CHAPTER 50—KIDNEY DISEASES AND DISORDERS
FLUID AND ELECTROLYTE DISTURBANCES
CLINICAL PRESENTATIONS OF KIDNEY DISEASES
IMAGING TECHNIQUES AND KIDNEY BIOPSY
DISEASES OF THE KIDNEY AND VASCULAR SYSTEM
Kidney function declines after age 40 years at a mean rate of approximately 1% per year, accelerating some in the later years. This observation was first reported in cross-sectional studies and confirmed in a population of normal aging persons followed over time. However, although two thirds of individuals followed for up to 20 years in the Baltimore Longitudinal Study developed a decline in glomerular filtration rate (GFR) with aging, one third had no decline, indicating that a decline in kidney function with age is not inevitable.
Although there is loss of glomerular mass with aging, the loss of tubular mass is proportional, so that glomerular-tubular balance is usually maintained. Despite significant anatomic and functional changes, the older kidney is capable of maintaining homeostasis of body fluids and electrolytes under most circumstances. However, under environmental and disease-related stresses, such as volume changes or alterations in acid-base status, the older kidney is slower to respond to correct the abnormality.
Surveys of older adults in both acute and long-term-care facilities show a high prevalence of hyponatremia (serum sodium concentration < 132 mmol/L). By definition, these persons have an excess of water relative to solute. Clinically, older adults with hyponatremia can be separated into those with decreased extracellular fluid (ECF) volume (eg, gastrointestinal losses, adrenal and renal salt-losing conditions), increased ECF volume (eg, heart failure), or normal ECF volume (eg, syndrome of inappropriate antidiuretic hormone, or SIADH). The last is the most common. Regardless of cause, nonosmotic (baroreceptor) stimulation of arginine vasopressin (AVP) release is a major factor in the development of hyponatremia. Older persons appear to have an increased osmoreceptor sensitivity, as evidenced by the greater increase in serum AVP in response to any given increase in serum osmolality. Postoperative and diuretic-induced hyponatremia are much more common in older than in younger persons.
Hyponatremia does not usually produce symptoms until the serum sodium concentration falls below 125 mmol/L. At about this level, central nervous symptoms begin to appear, including somnolence, cognitive impairment, seizures, and ultimately coma, secondary to brain edema. Although therapy is not different for older adults, it is important to proceed slowly and to monitor regularly the older patient’s response to avoid the development of cardiovascular or neurologic symptoms, or both.
Hypertonic dehydration (serum sodium > 148 mmol/L) is common in older adults, especially among acutely hospitalized and nursing-home patients. It also is largely avoidable. A number of factors may contribute to this condition. Body water is decreased as a proportion of total body weight because of the relative increase in fat content of normal older adults. Although AVP release from the posterior pituitary is normal (or even supernormal) in response to hypertonicity in older adults, the ability to concentrate the urine in response to AVP is decreased. Probably most important is the blunted or even absent thirst response to hypertonicity seen in normal older adults. This thirst response is even more impaired in patients with cerebral disease, such as stroke. In hot weather and in the absence of air conditioning, it is therefore important to make certain that older adults know to increase their consumption of fluids. An inability to obtain water because of functional or cognitive barriers may further limit the older person’s ability to adequately replenish lost body fluids. It is helpful to instruct older adults to drink a specific amount of water each day. For institutionalized older adults, particularly those with decreased mobility or impaired cognition, placing a specific amount of fluid within easy reach and assuring that it is gone by the end of the day is helpful. In addition, on very hot days, it may be wise to hold or decrease the dose of diuretics in some patients. Symptoms of hypernatremia (obtundation, lethargy, coma) are predominantly neurologic, presumably because of shrinkage of the brain cells. As intravascular volume is preserved at the expense of cell water, changes in blood pressure, pulse rate, and skin turgor may not be evident early on.
There is a long list of potential causes of hypokalemia in older adults. A low serum potassium measurement usually represents total body potassium depletion. This may be secondary to gastrointestinal losses, as occurs with vomiting, diarrhea, nasogastric suction, or fistula drainage. Vomiting produces a metabolic alkalosis that shifts potassium into cells and increases urinary potassium losses. Another commonly overlooked cause of hypokalemia is excessive use of purgatives and enemas.
