Prim Care Clin Office Pract

Approach to the Patientwith Renal Disease

Edgar V. Lerma, MD, FACP, FASN, FAHAa,b,*aSection of Nephrology, Department of Medicine, University of Illinois at Chicago

College of Medicine, 820 S. Wood Street, Chicago, IL 60612, USAbAssociates in Nephrology, SC, 210 South Desplaines, Chicago, IL 60661, USA

There are various ways by which a patient who has renal disease can pres-ent as an initial outpatient or through inpatient consultation. Some patientsmay be referred because of abnormal urinary findings such as hematuria orproteinuria that may have been incidentally discovered during routineclinical evaluation or as part of initial employment requirements. Dependingon the stage of renal disease, patients can present with mild edema, general-ized pruritus, or more advanced signs and symptoms of uremia, such as de-creased appetite, weight loss, and alterations in mental status. Still othersmay present only with elevation in serum creatinine.

To narrow the differential diagnosis, the first question that needs to beaddressed is whether the disease is acute, subacute, or chronic on presenta-tion. Because there is usually an overlap in these stages, this determinationmay not always be clear. Certainly, a patient who presents with an elevatedserum creatinine level that was documented to be normal a few days previ-ously has an acute presentation, and a patient who presents with a previouslyelevated serum creatinine level that has been rising steadily over the past sev-eral months to years has a chronic disease. Oftentimes, acute exacerbationsof chronic renal disease are common presentations.

The next question addresses which particular segment or component ofthe renal anatomy is involved: prerenal, postrenal, or renal.

Prerenal disease refers to any process that decreases renal perfusion, suchas intravascular volume depletion, hypotension, massive blood loss, or thirdspacing of fluids. It can also be due to congestive heart failure, whereby de-creased effective circulating volume decreases blood flow toward the kidneys(see the article by Khalil and colleagues found elsewhere in this issue).

35 (2008) 183–194

* Section of Nephrology, Department of Medicine, University of Illinois at Chicago

College of Medicine, Chicago, IL.

E-mail address: edgarvlermamd@pol.net

0095-4543/08/$ - see front matter � 2008 Elsevier Inc. All rights reserved.

doi:10.1016/j.pop.2008.02.001 primarycare.theclinics.com

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Postrenal disease refers to any obstruction that impedes urinary flowthrough the urinary tract. Examples include benign prostatic hypertrophyor cervical malignancy (see the article by Khalil and colleagues found else-where in this issue).

Renal involvement is further subdivided into vascular, glomerular, or tu-bulointerstitial disease (see the article by Beck and Salant found elsewhere inthis issue), depending on which segment is involved.

Assessment of renal function

The most common method of assessing renal function is by estimation ofthe glomerular filtration rate (GFR). The GFR gives an approximation of thedegree of renal function. Daily GFR in normal subjects ranges from 150 to250 L per 24 hours or 100 to 120 mL/min/1.73 m2 of body surface area.GFR is decreased in those who have renal dysfunction and is used to monitorrenal function in those who have chronic kidney disease. It is also used to de-termine the appropriate timing for initiation of renal replacement therapy.

To date, there are several methods by which GFR is measured, namely,serum creatinine concentration, 24-hour creatinine clearance, and estima-tion equations such as the Cockroft-Gault formula and the Modificationof Diet in Renal Disease Study (MDRD) formula.

Using the serum creatinine alone to estimate renal functioning is inaccu-rate for several reasons. First, a small amount of creatinine is normally se-creted by the tubules, and this amount tends to increase as progressive renaldecline occurs, thereby overestimating the true GFR value. Similarly, thereare factors that increase serum creainine without truly affecting renal func-tion, such as dietary meat (protein) intake, volume of muscle mass, andmedications that interfere with tubular secretion of creatinine (eg, cimeti-dine, trimethoprim, and probenecid). Elderly patients, patients who have ca-chexia, amputees, and patients who have spinal cord injury or disease tendto have lesser muscle mass; hence, lower serum creatinine values.

The24-hoururine collection is used todetermine creatinine clearance. Itsmainlimitation is that it is cumbersome, and particularly in elderly individuals or thosewho have fecal or urinary incontinence, an incomplete or prolonged (over24 hours) urine specimen collection tends to provide erroneous information.

