Clinical Skills

Acute Potassium Disorders

July 15, 2017 Cardiology, Clinical Skills, Critical Care, Differential Diagnosis, EKG/ECG No comments , , , , ,

Disorders of potassium homeostasis are common in hospitalized patients and may be associated with severe adverse clinical outcomes, including death. Prevention and proper treatment of hyper- and hypokalemia depend on an understanding of the underlying physiology.

The total body potassium content of a 70-kg adult is about 3500 mmol (136.5 g), of which only 2% (about 70 mmol / 2.73 g) is extracellular. It is not surprising that the extracellular potassium concentration is tightly regulated. In fact, two separate and cooperative systems participate in potassium homeostasis. One system regulates external potassium balance: the total body parity of potassium elimination with potassium intake. The other system regulates internal potassium balance: the distribution of potassium between the intracellular and extracellular fluid compartments. This latter system provides a short-term defense against changes in the plasma potassium concentration that might otherwise result from total body potassium losses or gains.

Disorders of Potassium Homeostasis

Disorders of potassium homeostasis may be conveniently divided according to the duration of the disturbance: acute (<48 hours’ duration) or chronic.

Acute Hyperkalemia

Excessive potassium intake. Given an acute potassium load, a normal individual will excrete about 50% in the urine and transport about 90% of the remainder into cells over 4 to 6 hours. It is possible to overwhelm this adaptive mechanism such that if too much potassium is taken in too quickly, significant hyperkalemia will result. Such events are almost always iatrogenic. One’s ability to tolerate a potassium load declines with disordered internal balance and impaired renal potassium excretory capacity. In such circumstances, an otherwise tolerable increase in potassium intake may cause clinically significant hyperkalemia: Doses of oral potassium supplements as small as 30 to 45 mmol have resulted in severe hyperkalemia in patients with impaired external or internal potassium homeostasis.

KCl, used as a supplement, is the drug most commonly implicated in acute hyperkalemia. Banked blood represents a trivial potassium load under most circumstances, because a unit of fresh banked blood, either whole or packed cells, contains only 7 mmol (273 mg) of potassium. Thus, severe hyperkalemia would result only from massive transfusion of compatible blood. However, the potassium concentration in banked blood does increase substantially as the blood ages.

Patients undergoing open heart surgery are exposed to cardioplegic, solutions containing KCl typically at about 16 mmol/L, which may lead to clinically significant hyperkalemia in the postoperative period, especially in patients with diabetes mellitus with or without renal failure.

Abnormal potassium distribution. Acute hyperkalemia may result from sudden redistribution of intracellular potassium to the extracellular space. If only 2% of intracellular potassium were to leak unopposed from cells, serum potassium level would immediately double. Fortunately, such dramatic circumstances are rarely encountered. Nevertheless, smaller degrees of potassium redistribution commonly result in clinically significant hyperkalemia.

Among the most impressive syndromes associated with acute hyperkalemia are those involving rapid cell lysis. The tumor lysis syndrome results from treatment of chemosensitive bulky tumors with release of intracellular contents, including potassium, into the ECF. Extreme hyperkalemia even causing sudden death has featured prominently in some series of patients. Most of such patients were in renal failure from acute uric acid nephropathy, thus impairing their ability to excrete the potassium load. Rhabdomylosis, either traumatic or nontraumatic, may result in sudden massive influx of potassium to the extracellular space. Other circumstances that may result in redistributive hyperkalemia include severe extensive burns, hemolytic transfusion reactions, and mesenteric ischemia or infarction.

Pharmacologic agents. Two drugs may rarely cause acute hyperkalemia by redistribution: digitalis glycosides and succinylcholine. Massive digitalis overdose has been associated with extreme hyperkalemia. Succinylcholine depolarizes the motor end plate and in normal individuals causes a trivial amount of potassium leak from muscle, resulting in an increase in serum potassium level by about 0.5 mmol/L. In patients with neuromuscular disorders, muscle damage, or prolonged immobilization, however, muscle depolarization may be more widespread, causing severe hyperkalemia. Prolonged use of nondepolarizing non depolarizing neuromuscular blockers in critically ill patients may predispose to succinylcholine-induced hyperkalemia.

Hyperkalemic periodic paralysis. This rare syndrome of episodic hyperkalemia and paralysis is caused by a mutation of the skeletal muscle sodium channel, inherited in an autosomal dominant pattern. Attacks may be precipitated by exercise, fasting, exposure to cold, and potassium administration, and prevented by frequent carbohydrate snacks. Attacks are usually brief and treatment consists of carbohydrate ingestion. Severe attacks may require intravenous glucose infusion.

Acute renal failure. Hyperkalemia accompanies acute renal failure in 30% to 50% of cases. It is seen most commonly in oliguric renal failure. Contributing factors include tissue destruction and increased catabolism.

Pseudohyperkalemia. It refers to a measured potassium level that is higher than that circulating in the patient’s blood. It has a number of possible causes. First, it may be caused by efflux of potassium out of blood cells in the test tube after phlebotomy. This may be seen in a serum specimen in cases of thrombocytosis or leukocytosis, when the clot causes cell lysis in vitro. These days, many clinical laboratories measure electrolytes in plasma (unclotted) specimens. Even under these conditions, extreme leukocytosis may cause pseudohyperkalemia if the specimen is chilled for a long time before the plasma is separated, leading to passive potassium leak from cells. Hemolysis during specimen collection with false raise [K+] or plasma potassium concentration by liberating intraerythrocyte to potassium. Second, if the patient’s arm is exercised by fist clenching with a tourniquet in place before the specimen is drawn, the sampled blood potassium concentration will rise significantly as a result of local muscle release of intracellular potassium.

Acute Hypokalemia

Treatment of diabetic ketoacidosis. It is well recognized that patients presenting in DKA are always severely depleted in total body potassium as a result of glucose-driven osmotic diuresis, poor nutrition, and vomiting during the development of DKA. Paradoxically, most patients in DKA have a normal serum potassium level upon admission. Insulin deficiency and hyperglycemia appear to account for the preservation of a normal [K+] despite severe total body potassium depletion. Once therapy for DKA is instituted, however, [K+] typically plummets as potassium is rapidly taken up by cells. Potassium replacement at rates up to 120 mmol (4.68 g) per hour have been reported, with total potassium supplementation of 600 to 800 mmol (23.5 to 31.2 g) within the first 24 hours of treatment. Hypokalemia in this setting may lead to respiratory arrest.