Total body depletion of potassium may also occur secondary to renal losses. In older adults this is commonly secondary to diuretic usage and may be completely avoided with supplemental potassium. Although the liquid form of potassium supplement has an unpleasant taste, it is generally absorbed better than potassium tablets and is not associated with the same risk of gastric ulceration. Potassium wasting may also result from excessive adrenal hormone production or a primary underlying kidney disease. Primary and secondary aldosteronism (the latter from renal artery stenosis or volume contraction resulting from diuretic usage in patients with heart, liver, or kidney disease) may be a contributing factor. Hypomagnesemia-induced hypokalemia with ongoing renal potassium wasting is also seen with diuretic usage.
Potassium deficiency affects the cardiovascular system, neurologic system, muscles, and kidneys. The major side effects affecting the cardiovascular system are hypokalemia-induced ventricular arrhythmias. Muscle symptoms include weakness, easy fatigability, cramping, myalgias, and muscle tenderness secondary to rhabdomyolysis. Effects on the kidneys result in polyuria and development of a metabolic alkalosis with paradoxical aciduria (low urine pH).
Since an alkalosis (chloride depletion) usually accompanies hypokalemia and is responsible for a shift of potassium intracellularly, replacement therapy should be with potassium chloride. The exception is the patient with renal tubular acidosis, in which case the alkaline salts of potassium should be given. Azotemia and age are the two significant risk factors for life-threatening hyperkalemia in potassium-supplemented patients. The latter may be related to the lower levels of aldosterone seen in the elderly patient under any given set of conditions (low-salt versus high-salt diet, supine versus upright posture).
Most episodes of hyperkalemia are seen in patients with chronic kidney disease (CKD). However, significant hyperkalemia is uncommon until the azotemia becomes life threatening or another factor contributes, such as an increased endogenous or ingested potassium load, severe acidosis, administration of a diuretic to block sodium potassium exchange (triamterene, spironolactone), a deficiency of endogenous aldosterone or mineralocorticoid, or, importantly, administration of drugs, such as nonsteroidal anti-inflammatory drugs (NSAIDs) or angiotensin-converting enzyme (ACE) inhibitors. Older persons with an interstitial nephritis, especially diabetic patients, develop a failure of the renin-aldosterone system with a hyperkalemia and mild metabolic acidosis, often referred to as type IV renal tubular acidosis.
In general, the presentation of kidney disease in older and younger adults is not significantly different. It is important to recognize a decline in kidney function to permit early diagnosis of treatable causes of renal insufficiency. If no treatment is available, then interventions to retard disease progression should be started whenever possible. As detailed below, national guidelines have been developed to guide pre–end-stage renal disease (ESRD) care. Equally important, the impact of kidney function on other aspects of a person’s health care needs to be considered. For example, medications that are excreted by the kidney may need a dose adjustment to prevent toxic drug levels. In addition, some medications may adversely affect kidney function or complicate kidney disease. In patients with CKD there may be alterations in feelings of well-being and changes in functional status that must be addressed.
The medical history and physical examination may be very helpful in determining the cause of renal insufficiency. The clinical symptoms and signs are variable but often are related to the underlying disease. Nephrotic syndrome may present with edema and hypertension. Kidney stones may present with flank pain, hematuria, nausea, and vomiting. These same symptoms are also seen with acute renal artery embolization. Renal artery stenosis may be silent or present with multiple episodes of pulmonary edema. The symptoms commonly reported as a direct result of CKD (eg, fatigue, nausea, cognitive difficulties) are generally not experienced until the creatinine clearance (CrCl) is less than 20 mL/min. However, complications of CKD, including anemia, metabolic acidosis, and alterations in calcium-phosphate metabolism, may develop as the GFR falls below 60 mL/min.
The first hint of kidney disease may be seen on a screening urinalysis with asymptomatic abnormalities (hematuria, proteinuria, pyuria, casts). It may also present with an asymptomatic elevated serum urea nitrogen or serum creatinine concentration. It is important to remember that muscle mass decreases with age. Therefore, a normal serum creatinine may represent a decline in kidney function. For example, a serum creatinine of 1.0 mg/dL in an 80-year-old person weighing 65 kg corresponds to an estimated CrCl of 54 mL/min. It also is helpful to look for changes in serum creatinine over time. A change in serum creatinine from a steady-state level of 0.7 mg/dL to 1.4 mg/dL indicates that the kidney function has decreased by 50% and signals the need for further evaluation.
