When hematuria is found on dipstick examination of the urine and no red cells are seen on microscopic examination, one needs to test for urinary myoglobin to rule out rhabdomyolysis.
Hematuria in patients on Coumadin is not normal. Further studies are warranted to find the source of the bleeding.
If one encounters persistent pyuria with negative urine cultures, consider tuberculosis as a possible diagnosis.
The serum urea nitrogen (SUN) to creatinine ratio is useful in distinguishing prerenal azotemia (e.g., dehydration, congestive heart failure) and postrenal azotemia (e.g., obstruction) from azotemia due to primary renal disease. A ratio >20 to 1 suggests one of the two former etiologies.
A rapid rise in SUN and serum creatinine concentrations after starting a patient with hypertension on an ACE (ACE) inhibitor or angiotensin II receptor blocker (ARB) should suggest the possibility of bilateral renal artery stenosis.
Nonsteroidal anti-inflammatory drugs (NSAIDs) can cause acute onset of nephrotic syndrome and/or deterioration of renal function (acute interstitial nephritis) months after starting these agents.
When a previously healthy older person comes in with acute onset of hypertension/heart failure, consider acute postinfectious glomerulonephritis, even if protein and cellular elements are scant or absent in the urine.
Multiple myeloma/light chain cast nephropathy should be ruled out in any elderly patient with unexplained renal insufficiency.
An important clue in distinguishing hyponatremia associated with primary salt depletion from the syndrome of inappropriate antidiuretic hormone (SIADH) is the SUN level. The SUN is elevated in the former and tends to be normal or subnormal in the latter, unless preexisting renal disease was present.
If an elderly patient is found to have unexplained hypokalemia, question him about the heavy use (abuse) of cathartics and enemas. Patients usually will not tell you unless you ask specifically.
Be aware of the potential for life-threatening hyperkalemia in elderly patients with cardiovascular disease (CVD) (especially those with preexisting renal disease) when started on any of a number of CVD medications that compromise the renin-angiotensin-aldosterone system, specifically ACE inhibitors, ARB, β-adrenergic antagonists (blockers), and the potassium-sparing diuretics. Potassium supplements given along with thiazide or loop diuretics are usually not necessary in the treatment of hypertension, and they can be dangerous unless closely monitored.
RENAL FUNCTION WITH NORMAL AGING
Renal function, as measured by the glomerular filtration rate (GFR), declines after the age of 40 years at a mean rate of approximately 1% per year, accelerating in later years. This observation was first reported in cross-sectional studies. In the Baltimore Longitudinal Study of Aging,1 however, one third of the participating volunteers followed serially, many for periods >20 years, showed no decline in renal function over time, although the whole study population showed a mean decrease similar to that observed in cross-sectional studies. This would appear to indicate that a decline in renal function with age is not inevitable (i.e., there is no involutional senescence), but rather the decrease in mean values is related to intervening pathology (e.g., atherosclerosis) in only part of the population. Renal mass also is lost with age.
Despite significant anatomic changes and loss of kidney function with age, the older kidney is capable of maintaining body fluid, electrolyte, and acid-base balance within the normal range under most circumstances. However, when challenged by environmental and disease-related stressors, such as large volume changes or acid loads, it takes the older kidney longer to correct abnormalities that develop.
CLINICAL PRESENTATIONS OF RENAL DISEASE
The clinical presentations of renal disease are not significantly different in old compared to young adults. Early recognition of a decline in renal function is important to permit early diagnosis and treatment of treatable causes. Even if no specific curative treatment is available, there are usually interventions (e.g., aggressive control of hypertension and nutritional measures) that can at least slow the progression of the disease process.
The first indication of renal disease may be picked up on a routine screening urinalysis (proteinuria, hematuria, pyuria, casts) without associated signs or symptoms. Loss of large amounts of protein in the urine can lead to hypoalbuminemia (nephrotic syndrome) and edema formation. Renal disease is often asymptomatic until more than two thirds of normal renal function is lost. The first symptoms associated with azotemia (increased serum urea nitrogen [SUN]) are fatigue, anorexia, nausea, somnolence, and confusion. By the time the patient develops these symptoms, unless a reversible cause can be found, they are at a point where dialysis is generally necessary.
