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Tuesday, January 5, 2016

Medical Biochemistry Tips (7): Kidney Problems

Dr. James Manos (MD)
January 5, 2016


    

       Review: Tips in Medical Biochemistry
            Volume (7)





CONTENTS

ACUTE KIDNEY INJURY (AKI)

Acute kidney injury (AKI)
Acute kidney injury (AKI) workup
Biochemical markers on renal failure 
Blood Urea Nitrogen (BUN)
Urea to BUN (blood urea nitrogen) conversion calculator
Urine urea nitrogen (UUN)
Nitrogen balance
Nitrogen balance calculator
Protein intake calculator
Creatinine Clearance
Creatinine clearance calculators
Cystatin C
Fractional excretion of uric acid (FEUa)
Fractional excretion of uric acid calculator  
Diagnostic approach of acute kidney injury (AKI) (algorithm)
GFR (glomerular filtration rate) calculators
Renal failure diagnostic calculators


OTHER KIDNEY PROBLEMS

Fanconi’s syndrome
Renal tubular acidosis (RTA)
Renal tubular acidosis diagnostic algorithm



         ACUTE KIDNEY INJURY (AKI)

·         Acute kidney injury (AKI): Overview: Acute kidney injury (AKI) (previously termed acute renal failure (ARF)) is defined as an abrupt or rapid decline in renal (kidney) filtration function. This condition is usually marked by a rise in serum creatinine concentration or by 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, while a rise in the BUN level can also occur without renal injury, resulting instead from such sources as gastrointestinal (GI) or mucosal bleeding, steroid use, or protein loading. A careful inventory must be taken before concluding that a kidney injury is present.

·         Epidemiology: In the USA, approximately 1% of patients admitted to hospitals have AKI at the time of admission. The estimated incidence rate of AKI during hospitalization is 2 – 5%. AKI develops within 30 days postoperatively in approximately 1% of general surgery cases and arises in up to 67% of intensive care unit (ICU) patients.

·         Risk factors: People with the following comorbid conditions are at a higher risk for developing AKI: hypertension, chronic heart failure (CHF), diabetes mellitus, multiple myeloma, chronic infection, myeloproliferative disorder, connective tissue disorders & autoimmune diseases.

·         Urine output: Patients who develop AKI can be oliguric or non-oliguric, can have a rapid or slow rise in creatinine levels and may have qualitative differences in urine solute concentrations and cellular content. About 50 – 60% of all causes of AKI are non-oliguric.

·         Classifying AKI as oliguric or non-oliguric from daily urine excretion has prognostic value.

·         Oliguria is defined as a daily urine volume of less than 400 mL and has a worse prognosis, except in prerenal injury.

·         Anuria is defined as a urine output of less than 100 mL/day and, if abrupt in onset, suggests bilateral obstruction or catastrophic injury to both kidneys.

·         Diagnosis. Several diagnostic approaches occur. For example, Acute Kidney Injury Network (AKIN) defines AKI as abrupt (within 48 hours) reduction of kidney function, manifested by any 1 of the following:

·         a) An absolute increase in serum creatinine of 0.3 mg/dL or higher (≥26.4 µmol/L).

·         b) A percentage (%) increase in serum creatinine of 50% or greater (1.5-fold from baseline).

·         c) A reduction in urine output, defined as less than 0.5 mL/kg/h for more than 6 hours.

·         Classification. AKI may be classified into 3 general categories:

·         a) Prerenal: an adaptive response to severe volume depletion and hypotension, with structurally intact nephrons.

·         b) Intrinsic: in response to cytotoxic, ischemic, or inflammatory insults to the kidney, with structural and functional damage.

·         c) Postrenal: obstruction to the passage of urine.

·         Causes of acute kidney injury (AKI):  

·         I) Prerenal AKI. It represents the most common form of kidney injury and often leads to intrinsic AKI if it is not promptly corrected.

·         Causes:

·         a) Volume loss can provoke this syndrome.

·         Causes: Volume depletion can be caused by renal losses (diuretics, polyuria); GI (gastrointestinal) losses (vomiting, diarrhea; cutaneous (skin) losses (burns, Stevens-Johnson syndrome), hemorrhage (internal or external), and pancreatitis.

·         b) Decreased cardiac output.

·         Causes: heart failure, pulmonary embolus (PE), acute myocardial infarction, severe valvular disease, abdominal compartment syndrome (tense ascites).

·         c) Systemic vasodilation.

·         Causes: sepsis, anaphylaxis, anesthetics, drug overdose.

·         d) Medications.

·         Several classes of medications can induce prerenal AKI in volume-depleted states, including ACE inhibitors and angiotensin receptor blockers (ARBs) (antihypertensives), which are otherwise safely tolerated and beneficial in most patients with chronic kidney disease. Other medications include aminoglycosides (antibiotics), amphotericin B (antifungal), and radiologic contrast.

·         e) Afferent arteriolar vasoconstriction.

·         Causes: hypercalcemia; drugs (NSAIDs, amphotericin B, calcineurin inhibitors, norepinephrine and other pressor agents, and radiocontrast agents); hepatorenal syndrome (can also be considered a form of prerenal AKI, because functional renal failure develops from diffuse vasoconstriction in vessels supplying the kidney).

·         f) Diseases that decrease effective arterial blood volume include the following: hypovolemia; heart failure; liver failure; sepsis.

·         g) Renal arterial diseases: renal arterial stenosis (especially in the setting of hypotension or initiation of ACE inhibitors or ARBs). Renal artery stenosis typically results from atherosclerosis or fibromuscular dysplasia (*), but it may also be a feature of the genetic syndromes type 1 neurofibromatosis, Williams syndrome (**), and Alagille syndrome (***).

·         Patients can also develop a septic embolic disease (e.g., from endocarditis) or cholesterol emboli, often as a result of instrumentation or cardiovascular surgery.

·         (*) Fibromuscular dysplasia (FMD): FMD is a non – atherosclerotic, non-inflammatory disease of the blood vessels that causes abnormal growth within the wall of an artery.   FMD has been found in nearly every arterial bed in the body. However, the most common arteries affected are the renal & carotid arteries. There are various types of FMD, with medial fibroplasia being the most common. Intimal and adventitial are less common forms. FMD predominantly affects middle-aged women. However, it has been found in men and people of all ages. Pediatric cases of FMD are different from that of the adult population.