Refeeding. A situation analogous to DKA arises during aggressive refeeding after prolonged starvation or with aggressive “hyperalimentation” of chronically ill patients. The glucose-stimulated hyperinsulinemia and tissue anabolism shift potassium into cells, rapidly depleting extracellular potassium.

Pharmacologic agents. Specific beta2-adrenergic receptor agonists may cause electrophysiologically significant hypokalemia, especially when given to patients who are potassium depleted from the use of diuretic drugs. Epinephrine, given intravenously in a dose about 5% of that recommended for cardiac resuscitation, cause a fall in [K+] by about 1 mmol/L. A rare cause of severe hypokalemia is poisoning with soluble barium salts such as chloride, carbonate, hydroxide, and sulfide. Soluble barium salts are used in pesticides and some depilatories, which may be ingested accidentally or intentionally. Thiopentone, a barbiturate used to induce coma for refractory intracranial hypertension, is associated with redistributive hypokalemia in the majority of treated patients within 12 hours of initiating therapy.

Hypokalemic periodic paralysis. Three forms of this rare syndrome have been described: familial, sporadic, and thyrotoxic. All have in common attacks of muscle weakness accompanied by acute hypokalemia caused by cellular potassium uptake.

Pseudohypokalemia. Severe leukocytosis may cause spuriously low plasma potassium concentrations if blood cells are left in contact with the plasma for a long time at room temperature or higher. This phenomenon results from ongoing cell metabolism in vitro with glucose and potassium uptake. Unexpected hypokalemia and hypoglycemia in the setting of leukocytosis should alert the clinician to this phenomenon.


Potassium exchange between ECF and ICF: insulin, epinephrine, and [H+]

Potassium renal secretion: [K+], dietary intake of potassium, AngII, aldosterone, tubular sodium delivered to principal cells (at distal nephron).

EKG Changes of Potassium Disturbances



Hyperkalemia produces a progressive evaluation of changes in the EKG that can culminate in ventricular fibrillation and death. The presence of electrocardiographic changes is a better measure of clinically significant potassium toxicity than the serum potassium level. As the potassium begins to rise, the T waves across the entire 12-lead EKG begin to peak. This effect can easily be confused with the peaked T waves of an acute myocardial infarction. One difference is that the changes in an infarction are confined to those leads overlying the area of the infarct, whereas in hyperkalemia, the changes are diffuse. With a further increase in the serum potassium, the PR interval becomes prolonged, and the P wave gradually flattens and then disappears. Ultimately, the QRS complex widens until it merges with the T wave, forming a sine wave pattern. Ventricular fibrillation may eventually develop.

It is important to note that whereas these changes frequently do occur in the order described as the serum potassium rises, they do not always do so. Progression to ventricular fibrillation can occur with devastating suddenness. Any change in the EKG due to hyperkalemia mandates immediate clinical attention.


With hypokalemia, the EKG may again be a better measure of serious toxicity than the serum potassium level. Three changes can be seen, occurring in no particular order, including: ST-segment depression, flattening of the T wave with prolongation of the QT interval, and appearance of a U wave. The term U wave is given to a wave appearing after T wave in the cardiac cycle. It is usually has the same axis as the T wave and is often best seen in the anterior leads. Its precise physiologic meaning is not fully understood. Although U waves are the most characteristic feature of hypokalemia, they are not in and of themselves diagnostic. Other conditions can produce prominent U waves, and U waves can sometimes be seen in patients with normal hearts and normal serum potassium levels. Rarely, severe hypokalemia can cause ST-segment elevation. Whenever you see ST-segment elevation or depression on an EKG, you first instinct should always be to suspect some form of cardiac ischemia, but always keep hypokalemia in your differential diagnosis.

Evaluation of Renal Function

May 3, 2017 Clinical Skills, Critical Care, Nephrology No comments , , , , , , , ,

Assessment of kidney function using both qualitative and quantitative methods is an important part of the evaluation of patients and an essential characterization of individuals who participate in clinical research investigations. Estimating of creatinine clearance has been considered the clinical standard for assessment of kidney function for nearly 50 years, and continues to be used as the primary method of stratifying kidney function in drug pharmacokinetic studies submitted to the United States Food and Drug Administration (FDA). New equations to estimate glomerular filtration rate (GFR) are now used in many clinical settings to identify patients with CKD, and in large epidemiology studies to evaluate risks of mortality and progression to stage 5 CKD, that is , ESKD. Other tests, such as urinalysis, radiographic procedures, and biopsy, are also valuable tools in the assessment of kidney disease, and these qualitative assessments are useful for determining the pathology and etiology of kidney disease.

Quantitative indices of GFR or Clcr are considered the most useful diagnostic tools for identify the presence and monitoring the progression of CKD. These measures can also be used to quantify changes in function that may occur as a result of disease progression, therapeutic intervention, or a toxic insult. It is important to note that the term kidney function includes the combined processes of glomerular filtration, tubular secretion, and reabsorption, as well as endocrine and metabolic functions. This thread critically evaluates the various methods that can be used for the quantitative assessment of kidney function in individuals with normal kidney function, as well as in those with CKD and acute kidney injury (AKI). Where appropriate, discussion regarding the qualitative assessment of the kidney function is also presented, including the role of imaging procedures and invasive tests such as kidney biopsy.

Excretory Function

The kidney is largely responsible for the maintenance of body homeostasis via its role in regulating urinary excretion of water, electrolytes, endogenous substances such as urea, medications, and environmental toxins. It accomplishes this through the combined processes of glomerular filtration, tubular secretion, and reabsorption.

The “intact nephron hypothesis” described by Bricker, more than 40 years ago, proposes that “kidney function” of patients with renal disease is the net result of a reduced number of appropriately functioning nephrons. As the number of nephrons is reduced from the initial complement of 2 million, those that are unaffected compensate; that is, they hyper function. The cornerstone of this hypothesis is that glomerulotubular balance is maintained, such that those nephrons capable of functioning will continue to perform in an appropriate fashion. Extensive studies have indeed shown that single-nephron GFR increases in the unaffected nephrons; thus, the whole-kidney GFR, which represents the sum of the single-nephron GFRs of the remaining functional nephrons, may remain close to normal until there is extensive injury. Based on this, one would presume that a measure of one component of nephron function could be used as an estimate of all renal functions. This, indeed, has been and remains our clinical approach. We estimate GFR and assume secretion and reabsorption remain proportionally intact.