To determine whether a 24-hour urine collection is complete, the follow-ing reference is used: for male patients, urine creatinine � volume ¼ 20 to25 mg/kg/24 hours; for female patients, urine creatinine � volume ¼ 15to 20 mg/kg/24 hours.

A commonmethod of assessingGFR is by the use of estimation equations.Cockroft-Gault formula:

Creatinine Clearance ¼ ð140 � Age in yearsÞ � Weight ðkgÞPlasma creatinine � 72

185APPROACH TO THE PATIENT WITH RENAL DISEASE

Due to less muscle mass in female patients, a factor of 0.85 is multipliedto the creatinine clearance to arrive at the estimated GFR.

The Cockroft-Gault formula also has limitations: it tends to overestimateGFR in patients who are morbidly obese or who have significant edema.

MDRD formula:

GFR; in mL=min per 1:73 m2 ¼ 175 � serum creatinine�1:154

� age in years�0:203

� ½0:742 if female�� ½1:21 if black�

The MDRD formula is recommended for use when staging chronic kidneydisease. According to recent published reports, this formula is reasonablyaccurate inpatientswhohave stable chronickidneydisease. Similar to theCock-roft-Gault formula, it appears to be inaccurate in morbidly obese individuals,normal subjects, andpopulationsofdifferent ethnicities fromoutside theUnitedStates. In suchpopulations outside theUnitedStates, theMDRDformula tendsto overestimate GFR due to differences in body mass and dietary habits.

Clinical findings

Symptoms and signs

Most patients who have renal disease are asymptomatic and only inciden-tally discovered on routine examination to have abnormal laboratory find-ings (eg, elevated serum creatinine or abnormal findings on urinalysis).

For those who have symptomatic renal disease, most of the symptoms arenonspecific and can be referred to almost any body organ. Examples includeconstitutional symptoms such as generalized weakness, lack of energy,decreased appetite, shortness of breath, difficulty sleeping, and so forth.Some patients can present with symptoms referable to the urinary tractsuch as gross hematuria or flank discomfort. Although abnormalities in uri-nation such as increased urgency or frequency may commonly indicateunderlying urologic pathology, they are also seen in infections or inflamma-tory diseases involving the urinary tract.

Laboratory studies

Urinalysis

The most important diagnostic test used in the patient who has renal dis-

ease is the urinalysis. The urine specimen is obtained by doing a midstreamcatch for male patients, whereas for female patients, the labia majora shouldbe cleaned and then separated to avoid contamination. After collection, theurine specimen should be examined within 60 minutes of voiding.

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Initially, a dipstick examination is performed, which includes assessmentof the urine specific gravity, pH, protein, blood, glucose, ketones, bilirubin,nitrite, and leukocyte esterase (Table 1).

Microscopic examination of the urine sediment corroborates the findingson the initial dipstick analysis. The presence of various crystals, cells, casts,bacteria, and fungal elements are then reported (Table 2).

Certain patterns of findings on urinalysis are indicative of certain specificdiagnoses. For instance, in the patient presenting with acute renal failure,the finding of muddy brown, granular casts points to acute tubular necrosis,whereas the presence of red blood cell casts and dysmorphic red blood cellsis indicative of glomerulonephritis. High-grade proteinuria may be sugges-tive of glomerular disorders.

Urinary indices

Measurement of urine sodium (urine Na) in a random urine specimen is

helpful in the differential diagnosis of acute renal failure. A urine Na levelless than 20 mEq/L points to prerenal causes of acute renal failure (eg,

Table 1

Urine dipstick testing

Measure False-negative results False-positive results

Specific gravity Reduced values in the presence

of glucose, urea, alkaline urine

Increased values in the presence

of protein O1 g/L, ketoacids

PH Reduced values in the presence

of formaldehyde

–

Hemoglobin Ascorbic acid, high nitrite

concentration, delayed

examination, high density of

urine, formaldehyde (0.5 g/L)