·         (**) Williams syndrome (WS): Williams syndrome (WS), also known as Williams–Beuren syndrome(WBS), is a rare neurodevelopment disorder characterized by a distinctive, ‘elfin’ facial appearance, low nasal bridge; an unusually cheerful demeanor and ease with strangers; developmental; delay coupled with strong language skills; and cardiovascular problems, such as supra valvular aortic stenosis and hypercalcemia. Renal artery stenosis (RAS) has been reported in 7% to 58% of patients with WS.  Rose et al. demonstrated that about 40% of patients with WS with systemic hypertension have RAS. Systemic hypertension is present in about 50% of adult patients with WS.

·         (***) Alagille syndrome: Alagille syndrome is a genetic disorder that affects the liver, heart kidney, and other systems of the body. Problems generally become evident in infancy or early childhood. The disease is inherited in an autosomal dominant pattern, and the estimated prevalence of Alagille syndrome is 1 in every 100,000 live births. Signs and symptoms arising from liver damage in Alagille syndrome may include jaundice, pruritus (itching), and skin xanthomas. A liver biopsy may show in some cases biliary paucity or even biliary atresia. Other signs include congenital heart problems, an unusual butterfly shape of one or more of the bones of the spinal column that can be seen in an X-ray; specific eye defects such as posterior embryotoxon, and narrowed pulmonary arteries that can contribute to increased pressure on the right heart valves. Tetralogy of Fallot is a heart defect common in Alagille's syndrome patients. Many people with Alagille syndrome have similar facial features, including a broad, prominent forehead, deep-set eyes, and a small pointed chin. The kidneys and the central nervous system (CNS) may also be affected.


·         II) Intrinsic AKI: Structural injury in the kidney is the hallmark of intrinsic AKI; the most common form is ATN (acute tubular necrosis), either ischemic or cytotoxic.

·         Causes:

·         a) Vascular (large- and small-vessel) causes of intrinsic AKI include: renal artery obstruction (thrombosis, emboli, dissection, vasculitis); renal vein obstruction (thrombosis); microangiopathy [thrombotic thrombocytopenic purpura (TTP), hemolytic uremic syndrome (HUS), disseminated intravascular coagulation (DIC), pre-eclampsia]; malignant hypertension; scleroderma renal crisis; transplant rejection; atheroembolic disease.

·         b) Glomerular. Glomerulonephritis can be a cause of AKI and usually falls into a class referred to as rapidly progressive (RP) glomerulonephritis. Glomerular crescents (glomerular injury) are found in RP glomerulonephritis on biopsy; if more than 50% of glomeruli contain crescents, this usually results in a significant decline in renal function. Causes include anti-glomerular basement membrane (GBM) disease (as part of Goodpasture syndrome or limited renal disease); anti-neutrophil cytoplasmic antibody-associated glomerulonephritis (ANCA-associated glomerulonephritis) [Wegener granulomatosis, Churg-Strauss syndrome, microscopic polyangiitis]; immune complex glomerulonephritis (lupus, postinfectious glomerulonephritis, cryoglobulinemia, primary membranoproliferative glomerulonephritis).

·         c) Tubular etiologies include:

·         i) Ischemia.

·         ii) Cytotoxic etiologies.

·         They include 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).

·         d) Interstitial causes include: drugs [penicillins, cephalosporins, NSAIDs (non – steroidal anti-inflammatory drugs), proton-pump inhibitors (PPIs), allopurinol, rifampin, indinavir, mesalamine, sulfonamides]; infection (pyelonephritis, viral nephritides); systemic disease (Sjogren syndrome, sarcoid, lupus, lymphoma, leukemia, tubulonephritis, uveitis).

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

·         Causes of obstruction include:

·         a) Ureteric obstruction

·         Causes: (stone disease, tumor, fibrosis, ureter ligation during pelvic surgery including gynecological surgery such as hysterectomy).

·         b) Bladder neck obstruction

·         Causes: benign prostatic hypertrophy (BPH), cancer of the prostate, neurogenic bladder, tricyclic antidepressants, ganglion blockers, bladder tumor, stone disease, hemorrhage/clot

·         c) Urethral obstruction

·         Causes: strictures, tumor, phimosis

·         d) Intra-abdominal hypertension

·         Causes: tense ascites

·         e) Renal vein thrombosis.

·         Diseases causing urinary obstruction from the level of the renal tubules to the urethra include:
·         a) Tubular obstruction from crystals (e.g., uric acid, calcium oxalate, acyclovir, sulfonamide, methotrexate, myeloma light chains).

·         b) Ureteral obstruction

·         Causes: retroperitoneal tumor, retroperitoneal fibrosis (methysergide, propranolol, hydralazine), urolithiasis (kidney stones), or papillary necrosis

·         c) Urethral obstruction

·         Causes: benign prostatic hypertrophy; prostate, cervical, bladder, or colorectal carcinoma; bladder hematoma; bladder stone; obstructed Foley catheter; neurogenic bladder; stricture.

·         Tumors that cause obstruction may be intraluminal, extraluminal, or intramural tumors.
·         Compressive hematoma may also cause obstruction.

·         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 an obstruction at the level of the bladder or downstream to it.

·         If the site of obstruction is unilateral, then a rise in the serum creatinine level may not be apparent, because of a preserved function of the contralateral kidney. Nevertheless, even 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.

·         Newborns & infants – causes of AKI:

·         a) Prerenal AKI. In newborns and infants, causes of prerenal AKI include:

·         i) Perinatal hemorrhage

·         Causes: twin-twin transfusion, complications of amniocentesis, abruptio placenta, birth trauma.

·         ii) Neonatal hemorrhage

·         Causes: severe intraventricular hemorrhage, adrenal hemorrhage.

·         iii) Perinatal asphyxia and hyaline membrane disease (newborn respiratory distress syndrome). Both may result in preferential blood shunting away from the kidneys (i.e., prerenal) to the central circulation.

·         b) Intrinsic AKI.

·         Causes of intrinsic AKI include:

·         i) ATN (acute tubular necrosis).  It can occur in the setting of perinatal asphyxia; ATN also has been observed secondary to medications (e.g., aminoglycosides, NSAIDs) given to the mother perinatally.

·         ii) ACE inhibitors medications. Can traverse the placenta, resulting in a hemodynamically mediated form of AKI.

