH level and to maintain serum calcium levels at 9-10 mg/dL

Pediatric Dose
Initial: 15 ng/kg/d PO
Maintenance: 5-40 ng/kg/d PO

Contraindications
Documented hypersensitivity; hypercalcemia; malabsorption syndrome

Interactions
Cholestyramine and colestipol decrease absorption; magnesium-containing antacids and thiazide diuretics can increase calcitriol effects

Pregnancy
C - Safety for use during pregnancy has not been established.

Precautions
Adequate response to calcitriol in improving hypocalcemia depends on adequate dietary calcium intake; serum calcium phosphate product must not exceed 70 mg/dL to minimize metastatic tissue and blood vessel calcification; avoid hypercalcemia

Drug Name
Doxercalciferol (Hectorol) -- A vitamin D analog (1-alpha-hydroxyergocalciferol) that does not require activation by the kidneys. Indicated for the treatment of secondary hyperparathyroidism in end-stage renal disease.

Adult Dose
10 mcg PO 3 times/wk at dialysis; adjust dose as needed to lower blood iPTH to 150-300 pg/mL; increase dose by 2.5 mcg/8 wk if iPTH is not lowered by 50% and fails to reach the target range; not to exceed 20 mcg/3 times/wk
Alternatively, 4 mcg IV 3 times/wk; may adjust dose by 1-2 mcg/8 wk to maintain iPTH levels

Pediatric Dose
Not established

Contraindications
Documented hypersensitivity; recent hypercalcemia or hyperphosphatemia

Interactions
Coadministration with drugs that impair absorption of fat soluble vitamins (eg, cholestyramine) may decrease doxercalciferol absorption; increases the risk of hypermagnesemia with magnesium-containing products (eg, antacids)

Pregnancy
B - Usually safe but benefits must outweigh the risks.

Precautions
May cause headache, malaise, dyspnea, or hypercalcemia; caution in renal osteodystrophy with hyperphosphatemia (potential for metastatic calcification)

Drug Name
Lanthanum carbonate (Fosrenal) -- Noncalcium, nonaluminum phosphate binder indicated for reduction of high phosphorus levels in patients with end-stage renal disease. Directly binds dietary phosphorus in upper GI tract, thereby inhibiting phosphorus absorption.

Adult Dose
Initial: 250-500 mg PO tid pc (chewable tabs); adjust dose q2-3wk to target serum phosphorus level
Maintenance: 500-1000 mg PO tid pc

Pediatric Dose
Not established

Contraindications
Documented hypersensitivity; bowel obstruction; hypophosphatemia

Interactions
Drugs known to interact with antacids (eg, alendronate, amprenavir, ciprofloxacin, itraconazole, tetracycline, thyroid hormones) should not be administered within 2 h

Pregnancy
C - Safety for use during pregnancy has not been established.

Precautions
Deposited into developing bone, including growth plate (long-term effects unknown); common adverse effects typically diminish over time but include headache, abdominal pain, nausea, diarrhea, constipation, and vomiting; in clinical trials, dialysis graft occlusion occurred more frequently than with placebo; caution with GI motility diseases (eg, Crohn disease, ulcerative colitis) or recent GI surgery

Drug Name
Sevelamer (Renagel) -- Indicated for the reduction of serum phosphorous in patients with ESRD. Binds dietary phosphate in the intestine, thus inhibiting its absorption. In patients on hemodialysis, it decreases the frequency of hypercalcemic episodes relative to patients on calcium acetate treatment.

Adult Dose
Initial: 800-1600 mg PO tid with meals
Maintenance: Increase or decrease by 400-800 mg per meal q2wk to maintain serum phosphorous at 6 mg/dL or less

Pediatric Dose
Not established

Contraindications
Documented hypersensitivity; bowel obstruction; hypophosphatemia

Interactions
None reported

Pregnancy
C - Safety for use during pregnancy has not been established.

Precautions
Caution in patients with dysphagia, severe GI tract motility disorders, or swallowing disorders; does not contain calcium or alkali supplementation (monitor serum calcium, bicarbonate, and chloride levels)

Drug Name
Paricalcitol (Zemplar) -- For treatment of secondary hyperparathyroidism in ESRD. Reduces PTH levels, stimulates calcium and phosphorous absorption, and stimulates bone mineralization.

Adult Dose
0.04-0.1 mcg IV bolus 3 times per wk; adjust dose based on PTH levels

Pediatric Dose
Not established

Contraindications
Documented hypersensitivity; hypercalcemia; vitamin D toxicity

Interactions
Do not use phosphate or vitamin D-related compounds concomitantly with paricalcitol; caution if administered with digoxin (digitalis toxicity is potentiated by hypercalcemia)

Pregnancy
C - Safety for use during pregnancy has not been established.

Precautions
Caution in breastfeeding; adverse effects include GI tract distress, dry mouth, lightheadedness, edema, chills, or fever

Drug Category: Growth factors -- Used to treat anemia of CKD by stimulating RBC production.