Screen Shot 2017 04 20 at 9 53 00 PM


GFR is dependent on numerous factors, one of which is protein load. Bosch suggested that an appropriate comprehensive evaluation of kidney function should include the measurement of “filtration capacity.” Recently, the concept of renal function reserve (RFR) has been defined as the capacity of the kidney to increase GFR in response to physiological or pathologic conditions. This is similar in context to a cardiac stress test. The patient may have no hypoxic symptoms, for example, angina while resting, but it may become quite evident when the patient begins to exercise. Subjects with normal renal function administered an oral or intravenous (IV) protein load prior to measurement of GFR have been noted to increase their GFR by as much as 50%. As renal function declines, the kidneys usually compensate by increasing the single-nephron GFR. The RFR will be reduced in those individuals whose kidneys are already functioning at higher-than-normal levels because of preexisting kidney injury or subclinical loss of kidney mass. Thus, RFR ma be a complementary, insightful index of renal function for many individual with as yet unidentified CKD.

Quantification of renal function (excretory) is not only an important component of a diagnostic evaluation, but it also serves as an important parameter for monitoring therapy directed at the etiology of the diminished function itself, thereby allowing for objective measurement of the success of treatment. Measurement of renal function also serves as a useful indicator of the ability to the kidneys to eliminate drugs from the body. Furthermore, alterations of drug distribution and metabolism have been associated with the degree of renal function. Although several indices have been used for the quantification of GFR in the research setting, estimation of Clcr and GFR are the primary approaches used in the clinical arena.


Secretion is an active process that predominantly takes place in the proximal tubule and facilitates the elimination of compounds from the renal circulation into the tubular lumen. Several highly efficient transport pathways exist for a wide range of endogenous and exogenous substances, resulting in renal clearances of these actively secreted entities that often greatly exceed GFR and in some cases approximate renal blood flow. These transporters are typically found among the solute-linked carrier (SLC) and ATB-binding cassette (ABC) super families. Overall, the net process of tubular secretion for drugs is likely a result of multiple secretory pathways acting simultaneously.


Reabsorption of water and solutes occurs throughout the nephron, whereas the reabsorption of most medications occurs predominantly along the distal tubule and collecting duct. Urine flow rate and physicochemical characteristics of the molecule influence these processes: highly ionized compounds are not reabsorbed unless pH changes within the urine increase the fraction unionized, so that reabsorption may be facilitated.

Endocrine Function

The kidney synthesizes and secretes many hormones involved in maintaining fluid and electrolyte homeostasis. Secretion of renin by the cells of the juxtaglomerular apparatus and production and metabolism of prostaglandins and kinins are among the kidney’s endocrine functions. In addition in response to decreased oxygen tension in the blood, which is sensed by the kidney, erythropoietin is produced and secreted by peritubular fibroblasts. Because these functions are related to renal mass, decreased endocrine activity is associated with the loss of viable kidney cells.

Metabolic Function

The kidney perform a wide variety of metabolic functions, including the activation of vitamin D, gluconeogenesis, and metabolism of endogenous compounds such as insulin, steroids, and xenobiotics. It is common for patients with diabetes and stages 4 to 5 CKD to have reduced requirements for exogenous insulin, and require supplemental therapy with activated vitamin D3 or other vitamin D analogs to avert the bone loss and pain associated with CKD-associated metabolic bone disease. Cytochrome P450, N-acetyltransferase, glutathione transferase, renal peptidases, and other enzymes responsible for the degradation and activation of selected endogenous and exogenous substances have been identified in the kidney. The CYP enzymes in the kidneys are as active as those in the liver, when corrected for organ mass. In vitro and in vivo studies have shown that CYP-mediated metabolism is impaired in the presence of renal failure or uremia. In clinical studies using CYP3A probes in ESRD patients receiving hemodialysis, hepatic CYP3A activity was reported to be reduced by 28% from values observed in age-matched controls; partial correction was noted following the hemodialysis procedure.

Measurement of Kidney Function

The gold standard quantitative index of kidney function is a mGFR. A variety of methods may be used to measure and estimate kidney function in the acute care and ambulatory settings. Measurement of GFR is important for early recognition and monitoring of patients with CKD and as a guide for drug-dose adjustment.

Dipipharm10 ch42 f005

It is important to recognize conditions that may alter renal function independent of underlying renal pathology. For example, protein intake, such as oral protein loading or an infusion of amino acid solution, may increase GFR. As a result, inter- and intrasubject variability must be considered when it is used as a longitudinal marker of renal function. Dietary protein intake has been demonstrated to correlate with GFR in healthy subjects. The increased GFR following a protein load is the result of renal vasodilation accompanied by an increased renal plasma flow. The exact mechanism of the renal response to protein is unknown, but may be related to extra renal factors such as glucagon, prostaglandins, and angiotensin II, or intra renal mechanisms, such as alterations in tubular transport and tubuloglomerular feedback. Despite the evidence of a “renal reserve,” standardized evaluation techniques have not been developed. Therefore, assessment of a mGFR must consider the dietary protein status of the patient at the time of the study.

Measurement of Glomerular Filtration Rate

  • Measurement of the GFR is most accurate when performed following the exogenous administration of iohexol, iothalamate, or radioisotopes such as technetium-99m diethylenetriamine pentaacetic acid (99mTc-DTPA).

A mGFR remains the single best index of kidney function. As renal mass declines in the presence of age-related loss of nephrons or disease states such as hypertension or diabetes, there is a progressive decline in GFR. The rate of decline in GFR can be used to predict the time to onset of stage 5 CKD, as well as the risk of complications of CKD. Accurate measurement of GFR in clinical practice is a critical variable for individualization of the dosage regimens of renal excreted medications so that one can maximize their therapeutic efficacy and avoid potential toxicity.

