Month: May 2017

The Process of Differential Diagnosis

May 24, 2017 Uncategorized No comments , , , , ,

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Elements of the Differential Diagnosis

Decision-making on the Basis of Diagnosis. The physician endeavors to organize the subjective complaints and the objective findings of a patient in order to receive further indications to proceed. This approach is frequently chosen because a diagnosis in the conventional sense is not always easy to make, as more than one diagnosis can often be possible at the same time. Therefore, an important first step is to create a list of problems with a detail description.

Dynamics of Reaching a Diagnosis. The diagnosis is of utmost importance not only for the prognosis but also for the introduction of an appropriate therapy. An established diagnosis always needs to be reassessed. Secondary diseases, complications, and side-effects can supervene. Each diagnosis continues to be a differential diagnosis, since the particular symptoms, even during the course of a disease, have to be continually reevaluated, carefully considered, and differentiated. For a proper evaluation of the symptoms and risk factors, knowledge of their clinical meaning is crucial. Consequently, the purpose of differential diagnosis is to point out what disease can occur, when specific symptoms appear, and what risk factors with the utmost probability accompany specific diseases. In most cases, there are numerous possibilities and additional factors that have to be taken into account. Exclusively listing all the possibilities would not be beneficial.

Practical Procedure for Establishing a Diagnosis

The diagnosis is based on four essential aspects:

  • medical history
  • state of health
  • laboratory and other investigations
  • monitoring

In case of an unsolved disease, the number of possible remaining diagnoses can be reduced drastically via history-taking and clinical examination. The additional morphological, physical, chemical, and biological examinations allow the isolation of the most probable diagnosis. Monitoring is a critical quality control of the previous diagnostic process, as well as the subsequent therapeutic decisions.

Cardinal Symptoms. In differential diagnosis we proceed from a single dominant symptom, or group of symptoms or main symptoms, and try to classify as much as possible on the basis of the current research, in order to obtain a clinical picture. In most cases, a differential diagnosis is considered when a cardinal symptom indicates the direction of further measures. This leading symptom can emerge from the medical history, from clinical findings, as well as from laboratory work results. So-called problem-oriented patient care is practiced in a similar manner.

Correct Evaluation of Evident Findings and the Differential Diagnosis

Process of Clinical Judgement. The correct evaluation of findings is crucial for the diagnosis. Positive and negative predictive values play important roles in this context. Nevertheless, personal intuition with regard to the individual patient remains an important factor.

Pathognomonic symptoms or combinations of symptoms are rare, but must be recognized when present. Except in the most obvious cases, we are subject to continuous uncertainty in everyday clinical life – we must use the available resources to decide on the most probable diagnosis for our individual patients and select the most effective treatment. It is assumed that with additional clinical experience the correct clinical judgement will automatically be made. In this we are supported by studies that critically analyze individual investigative steps and diagnostic processes. Guidelines which critically assess current research and place it in context are often helpful.

Probability-based Decision Analysis. In cases of ambiguous and usually complex situations, the physician can decrease the probability of error when diagnosing or excluding a disease using reasoning based on decision analysis. He or she analyses the probability of a disease diagnosis on the basis of the findings (post-test probability), whereby both the sensitivity and specificity of the test must be given, as well as considering the pretest probability (current probability).

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Diagnostic Process. The path from unspecified disease to definitive diagnosis is only rarely a linear one by which data are first collected and then analyzed according to established criteria. Additional examinations are to be conducted as indicated, whereupon everything is reevaluated in order to make a definite diagnosis. Frequently, only a few minutes into a medical discussion, first working hypotheses are formulated that ultimately direct further history-taking and examination.

Preliminary Diagnosis and Immediate Therapeutic Consequences. The first impression is on the one hand crucial, but on the other hand can be dangerous if not continually challenged by results of ongoing examinations. It is essential to recognize serious disease as early as possible, and to quickly initiate the appropriate measures, which are often vital to the prognosis. During the diagnostic process it is therefore often necessary to introduce therapeutic measures without a firm diagnosis, and independent of the specific etiology. Treatment on the basis of a preliminary diagnosis is often acceptable for most common diseases.