·         iii) Acute glomerulonephritis. It is rare, and most commonly the result of a maternal-fetal transfer of antibodies against the neonate's glomeruli or transfer of chronic infections (syphilis, cytomegalovirus (CMV)) associated with acute glomerulonephritis.

·         c) Postrenal AKI. Causes included congenital malformations of the urinary collecting systems.

·         Children – causes of AKI

·         a) Prerenal AKI.

·         Causes: in children, gastroenteritis is the most common cause of hypovolemia and can result in prerenal AKI. Congenital and acquired heart diseases are also important causes of decreased renal perfusion.

·         b) Intrinsic AKI.

·         Causes include:

·         i) Acute post-streptococcal glomerulonephritis (it should be considered in any child who presents with hypertension, edema, hematuria, and renal failure).

·         b) HUS (hemolytic uremic syndrome). Often mentioned as the most common cause of AKI in children. The most common form of HUS is associated with a diarrheal prodrome caused by the Gram-negative bacterium Escherichia coli O157: H7. These children usually present with microangiopathic anemia, thrombocytopenia, colitis (diarrhea), mental status changes, and renal failure.


·         Acute kidney injury (AKI) workup:

·         I) Lab tests.

·         See also the above chapter: fractional excretion of sodium & fractional excretion of urea.
·         Several laboratory tests are useful for assessing the etiology of acute kidney injury (AKI) and can aid in the proper management of the disease. These include complete blood count (CBC; also called full blood count (FBC)), serum biochemistries, urine analysis (urinalysis) with microscopy; urine electrolytes. Although increased levels of blood urea nitrogen (BUN) and creatinine are the hallmarks of renal failure, the rate of rising depends on the degree of renal insult and, concerning BUN, on protein intake. BUN may be elevated in patients with gastrointestinal (GI) or mucosal bleeding, steroid treatment, or protein loading.

·         The ratio of BUN to creatinine can exceed 20:1 in conditions in which enhanced reabsorption of urea is favored (e.g., in volume contraction); this suggests prerenal AKI.

·         Assuming that the patient has no renal function, the rise in the BUN over 24 hours can be roughly predicted using the following formula: 24-hour protein intake in milligrams 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:

·         a) For males: Weight in kilograms [28 – 0.2 (age)] divided by total body water in mg/dL added to the creatinine value

·         b) For females: Weight in kilograms [23.8 – 0.17(age)] divided by total body water added to the creatinine value.  

·         The peripheral blood smear may show schistocytes in conditions such as hemolytic uremic syndrome (HUS) or thrombotic thrombocytopenic purpura (TTP). A finding of increased rouleaux formation may suggest multiple myeloma (then the workup should include immunoelectrophoresis of serum and urine & immunofixation). Also, echinocytes (burr cells) refer to a form of red blood cells (RBCs) that has an abnormal cell membrane characterized by many small, evenly spaced thorny projections. They may be present on peripheral blood smear in patients with uremia (an excess of amino acid and protein metabolism end products, such as urea & creatinine, in the blood that would be normally excreted in the urine).

·         The presence of the following, along with related findings, may help to further define the etiology of AKI: myoglobin or free hemoglobin (e.g., pigment nephropathy), increased serum uric acid level (e.g., tumor lysis syndrome), serum lactate dehydrogenase (LDH) (e.g., renal infarction).

·         Possible serologic tests include complement levels, antinuclear antibody (ANA), antineutrophil cytoplasmic antibody (ANCA), anti-glomerular basement membrane (anti-GBM) antibody, hepatitis B (HBV) and hepatitis C (HCV) virus studies, and antistreptolysin (ASO).

·         Urinalysis: findings of granular, muddy brown casts are highly suggestive of tubular necrosis. The presence of tubular cells or tubular cell casts also supports the diagnosis of ATN (acute tubular necrosis). 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 red blood cells (RBCs) on the microscopic examination. The dipstick assay may reveal significant proteinuria as a result of a tubular injury. The presence of RBCs in the urine is always pathologic. Eumorphic (with normal morphology) RBCs suggest bleeding along with the collecting system. Dysmorphic RBCs or RBC casts indicate glomerular inflammation, suggesting glomerulonephritis is present. The presence of white blood cells (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 (visualized with Wright stain or Hansel stain) suggests interstitial nephritis, however, it may also 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.

·          Emerging biomarkers: Creatinine elevation is a late marker for renal dysfunction and, once elevated, reflects a severe reduction in glomerular filtration rate (GFR). By the time serum creatinine is raised, the person may already have lost 50% of kidney function. Thus, some biomarkers are being investigated to stratify the risk and predict AKI in patients at risk for the disease.

·         The most promising biomarker to date is urinary neutrophil gelatinase-associated lipocalin (NGAL), which has been shown to detect AKI in patients undergoing cardiopulmonary bypass surgery

·         A study showed that combining the markers plasma B-type natriuretic peptide (BNP) and NGAL was a strong predictor of early AKI in patients with lower respiratory tract infection (the presence of a BNP level of over 267 pg/mL or an NGAL level of greater than 231 ng/mL correctly identified 15 of 16 early AKI patients, with a sensitivity of 94% and a specificity of 61%). In another study, the risk for worsened AKI stage or in-hospital death was approximately 3-fold higher for upper values than it was for lower ones for NGAL, kidney injury molecule-1 (KIM-1), interleukin-18 (IL-18), and microscopy score for casts and tubular cells. 

·         Cystatin C (see below) is also a promising biomarker.

·         The US Food and Drug Administration (FDA) has approved NephroCheck to evaluate the risk of developing moderate to severe AKI in hospitalized, critically ill patients. The test identifies the presence of two AKI-associated proteins (insulin-like growth factor binding protein 7 & tissue inhibitor of metalloproteinases). Based on the level of these proteins, a score is derived that indicates the likelihood that a patient will develop AKI within the next 12 hours. In 2 studies on critically ill patients, in patients with AKI, NephroCheck was 92% accurate in detecting the condition in one study and 76% accurate in the other. In both studies, however, the test reported false positives in about 50% of patients without AKI.

·         II) Other diagnostic approaches:

·         a) Bladder pressure.  An intra-abdominal pressure < 10 mm Hg is considered normal and suggests that abdominal compartment syndrome is not the cause of AKI. An intra-abdominal pressure > 10 mm Hg is abnormal, but patients who have pressures of 15 – 25 mm Hg are at particular risk for abdominal compartment syndrome, and those with bladder pressures > 25 mm Hg should be suspected of having AKI as a result of abdominal compartment syndrome.