The GFR is expressed as the volume of plasma filtered across the glomerulus per unit of time, based on total renal blood flow and capillary hemodynamics. The normal values for GFR are 127 +- 20 mL/min/1.73 m2 and 118 +- 20 mL/min/1.73 m2 in healthy men and women, respectively. These measured values closely approximate what one would predict if the normal renal blood flow were approximately 1.0 L/min/1.73 m2, plasma volume was 60% of blood volume, and filtration fraction across the glomerulus was 20%. In that situation the normal GFR would be expected to be approximately 120 mL/min/1.73 m2.

Optimal clinical measurement of GFR involves determining the renal clearance of a substance that is freely filtered without additional clearance because of tubular secretion or reduction as the result of reabsorption. Additionally, the substance should not be susceptible to metabolism within renal tissues and should not alter renal function. Given these conditions, the mGFR is equivalent to the renal clearance of the solute marker:

GFR = renal Cl = Ae / AUC 0>t

where renal Cl is renal clearance of the marker, Ae is the amount of marker excreted in the urine from time 0 to t, and AUC 0>t is the area under the plasma-concentration-versus-time curve of the marker.

Under steady-state conditions, for example during a continuous infusion of the marker, the expression simplifies to

GFR = renal Cl = Ae / (Css*t)

where Css is the steady-state plasma concentration of the marker achieved during continuous infusion. The continuous infusion method can also be employed without urine collection, where plasma clearance is calculated as Cl = infusion rate / Css. This method is dependent on the attainment of steady-state plasma concentrations and accurate measurement of infusatn concentrations. Plasma clearance can also be determined following a single-dose IV injection with the collection of multiple blood samples to estimate area under the curve (AUC 0>∞). Here, clearance is calculated as Cl = dose/AUC. These plasma clearance methods commonly yield clearance values 10% to 15% higher than GFR measured by urine collection methods.

Several markers have been used for the measurement of GFR and include both exogenous and endogenous compounds. Those administered as exogenous agents, such as inulin, sinistrin, iothalamate, iohexol, and radioisotopes, require specialized administration techniques and detection methods for the quantification of concentrations in serum and urine, but generally provide an accurate measure of GFR. Methods that employ endogenous compounds, such as creatinine or cyst, require less technical expertise, but produce results with greater variability. The GFR marker of choice depends on the purpose and cost of the compound which ranges from $2,000 per vial for radioactive for 125I-iothalamate to $6 per vial for nonradiolabeled iothalamate or iohexol.

Inulin and Sinistrin Clearance

Inulin is a large fructose polysaccharide, obtained from the Jerusalem artichoke, dahlia, and chicory plants. It is not bound to plasma proteins, is freely filtered at the glomerulus, is not secreted or reabsorbed, and is not metabolized by the kidney. The volume of distribution of inulin approximates extracellular volume, or 20% of ideal body weight. Because it is eliminated by glomerular filtration, its elimination half-life is dependent on renal function and is approximately 1.3 hours in subjects with normal renal function. Measurement of plasma and urine inulin concentrations can be performed using high-performance liquid chromatography. Sinistrin, another polyfructosan, has similar characteristics to inulin; it is filtered at the glomerulus and not secreted or reabsorbed to any significant extent. It is a naturally occurring substance derived from the root of the North African vegetable red squill, Urginea maritime, which has a much higher degree of water solubility than inulin. Assay methods for sinistrin have been described using enzymatic procedures, as well as high-performance liquid chromatography with electrochemical detection. Alternatives have been sought for inulin as a marker for GFR because of the problems of availability, high cost, sample preparation and assay variability.

Iothalamate Clearance

Iothalamate is an iodine-containing radio contrast agent that is available in both radiolabeled (125I) and nonradiolabeled forms. This agent is handled in a manner similar to that of inulin; it is freely filtered at the glomerulus and does not undergo substantial tubular secretion or reabsorption. The nonradiolabeled form is most widely used to measure GFR in ambulatory and research settings, and can safely be administered by IV bolus, continuous infusion, or subcutaneous injection. Plasma and urine iothalamate concentrations can be measured using high-performance liquid chromatography. Plasma clearance methods that do not require urine collections have been shown to be highly correlated with renal clearance, making them particularly well-suited for longitudinal evaluations of renal function. These plasma clearance methods require two-compartment modeling approaches because accuracy is dependent on duration of sampling. For example, Agarwal et al. demonstrated that short sampling intervals can overestimate GFR, particularly in patients with severely reduced GFR. In individuals with GFR more than 30 mL/min/1.73 m2 (greater than 0.29 mL/s/m2), a 2-hour sampling strategy yielded GFR values that were 54% higher compared with 10-hour sampling, whereas the 5-hour sampling was 17% higher. In individuals with GFR less than 30 mL/min/1.73 m2, the 5-hour GFR was 36% higher and 2-hour GFR was 126% higher than the 10-hour measurement. The authors proposed a 5- to 7- hour sampling time period with eight plasma samples to be the most appropriate and feasible approach for most GFR evaluations.


Lohexol, a nonionic, low osmolar, iodinated contrast agent, has also been used for the determination of GFR. It is eliminated almost entirely by glomerular filtration, and plasma and renal clearance values are similar to observations with other marker agents: Strong correlations of 0.90 or greater and significant relationships with iothalamate have been reported. These data support iohexol as a suitable alternative marker for the measurement of GFR. A reported advantage of this agent is that a limited number of plasma samples can be used to quantify iohexol plasma clearance. For patients with a reduced GFR more time must allotted – more than 24 hours if the eGFR is less  than 20 mL/min.

Radiolabeled Markers

The GFR has also been quantified using radiolabeled markers, such as 125I-iothalamate, 99mTc-DPTA, and 51Cr-ethylenediaminetetraacetic acid. These relatively small molecules are minimally bound to plasma proteins and do not undergo tubular secretion or reabsorption to any significant degree. 125I-iothalamate and 99mTc-DPTA are used in the United States, whereas 51Cr-EDTA is used extensively in Europe. The use of radiolabeled markers allows one to determine the individual contribution of each kidney to total renal function. Various protocols exist for the administration of these markers and subsequent measurement of GFR using either plasma or renal clearance calculation methods. The non renal clearance of these agents appears to be low, suggesting that plasma clearance is an acceptable technique except in patients with severe renal insufficiency (GFR less than 30 mL/min). Indeed, highly significant correlations between renal clearance among radiolabeled markers has been demonstrated. Although total radioactive exposure to patients is usually minimal, use of these agents does require compliance with radiation safety committees and appropriate biohazard waste disposal.