In cases of new symptoms or an “atypical” course of disease, the diagnosis should be challenged. The following possibilities must be considered:

  • The first diagnosis was wrong
  • The diagnosis was correct, a complication supervened
  • The diagnosis was correct, a secondary independent disease supervened
  • The diagnosis was correct, side effects from therapy occurred
  • The diagnosis was correct and the course of the disease is indeed atypical

Factors that Can Influence the Differential Diagnostic Thought Process

Prevalence of Disease

Differential diagnosis is based on the knowledge as to which symptoms and disease are common. According to an American study involving over 300 million cases of consultations in private practices of internists, the most common complaints are: abdominal pain, thoracic pain, back pain, headaches, fatigue, coughing and catarrhal symptoms, as well as leg pain, skin symptoms, and vertigo.

Differential diagnosis also takes into account the frequency of diseases according to the overall situation.

Age

The influence of age must always be considered. Knowledge of age distribution provides valuable clues for the diagnosis.

Gender

Some diseases occur more frequently in males than in females, and vice versa. This is especially true for occupational diseases as well as diseases caused by smoking or alcohol. Because on their anatomic configuration, women are susceptible to reoccurring urinary tract infections, pyelonephritis and iron deficiency due to menorrhea.

Lifestyle

Lifestyle is very important to people today. Some positive habits are healthy nutrition and fitness; harmful habits include addictive behaviors. The influence of alcohol especially on the liver, blood pressure, and nervous system is well known. Smoking, which is particularly on the rise in adolescents, is responsible for the emergence of vascular diseases as well as pulmonary diseases.

Eating Habits

Eating habits are at least partly responsible for many diseases. To a large extent, obesity is closely associated with disease. Diabetes mellitus type 2, arthrosis, and hypertension are more frequently observed in obese persons. Obesity is one of the risk factors in the development of arteriosclerosis and its consequences. Also the influence of eating habits with regard to malignant tumors is suggested.

Season, Time of Day, and Weather

Certain diseases are clearly dependent on the season:

  • Food-associated infectious diseases in particular, e.g., salmonellosis, occur more frequently in warm seasons.
  • The seasonal emergence of allergic coryza depends on airborne pollens (spring/summer)
  • Respiratory infections occur more frequently during the winter months and cause higher morbidity and mortality in the elderly population, especially in a humid climate and after sudden changes of weather (influenza, respiratory syncytial virus).

Circadian rhythms also plays a role. Chronic polyarthritis is a disease with an explicit circadian rhythm and reaches maximum activity in the early morning and a minimum of activity in the afternoon. Accordingly, a correlation with the circadian cortisone output and neutrophil count has been identified.

Geographic Distribution

The geographic distribution of diseases must often be considered. It is especially obvious in infectious diseases (tropical diseases), where climatic and hygienic conditions exert influence. The physician is obliged to consider “exotic” diseases in the differential diagnosis of patients with a history of travel (tourism). In addition, even similar clinical pictures (e.g., malaria) result in a different disease course depending on the country of infection (differences in resistance).

Ethnic Groups

The patient’s ethnic background can be of importance for the diagnosis. Thalassemia occurs primarily in populations bordering the Mediterranean. Sickle cell anemia is present nearly exclusively in black populations.

Profession and Leisure

The profession of a patient can provide diagnostic clues. Occupational diseases are defined by a clear correlation between occupational activity and disease.

Besides occupational diseases, leisure pursuits are to be considered. Diseases are often observed due to sporting activities.

Precluding or Promoting Diseases

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From medical experience, certain diseases rarely occur simultaneously, whereas others are associated with each other. Patients with chronic alcohol abuse seldom develop liver cirrhosis and chronic pancreatitis at the same time. Similarly, there are practically no incidences of malaria in patients with sickle cell anemia. Diseases of one organ can be the initial manifestation of an overall dysfunctional organism or a systemic disease that endangers practically all organs. Thus upon emergence of symptoms, other possible manifestations and locations should be carefully considered.

Differential Diagnosis by Groups of Diseases

When differentiating a clinical picture, very often it is initially impossible to identify the real diagnosis, namely the nosological entity. Until relevant findings are present, one has to be content with the classification into one of the groups of diseases. In all unclear cases, consideration is almost always given to this at the beginning of the differential diagnostic process.