Table 31.1 lists the most common disease entities (i.e., the diseases that should come to mind first in your differential diagnosis) by presenting manifestations. Hematuria (red cells) and pyuria (white cells) may present with or without red cell or white cell casts in the urine. Casts tell you that the cells are coming from the level of the glomerulus or tubule. Proteinuria may be either acute or chronic in onset, and may vary in quantity from nonnephrotic to nephrotic in quantity. Azotemia also may be acute or chronic at onset, and protein and cellular elements (red and white cells, casts) may or may not be present. An attempt has been made to list disease entities in the order of decreasing probability under each of the subcategories. This list would become too unwieldy if made all-inclusive, so it has been limited to the most common entities. Your nephrologist and/or urologist can help you sort out the more complex and puzzling cases.
CASE ONE
A 65-year-old man comes into your office noting the insidious onset of ankle edema during the day and waking up with swelling around the eyes in the mornings over the last month. His blood pressure is 150/86 mm Hg after 5 minutes of quiet lying, and he has 2+ edema of the lower extremities. The rest of the physical examination is unremarkable. A dipstick urine check reveals 3+ proteinuria with a few red cells and white cells per HPF on examination of the sediment.
His SUN is 18 mg per dL, his serum creatinine concentration is 1.5 mg per dL, and his electrolytes are all normal. His serum albumin is 2.8 g per dL and serum total cholesterol is 320 mg per dL. A 24-hour urine sample contains 8 g of protein.
He is referred to a nephrologist who is unable to determine the cause of his nephrotic syndrome after a battery of additional blood tests (antinuclear antibody [ANA], anti-DNA, antineutrophil cytoplasmic antibody [ANCA], etc.) are all negative. A renal biopsy is performed, which shows evidence on microscopic examination of a membranous glomerulopathy with diffuse thickening of the basement membrane, but no hypercellularity.
TABLE 31.1 DIFFERENTIAL DIAGNOSIS OF KIDNEY DISEASES BY PRESENTING MANIFESTATIONS
The list is not all-inclusive but gives the most common causes in the elderly in approximate order of frequency.
ICD-9 codes are shown after each diagnosis.
ICD-9 codes for diseases of the kidney and urinary tract (excluding diseases of the male and female genital organs) will fall between 580 and 600. Specific disease entities, for example, glomerular diseases, will have different codes, depending on whether they are acute (580) or chronic (582). They can also be classified on the basis of whether they have nephrotic proteinuria (581) or whether proteinuria is unspecified, presumably nonnephrotic (583).
Following this code number, there is a period and further qualifying code numbers that define the lesion better (0.0 to 0.7). Where renal involvement is secondary to some systemic disease, the systemic disease is first identified, followed by a code for the renal involvement. This ends with 0.81 if there is a specified pathologic renal lesion from a list provided, with 0.89 if there is a specific renal lesion identified but not on this list, and with 0.9 if the renal lesion is not identified by pathology.
Patients with nephrotic syndrome generally sleep lying flat so that eye puffiness is often noted on arising in the morning. In contrast, the patient with congestive failure and edema sleeps in a more upright position favoring development of lower extremity edema instead.
The most common primary renal lesion causing nephrotic syndrome in the older adult is membranous glomerulopathy. In one biopsy series, the incidence was 35% followed by minimal change disease (16%) and primary amyloidosis (12%).2
There exists considerable disagreement among nephrologists whether membranous glomerulopathy should be treated with immunosuppressive agents and/or corticosteroids. Although these patients will sometimes appear to respond to these agents, some patients will also improve spontaneously. The complications associated with the therapy must be weighed against the potential benefits. This decision is probably best left to the consulting nephrologist.