Optical Real-Time Glomerular Filtration Rate Markers

A clinically applicable technique to rapidly measure GFR, particularly in critically ill patients with unstable kidney function, is highly desirable. The currently available GFR measurement approaches, as outlined above, are technically demanding, time-consuming, and often cost-prohibitive. Research is underway to develop rapid, accurate, safe, and inexpensive techniques to address this need.


Although the measured (24-hour) CLcr has been used as an approximation of GFR for decades, it has limited clinical utility for a multiplicity of reasons. Short-duration witnessed mCLcr correlates well with mGFR based on iothalamate clearance performed using the single-injection technique. In a multicenter study of 136 patients with type 1 diabetic nephropathy, the correlations of simultaneous mCLcr, and 24-hour CLcr (compared to CLiothalamate) were 0.81 and 0.49, respectively, indicating increased variability with the 24-hour clearance determination. In a selected group of 110 patients, measurement of a 4-hour CLcr during water diuresis provided the best estimate of the GFR as determined by the CLiothalamate. Furthermore, the ratio of CLcr to CLiothalamate did not appear to increase as the GFR decreased. These data suggest that a short collection period with a water diuresis may be the best CLcr method for estimation of GFR.

A limitation of using creatinine as a filtration marker is that it undergoes tubular secretion. Tubular secretion arguments the filtered creatinine by approximately 10% in subjects with normal kidney function. If the nonspecific Jaffe reaction is used, which overestimates the Scr by approximately 10% because of the noncreatinine chromogens, then the measurement of CLcr is a very good measure of GFR in patients with normal kidney function. Tubular secretion, however, increases to as much as 100% in patients with kidney disease, resulting in mCLcr values that markedly overestimate GFR. For example, Bauer et al. reported that the CLcr-to-CLinulin ratio in subjects with mild impairment was 1.20; for those with moderate impairment, it was 1.87; and in those with severe impairment, it was 2.32. Thus, a mCLcr is a poor indicator of GFR in patients with moderate to severe renal insufficiency, that is, stages 3 to 5 CKD.

Because cimetidine blocks the tubular secretion of creatinine the potential role of several oral cimetidine regimens to improve the accuracy and precision of mCLcr as an indicator of GFR has been evaluated. The CLcr-to-CLDPTA ratio declined from 1.33 with placebo to 1.07 when 400 mg of cimetidine was administered four times a day for 2 days prior to and during the clearance determination. Similar results were observed when a single 800-mg dose of cimetidine was given 1 hour prior to the simultaneous determination of CLcr and CLiothalamate; the ratio of CLcr to CLiothalamate was reduced from a mean of 1.53 to 1.12. Thus a single oral dose of 800 mg of cimetidine should provide adequate blockade of creatinine secretion to improve the accuracy of a CLcr measurement as an estimate GFR in patients with stage 3 to 5 CKD.

To minimize the impact of diurnal variations in Scr on CLcr, the test is usually performed over a 24-hour period with the plasma creatinine obtained in the morning, as long as the patient has stable kidney function. Collection of urine remains a limiting factor in the 24-hour CLcr because of incomplete collections, and interconversion between creatinine and creatine that can occur if the urine is not maintained at a pH less than 6.

Estimating of Glomerular Filtration Rate

Because of the invasive nature and technical difficulties of directly measuring GFR in clinical settings, many equations for estimating GFR have been proposed over the past 10 years. A series of related GFR estimating equations have been developed for the primary purpose of identifying and classifying CKD in many patient populations. The initial equation was derived from multiple regression analysis of data obtained from the 1,628 patients enrolled in the Modification of Diet in Renal Disease Study (MDRD) where GFR was measured using the renal clearance of 125I-iothalamate methodology. A four-variable version of the original MDRD equation (MDRD4), based on plasma creatinine, age, sex, and race, was shown to provide a similar estimate of GFR results when compared to a six-variable equation predecessor. However, this equation was shown to be inaccurate at GFR more than 60 mL/min/1.73 m2, for reasons not associated with standardization of Screening assay results. A recent study conducted by the FDA compared the eGFR estimated by the MDRD4 equation to the CLcr estimated by the Cockcroft-Gault equation in 973 subjects enrolled in pharmacokinetic studies conducted for new chemical entities submitted to the FDA from 1998 to 2010. The MDRD4 eGFR results consistently overestimated the CLcr calculated by the CG method. The FDA investigators concluded that “For patients with advanced age, low weight, and modestly elevated serum creatinine concentration values, further work is needed before the MDRD equations can replace the CG equation for dose adjustment in approved product information labeling.”

A single eGFR equation may not be best suited for all populations, and choice of equation has been shown to impact CKD prevalence estimates. This has led to a revitalized interest in the development of new equations to estimate GFR. The newest equations to be proposed for the estimation of GFR have been derived from wider CKD populations than the MDRD study, and include the CKD-EPI and the Berlin Initiative Study (BIS). The CKD-EPI equation was developed from pooled study data involving 5,500 patients, with mean GFR values of 68 +- 40 mL/min/1.73 m2. It has been reported that the CKD-EPI equation is less biased but similarly imprecise compared to MDRD4.

CKD-EPI Equation

The CKD-EPI study equation was compared to the MDRD equation using pooled data from patients enrolled in research or clinical outcomes studies, where GFR was measured by any exogenous tracer. The results of the study indicated that the bias of CKD-EPI equation was 61% to 75% lower than the MDRD equation for patients with eGFR of 60 to 119 mL/min/1.73 m2. Based on these findings, the CKD-EPI equation is most appropriate for estimating GFR in individuals with eGFR values more than 60 mL/min/1.73 m2. Both KDOQI and the Australasian Creatinine Consensus Working Groups now recommend that clinical laboratories switch from the MDRD4 to CKD-EPI for routine automated reporting. If one’s clinical lab does not automatically calculate eGFR using the CKD-EPI, it becomes a bit of a challenge since the equation requires a more complex algorithm than the MDRD equation.