·         b) Renal ultrasonography. In some cases, renal imaging is useful, especially if renal failure is secondary to obstruction. The American College of Radiology recommends ultrasonography, preferably with Doppler methods, as the most appropriate imaging method in AKI. Renal ultrasonography is useful for evaluating existing renal disease and obstruction of the urinary collecting system. Kidneys images can be technically challenging to be obtained in patients who are obese, and those with abdominal distention from ascites, gas, or retroperitoneal fluid collection.

·         c) Doppler ultrasonography. Doppler scans are useful for detecting the presence and nature of renal blood flow. Because renal blood flow is reduced in prerenal and intrarenal AKI, findings are of little use in the diagnosis of AKI. However, 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.

·         d) Radionuclide imaging with technetium-99m-mercaptoacetyltriglycine (99m Tc-MAG3),99m Tc-diethylenetriamine penta-acetic acid (99m Tc-DTPA), or iodine-131 (131 I)-hippurate can be used to assess renal blood flow, as well as tubular function. However, there is a marked delay in the tubular excretion of the radionuclide in prerenal and intrarenal AKI, limiting the value of nuclear scans.

·         e) Aortorenal angiography can be helpful in establishing the diagnosis of renal vascular diseases.

·          f) Renal biopsy. A renal biopsy can be useful in identifying intrarenal causes of AKI and can be justified if the results may change management (e.g., the start of immunosuppressive medications).

·         A renal biopsy may also be indicated when the renal function does not return for a prolonged period, and the prognosis is required to develop long-term management.

·         In as many as 40% of cases, renal biopsy results reveal an unexpected diagnosis.

·         g) Other imaging tests including CT and MRI, as indicated (e.g., suspected tumor).
·         http://i.ytimg.com/vi/1zonru8G0M4/hqdefault.jpg   (kidney ultrasound)


·         Biochemical markers on renal failure: 

·         Ι) GFR (glomerular filtration rate) categories in chronic kidney disease (CKD) (KDIGO classification) (GFR in ml/min/1.73 m2):

·         a) GFR >_90 (G1): normal or high.  

·         b) GFR 60 – 89 (G2): mildly decreased.  

·         c) GFR 45 – 59 (G3a): mildly to moderately decreased.

·         d) GFR 30 – 44 (G3b): moderate to severely decreased.

·         e) GFR 15 – 29 (G4): severely decreased.

·         f) GFR < 15 (G5): kidney failure.

·         Note: G1 & G2 is defined as CKD only in case of moderately or severely increased albuminuria.

·         ΙΙ) Albuminuria categories in chronic kidney disease (CKD) (KDIGO classification):

·         a) A1 category (normal to mildly increased): AER (albumin excretion rate) < 30 mg/dl; ACR (albumin – to creatinine – ratio) (approximate equivalent) < 3 mg/mmol or < 30 mg/g.

·         b) A2 category (moderately increased relative to young adult level): AER 30 – 300 mg/dl; ACR (approximate equivalent) 3 – 30 mg/mmol or 30 – 300 mg/g.

·         c) A3 category (severely increased, including nephrotic syndrome where albumin excretion is usually > 2 200 mg/d (ACR > 2 220 mg/d; > 220 mg/mmol)): AER > 300 mg/dl; ACR (approximate equivalent) > 30 mg/mmol or > 300 mg/g.  

·         ΙΙΙ) Criteria for chronic kidney disease (CKD) (KDIGO classification) (either of the following criteria has to be present for > 3 months):

·         i) Markers of kidney damage (>_1):

·         a) Albuminuria. AER (albumin excretion rate) >_ 30 mg/dl; ACR (albumin – to creatinine – ratio) >_ 30 mg/g (>_3 mg/mmol/l).

·         b) Urine sediment abnormalities.

·         c) Electrolyte & other abnormalities due to tubular disorders. d) Abnormalities detected by histology (renal biopsy).

·         e) Structural abnormalities detected by imaging.

·         f) History of kidney transplantation.

·         ii) Decreased GFR (GFR < 60 ml/min/1.73 m2).

·         IV) Βlood urea nitrogen (BUN) and creatinine:

·         Although increased levels of blood urea nitrogen (BUN) and creatinine are the hallmarks of renal failure, the rate of rising depends on the degree of renal insult and, with respect to BUN, on protein intake. BUN may be elevated in patients with gastrointestinal (GI) or mucosal bleeding, steroid treatment, or protein loading. 

·          The ratio of BUN to creatinine can exceed 20:1 in conditions in which enhanced reabsorption of urea is favored (e.g., in volume contraction); this suggests prerenal AKI.
·         Creatinine elevation is a late marker for renal dysfunction and, once elevated, reflects a severe reduction in glomerular filtration rate (GFR). By the time serum creatinine is elevated, the person may already have lost 50% of kidney function.

·         V) Renal failure index (RFI):

·         It is estimated with the formula
·         RFI (%) = urine sodium / urine creatinine / serum creatinine  

·         It is used to differentiate between renal and prerenal acute kidney injury (AKI). RFI > 1% (> 0.01 fraction) indicates renal causes. RFI < 1% (< 0.01 fraction) indicates prerenal causes. 

·         Renal failure diagnostic indices:

·         a) FENa (%) (fractional excretion of sodium):  < 1% on prerenal causes; > 1% on renal causes (see also above: fractional excretion of sodium). 

·         b) FEUrea (%) (fractional excretion of urea): < 20 – 30 % on prerenal causes; > 40 – 70 % on renal causes.

·         c) Renal failure Index (RFI): < 1% on prerenal causes; > 1% on renal causes. 

·         d) FEUric acid (%) (fractional excretion of uric acid): < 10% on prerenal causes; > 10 % on renal causes.

·         e) BUN (blood urea nitrogen)/ creatinine serum (fraction):  > 20 on prerenal causes; < 10 – 15 on renal causes. The ratio BUN/ creatinine increases on AKI (acute kidney injury), GI (gastrointestinal) bleeding, elderly people, hypercatabolic states, high doses of glucocorticoids, and on resorption of large hematomas. 

·         f) Serum Urea/ creatinine: On prerenal causes urea/ creatinine > 100; on renal causes urea/ creatinine < 40.