Urinary Abnormalities
Proteinuria
The normal urine protein (albumin) excretion is <30 mg per day (<2 mg per dL on spot urine check) and is not different in the old compared to the young. Macroproteinuria (albuminuria) by definition is a urinary protein excretion of >300 mg per day (or >20 mg per dL). Urinary protein excretions between 30 and 300 mg per day represent microproteinuria (albuminuria). The urine dipstick is not very sensitive and is adequate only for screening purposes, because a 1+ reading will be obtained at a protein concentration of roughly 30 mg per dL and a 2+ reading at roughly 100 mg per dL. Anything more than a trace of urinary protein should warrant quantitation with a timed urine specimen. The dipstick does not detect low-molecular-weight proteins. If one suspects that Bence-Jones proteinuria (light chain immunoglobulins seen with multiple myeloma [MM] that are responsible for tubular toxicity/obstruction) or tubular proteins are present, a sulfosalicylic acid test of the urine is needed.
Early damage to kidneys from diabetes and/or hypertension can be detected by testing the urine for microalbuminuria using semiquantitative dipsticks (Chemstick Micral, Boehringer Mannheim Corporation, Indianapolis, Indiana 46256; Micral, Roche Laboratories; Hemacue Urine Albumin, Bayer DCA 2000).
When quantitative studies are performed, the ratio of urine protein (albumin) to urine creatinine in a random urine sample (normally <30 mg protein per g of creatinine) corrects for variations in urine concentration due to hydration and is far more convenient than timed urine collections. Recent studies3,4 have convincingly shown not only that microalbuminuria is a marker for risk of cardiovascular and renal disease, especially in patients with diabetes, but that treatment of those developing significant microalbuminuria with ACE inhibitors or angiotensin II receptor blockers (ARBs) reduces subsequent microalbuminuria and risk of cardiovascular and renal disease (Evidence Level A).
Definition
Nephrotic syndrome by definition is loss of >3 g of protein in the urine per day. Anything less than this is considered nonnephrotic proteinuria. The nephrotic syndrome is generally accompanied by hypoproteinemia, hyperlipidemia, and edema. There may also be evidence of hypercoaguability and increased susceptibility to infections due to loss of select proteins. Hypertension and impairment in renal function (increased SUN and serum creatinine concentrations) are part of the nephritic syndrome, but are also often present.
Table 31.2 lists the causes of nephrotic syndrome. For further descriptions as to the diagnosis, pathology, and treatment of these different entities, one may consult any of the following references: Cameron,2 Couser,5 Lindeman,6 or Burkhart.7 A number of serologic tests are important adjuncts to the differential diagnosis of glomerular and vascular (vasculitis) lesions responsible for the nephrotic syndrome. Serologic testing refers to the use of immunoassays to detect the presence of disease-relevant antibodies in serum or to determine the serum level of a specific antigen such as complement. Table 31.3 lists some of the more commonly used tests and the renal diseases they are designed to detect. Additional tests are described elsewhere in more detail.8
Hematuria
Hematuria exceeding 3 to 5 RBC/HPF deserves further evaluation. Red cell casts, best seen on an unspun urine specimen because they are so fragile, are indicative of a glomerular source (glomerulonephritis [GN]). Red cells that have lost their biconcave shape also suggest a glomerular origin, whereas biconcave red cells suggest that the bleeding is coming from the lower part of the urinary tract. Associated proteinuria and/or an elevated serum creatinine concentration also suggest renal parenchymal (glomerular) disease.
TABLE 31.2 CAUSES OF NEPHROTIC SYNDROME DUE TO GLOMERULAR DISEASE
Primary glomerular diseases
Membranous glomerulopathy (581.1)
Membranoproliferative GN (581.2)
Mesangial proliferative GN (IgA nephropathy) (581.2)
Focal and/or segmental glomerulosclerosis (581.1)
Minimal change disease (581.3)
Crescentic or rapidly progressive GN (anti-GBM, immune complex, pauci-immune) (580.4)
Glomerular diseases associated with systemic illnesses
Anti-GBM, antiglomerular basement membrane antibody; GN, glomerulonephritis; MM, multiple myeloma.