Limitations of the pooled analysis approach used to develop the MDRD and CKD-EPI equations include the use of different GFR markers between studies, different methods of administration of the GFR markers and different clearance calculations. These limitations may partly explain the reduced accuracy observed with the MDRD4 equation at GFR values more than 60 mL/min/1.73 m2. Additionally, a recent inspection of the MDRD GFR study data showed that large intrasubject variability in GFR measures was a likely contributor to the inaccuracy of the gold standard method that was used to create the MDRD equation.

Cystatin C-Based Equations

Addition of serum cysC as a covariate in equations to estimate GFR has been employed as a means to improve creatinine-based estimations of GFR that historically were limited to the following variables: lean body mass, age, sex, race, and Scr.

Screen Shot 2017 05 01 at 7 48 20 PM

  • Alb, serum albumin concentration (g/dL); BUN, blood/serum urea nitrogen concentration (mg/dL);CKD, chronic kidney disease; cysC, cystatin C; eGFR, estimated glomerular filtration rate; Scr, serum or plasma creatinine (mg/dL).
  • k is 0.7 for females and 0.9 for males, alpha is -0.329 for females and -0.411 for males, min indicates the minimum of Screening/k or 1, and max indicates the maximum of Scr/k or 1.

A significant limitation of serum cysC as a renal biomarker is the influence of body mass on serum concentrations. When using a serum cyst-based estimate of GFR, which incorporates the serum cysC, age, race, and sex, a higher prevalence of CKD was reported in obese patients when compared to the MDRD4 equation. In a recent retrospective analysis of over 1,000 elderly individuals (mean age 85 years) enrolled in Cardiovascular Health Study, GFR was estimated using the CKD-EPI and CKD-EPI-cysC equation, specifically equation 9 in Table e42-6. In this population, all-cause mortality rates were significantly different between equations, suggesting that cysC does not accurately predict mortality risk in patients with low Screening, reduced muscle mass, and malnutrition. The combined use of serum cysC and creatinine in modified CKD-EPI equations has recently been reported. The CKD-EPIcreatinine_cystatin C, equation 10 in Table e42-6 is now recommended for use in patients where unreliable serum creatinine values are anticipated, such as extremes in body mass, diet, or creatinine assay interferences.

Liver Disease

Evaluation of renal hemodynamics is particularly complicated in patients with liver disease and cirrhosis, where filtration fraction is associated with the degree of ascites, renal artery vasoconstriction, and vascular resistance. The estimation of CLcr or GFR can be problematic in patients with preexisting liver disease and renal impairment. Lower-than-expected Scr values may result from reduced muscle mass, protein-poor diet, diminished hepatic synthesis of creatine (a precursor of creatinine), and fluid overload can lead to significant overestimation of CLcr.

Evaluations of new eGFR equations for use in patients with liver disease have yield mixed results. In summary, renal function assessment in patients with hepatic disease should be performed by measuring glomerular filtration, and GFR estimation equations that combine creatinine and cysC are preferred.

Clinical Skills – Cluster the Clinical Findings

April 18, 2017 Clinical Skills, Differential Diagnosis, History Taking No comments

It is often challenging to decide whether clinical data fit into one problem or several problems. If there is relatively long list of symptoms and signs, and an equally long list of potential explanations, one approach is to tease out separate clusters of observations and analyze one cluster at a time. Several clinical characteristics may help.

Patient age: The patient’s age may help; younger adults are more likely to have a single disease, whereas older adults tend to have multiple diseases.

Timing of symptoms: The timing of symptoms is often useful. For example, an episode of pharyngitis 6 weeks ago is probably unrelated to the fever, chills, pleuritic chest pain, and cough that prompted an office visit today. To use timing effectively, you need to know the natural history of various diseases and conditions.

Involvement of different body systems: Involvement of the different body systems may help group clinical data. If symptoms and signs occur in a single system, one disease may explain them. Problems in different, apparently unrelated, systems often require more than one explanation. Again, knowledge of disease patterns is necessary.

Multisystem conditions: With experience, you will become increasingly adept at recognizing multi system conditions and building plausible explanations that link manifestations that are seemingly unrelated. To explain cough, hemoptysis, and weight loss in a 60-year-old plumber who has smoked cigarettes for 40 years, you would rank lung cancer high in your differential diagnosis. You might support your diagnosis with your observation of the patient’s cyanotic nailbeds. With experience and continued reading, you will recognize that his other symptoms and signs fall under the same diagnosis. Dysphagia would reflect extension of the cancer to the esophagus, pupillary asymmetry would suggest pressure on the cervical sympathetic chain, and jaundice could result from metastases to the liver. Related risk factors should be explored promptly.

Key questions: You can also ask a series of key questions that may steer your thinking in one direction and allow you to temporarily ignore the others. For example, you may ask what produces and relieves the patient’s chest pain. If the answer is exercise and rest, you can focus on the cardiovascular and musculoskeletal systems and set the gastrointestinal (GI) system aside. If the pain is more epigastric, burning, and occurs only after meals, you can logically focus on the GI tract. A series of discriminating questions helps you analyze the clinical data and reach logical explanations.

The Comprehensive Adult Health History

April 16, 2017 Clinical Skills, EHR/EMR, History Taking, Practice No comments , , , ,

Screen Shot 2017 04 16 at 7 31 40 PM

Initial Information

Data and Time of History

The date is always important. Be sure to document the time you evaluate the patient, especially in urgent, emergent, or hospital setitngs.

Identify Data

These include age, gender, marital status, and occupation. The source of history or referral can be the patient, a family member or friend, an officer, a consultant, or the clinical record. Identifying the source of referral helps you assess the quality of the referral information, questions you may need to address in your assessment and written response.


Document this information, if relevant. This judgment reflects the quality of the information provided by the patient and is usually made at the end of the interview. For example, “The patient is vague when describing symptoms, and the details are confusing,” or, “The patient is a reliable historian.”

Chief Complaint(s)

Make every attempt to quote the patient’s own words. For example, “My stomach hurts and I feel awful.” If patients have no specific complaints, report their reason for the visit, such as “I have come for my regular check-up” or “I’ve been admitted for a thorough evaluation of my heart.”

Present Illness

This Present Illness is a complete, clear, and chronologic description of the problems promoting the patient’s visit, including the onset of the problem, the setting in which it developed, its manifestations, and any treatments to date.