Myoglobin, microbial

peroxidases, oxidizing

detergents,

hydrochloric acid

Glucose Ascorbic acid, urinary tract

infection

Oxidizing detergents,

hydrochloric acid

Albumin Immunoglobulin light chains,

hydrochloric acid, tubular

proteins, globulins, colored urine

Alkaline urine (pH 9),

quaternary ammonium

detergents, chlorhexidine,

polyvinylpyrrolidone

Leukocyte

esterase

Isotonic urine, vitamin C

(intake g/d), protein O5 g/L,

glucose O20 g/L, mucous specimen,

cephalosporins, nitrofurantoin;

mercuric salts, trypsin inhibitor

oxalate, 1% boric acid

Oxidizing detergents,

formaldehyde (0.4 g/L),

sodium azide, colored urine

due to beet ingestion,

or bilirubin

Nitrites No vegetables in diet, short bladder

incubation time, vitamin C,

gram-positive bacteria

Colored urine

Ketones Improper storage Free sulfhydryl groups

(eg, captopril) L-dopa,

colored urine

From Fogazzi GB. Urinalysis. In: Johnson R, Feehally J, editors. Comprehensive clinical

nephrology. 2nd edition. Philadelphia: Elsevier; with permission.

Table 2

Clinical significance of urinary casts

Cast Main clinical associations

Hyaline Normal subject

Renal disease

Granular Renal disease

Waxy Renal insufficiency

Rapidly progressive

Glomerulonephritis

Fatty Marked proteinuria

Nephrotic syndrome

Erythrocyte Glomerular bleeding

Proliferative/necrotizing glomerulonephritis

Hemoglobin Glomerular bleeding

Proliferative/necrotizing glomerulonephritis

Hemoglobinuria

Leukocyte Acute pyelonephritis

Acute interstitial nephritis

Proliferative glomerulonephritis

Epithelial Acute tubular necrosis

Acute interstitial nephritis

Glomerulonephritis

Myoglobin Rhabdomyolysis

From Fogazzi GB. Urinalysis. In: Johnson R, Feehally J, editors. Comprehensive clinical

nephrology. 2nd edition. Philadelphia: Elsevier; with permission.

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intravascular volume depletion due to fluid losses or sequestration, hypoten-sion, sepsis, and so forth). A urine Na level greater than 40 mEq/L suggestsacute tubular necrosis. To adjust for the influence of urine output, the fol-lowing equation is recommended:

Fractional Excretion of Na ðFE Na%Þ

¼ Urine Na � Plasma Creatinine � 100

Plasma Na � Urine Creatinine

A FE Na value less than 1% points to prerenal disease, whereas a FE Navalue greater than 2% suggests acute tubular necrosis. Limitations to theuse of urinary indices include prior infusion with normal saline and prioradministration of diuretics. This topic is discussed further in the article byKhalil and colleagues found elsewhere in this issue.

Imaging studies

In the evaluation of the patient who has renal disease, various radiographic

studies are available. They are performed alone or in combination to diagnosethe different pathologies affecting the genitourinary tract (Table 3).

The most common imaging modality used is that of renal ultrasonographybecause it is safe, easy to do, and avoids the use of radiation or contrast mediathat can be nephrotoxic. Important detailed information that can be obtained

Table 3

First choice imaging techniques in renal disease

Disease Imaging technique

Renal failure, unknown cause Ultrasound

Hematuria Intravenous urography or ultrasound þ plain

radiograph of kidneys, ureter, and bladder

Proteinuria/nephrotic syndrome Ultrasound

Hypertension

with normal renal function CT angiography including imaging of the

adrenal glands

with impaired renal function MRA

Renal artery stenosis

with normal renal function MRA

with impaired renal function MRA

Renal infection CT

Hydronephrosis detected by ultrasound Intravenous urography (if renal function is

preserved) or Tc 99m DTPA renography

Retroperitoneal fibrosis CT

Papillary necrosis Intravenous urography

Cortical necrosis Contrast-enhanced CT

Renal vein thrombosis Contrast-enhanced CT

Renal infarction Contrast-enhanced CT

Nephrocalcinosis Noncontrast CT

Abbreviations: DTPA, diethylene triamine pentaacetic acid; MRA, magnetic resonance

angiography.