·         g) Creatinine urine/ creatinine serum (fraction):    > 40 on prerenal causes; < 20 on renal causes.

·         h) UUN (urine urea nitrogen)/ BUN (blood urea nitrogen) (fraction):  > 8 on prerenal causes; < 3 on renal causes.

·         i) Urine/ plasma osmolality (mOsm/kg) (fraction): > 1.3 on prerenal causes; < 1.1 on renal causes.

·         j) Urine sodium (Na+) (mmol/L): < 10 on prerenal causes; > 20 on renal causes.

·         k) Urine osmolality (mOsm/kg): > 500 on prerenal causes; < 250 on renal causes. On intrinsic acute kidney injury (AKI) urine osmolality is 250 – 300 mOsm.

·         l) Urine specific gravity: >1 018 on prerenal causes; < 1 012 on renal causes.

·         m) Urine sediment:  hyaline casts on prerenal causes; muddy brown granular casts on renal causes.


·         Blood Urea Nitrogen (BUN): The liver produces urea in the urea cycle as a waste product of the digestion of protein. Normal human adult blood should contain between 6 – 20 mg of urea nitrogen/100 ml (6–20 mg/ dl) of blood. Individual laboratories may have different reference ranges. BUN is estimated with the equation                                                                                                       BUN (mg/dl) = 0.466 x urea (mg/dl) or BUN (mg/dl) = urea (mg/dl)/ 2.1428
·          Blood urea nitrogen (BUN) is an indication of kidney health.
·         Normal ranges are 1.8 – 7.1 mmol/L. 

·         Causes of increased BUN:  increased BUN levels suggest impaired kidney function due to acute or chronic kidney disease, damage, or failure.
·         It may also be due to a condition that results in decreased blood flow to the kidneys, such as congestive heart failure (CHF), shock, reduced blood volume (hypovolemia), stress, recent heart attack, severe burns, conditions that cause obstruction of urine flow, and also dehydration. BUN concentrations may also be elevated when there is excessive protein breakdown (catabolism), significantly increased protein in the diet, or gastrointestinal bleeding (because of the proteins present in the blood). Also, a wide variety of drugs can cause an increase in BUN. Drugs that can increase BUN include the antibiotics chloramphenicol and streptomycin (used, e.g., for tuberculosis (TB)). BUN may also increase fever and catabolism.

·         Causes of decreased BUN: low BUN levels are not common and are not usually a cause for concern. They may be seen in severe liver disease, malnutrition, and sometimes when a person is overhydrated (too much fluid volume), however, the BUN test is not usually used to diagnose or monitor these conditions. BUN may also be decreased in anabolic state, and on the syndrome of inappropriate antidiuretic hormone (SIADH).

·         Another cause of a reduced BUN is ornithine transcarbamylase deficiency, a genetic disorder inherited in an X-linked recessive pattern which is also accompanied by hyperammonemia and high orotic acid levels.

·         Note:
·         a) Both decreased and increased BUN concentrations may be seen during normal pregnancy.

·         b) If one kidney is fully functional, BUN concentrations may be normal even when significant dysfunction is present in the other kidney.

·         c) BUN levels can increase with the amount of protein in the diet. High-protein diets may cause abnormally high BUN levels while very low-protein diets can cause an abnormally low BUN.


·         Urea to BUN (blood urea nitrogen) conversion calculator:


·         Urine urea nitrogen (UUN):  Urea nitrogen is the end product of the breakdown of proteins in the body. In individuals with normal kidney and liver functions, urea is excreted via urine. When the body breaks down protein, one of the waste products is ammonia, which contains nitrogen. The nitrogen mixes with other elements in the body and forms urea, which is a waste product. Urea is then excreted by the kidneys and then in the urine.

·         The urine urea nitrogen (UUN) test determines how much urea is in the urine to assess the amount of protein breakdown.

·         The test can help determine how well the kidneys are functioning, and if the intake of protein is too high or low. Most commonly a doctor will recommend a urea test to determine protein levels in the body. The test can determine how much protein someone is eating and if it is an adequate amount. Urea nitrogen levels may also rise on heart failure or dehydration. The urine urea nitrogen test is performed by collecting a 24-hour urine sample. A normal urea level in the urine is 12 to 20 grams over 24 hours. 

·         Causes of low levels of urea in the urine: malnutrition; too little protein in the diet; kidney problems.

·          Causes of high levels of urea in the urine: too much protein in the diet; too much protein breakdown in the body.

·         Note: As UUN test is based on 24-hour urine, in individuals with kidney disease with less than 1,000 ml of urine out/day or on dialysis, this test cannot be applied.


·         Nitrogen balance: By testing for UUN, clinicians can assess one's nitrogen balance.
·         Calculating nitrogen balance is a useful tool in assessing the adequacy of protein provision in:
·          a) Patients with questionable protein intake.
·         b) Patients with confirmed or suspected protein digestion and absorption problems.
·         c) Patients with increased metabolic demand due to catabolic disease status.
·         d) Patients on long-term enteral nutrition or parenteral nutrition.
·         The formula is:
                                                                                                                                                 Nitrogen Balance = Protein intake/6.25- (UUN + 4* + 6 for every L output). 

·         * For average loss via sweat.
·         Also, the formula:
                                                                                                                                          
(24 Hour Protein Intake (Total grams)/6.25) – (24 Hour Urinary Urea Nitrogen + 4).

Nitrogen balance value of 0 indicates maintenance. If nitrogen balance is negative, nutrition intervention should address increased protein provision until equilibrium is achieved.

·         Nitrogen balance calculator:

·         Protein intake calculator:


·         Creatinine Clearance (CCr): the definition and staging of chronic kidney disease depend on the assessment of glomerular filtration rate (GFR).

·         Inulin clearance is widely regarded as the gold standard for measuring GFR, but requires an intravenous infusion and timed urine collection making it costly and cumbersome. The most widely used measures of GFR in clinical practice are the serum creatinine concentration and the 24-hour creatinine clearance calculation.

·         The formula for the creatinine clearance is:                                                                             Creatinine Clearance  = Urine Creatinine x  24h Urine Volume/  serum Creatinine x 1440           
·         The diagnostic usefulness of serum creatinine as an indicator of glomerular filtration rate (GFR) is based upon its constant production from muscle creatine and its relatively constant renal excretion rate. About 1 – 2% of the creatine in muscle is converted to creatinine daily. The amount of creatinine formed is proportional to muscle mass, resulting in differences in serum creatinine concentration related to age, gender, and race.