  • Each principal symptoms should be well characterized, and should include the seven attributes of a symptom: 1) location; 2) quality; 3) quantity or severity; 4) timing, including onset, duration, and frequency; 5) the setting in which it occurs; 6) factors that have aggravated or relieved the symptom; 7) associated manifestations. It is also important to query the “pertinent positives” and “pertinent negatives” drawn from sections of the Review of Systems that are relevant to the Chief Complaint(s). The presence or absence of these additional symptoms helps you generate the differential diagnosis, which includes the most likely and, at times, the most serious diagnoses, even if less likely, which could explain the patient’s condition.
  • Other information is frequently relevant, such as risk factors for coronary artery disease in patients with chest pain, or current medications in patients with syncope.
  • The Present Illness should reveal the patient’s response to his or her symptoms and what effect the illness has had on the patient’s life. Always remember, the data flow spontaneously from the patient, but the task of oral and written organization is yours.
  • Patients often have more than one symptoms or concern. Each symptom merits its own paragraph and a full description.
  • Medications should be noted, including name, dose, route, and frequency of use. Also, list home remedies, nonprescription drugs, vitamins, mineral or herbal supplements, oral contraceptives, and medicines borrowed from family members or friends. Ask patients to bring in all their medications so that you can see exactly what they take.
  • Allergies, including specific reactions to each medication, such as rash or nausea, must be recorded, as well as allergies to foods, insects, or environmental factors.
  • Note tobacco use, including the type. Cigarettes are often reported in pack-years. If someone has quit, note for how long.
  • Alcohol and drug use should always be investigated and is often pertinent to the Present Illness.

Past History

  • Childhood illnesses: These include measles, rubella, mumps, whooping cough, chickenpox, rheumatic fever, scarlet fever, and polio. Also included are any chronic childhood illnesses.
  • Adult illnesses: Provide information relative to adult illnesses in each of the four areas: 1) medical: illnesses such as diabetes, hypertension, hepatitis, asthma, and human immunodeficiency virus; hospitalizations; number and gender of sexual partners; and risk-taking sexual practices; 2) surgical: dates, indications, and types of operations; 3) obstetric/gynecologic: obstetric history, menstrual history, methods of contraception, and sexual function; 4) psychiatric: illness and time frame, diagnoses, hospitalizations, and treatments.

Family History

Under family history, outline or diagram the age and health, or age and cause of death, of each immediate relative including parents, grandparents, siblings, children, and grandchildren. Review each of the following conditions and record whether they are present or absent in the family: hypertension, coronary artery disease, elevated cholesterol levels, stroke, diabetes, thyroid or renal disease, arthritis, tuberculosis, asthma or lung disease, headache, seizure disorder, mental illness, suicide, substance abuse, and allergies, as well as symptoms reported by the patient. Ask about any history of breast, ovarian, colon, or prostate cancer. Ask about any genetically transmitted diseases.

Personal and Social History

The personal and social history captures the patient’s personality and interests, sources of support, coping style, strengths, and concerns. It should include occupation and the last year of schooling; home situation and significant others; sources of stress, both recent and long-term; important life experiences such as military service, job history, financial situation, and retirement; leisure activities; religious affiliation and spiritual beliefs; and activities of daily living. Baseline level of function is particularly important in older or disabled patients. The personal and social history includes lifestyle habits that promote health or create risk, such as exercise and diet, including frequency of exercise, usual daily food intake, dietary supplements or restrictions, and use of coffee, tea, and other caffeinated beverages, and safety measures, including use of seat belts, bicycle helmets, sunblock, smoking detectors, and other devices related to specific hazards. Include sexual orientation and practices and any alternative health care practices. Avoid restricting the personal and social history to only tobacco, drug, and alcohol use. An expanded personal and social history personalizes your relationship with the patient and builds rapport.

Review of Systems

  • General: Usual weight, recent weight change, clothing that fits more tightly or loosely than before, weakness, fatigue, or fever.
  • Skin: Rashes, lumps, sores, itching, dryness, changes in color; change in hair or nails; changes in size or color of moles.
  • HEENT: 1) head: headache, head injury, dizziness, lightheadedness; 2) eyes: vision, glasses or contact lenses, last examination, pain, redness, excessive tearing, double or blurred vision, spots, specks, flashing lights, glaucoma, cataracts; 3) ears: hearing, tinnitus, vertigo, earaches, infection, discharge. If hearing is decreased, use or nonuse of hearing aids; 4) nose and sinuses: frequent colds, nasal stuffiness, discharge, or itching, hay fever, nosebleeds, sinus trouble; 5) throat: condition of teeth and gums, bleeding gums, dentures, if any, and how they fit, last dental examination, sore tongue, dry mouth, frequent sore throats, hoarseness.
  • Neck: “Swollen glands,” goiter, lumps, pain, or stiffness in the neck.
  • Breasts: Lumps, pain, or discomfort, nipple discharge, self-examination practices.
  • Respiratory: Cough, sputum (color, quantity; presence of blood or hemoptysis), shortness of breath (dyspnea), wheezing, pain with a deep breath (pleuritic pain), last chest x-ray. You may wish to include asthma, bronchitis, emphysema, pneumonia, and tuberculosis.
  • Cardiovascular: “Heart trouble”; high blood pressure; rheumatic fever; heart murmurs; chest pain or discomfort; palpitations; shortness of breath; need to use pillows at night to ease breathing (orthopnea); need to sit up at night to ease breathing (paroxysmal nocturnal dyspnea); swelling in the hands, ankles, or feet (edema); results of past electrocardiograms or other cardiovascular tests.
  • Gastrointestinal: Trouble swallowing, heartburn, appetite, nausea. Bowel movements, stool color and size, change in bowel habits, pain with defecation, rectal bleeding or black or tarry stools, hemorrhoids, constipation, diarrhea. Abdominal pain, food intolerance, excessive belching or passing of gas. Jaundice, liver, or gallbladder trouble; hepatitis.
  • Peripheral vascular: Intermittent leg pain with exertion (claudication); leg cramps; varicose veins; past clots in the veins; swelling in calves, legs, or feet; color change in fingertips or toes during cold weather; swelling with redness or tenderness.
  • Urinary: Frequency of urination, polyuria, nocturia, urgency, burning or pain during urination, blood in the urine (hematuria), urinary infections, kidney or flank pain, kidney stones, ureteral colic, suprapubic pain, incontinence; in males, reduced caliber or force of the urinary stream, hesitancy, dribbling.
  • Genital: Male: Hernias, discharge from or sores on the penis, testicular pain or masses, scrotal pain or swelling, history of sexually transmitted infections and their treatments. Sexual habits, interest, function, satisfaction, birth control methods, condom use, and problems. Concerns about HIV infection. Female: Age at menarche, regularity, frequency, and duration of periods, amount of bleeding; bleeding between periods or after intercourse, last menstrual period, dysmenorrhea, premenstrual tension. Age at menopause, menopausal symp- toms, postmenopausal bleeding. If the patient was born before 1971, exposure to diethylstilbestrol (DES) from maternal use during pregnancy (linked to cervical carcinoma). Vaginal discharge, itching, sores, lumps, sexually transmitted infec- tions and treatments. Number of pregnancies, number and type of deliveries, number of abortions (spontaneous and induced), complications of pregnancy, birth-control methods. Sexual preference, interest, function, satisfaction, any problems, including dyspareunia. Concerns about HIV infection.
  • Musculoskeletal: Muscle or joint pain, stiffness, arthritis, gout, backache. If present, describe location of affected joints or muscles, any swelling, redness, pain, tenderness, stiffness, weakness, or limitation of motion or activity; include timing of symptoms (e.g., morning or evening), duration, and any history of trauma. Neck or low back pain. Joint pain with systemic symptoms such as fever, chills, rash, anorexia, weight loss, or weakness.
  • Psychiatric: Nervousness, tension, mood, including depression, memory change, suicidal ideation, suicide plans or attempts. Past counseling, psycho- therapy, or psychiatric admissions.
  • Neurologic: Changes in mood, attention, or speech; changes in orientation, memory, insight, or judgment; headache, dizziness, vertigo, fainting, black- outs; weakness, paralysis, numbness or loss of sensation, tingling or “pins and needles,” tremors or other involuntary movements, seizures.
  • Hematologic: Anemia, easy bruising or bleeding, past transfusions, transfusion reactions.
  • Endocrine: “Thyroid trouble,” heat or cold intolerance, excessive sweating, excessive thirst or hunger, polyuria, change in glove or shoe size.