From Parsons RB, SimpsonWL Jr. Investigation of renal disease. In: Johnson R, Feehally J,

editors. Comprehensive clinical nephrology. 2nd edition. Philadelphia: Elsevier; with

permission.

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through ultrasonography includes the size and shape of the kidneys, the pres-ence of calculi, and the differentiation of the presence of a mass or a cyst.Asymmetry of the kidneys usually indicates a unilateral disease process.The presence of hydronephrosis is an indication of obstruction along the ip-silateral ureter (if unilateral) or at the level of the bladder or lower (if bilateral).

Increased echogenicity is a common finding that signifies chronic medicalrenal disease.

The plain film of the abdomen gives information about the kidney sizeand shape in addition to radiopaque (calcium-containing) calcifications.A common limitation of plain film is its inability to detect radiolucent stones(uric acid).

CT scanning provides more detailed information about the structure ofthe kidneys because it can differentiate simple cysts from complex cysts.Noncontrast-enhanced spiral CT scan is the imaging modality of choicefor the diagnosis of nephrolithiasis. CT angiography is used in the stagingof renal cell carcinoma and in demonstrating renal vein thrombosis. Themain disadvantages to using this modality are the use of large volumes ofcontrast media and radiation.

MRI also provides detailed structural information about the kidneys.In the past, magnetic resonance angiography with gadolinium contrast

189APPROACH TO THE PATIENT WITH RENAL DISEASE

has been used extensively in the evaluation of the renal vasculature(eg, renovascular diseases). Recently, however, with several published re-ports on nephrogenic systemic fibrosis linked to the use of gadolinium, therehas been a significant decline in its use. Some experts recommend to avoidthe use of gadolinium as contrast agent in those who have an estimatedGFR of less than or equal to 30 mL/min, including those who are dependenton renal replacement therapy or dialysis.

Renal angiography is commonly used in the diagnosis of renal arterystenosis. Because iodinated contrast media is used, caution is advised, espe-cially in patients who have baseline renal insufficiency due to increased riskof contrast-induced nephropathy.

The main indications for radionuclide studies (radioisotope scanning withtechnetium 99m dimercaptosuccinic acid) include early detection of urinaryobstruction, urine leak, and vesicoureteric reflux (voiding cystourethrogram).

Retrograde and antegrade pyelography are used primarily during place-ment of ureteral stents or nephrostomy tubes. Because pyelography usesradiation and potentially nephrotoxic contrast media, other noninvasive im-aging modalities such as ultrasonography and CT scanning have been usedmore commonly in the diagnosis of urinary tract obstruction, includingidentification of the site of obstruction.

Renal biopsy

Percutaneous renal biopsy is used in situations in which evaluation of thepatient’s history, physical examination, and noninvasive testing (includingserum and urine tests and imaging studies) has failed to reveal a diagnosis.

The major indications for doing a renal biopsy include (1) unexplainedpersistent hematuria or proteinuria, especially when accompanied by pro-gressive renal decline; (2) nephritic syndrome; (3) acute nephritis; and (4)unexplained acute or rapidly progressive renal decline.

The most common complication arising from a percutaneous renal bi-opsy is bleeding. The patient’s ability to coagulate normally should be ascer-tained by closely monitoring the coagulation profile (partial thromboplastintime, prothrombin time, international normalized ratio, platelet count, andbleeding time). Patients should also be advised to hold off aspirin and non-steroidal anti-inflammatory drugs at least 1 week before the planned renalbiopsy. Patients requiring maintenance chronic anticoagulation should beplaced on heparin the day before the biopsy.

Post biopsy, most patients develop transient microscopic hematuria,whereas transient gross hematuria has been described in 3% to 10% ofcases. Rare case reports of arteriovenous fistulae arising as complicationsof renal biopsies and demonstrated by color Doppler studies have beendescribed in the literature.