Drug Name
Epoetin alfa (Epogen, Procrit) -- Stimulates division and differentiation of committed erythroid progenitor cells. Induces release of reticulocytes from bone marrow into blood stream.

Adult Dose
50-150 U/kg IV/SC 3 times per wk

Pediatric Dose
Not established

Contraindications
Documented hypersensitivity; uncontrolled hypertension

Interactions
None reported

Pregnancy
C - Safety for use during pregnancy has not been established.

Precautions
Caution in porphyria, hypertension, and history of seizures; decrease dose if hematocrit increase exceeds 4 U in any 2-wk period

Drug Category: Iron salts -- Nutritionally essential inorganic substances used to treat anemia.

Drug Name
Ferrous sulfate (Feosol, Feratab, Slow FE) -- Used as a building block for hemoglobin synthesis in treating anemia of CKD with erythropoietin.

Adult Dose
325 mg PO qd/tid

Pediatric Dose
<15 kg: 5 mg/kg/d PO
15-30 kg: 160 mg PO qd

Contraindications
Documented hypersensitivity

Interactions
Absorption is enhanced by ascorbic acid; interferes with tetracycline absorption; food and antacids impair absorption

Pregnancy
A - Safe in pregnancy

Precautions
GI tract upset; iron toxicity is observed with ingestion of large amount and can be fatal, especially in children; parenteral (IV) administration may cause several reactions, including headaches, malaise, fever, generalized lymphadenopathy, arthralgia, and urticaria; can cause severe anaphylaxis; other reactions include phlebitis at infusion site

Drug Name
Iron dextran (DexFerrum, InFed) -- Used to treat microcytic, hypochromic anemia resulting from iron deficiency when oral administration is unfeasible or ineffective.
Utilized to replenish iron stores in individuals on erythropoietin therapy who cannot take or tolerate oral iron supplementation.
A 0.5-mL (0.25 mL in children) test dose should be administered prior to starting therapy.
Available as 50 mg iron/mL (as dextran).

Adult Dose
>50 kg: 100 mg IV (2 mL); not to exceed 2 mL/d

Pediatric Dose
5-10 kg: 50 mg IV (1 mL)

Contraindications
Documented hypersensitivity; anemias that are not involved with iron deficiency; hemochromatosis; hemolytic anemia; acute phase of infectious kidney disease

Interactions
Chloramphenicol-induced bone marrow toxicity may cause increased iron levels

Pregnancy
C - Safety for use during pregnancy has not been established.

Precautions
Monitor for allergic reactions (eg, flushing, hypotension, nausea)

Drug Name
Iron sucrose (Venofer) -- Used to treat iron deficiency (in conjunction with erythropoietin) due to chronic hemodialysis. Iron deficiency is caused by blood loss during the dialysis procedure, increased erythropoiesis, and insufficient absorption of iron from the GI tract. Iron sucrose has shown a lower incidence of anaphylaxis than other parenteral iron products.

Adult Dose
5 mL (100 mg elemental iron) IV by slow injection or infusion during dialysis session; typically requires a minimum cumulative dose of 1000 mg of elemental iron over 10 consecutive dialysis sessions to achieve a favorable hemoglobin or hematocrit response; not to exceed 3 doses per wk

Pediatric Dose
Not established

Contraindications
Documented hypersensitivity; iron overload; anemia unrelated to iron deficiency

Interactions
Decreases bioavailability of orally administered iron

Pregnancy
B - Usually safe but benefits must outweigh the risks.

Precautions
May cause hypotension (related to IV administration rate or cumulative dose), cramps, headache, nausea, vomiting, diarrhea, or anaphylaxis

Drug Name
Ferric gluconate (Ferrlecit) -- Replaces iron found in hemoglobin, myoglobin, and specific enzyme systems. Allows transportation of oxygen via hemoglobin.

Adult Dose
125 mg elemental iron/10 mL IV; may require cumulative dose of 1 g elemental iron to achieve favorable response in patients receiving hemodialysis

Pediatric Dose
Not established

Contraindications
Documented hypersensitivity; hemochromatosis; hemolytic anemia

Interactions
Vitamin C may increase absorption of oral iron when administered concurrently; absorption of oral preparation of iron and tetracyclines decreased when administered concurrently; concurrent administration of H2 blockers or proton pump inhibitors may inhibit iron absorption

Pregnancy
B - Usually safe but benefits must outweigh the risks.

Precautions
Flushing and transient hypotension may occur; may augment hemodialysis-induced hypotension

Drug Category: Recombinant human erythropoietin -- Stimulates development of erythroid progenitor cells.

Drug Name
Darbepoetin (Aranesp) -- Erythropoiesis stimulating protein closely related to erythropoietin, a primary growth factor produced in kidney that stimulates development of erythroid progenitor cells. Mechanism of action is similar to that of endogenous erythropoietin, which interacts with stem cells to increase red cell production. Differs from epoetin alfa (recombinant human erythropoietin) in containing 5 N-linked oligosaccharide chains, whereas epoetin alfa contains 3. Has longer half-life than epoetin alfa (may be administered weekly or biweekly).