·         Serum creatinine is decreased in individuals with small stature, cachexia, amputations, muscle disease, vegetarian diets, and advanced liver disease (the last causes low serum creatinine because of decreased hepatic conversion of creatine to creatinine).

·         Serum creatinine is a relatively insensitive indicator of renal disease. A change in serum creatinine from 0.6 – 1.2 mg/dL reflects a 50% decline in GFR, even though creatinine is still within the normal range.

·         Calculation of CCr requires the collection of 24-hour urine and a blood sample during the same interval.

·         The accuracy of the CCr calculation depends on the quality of the 24-hour collection. Errors often occur during collection, transportation, or processing.

·         CCr overestimates GFR by 10 to 40% in normal individuals and is even more unpredictable in patients with chronic kidney disease.

·         CCr may not be an accurate estimate of GFR in the following situations:

·         a) It is overestimated on liver cirrhosis, muscle wasting, malnutrition, vegetarian diet, obesity, and edema.

·         b) It is underestimated on bodybuilding, anabolic steroids use, protein & creatinine supplements, congestive heart failure (CHF), dehydration, and the medications trimethoprim (an antibiotic, usually combined with sulfamethoxazole and used e.g. on urinary tract infections (UTIs); also used on Pneumocystis jiroveci infections e.g. on patients HIV positive) and cimetidine (a histamine H2 – receptor antagonist that inhibits stomach acid production; largely used in the treatment of heartburn & peptic ulcer disease).

·         Measurement of creatinine clearance using a 24-hour urine collection is no more accurate than a GFR prediction equation.

·         Creatinine clearance is a better estimate of GFR for patients with exceptional dietary intakes (vegetarian diet or creatine supplements) or muscle mass (amputation, muscle wasting, malnutrition).
·    The Cockcroft-Gault equation for calculating creatinine clearance is:                                          Ccr (mL/min) = (140 – age) (weight in kg) (0.85 if female)/72 x serum creatinine

·         Creatinine clearance calculators:
·         Simple calculator:
·         Corrected creatinine clearance (for body surface area, weight & height) calculator:
·         Corrected creatinine clearance (for sex, age, weight) calculator:
·         Corrected creatinine clearance (for sex, age, weight) calculator (Cockcroft-Gault Equation):
·         Corrected creatinine clearance (for sex, age, weight & height) calculator (Cockcroft-Gault Equation):


·         Cystatin C:  Cystatin C may be used as an alternative to creatinine & creatinine clearance to screen and monitor kidney dysfunction in those with known or suspected renal (kidney) disease. It may be especially useful in those cases where creatinine measurement is not appropriate, for instance, in those who have liver cirrhosis, are very obese, are malnourished, or have reduced muscle mass.

·         Measuring cystatin C may also be useful in the early detection of kidney disease when other test results may still be normal, and an affected person may have few, if any, symptoms. A recent study found that an equation for eGFR that includes both creatinine and cystatin C was more accurate than one that uses either of these alone and could be used to confirm chronic kidney disease (CKD) in people with an eGFR near 60, the threshold for CKD.

·         Interpretation: a high level of cystatin C in the blood corresponds to a decreased glomerular filtration rate (GFR) and to kidney dysfunction (since cystatin C is produced throughout the body at a constant rate and removed and broken down by the kidneys, it should remain at a steady level in the blood if the kidneys are working efficiently and the GFR is normal). Increased levels of cystatin C may also indicate an increased risk of heart disease, heart failure, stroke, and mortality. In addition to kidney dysfunction, cystatin C has been associated with an increased risk of cardiovascular disease and heart failure in older adults.

·         Corticosteroids can increase levels cystatin C levels, while cyclosporine (an immunosuppressant) can decrease them. Cystatin C has been associated with hyperhomocysteinemia (increased blood homocysteine), which is often found in kidney transplant patients, and it has been shown to increase with the progression of liver disease. Also, a study compared cystatin C levels in serum with that found in pleural effusion to help determine the cause of the effusion. In the absence of kidney disease, cystatin C levels may be elevated in rheumatic diseases and also in malignant diseases, although they are not affected by tumor burden (the amount of cancer that someone has).


·         Fractional excretion of uric acid (FEUa): It is measured with the formula                                                                                   FEuric acid (FEUa)%= (Urine uric acid x plasma Creatinine) / (Plasma uric acid x Urine Creatinine)           

·         It is used to differentiate between renal and prerenal acute kidney injury (AKI).

·         FEUa > 10% (>0.1 fraction) indicates SIADH or renal causes (including acute tubular necrosis (ATN)).
·         FEUa < 10% (<0.1 fraction) indicates prerenal causes.

·         Fractional excretion of uric acid is not affected by the loop or thiazide diuretics.

·         In a study of 46 patients with AKI (acute kidney injury) cited in the preceding section, fractional excretion of uric acid < 12% was suggestive of prerenal disease (sensitivity 68% percent [much lower than the sensitivity of the FELi (fractional excretion of lithium) in the same study], specificity 78%), while values > 20% were highly suggestive of ATN), although the specificity was low (sensitivity 96%, specificity 33%). In another study, 86 consecutive hyponatremic patients (serum Na <130 mmol/liter) were classified based on their history, clinical evaluation, osmolality, and saline response to isotonic saline into a SIAD (syndrome of inappropriate antidiuresis) and a non-SIAD group. A total of 31 patients (36%) had a diagnosis of SIAD, and 55 (64%) were classified as non-SIAD. There were 57 patients (68%) who were on diuretics. In the absence of diuretic therapy, SIAD was accurately diagnosed using U-Na (urinary sodium (Na) excretion). However, in patients on diuretics, the diagnosis was unreliable. There, FE-UA (fractional excretion of uric acid) performed best compared with all other markers tested, resulting in a positive predictive value of 100% if a cutoff value of 12% was used. The study concluded that FE-UA allows the diagnosis of SIAD (syndrome of inappropriate antidiuresis) with excellent specificity. Combining the information on U-Na (urinary sodium (Na) excretion) and FE-UA (fractional excretion of uric acid) leads to a very high diagnostic accuracy in hyponatremic patients with and without diuretic treatment.