Supplement Documents

Principle Symptoms

  • Abdominal pain
  • Acid-base abnormalities
  • AIDS/HIV infection
  • Anemia
  • Back pain
  • Bleeding disorders
  • Chest pain
  • Cough, fever, and respiratory infections
  • Delirium and dementia
  • Diabetes
  • Diarrhea, acute
  • Dizziness
  • Dyspnea
  • Dysuria
  • Edema
  • Fatigue
  • GI bleeding
  • Headache
  • Hematuria
  • Hypercalcemia
  • Hypertension
  • Hyponatremia and hypernatremia
  • Hypotension
  • Jaundice and abnormal liver enzymes
  • Joint pain
  • Kidney injury, acute
  • Rash
  • Sore throat
  • Syncope
  • Weight loss, unintentional
  • Wheezing and stridor

Creatinine Clearance Estimation – Non-Steady State

March 8, 2017 Clinical Skills, Laboratory Medicine, Nephrology, Pharmacokinetics, Practice 2 comments , ,

Using non-steady-state serum creatinine values to estimate creatinine clearance is difficult, and a number of approaches have been proposed. The author use Equation 1 below to estimate creatinine clearance when steady-state conditions have not been achieved.

ClCr (mL/min) = { (Production of Creatinine in mg/day) – [(SCr 2 – SCr 1)(V Cr) / t]*(10 dL/L)} * [(1000 mL/L) / (1440 min/day)] / [(SCr 2)(10 dL/L)] [Equation 1]

Screen Shot 2017 03 08 at 7 25 08 PM

The daily production of creatinine in milligram is calculated by multiplying the daily production value in mg/kg/day from Table 5 by the patient’s weight in kg. The serum creatinine values in Equation 1 are expressed in units of mg/dL; t is the number (or fraction) of days between the first serum creatinine measurement (SCr1) and the second (SCr2). The volume of distribution of creatinine (Vcr) is calculated by multiplying the patient’s weight in kg times 0.65 L/kg. Equation 1 (or 79) is essentially a modification of the mass balance equation (we will discuss it in another thread later).

Screen Shot 2017 03 08 at 9 11 53 PM

where the daily production of creatinine in milligram has replaced the infusion rate of the drug and the second serum creatinine value replaced C ave. The second serum creatinine is used primarily because Equation 1 is most commonly applied when creatinine clearance is decreasing (serum creatinine rising), and using the higher of the two serum creatinine values results in a lower, more conservative estimate of renal function. Some have suggested that the iterative search process, as represented by the combination of Equation 28 and 37 (won’t be discussed here; if needed, please contact Tom for detail), be used:

Screen Shot 2017 03 08 at 9 29 36 PMwhere C2 represents SCr2, and C represents SCr1. (S)(F)(Dose/tau) represents the daily production of creatinine, and t represents the time interval between the first and second serum creatinine concentrations. Cl represents the creatinine clearance with the corresponding elimination rate constant K being Cl/V or the creatinine clearance divided by the creatinine volume of distribution. As discussed previously, the solution would require an iterative search, and the inherent errors in the calculation process probably do not warrant this type of calculation.

Screen Shot 2017 03 02 at 10 47 36 PM

Although Equation 1 (or Equation 79) can be used to estimate a patient’s creatinine clearance when a patient’s serum creatinine is rising or falling, there are potential problems associated with this and all other approaches using non-steady-state serum creatinine values. First, a rising  serum creatinine concentration may represent a continually declining renal function. To help compensate for the latter possibility, the second creatinine (SCr2) rather than the average is used in the denominator of Equation 1/79. Furthermore, there are non-renal routes of creatinine elimination that become significant in patients with significantly diminished renal function. Because as much as 30% of a patient’s daily creatinine excretion is the result of dietary intake, the ability to predict a patient’s daily creatinine production in the clinical setting is limited. One should also consider the potential errors in estimating creatinine production for the critical ill patient, the errors in serum creatinine measurements, and the uncertainty in the volume of distribution estimate for creatinine. Estimating creatinine clearance in a patient with a rising or falling serum creatinine should be viewed as a best guess under difficult conditions, and ongoing reassessment of the patient’s renal function is warranted.