  • Degenerative conditions
  • Infectious disease
  • Immune mediated diseases
  • Tumors
  • Metabolic diseases
  • Dysfunction of the endocrine system
  • Mental disorders
  • Hereditary diseases
  • Allergies
  • Intoxications

Conceiving the Research Question and Developing the Study Plan

May 13, 2017 Clinical Research, Clinical Trials, Uncategorized No comments , ,

The research question is the uncertainty that the investigator wants to resolve by performing his/her study. There is no shortage of good research questions, and even as we succeed in answering some questions, we remain surrounded by others. Clinical trials, for example, established that treatments that block the synthesis of estradiol (aromatase inhibitors) reduce the risk of breast cancer in women who have had early stage cancer. But this led to new questions: How long should treatment be continued; does this treatment prevent breast cancer in patients with BRCA 1 and BRCA 2 mutations; and what is the best way to prevent the osteoporosis that is an adverse effect of these drugs? Beyond that are primary prevention questions: Are these treatments effective and safe for preventing breast cancer in healthy women?

Origins of A Research Question

For an established investigator the best research questions usually emerge from the findings and problems she has observed in her own prior studies and in those of other workers in the field. A new investigator has not yet developed this base of experience. Although a fresh perspective is sometimes useful by allowing a creative person to conceive new approaches to old problems, lack of experience is largely an impediment.

A good way to begin is to clarify the difference between a research question and a research interest. Consider this research question:

  • Dose participation in group counseling sessions reduce the likelihood of domestic violence among women who have recently immigrated from Central America?

This might be asked by someone whose research interest involves the efficacy of group counseling, or the prevention of domestic violence, or improving health in recent immigrants. The distinction between research questions and research interests matters because it may turn out that the specific research question cannot be transformed into a viable study plan, but the investigator can still address research interest by asking a different question.

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Of course, it’s impossible to formulate a research question if you are not even sure about your research interest (beyond knowing that you’re supposed to have one). If you find yourself in this boat, you’re not alone: Many new investigators have not yet discovered a topic that interests them and is susceptible to a study plan they can design. You can begin by considering what sorts of research studies have piqued your interest when you’ve seen them in a journal. Or perhaps you were bothered by a specific patient whose treatment seemed inadequate or inappropriate: What could have been done differently that might have improved her outcome? Or one of your attending physicians told you that hypokalemia always caused profound thirst, and another said the opposite, just as dogmatically.

Mastering the Literature

It is important to master the published literature in an area of study: Scholarship is a necessary precursor to good research. A new investigator should conduct a thorough search of published literature in the areas pertinent to the research question and critically read important original papers. Carrying out a systematic review is a great next step for developing and establishing expertise in a research area, and the underlying literature review can serve as background for grant proposals and research reports. Recent advances may be known to active investigators in a particular field long before they are published. Thus, mastery of a subject entails participating in meetings and building relationships with experts in the field.

Being Alert to New Ideas and Techniques

In addition to the medical literature as a source of ideas for research questions, it is helpful to attend conferences in which new work is presented. At least as important as the formal presentations are the opportunities for informal conversations with other scientists at posters and during the breaks. A new investigator who overcomes her shyness and engages a speaker at the coffee break may find the experience richly rewarding, and occasionally she will have a new senior colleague. Even better, for a speaker known in advance to be especially relevant, it may be worthwhile to look up her recent publications and contact her in advance to arrange a meeting during the conference.

A skeptical attitude about prevailing beliefs can stimulate good research questions. For example, it was widely believed that lacerations which extend through the dermis required sutures to assure rapid healing and a satisfactory cosmetic outcome. However, Quinn et al. noted personal experience and case series evidence that wounds of moderate size repair themselves regardless of whether wound edges are approximated. They carried out a randomized trial in which all patients with hand lacerations less than 2 cm in length received tap water irrigation and a 48-hour antibiotic dressing. One group was randomly assigned to have their wounds sutured, and the other group did not receive sutures. The suture group had a more painful and time-consuming treatment in the emergency room, but blinded assessment revealed similar time to healing and similar cosmetic results. This has now become a standard approach used in clinical practice.

The application of new technologies often generates new insights and questions about familiar clinical problems, which in turn can generate new paradigms. Advances in imaging and in molecular and genetic technologies, for example, have spawned translational research studies that have led to new treatments and tests that have changed clinical medicine. Similarly, taking a new concept, technology, or finding from one field and applying it to a problem in a different field can lead to good research questions. Low bone density, for example, is a risk factor for fractures. Investigators applied this technology to other outcomes and found that women with low bone density have higher rates of cognitive decline, stimulating research for factors, such as low endogenous levels of estrogen, that could lead to loss of both bone and memory.