In summary, the finding in an older adult of hematuria, proteinuria, abnormal urinary sediment, or a decreased CrCl indicates the need to more fully evaluate kidney function. Although it is not clear that age alone is a risk factor for CKD, the comorbidity associated with the aging process, including vascular disease, diabetes mellitus, and cardiac disease, places older adults at increased risk for a renal insult.
Whether macroscopic or microscopic (> 3 to 5 red blood cells per high-power field), hematuria in older adults deserves evaluation. A microscopic examination of the urine may suggest the source of the hematuria. Dysmorphic red blood cells (normal biconcave shape is distorted) or red cell casts in freshly voided urine suggest a glomerular source. Associated proteinuria or an elevated serum creatinine concentration also suggest kidney parenchymal disease. Biconcave red blood cells suggest a disease of the collecting system. It is also important to consider systemic coagulation defects. In addition to a microscopic urine evaluation, the work-up of isolated hematuria should include a urine culture, imaging (kidney ultrasound or intravenous pyelography) to exclude a renal parenchymal mass, and, if these are nondiagnostic, a urologic consultation for cystoscopy. In addition, a platelet count, prothrombin time, and partial thromboplastin time should be obtained to exclude a coagulopathy. In approximately 80% of older adults, the source of hematuria is the bladder, prostate, or urethra. Malignancies, most often bladder but also hypernephroma and prostate, account for one third of the cases of hematuria. Less than 10% of the hematuria is glomerular in origin (in the absence of proteinuria). It is important to remember that hematuria in patients on warfarin is not normal and suggests underlying pathology. Hematuria with proteinuria in a patient with diabetic nephropathy also needs evaluation to exclude underlying malignancy. Where hematuria is noted on dipstick examination of the urine and no red blood cells are seen on the microscopic examination, the clinician needs to consider the presence of myoglobin.
Normal protein excretion in older and younger adults does not differ significantly. Significant proteinuria is defined as greater than 150 mg per 24 hours. The urine dipstick is a good screening method for the detection of proteinuria, but it detects only albumin; light chains, which would be present in a patient with multiple myeloma, and low-molecular-weight protein (tubular protein) need to be detected by the use of a sulfa salicylic acid test. This test may be easily performed in the outpatient clinical setting.
When urinary proteins are primarily albumin and higher-molecular-weight proteins, the pathology is likely glomerular. Three grams of protein in a 24-hour urine sample is used to distinguish nephrotic from non-nephrotic proteinuria. The evaluation of proteinuria should begin with a careful examination of fresh urinary sediment (cells, casts), as this can provide helpful clues as to the mechanism of the proteinuria.
The urine dipstick method for detection of proteinuria is relatively insensitive, requiring urinary albumin concentrations of nearly 30 mg/dL. This means that a person with a urine output of 1 liter per day must be excreting nearly 300 mg of albumin per day before proteinuria can be detected. Microalbuminuria, defined as a urinary albumin excretion of more than 30 mg per day (less than that detectable with the dipstick method), is an early indicator of progressing renal injury. This has become important because antihypertensive therapy, specifically ACE inhibitors, are being used to lower glomerular capillary pressures. This therapy reduces the proteinuria, which itself may be nephrotoxic, and retards the further development of renal damage, not only in diabetic but in nondiabetic kidney disease. Quantification of the severity of microalbuminuria does not require a 24-hour urine sample, as accurate enough estimates can be obtained with a timed early morning sample or simultaneous measurement of urinary creatinine concentration, or both.