Adult Dose
0.45 mcg/kg IV/SC qwk initially; adjust dose (not to exceed 3 mcg/kg/wk) or frequency (eg, q2wk); to maintain target Hgb (not to exceed 12 g/dL); do not increase dose more frequently than qmo
Switching from epoetin alfa: Base dose on total weekly erythropoietin dose and frequency of administration

Pediatric Dose
Not established

Contraindications
Documented hypersensitivity; uncontrolled hypertension

Interactions
None reported

Pregnancy
C - Safety for use during pregnancy has not been established.

Precautions
Elevation in Hgb >1 g/dL/2wk increases risk of MI, neurologic events (eg, seizures, stroke) and exacerbations of hypertension, CHF, thrombosis, ischemia, and edema; adverse effects include infection, hypertension, hypotension, myalgia, headache, and diarrhea (some of adverse events may be due to chronic renal failure or dialysis); severe skin rash may occur (rare)

Drug Category: Calcimimetic agents -- These agents reduce parathyroid hormone levels.

Drug Name
Cinacalcet (Sensipar) -- Directly lowers intact parathyroid hormone (iPTH) levels by increasing sensitivity of calcium sensing receptor on chief cell of parathyroid gland to extracellular calcium. Also results in concomitant serum calcium decrease. Indicated for secondary hyperparathyroidism in patients with chronic kidney disease on dialysis.

Adult Dose
30 mg PO qd initially; titrate upward slowly (no more frequent than q2-4wk intervals) by 30 mg increments to target iPTH of 150-300 pg/mL
Take with meals or immediately following; do not crush, chew or cut tablets

Pediatric Dose
Not established

Contraindications
Documented hypersensitivity

Interactions
Strong CYP450 2D6 inhibitor; may increase serum levels of CYP 2D6 substrates (eg, flecainide, vinblastine, thioridazine, tricyclic antidepressants); coadministration with CYP450 3A4 inhibitors (eg, ketoconazole, erythromycin, itraconazole)) may decrease cinacalcet clearance

Pregnancy
C - Safety for use during pregnancy has not been established.

Precautions
Serum calcium reduction may cause lowered seizure threshold, paresthesia, myalgia, cramping, and tetany; monitor calcium and phosphorus levels closely within 1 wk following initial dose or dose changes, and then monthly (secondary hyperparathyroidism) and q2 mo (parathyroid carcinoma); do not initiate treatment if serum calcium below 8.4 mg/dL; adynamic bone disease may occur if iPTH levels suppressed below 100 pg/mL; caution with hepatic impairment; common adverse effects include nausea and vomiting

 

FOLLOW-UP

Further Inpatient Care:

• Patients who develop potentially life-threatening complications of CKD should be hospitalized and closely monitored.

Further Outpatient Care:

• Patients with CKD should be referred to a nephrologist early in the course of their disease and have continued nephrologic follow-up until initiation of chronic renal replacement therapy.

• A multidisciplinary approach to care, including involvement of the nephrologist, primary care physician, renal dietitian, nurse, and social worker, should be initiated early in the course of CKD, with close patient follow-up.

Transfer:

• Patients with CKD acutely presenting with indications for dialytic therapy should be transferred to a hospital center where acute dialysis can be performed.

Prognosis:

• Patients with CKD generally progress to ESRD. The rate of progression depends on the underlying diagnosis, on the successful implementation of secondary preventative measures, and on the individual patient.

• Patients on chronic dialysis have a high incidence of morbidity and mortality.

• Patients with ESRD who undergo renal transplantation survive longer than those on chronic dialysis.

Patient Education:

• Patients with CKD should be educated about the importance of compliance with secondary preventative measures, natural disease progression, prescribed medications (highlighting their potential benefits and adverse effects), avoidance of nephrotoxins, diet, chronic renal replacement modalities, including peritoneal dialysis, hemodialysis, and transplantation, and permanent vascular access options for hemodialysis.

• For excellent patient education resources, visit eMedicine's
Diabetes Center. Also, see eMedicine's patient education article Chronic Kidney Failure.

MISCELLANEOUS

Medical/Legal Pitfalls:

• Early diagnosis and treatment of the underlying cause or/and institution of secondary preventative measures in CKD is imperative to try to delay, or possibly halt, progression. Early nephrologic referral is of extreme importance.

• Timely initiation of chronic renal replacement therapy is imperative to prevent the uremic complications of CKD that can lead to significant morbidity and death.

• In CKD, doses and intervals of drugs that are excreted or metabolized renally should be adjusted accordingly for the residual GFR. Some drugs are contraindicated in moderate-to-severe renal impairment because of potentially serious effects from drug or metabolite accumulation. Routine consultation of the appropriate references should be undertaken when prescribing any new drug to a patient with CKD.

Special Concerns:

• Female patients with advanced CKD commonly develop menstrual irregularities; women with ESRD are typically amenorrheic and infertile.

• Pregnancy in CKD can be associated with accelerated renal decline. In advanced CKD and ESRD, pregnancy is associated with markedly decreased fetal survival.

 

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