The major contraindications to percutaneous renal biopsy can be dividedinto those involving the kidneys and those involving the patient. Examples

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of contraindications affecting the kidneys are presence of multiple unilateralor bilateral cysts, presence of a renal mass, a solitary functioning kidney,presence of active renal or perirenal infection, and unilateral or bilateralhydronephrosis. Patient-related contraindications include an uncooperativepatient, uncontrolled severe hypertension, intractable bleeding disorder, andmorbid obesity. It must be noted, however, that with the exception of intrac-table bleeding disorder, most of the contraindications are relative ratherthan absolute. Therefore, the actual clinical situation often dictates whethera contraindication can be overridden. Recently, it has been shown thatpercutaneous renal biopsy may be performed in those who have solitary kid-neys. Several published reports have demonstrated that even for those whohave solitary functioning kidneys, the risk of general anesthesia during openrenal biopsy far outweighs the risk of requiring surgery and subsequentnephrectomy. Therefore, in selected cases, percutaneous renal biopsy maybe performed in the presence of a solitary functioning kidney.

Asymptomatic urinary findings

Hematuria

Hematuria can be gross or microscopic. Gross hematuria is the presenceof red or brown urine. In the initial evaluation of a patient who has grosshematuria, it must be determined whether the urine discoloration is trulysecondary to pathologic bleeding within the urinary tract. It is not idealto evaluate a female patient for hematuria if she is menstruating or in thepostpartum state. Conditions in which the urine may appear grossly redin the absence of actual bleeding include intake of certain medicationssuch as rifampin, phenothiazine, or phenazopyridine (analgesic) and intakeof beets in certain predisposed individuals. It is also important to differen-tiate hematuria from other causes of red urine, such as hemoglobinuriaand myoglobinuria. The latter is usually seen in those who have acuterhabdomyolysis.

Microscopic hematuria is defined as the presence of more than two redblood cells per high-power field. It is usually detected incidentally by urinedipstick examination (Fig. 1).

Careful history taking is of paramount importance in the evaluation ofpatients who have hematuria. Important historical information usually pro-vides diagnostic clues. For instance, the occurrence of concomitant flankpain with radiation to the ipsilateral testicle or labia suggests underlyingnephrolithiasis; burning on urination or dysuria may point to possible uri-nary tract infection; and a recent upper respiratory tract infection may sug-gest postinfectious glomerulonephritis or immunoglobulin A nephropathy.A family history of hematuria is also vital because certain diseases tend torun in families, such as polycystic kidney disease or sickle cell nephropathy.Likewise, thin basement membrane disease and benign familial hematuria

Fig. 1. Workup for hematuria. (From Mazhari R, Kimmel PL. Hematuria: an algorithmic

approach to finding the cause. Cleve Clin J Med 2002;69:870–84; with permission. Copyright

� 2002 Cleveland Clinic. All rights reserved.)

191APPROACH TO THE PATIENT WITH RENAL DISEASE

tend to occur in families and are notable for having a benign course despitethe presentation. Exercise-induced hematuria is seen in adolescents who ex-ercise vigorously.

In elderly individuals or in those older than 50 years, the finding of grossor microscopic (even transient) hematuria should trigger an extensive eval-uation to rule out malignancy involving the genitourinary tract. The inci-dence of bladder cancer and other malignancies involving the kidneys andthe ureters is significantly elevated, particularly in those who have a pro-longed history of chronic smoking and analgesic use. The occurrence ofsymptoms of increased urgency and frequency with hematuria in this popu-lation should suggest urinary tract obstruction secondary to benign pros-tatic hypertrophy or prostatic malignancy.

An important aspect of the evaluation of patients who have hematuria isto differentiate glomerular from extraglomerular bleeding (Table 4).

For those who have glomerular bleeding, especially in the presence ofprogressive renal decline, a percutaneous renal biopsy may be necessary.

Proteinuria

Normal urine protein excretion is 150 mg/d. Any value higher than this isconsidered overt proteinuria. Proteinuria usually implies that there is a de-fect in glomerular permeability. In general, proteinuria can be classified intothree types: glomerular, tubular, or overflow.