The most useful measure of kidney function is an estimate of the GFR, as reductions in other functions (eg, tubular functions, concentrating ability, acid excretion) tend to parallel decline in GFR. The CrCl is the most reproducible measure of GFR available for clinical decision making. In older persons creatinine production falls at nearly the same rate as the renal clearance of creatinine and, as noted previously, a normal serum creatinine may actually reflect a decline in kidney function. This pattern of change is important to recognize when the older patient is using drugs cleared primarily by the kidney. The relationship between serum creatinine and GFR has prompted a number of investigators to suggest that one could properly correct for the confounding variables, so they have developed formulas to estimate CrCl as a measure of GFR. The most widely used formula is that of Cockcroft and Gault:
(140 − age) × weight
CrCl = ——————————————
72 × serum creatinine
Weight in kg; serum creatinine in mg/100 mL; 85% less in women.
This formula was developed and validated on highly selected samples of older adults that did not include many very old individuals. Only moderate correlations have subsequently been found between calculated and actual CrCls, especially in older populations.
Currently, no available method of estimating GFR from easily obtainable variables, such as age, sex, weight, and serum creatinine, is very accurate, and no method will be available until we have an easy method for estimating muscle mass. In older adults, the lower limit of a normal GFR is not well defined. Nevertheless, in clinical practice, the use of an estimated GFR from the Cockcroft and Gault formula will provide a prompt and reasonable guide for clinical decision making in most situations. Finally, it is important to recognize that certain commonly prescribed drugs (trimethoprim-sulfamethoxazole, cimetidine, and cefoxitin) compete with creatinine for tubular secretion, causing an increase in serum creatinine concentration without changing GFR. (See also the section on elimination in Pharmacotherapy.)
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 parenchymal renal masses. An intravenous pyelogram shows more detail of the collecting system, including sites of obstruction and other pathology, such as papillary necrosis. However, it is best to avoid intravenous contrast in older adults with diabetes mellitus, CKD, hypertension, and, most notably, multiple myeloma, given the increased risk for contrast media–induced acute renal failure (ARF), especially if the person is dehydrated. If intravenous contrast absolutely must be used, the patient should be well hydrated before the procedure and for at least 24 hours after the procedure. Although the studies are controversial, most clinical centers now use N-acetylcysteine prior to procedures with contrast dye in high-risk patients. Computed tomography scans, magnetic resonance imaging, isotopic renography, and angiography are additional techniques available to further evaluate selected kidney disorders.
For patients with suspected primary glomerular disease or unexplained kidney failure, a kidney biopsy may be indicated after all other available means for establishing a diagnosis have been exhausted. Kidney 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 (eg, membranous glomerulopathy, minimal-change disease, vasculitis), and trials of immunosuppressive or corticosteroid therapies, or both, are warranted. On the other hand, when a lesion unresponsive to these agents is diagnosed, such as primary amyloidosis, it is important not to subject older adults to the potentially serious side effects of these medications. One study looked at more than 200 kidney biopsy samples in adults aged 60 and over with ARF to evaluate whether the biopsy was useful in predicting organ and patient survival. The authors found that in more than 90% of the biopsies, a diagnosis was made for ARF; in many of these cases, a treatment was available; and in 30% of the cases, the diagnosis on biopsy did not match the clinical diagnosis. In summary, when a cause for ARF is unclear on the basis of clinical and laboratory evaluation, a kidney biopsy is warranted. The exception would be the older adult who is unable to tolerate the indicated treatment for ARF because of comorbidity. It is important to work with the nephrologist and make certain that the patient is clinically stable for the procedure. This includes optimum blood-pressure control and holding medications that might increase the risk of bleeding, for example, aspirin.
A retrospective analysis examining the reason for kidney biopsy in 1368 older adults showed that the three most common reasons for referral were nephrotic syndrome (31%), acute renal insufficiency (26%), and chronic renal insufficiency (25%).
The incidence of nephrotic syndrome is at least as common in older adults as it is in younger persons. The most common cause in older adults is membranous nephropathy (35%), followed by minimal-change disease (16%) and primary amyloidosis (12%). The incidence rates for membranous nephropathy, crescentic glomerulonephritis (GN), and amyloidosis are higher in older adults, those for proliferative GN and immunoglobulin A nephropathy are lower, and the incidence rate for minimal-change disease is comparable to that for young adults but much lower than the rate seen in children. Diabetic nephropathy is probably the most common cause of nephrotic syndrome in older adults. The diagnosis is usually made on the basis of a long (15- to 20-year) history of diabetes mellitus and the finding of diabetic retinopathy, and a biopsy is not necessary. Glomerulopathies resulting from systemic disease are more common in older adults because of the increased incidence of underlying diseases, such as amyloidosis (dysproteinemias), collagen vascular diseases (vasculitis), and neoplastic disease.