TABLE 31.3 SEROLOGIC TESTS AVAILABLE FOR THE EVALUATION OF THE PATIENT WITH EVIDENCE OF GLOMERULAR AND/OR VASCULAR DISEASE (NEPHROTIC SYNDROME/RENAL INSUFFICIENCY), INDICATIONS FOR THEIR USE (TO RULE OUT SPECIFIC DISEASE ENTITIES), AND ESTIMATED FREQUENCY OF POSITIVE TESTS FOR THESE INDICATIONS
Serologic Test
Indications
Percent Positive (%)
Antistreptolysin antibody
Recent β-hemolytic streptococcal infection
>80
Streptozyme (rapid test kit)
APSGN
Anti-DNase B antibody
Pyoderma-associated APSGN
80-90
Complement (C3, C4, CH50)
Acute GN—Low in APSGN
90
Diffuse SLE
90
Focal SLE
75
Membranoproliferative GN
50-90
Antinuclear antibody
SLE
95-99
Anti-dsDNA
Same (more conclusive when positive)
40-70
(Anti-dsDNA)
Used to monitor response to therapy
ANCA
Rapidly progressive GN
80-90
(p-ANCA/c-ANCA)
Wegener granulomatosis (pauci-immune crescentic and necrotizing GN/vasculitis)
Anti-GBM
Goodpasture syndrome (pulmonary-renal syndromes)
90-100
IgA
IgA nephropathy
40-50
HBV and HCV serologies
HBV and HCV-associated glomerular diseases
HIV serology
HIV-associated glomerular diseases
Serum protein electrophoresis
MM amyloidosis, macroglobulinemia, etc.
80
Urine protein electrophoresis
Bence-Jones proteinuria (MM)
20
Serum immunoelectrophoresis
MM, amyloidosis, macroglobulinemia, etc.
Cryoglobulin
Cryoglobulinemia-associated GN
APSGN, acute poststreptococcal glomerulonephritis; Anti-dsDNA, anti-double-stranded DNA antibody; ANCA, antineutrophil cytoplasmic antibody; SLE, systemic lupus erythematosis; Anti-GBM, antiglomerular basement membrane antibody; IgA, immunoglobulin A; HBV, hepatitis B virus; HCV, hepatitis C virus; MM, multiple myeloma.
Work-up for isolated hematuria should include a urine culture, a platelet count, prothrombin time (PT), and partial thromboplastin time (PTT) to rule out a coagulopathy, and imaging studies of the kidney and urinary tract (renal ultrasound or intravenous pyelography). If these are nondiagnostic, a urologic consult for cystoscopy is warranted. In approximately 80% of older adults, the source of bleeding is the bladder, prostate, or urethra. Malignancies account for one third of all cases of hematuria in adults, most commonly involving the bladder, but the kidney (hypernephroma) and prostate may also be sources. After a comprehensive evaluation, no cause for bleeding will be found in approximately 10% of cases. In the absence of significant proteinuria, <10% of the cases of hematuria will be glomerular in origin.
Pyuria and casts
White cells and white cell casts result from infectious or inflammatory reactions in the kidney and urinary tract. White cell and granular casts indicate a renal origin that can be either glomerular (GN) or tubular (interstitial nephritis) in origin. Sterile pyuria should suggest the possibility of tuberculosis.
Azotemia
The primary clinical function of the kidney that requires monitoring is the GFR. The most practical and reproducible clinical measure of the GFR is the creatinine clearance. Participants in the Baltimore Longitudinal Study of Aging showed a 30% decline in mean clearances between the age of 30 and 80 years, yet the mean serum creatinine concentrations rose insignificantly (from 0.81 to 0.84 mg per dL).9 As creatinine clearance rates decrease with age, the production of creatinine added to the circulation from muscle metabolism also falls at nearly the same rate. The practical implication of this observation is that the serum creatinine concentration of the older person must be interpreted with this in mind when used to determine or modify dosages of drugs cleared totally, such as aminoglycoside antibiotics (gentamycin), or partially, such as digoxin, by the kidney. Additionally, some drugs, for example, trimethoprim, cimetidine, and cephoxitin, compete with creatinine for tubular secretion, resulting in an increase in serum creatinine concentration without any change in creatinine clearance.