Keeping the Imagination Roaming

Careful observation of patients has led to many descriptive studies and is fruitful source of research questions. Teaching is also an excellent source of inspiration; ideas for studies often occur while preparing presentations or during discussions with inquisitive students. Because there is usually not enough time to develop these ideas on the spot, it is useful to keep them in a computer file or notebook for future reference.

There is a major role for creativity in the process of conceiving research questions, imagining new methods to address old questions, and playing with ideas. Some creative ideas come to mind during informal conversations with colleagues over lunch; others arise from discussing recent research or your own ideas in small groups. Many inspirations are solo affairs that strike while preparing a lecture, showering, perusing the Internet, or just sitting and thinking. Fear of criticism or seeming unusual can prematurely quash new ideas. The trick is to put an unresolved problem clearly in view and allow the mind to run freely around it. There is also a need for tenacity, returning to a troublesome problem repeatedly until a resolution is reached.

Choosing and Working with a Mentor

Nothing substitutes for experience in guiding the many judgements involved in conceiving a research question and fleshing out a study plan. Therefore an essential strategy for a new investigator is to apprentice herself to an experienced mentor who has the time and interest to work with her regularly.

A good mentor will be available for regular meetings and informal discussions, encourage creative ideas, provide wisdom that comes from experience, help ensure protected time for research, open doors to networking and funding opportunities, encourage the development of independent work, and put the new investigator’s name first on grants and publications whenever appropriate. Sometimes it is desirable to have more than one mentor, representing different disciplines. Good relationships of this sort can also lead to tangible resources that are needed – office space, access to clinical populations, data sets and specimen banks, specialized laboratories, financial resources, and a research team.

Characteristics of A Good Research Question

  • Feasible

It is best to know the practical limits and problems of studying a question early on, before wasting much time and effort along unworkable lines.

Number of subjects. Many studies do not achieve their intended purposes because they can not enroll enough subjects. A preliminary calculation of the sample size requirements of the study early on can be quite helpful, together with an estimate of the number of subjects likely to be available for the study, the number who would be excluded or refuse to participate, and the number who would be lost to follow up. Even careful planning often produces estimates that are overly optimistic, and the investigator should assume that there are enough eligible and willing subjects. It is sometimes necessary to carry out a pilot survey or chart review to be sure. If the number of subjects appears insufficient, the investigator can consider several strategies: expanding the inclusion criteria, eliminating unnecessary exclusion criteria, lengthening the time frame for enrolling subjects, acquiring additional sources of subjects, developing more precise measurement approaches, inviting colleagues to join in a multi center study, and using a different study design.

Technical expertise. The investigators must have skills, equipment, and experience needed for designing the study, recruiting the subjects, measuring the variables, and managing and analyzing the data. Consultants can help to shore up technical aspects that are unfamiliar to the investigators, but for major areas of the study it is better to have an experienced colleague steadily involved as a coinvestigator; for example, it is wise to include a statistician as a member of the research team from the beginning of the planning process. It is best to use familiar and established approaches, because the process of developing new methods and skills is time-consuming and uncertain. When a new approach is needed, such as measurement of a new biomarker, expertise in how to accomplish the innovation should be sought.

Cost in time and money. It is important to estimate the costs of each component of the project, bearing in mind that the time and money needed will generally exceed the amounts projected at the outset. If the projected costs exceed the available funds, the only options are to consider a less expensive design or to develop additional sources of funding. Early recognition of a study that is too expensive or time-consuming can lead to modification or abandonment of the plan before expending a great deal of effort.

Scope. Problems often arise when an investigator attempts to accomplish too much, marking many measurements at repeated contacts with a large group of subjects in an effort to answer too many research questions. The solution is to narrow the scope of the study and focus only on the most important goals. Many scientists find it difficult to give up the opportunity to answer interesting side questions, but the reward may be a better answer to the main question at hand.

Fundability. Few investigators have the personal or institutional resources to fund their own research projects, particularly if subjects need to be enrolled and followed, or expensive measurements must be made. The most elegantly designed research proposal will not be feasible if no one will pay for it.

  • Interesting

An investigator may have many motivations for pursuing a particular research question: because it will provide financial support, because it is a logical or important next step in building a career, or because getting at the truth of the matter is interesting. We like this last reason; it is one that grows as it is exercised and that provides the intensity of effort needed for overcoming the many hurdles and frustrations of the research process. However, it is wise to confirm that you are not the only one who finds a question interesting. Speak with mentors, outside experts, and representatives of potential funders such as NIH project officers before devoting substantial energy to develop a research plan or grant proposal that peers and funding agencies may consider dull.