Table 4

Glomerular versus extraglomerular bleeding

Evaluation Glomerular Extraglomerular

Color (if macroscopic) Red or pink Red, smoky brown, or Coca-Cola

Clots May be present Absent

Proteinuria !500 mg/d May be O500 mg/d

Red blood cell morphology Normal Dysmorphic

Red blood casts Absent May be present

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Examples of glomerular proteinuria include diabetic nephropathy andother common glomerular disorders (see the article by Beck and Salantfound elsewhere in this issue). It is usually caused by increased filtrationof albumin across the glomerular capillary wall. There are also causes of glo-merular proteinuria that have a benign course, such as orthostatic and exer-cise-induced proteinuria. These causes are characterized by significantlylesser degrees of proteinuria (!2 g/d).

Tubular proteinuria is usually seen in those who have underlying tubu-lointerstitial diseases. These patients usually have defective reabsorptivecapacities in the proximal tubules, such that instead of the proteins being

Fig. 2. Algorithm A: evaluation of proteinuria. BUN, blood urea nitrogen. (Reproduced with

permission from Rose BD, Fletcher SW. Proteinuria: the primary care approach. In: Rose

BD, editor. UpToDate. UpToDate: Waltham, MA; 2007. Copyright 2007 UpToDate Inc.

For more information, visit www.uptodate.com.)

193APPROACH TO THE PATIENT WITH RENAL DISEASE

normally reabsorbed, they are excreted in the urine. In contrast to glomer-ular proteinuria, whereby macromolecules such as albumin are leaked out,in tubular proteinuria, it is mostly low molecular weight proteins such asimmunoglobulin light chains and so forth.

Lastly, overflow proteinuria is exemplified by multiple myeloma in whichthere is an overabundance of immunoglobulin light chains secondary tooverproduction. Simply put, proteinuria occurs as a result of the amountof protein produced, basically exceeding the maximum threshold for reab-sorption in the tubules.

Glomerular and tubular proteinuria are secondary to abnormalitiesinvolving the glomerular capillary and tubular walls, respectively, whereasin overflow proteinuria, the problem lies in overproduction of certainproteins.

When performing a urinalysis, the dipstick examination can detect onlyalbumin, not the low molecular weight proteins. In fact, it can only detectalbumin when proteinuria is greater than 300 to 500 mg/d. Hence, one ofthe dipstick examination’s most important limitations is its inability to detectmicroalbuminuria, which corresponds to the earliest phase of diabeticnephropathy. The sulfosalicylic acid test, however, can detect all types ofproteins in the urine, including the low molecular weight proteins and others.

Fig. 3. Algorithm B: evaluation of proteinuria. BUN, blood urea nitrogen; CBC, complete

blood count. (Reproduced with permission from Rose BD, Fletcher SW. Proteinuria: the primary

care approach. In: Rose BD, editor. UpToDate. UpToDate: Waltham, MA; 2007. Copyright

2007 UpToDate Inc. For more information, visit www.uptodate.com.)

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Quantification of the degree of proteinuria is accomplished by performinga 24-hour urine collection, which can be cumbersome, especially in elderly in-dividuals or those who have concomitant fecal or urinary incontinence.

The urine protein-to-creatinine ratio (using a random urine specimen) hasbeen shown have a good correlation with the 24-hour urine protein determi-nation (Figs. 2 and 3).

Orthostatic or postural proteinuria, by definition, is demonstration ofincreased urine protein excretion in the upright position and normal urineprotein excretion in the supine position. It is a benign condition, mostlyseen among adolescents, the mechanism of which is not clearly understood.The diagnosis is established by performing a split urine collection. The pro-tocol for a split urine collection is as follows: (1) the first morning void isdiscarded; (2) a 16-hour upright collection is obtained between 7 AM and11 PM, with the patient performing normal activities and finishing the collec-tion by voiding just before 11 PM (the times can be adjusted according to thenormal times at which the patient awakens and goes to sleep); (3) the patientshould assume the recumbent position 2 hours before the upright collectionis finished to avoid contamination of the supine collection with urine formedwhen in the upright position; and (4) a separate overnight 8-hour collectionis obtained between 11 PM and 7 AM.

Patients who have orthostatic proteinuria do not progress to end-stagerenal disease; in fact, orthostatic proteinuria resolves spontaneously inmost affected patients.