The SUN and urea clearance similarly make use of endogenously produced urea as the test substance. Because much of the filtered urea can be reabsorbed in the tubules at low flow rates, vigorous hydration is necessary to make the clearance results interpretable. SUNs are also affected by the rate of urea production (that is, protein intake and tissue catabolism) and hence serum creatinine concentrations are generally more useful in estimating GFR. As discussed in the following text, however, the SUN to serum creatinine ratio can be useful in separating pre- and postrenal causes of azotemia from azotemia due to primary renal disease.
A formula derived by Cockroft and Gault has been widely used to predict creatinine clearances using serum creatinine concentration, age, and weight for men as follows:
Creatinine clearance (milliliters per minute)
For women, this value is multiplied by 0.85. Investigators from the Multicenter Diet in Renal Disease study (MDRD)10 have developed a series of new predictors of creatinine clearance using serum creatinine concentration and additional confounders that they feel produce a more accurate estimate.
LABORATORY TESTS AND DIAGNOSTIC PROCEDURES
Laboratory Tests
Table 31.2 lists laboratory (serologic) tests that are available to help distinguish between the different pathologic entities responsible for nephrotic syndrome and/or acute and chronic renal insufficiency. The indications for each of these tests are also shown. Additional tests can be found elsewhere in more detail.8 Interpretation of serum and urine osmolality and electrolytes (sodium, potassium) will be discussed later.
Imaging Techniques
A variety of imaging techniques are available to evaluate the genitourinary system.
Ultrasonography is noninvasive and safe, and it can provide many diagnostic clues, showing kidney size, hydronephrosis of the collecting system, and solid and cystic renal masses. An intravenous pyelogram (IVP) shows more detail of the collecting system, including sites of obstruction and other pathology, (for example, papillary necrosis). However, it is best to avoid use of intravenous contrast in older patients with diabetes mellitus, renal insufficiency, hypertension, and especially MM, as these patients are prone to develop acute renal failure (ARF). If it becomes necessary to use contrast agents, it is important to ensure that the patient is well hydrated. Computed tomography (CT) scans, magnetic resonance imaging (MRI), isotopic renography, and angiography are additional procedures available to further evaluate selected renal disorders.
Renal Biopsy
For patients with suspected primary glomerular disease or unexplained renal failure, a renal biopsy may be indicated after all other available means for establishing a diagnosis have been exhausted. Renal biopsy should not be withheld because of age alone. At least half of all primary glomerular lesions responsible for the nephrotic syndrome are potentially treatable (e.g., membranous glomerulopathy, minimal change disease, vasculitis), and so trials of immunosuppressive and/or corticosteroid therapy may be warranted. However, when a lesion known to be unresponsive to these agents is diagnosed, for example, primary amyloidosis, it is important to not subject older patients to the potentially serious side effects of these drugs.
ACUTE RENAL INSUFFICIENCY OR FAILURE
The primary care clinician is in a unique position to impact care in patients with acute renal insufficiency (ARI), both in terms of prevention and early detection. With a careful medical history, physical examination, and laboratory values (urinalysis, SUN, and creatinine concentrations), one can usually determine whether the cause is prerenal, intrarenal, or postrenal in origin.
Prerenal Acute Renal Insufficiency
Prerenal ARI occurs when poor perfusion of the kidney causes a failure in renal function. Loss of sodium and body fluids (intravascular volume depletion), decreased cardiac output (congestive heart failure), sepsis, internal redistribution of fluid volume, and certain drugs (diuretics, ACE inhibitors, ARBs) contribute in different combinations in most cases. In several reports, intravascular volume depletion accounted for over half of the cases of ARF. The decreased ability of the older patient to retain sodium and concentrate urine and, most importantly, the impairment of the thirst mechanism all contribute to their susceptibility. With acute hypotension from any cause, the decrease in renal perfusion stimulates sympathetic activity and release of vasoconstrictor substances that further reduce GFR. If the hemodynamic disturbances are promptly corrected, the patient usually, but not always, recovers. Older patients are generally slower to respond.
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