·         Fractional excretion of uric acid calculator:  

·         Diagnostic approach of acute kidney injury (AKI) (algorithm):


·         GFR (glomerular filtration rate) calculators:
·         Calculator including cystatin C:
·         http://touchcalc.com/e_gfr
·         Cockroft – Gault GFR & MDRD GFR:
·         http://medcalc.com/gfr.html
·         estimated GFR (eGFR):
·         Cockroft – Gault GFR:
·         MDRD GFR:
·         http://nephron.org/mdrd_gfr_si
·         Paediatric GFR calculator (including cystatin C):
·         Renal failure diagnostic calculators:
·         Multicalculator:
·         Renal failure index:  


         OTHER KIDNEY PROBLEMS

·         Fanconi’s syndrome: it should not be confused with Fanconi’s anemia.  Renal Fanconi syndrome refers to the generalized dysfunction of the proximal tubule. In its isolated form, renal Fanconi syndrome only affects the proximal tubule and not the other nephron segments. Fanconi's syndrome may be inherited or acquired.

·         It leads to aminoaciduria, glycosuria, phosphaturia, renal tubular acidosis (RTA) type 2 (proximal), hypophosphataemic rickets (children), or osteomalacia (adults), and renal glycosuria.  

·         The incidence of each cause of Fanconi's syndrome is different, although almost all of them are somewhat rare. Fanconi's syndrome may occur at any age, again according to the cause.
·         Cystinosis occurs almost exclusively in Caucasians.  

·         Causes: renal Fanconi syndrome is caused by a variety of predominantly rare causes:

·         I) Inherited:

·         a) Primary idiopathic: sporadic or familial (autosomal dominant - chromosome 15). Occurs in the absence of any identifiable cause, and most cases are sporadic. Some cases are inherited, but the mode of inheritance appears to be variable (autosomal-dominant, autosomal-recessive, X-linked).

·         b) Secondary: cystinosis, tyrosinemia, Wilson's disease, Lowe's syndrome (oculo-cerebro-renal syndrome that includes bilateral congenital cataracts, glaucoma, general hypotonia, hyporeflexia, severe learning disability, and Fanconi's syndrome), galactosemia, fructose intolerance, glycogen storage disorders, and mitochondrial cytopathies.

·         II) Acquired:

·         a) Intrinsic renal disease: acute tubular necrosis, interstitial nephritis, hypokalaemic nephropathy, myeloma, amyloidosis, Sjogren's syndrome, and rejected transplant.

·         b) Endocrinological problems: Hyperparathyroidism.

·         c) Drugs such as cisplatin, ifosfamide, tenofovir, sodium valproate, aminoglycoside antibiotics, and deferasirox.

·         d) Toxins: glue sniffing, heavy metals, bee stings. 

·         Signs & symptoms:  polyuria, polydipsia, and episodes of dehydration (sometimes associated with fever), bone deformities (rickets in children or osteomalacia in adults).
·         Its pathogenesis includes excessive urinary losses of calcium and phosphate and of a defect in the hydroxylation of 25-hydroxyvitamin D3 into 1,25-dihydroxy vitamin D3.

·         Investigations: The diagnosis is based on excessive loss of substances in the urine (e.g., amino acids, glucose, phosphate, bicarbonate) in the absence of high plasma concentrations. Further investigations are required to identify the cause. Other characteristics are proteinuria (usually, however, only in small quantities), hypokalemia, hypophosphatemia, and hyperchloraemic metabolic acidosis


·         Renal tubular acidosis (RTA): is acidosis and electrolyte disturbances due to impaired renal hydrogen ion excretion (type 1), impaired HCO3 resorption (type 2), or abnormal aldosterone production or response (type 4). Type 3 is extremely rare.

·         RTA defines a class of disorders in which excretion of hydrogen ions or reabsorption of filtered HCO3 is impaired, leading to chronic metabolic acidosis with a normal anion gap. Hyperchloremia is usually present, and secondary derangements may involve other electrolytes, such as potassium (frequently) and calcium (rarely). Chronic RTA is often associated with structural damage to renal tubules and may progress to chronic kidney disease.


·         Features – Overview of RTAs:

·         a) Type 1: incidence: rare; location: distal tubules; mechanism: impaired H+ (hydrogen ion) excretion in the distal tubule, resulting in a persistently high urine pH (> 5.5) and systemic acidosis.  [mechanism: failure of H+ secretion by the alpha-intercalated cells and reclaim potassium]; acidemia: yes (severe); plasma HCO3 (mEq/L): usually < 15, often < 10; plasma potassium: usually low (hypokalemia), but tends to normalize with alkalinization; urine PH: < 5.5. Hypercalciuria and decreased citrate excretion are often present. Hypercalciuria is the primary abnormality in some familial cases, with calcium-induced tubulointerstitial damage causing distal RTA. Nephrocalcinosis and nephrolithiasis are possible complications of hypercalciuria and hypocitraturia if urine is relatively alkaline.

·         This syndrome is rare. Sporadic cases occur most often in adults and may be primary (nearly always in women) or secondary. Familial cases usually first manifest in childhood and are most often autosomal dominant. Secondary type 1 RTA may result from various disorders including autoimmune disease with hypergammaglobulinemia, particularly Sjogren syndrome or rheumatoid arthritis (RA); kidney transplantation; nephrocalcinosis; medullary sponge kidney; chronic obstructive uropathy; medications (especially amphotericin B, ifosfamide, and lithium); liver cirrhosis; and sickle cell anemia. Potassium levels may be high in patients with chronic obstructive uropathy or sickle cell anemia.