  • Novel
Good clinical research contributes new information. A study that merely reiterates what is already established is not worth the effort and cost and is unlikely to receive funding. The novelty of a proposed study can be determined by thoroughly reviewing the literature, consulting with experts who are familiar with unpublished ongoing research, and searching for abstracts of projects in your area of interest that have been funded using the NIH Research Portfolio Online Reporting Tools (RePORT) website. Reviews of studies submitted to NIH give considerable weight to whether a proposed study is innovative such that a successful result could shift paradigms of research or clinical practice through the use of new concepts, methods, or interventions. Although novelty is an important criterion, a research question need not be totally original – it can be worthwhile to ask whether a previous observation can be replicated, whether the findings in one population also apply to others, or whether a new measurement method can clarify the relationship between known risk factors and a disease. A confirmatory study is particularly useful if it avoids the weaknesses of previous studies or if the result to be confirmed was unexpected.
  • Ethical
A good research question must be ethical. If the study poses unacceptable physical risks or invasion of privacy, the investigator must seek other ways to answer the question. If there is uncertainty about whether the study is ethical, it is helpful to discuss it at an early stage with a representative of the institutional review board (IRB).
  • Relevant
A good way to decide about relevance is to imagine the various outcomes that are likely to occur and consider how each possibility might advance scientific knowledge, influence practice guidelines and health policy, or guide further research. NIH reviewers emphasize the significance of a proposed study: the importance of the problem, how the project will improve scientific knowledge, and how the result will change concepts, methods, or clinical services.
 
Developing the Research Question and Study Plan
 
It helps a great deal to write down the research question and a brief (one-page) outline of the study plan at an early stage (detail here http://www.tomhsiung.com/wordpress/2017/05/outline-of-a-study/). This requires some self-discipline, but it forces investigator to clarify her ideas about the plan and to discover specific problems that need attention. The outline also provides a basis for specific suggestions from colleagues.

Outline of A Study

May 10, 2017 Clinical Research, Clinical Trials No comments

This is the one-page study plan of a project carried out by Valerie Flaherman, MD, MPH, begun while she was a general pediatrics fellow at UCSF. Most beginning investigators find observational studies easier to pull off, but in this case a randomized clinical trial of modest size and scope was feasible, the only design that could adequately address the research question, and ultimately successful.

Title: Effect of Early Limited Formula Use on Breastfeeding

Research question:

Among term newborns who have lost >=5% of their birth weight before 36 hours of age, does feeding 10 cc of formula by syringe after each breastfeeding before the onset of mature milk production increase the likelihood of subsequent successful breastfeeding?

Significance:

  1. Breast milk volume is low until mature milk production begins 2-5 days after birth.
  2. Some mothers become worried if the onset of mature milk production is late and their baby loses a lot of weight, leading them to abandon breastfeeding within the first week. A strategy that increased the proportion of mothers who succeed in breastfeeding would have many health and psycho-social benefits to mother and child.
  3. Observational studies have found that formula feeding in the first few days after birth is associated with decreased breastfeeding duration. Although this could be due to confounding by indication, the finding has led to WHO and CDC guidelines aimed at reducing the use of formula during the birth hospitalization.
  4. However, a small amount of formula combined with breastfeeding and counseling might make the early breastfeeding experience more positive and increase the likelihood of success. A clinical trial is needed to assess possible benefits and harms of this strategy.

Study design:

Unblinded randomized control trial with blinded outcome ascertainment

Subjects:

  • Entry criteria: Healthy term newborns 24-48 hours old who have lost >=5% of their birth weight in the first 36 hours after birth.
  • Sampling design: Consecutive sample of consenting patients in two Northern California academic medical centers

Predictor variable, randomly assigned but not blinded:

  • Control: Parents are taught infant soothing techniques.
  • Intervention: Parents are taught to syringe-feed 10 cc of formula after each breastfeeding until the onset of mature milk production.

Outcome variables, blindly ascertained:

  1. Any formula feeding at 1 week and 1, 2, and 3 months
  2. Any breastfeeding at 1 week and 1, 2, and 3 months
  3. Weight nadir

Primary null hypothesis:

Early limited formula does not affect the proportion of women who are breastfeeding their baby at 3 months.

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.

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Filtration

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

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

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.

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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.

Iohexol

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.

Creatinine

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.

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  • 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.