·         b) Type 2: incidence: very rare; location: proximal tubules; mechanism: impaired HCO3 excretion in the proximal tubules, producing a urine pH > 7 if plasma HCO3 concentration is normal, and a urine pH < 5.5 if plasma HCO3 level is already depleted as a result of ongoing losses [mechanism: failed HCO3reabsorption from the urine by the proximal tubular cells]; acidemia: yes; plasma HCO3 (mEq/L): usually 12 – 20; plasma potassium: usually low (hypokalemia) and decreased further by alkalinization; urine PH: > 7 if plasma HCO3 is normal; < 5.5 if plasma HCO3 is depleted (e.g. < 15 mEq/L). This syndrome may occur as part of a generalized dysfunction of proximal tubules and patients can have increased urinary excretion of glucose, uric acid, phosphate, amino acids, citrate, Calcium, potassium, and protein. Osteomalacia or osteopenia (including rickets in children) may develop. Mechanisms may include hypercalciuria, hyperphosphaturia, alterations in vitamin D metabolism, and secondary hyperparathyroidism. Type 2 RTA is scarce and most often occurs in patients with Fanconi syndrome (see above), or light chain nephropathy due to multiple myeloma. It may also occur in patients taking medications such as acetazolamide, sulfonamides, ifosfamide, outdated tetracycline, or streptozocin. Other etiologies include vitamin D deficiency, chronic hypocalcemia with secondary hyperparathyroidism, kidney transplantation, heavy metal exposure, and other inherited diseases such as fructose intolerance, Wilson disease, oculo-cerebro-renal syndrome (Lowe syndrome), and cystinosis.

·         c) Type 4: incidence: common; location: adrenal; mechanism: decrease in aldosterone secretion or activity; results from aldosterone deficiency or unresponsiveness of the distal tubule to aldosterone. Because aldosterone triggers sodium resorption in exchange for potassium and hydrogen, there is reduced potassium excretion, causing hyperkalemia, and reduced acid excretion. Hyperkalemia may decrease ammonia excretion, contributing to metabolic acidosis. Acidemia: mild when present [mechanism: deficiency of aldosterone, or a resistance to its effects (hypoaldosteronism or pseudohypoaldosteronism)]; plasma HCO3 (mEq/L): usually> 17; plasma potassium: high (hyperkalemia). Urine pH is usually appropriate for serum pH (usually < 5.5 when there is serum acidosis). Plasma HCO3 is usually > 17 mEq/L. It is the most common type of RTA. It typically occurs sporadically secondary to impairment in the renin-aldosterone-renal tubule axis (hyporeninemic hypoaldosteronism), which occurs in patients with: diabetic nephropathy; or chronic interstitial nephritis. It may also be related to ACE inhibitor use; aldosterone synthase type I or II deficiency; angiotensin II receptor blocker use; chronic kidney disease (usually due to diabetic nephropathy or chronic interstitial nephritis); congenital adrenal hyperplasia (particularly 21-hydroxylase deficiency); critical illness; medications such as cyclosporine, heparin (including low molecular weight heparins), NSAIDs (non – steroidal anti-inflammatory drugs), potassium-sparing diuretics (such as amiloride, eplerenone, spironolactone, triamterene), or other drugs (including pentamidine and trimethoprim); HIV nephropathy (due, possibly in part, to infection with Mycobacterium avium complex or cytomegalovirus (CMV)); interstitial renal damage (eg, due to SLE (systemic lupus erythematosus), obstructive uropathy, or sickle cell disease; primary adrenal insufficiency; pseudohypoaldosteronism (type I or II) and volume expansion (eg, in acute glomerulonephritis or chronic kidney disease).

·         Type 3 RTA: In some patients, RTA shares features of both dRTA and pRTA. This rare pattern was observed in the 1960s and 1970s as a transient phenomenon in infants and children with dRTA (possibly in relation to some exogenous factor such as high salt intake) and is no longer observed. This form of RTA has also been referred to as juvenile RTA. Combined dRTA and pRTA is also found as the result of inherited carbonic anhydrase II deficiency. Mutations in the gene encoding this enzyme give rise to an autosomal recessive syndrome of osteopetrosis (an extremely rare inherited disorder in which the bones harden, becoming denser; it can cause bones to dissolve and break); renal tubular acidosis, cerebral calcification, and mental retardation. It is very rare, and cases from all over the world have been reported, of which about 70% are from the Maghreb region of North Africa, possibly due to the high prevalence of consanguinity. There is no treatment for osteopetrosis or cerebral calcification.

·         Signs & symptoms: RTA is usually asymptomatic. However, bone involvement (e.g., bone pain and osteomalacia in adults and rickets in children) may occur in type 2 and sometimes in type 1 RTA. Nephrolithiasis and nephrocalcinosis are possible, particularly with type 1 RTA. Severe electrolyte disturbances are rare but can be life-threatening. People with type 1 or type 2 RTA may show symptoms and signs of hypokalemia, including muscle weakness, hyporeflexia, and paralysis. Type 4 RTA is usually asymptomatic with only mild acidosis, but cardiac arrhythmias or paralysis may develop if hyperkalemia is severe. Signs of ECF (extracellular fluid) volume depletion may develop from urinary water loss accompanying electrolyte excretion in type 2 RTA.

·         Diagnosis:  RTA is suspected in any patient with unexplained metabolic acidosis (low plasma HCΟ3 and low blood pH) with a normal anion gap.

·         Type 4 RTA should be suspected in patients who have persistent hyperkalemia with no apparent cause, such as potassium supplements, potassium-sparing diuretics, or chronic kidney disease.

·         Type 1 RTA is confirmed by a urine pH that remains > 5.5 during systemic acidosis. The acidosis may occur spontaneously or be induced by an acid load test (administration of ammonium Cl, 100 mg/kg PO). Normal kidneys reduce urine pH to < 5.2 within 6 hours of acidosis.

·         Type 2 RTA is diagnosed by measurement of the urine pH and fractional HCO3 excretion during an HCO3 infusion (NaHCO3, 0.5 to 1.0 mEq/kg/h IV). In type 2, urine pH rises above 7.5, and the fractional excretion of HCO3 is > 15%. Note: because IV (intravenous) HCO3 can contribute to hypokalemia, potassium supplements should be given in adequate amounts before infusion.

·         Type 4 RTA is confirmed by a trans-tubular potassium concentration gradient of < 5 (normal value > 10 if serum potassium is high), which indicates inappropriately low urinary potassium excretion, suggesting hypoaldosteronism or tubular unresponsiveness to aldosterone. Calculation of the gradient assumes that the urine sodium is > 25 mEq/L and urine osmolality is greater than serum. It is calculated by the formula:

·         Transtubular potassium gradient= (urine potassium/ plasma potassium)/ (urine osmolality/ plasma osmolality)

·         On type 4 RTA, definitive diagnosis of hyporeninemic hypoaldosteronism can be obtained by measuring plasma renin and aldosterone levels after provocation (e.g., administering a loop diuretic and having the patient remain upright for 3 hours) but is usually not necessary.


·         Renal tubular acidosis diagnostic algorithm:

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