Membranous nephropathy (MN) is the most common form of primary kidney disease in older adults and is twice as common in older than in younger persons. In a cohort of 155 patients over age 60 years followed for 20 years, older patients were found more likely to be hypertensive, have worse kidney function, and experience more thrombotic complications than younger patients. Possible causes of MN include medications (eg, NSAIDs, penicillamine), malignancies, and hepatitis B infection. One review reported that 11% of patients with MN had an underlying malignancy. In most patients the malignancy is clinically evident when the diagnosis of MN is made, and probably only 1% to 2% of patients have an occult malignancy. Screening older adults with MN for malignancy should probably include a complete history and physical examination, chest radiograph, fecal occult blood tests, and colonoscopy. It does appear that older patients are more susceptible to the extra-renal complications of the nephrotic syndrome and its treatment, most notably, cardiovascular, thrombotic, and infectious events. As the primary care physician is likely the first person called when acute symptoms develop, it is essential he or she be aware of these potential complications.
Minimal-change nephropathy presents similarly in young and old patients, but older persons are more likely to have nonselective proteinuria, microscopic hematuria, hypertension, and renal insufficiency.
Most older adults with diabetic nephropathy have type 2 (non-insulin-dependent) diabetes. Control of blood pressure is important in slowing the rate of deterioration of kidney function. The use of ACE inhibitors or angiotensin-II receptor blockers, even in normotensive diabetic patients, promotes efferent arteriolar vasodilatation and decreases glomerular capillary pressure, which also slows the rate of deterioration of kidney function. Current recommendations are that in most patients with hypertension and CKD, an ACE inhibitor or an angiotensin-II receptor blocker in combination with an ACE inhibitor should be used.
After diabetes, the next most common group of systemic diseases associated with kidney disease in older adults is the dysglobulinemias. These include amyloidosis, multiple myeloma, fibrillary GN, essential mixed cryoglobulinemia, and macroglobulinemia.
ARF is at least as common in older as in younger adults. Controversy remains as to whether the prognosis is poorer in older adults, but there are no reasons to deny treatment for ARF, using any of the available techniques, on the basis of age. In older adults, azotemia and other consequences of ARF may induce acute behavioral changes that are usually reversible, and treatment should not be stopped on the assumption that the patient’s mental status is irreversible. The primary physician is in a unique position to impact acute renal insufficiency, both in terms of prevention and early detection. With a comprehensive medical history, physical examination, laboratory values, and urinalysis, it is usually possible to determine whether the cause of acute renal insufficiency is pre-renal, intra-renal, or post-renal. In general, a normal urinalysis suggests the cause is either pre-renal or post-renal.
There are two clinical situations to consider. The first is the development of acute renal insufficiency in the hospitalized or institutionalized patient being treated for a non-nephrologic illness. In this setting, intravascular volume depletion and acute tubular necrosis (ATN) are the major contributors—both of which may often be avoided with appropriate measures. The diagnosis is usually made on the basis of the history, physical examination, and laboratory data, so that a kidney biopsy is not necessary. ARF has been reported in up to 8% of acutely hospitalized older adults aged 60 years and older. Although the studies vary, in general, ATN accounts for approximately 40% to 50% of the cases of ARF, and intravascular volume depletion for most of the remaining cases.
The second clinical situation to consider is whether acute renal insufficiency results from a primary kidney disease or is secondary to a systemic disease, such as diabetes mellitus, hypertensive or atherosclerotic vascular disease, or collagen vascular disease. Post-renal obstruction should always be excluded, as it is usually amenable to treatment.
Pre-renal ARF occurs when poor perfusion is causing the failure of kidney function. This type of ARF is of special importance in older adults. With acute hypotension, the decrease in kidney perfusion stimulates sympathetic activity and release of vasoconstrictor substances that further reduce GFR, contributing to ARF. Once the hemodynamic disturbances are corrected, the patient usually, but not always, recovers from the ARF. Loss of fluids (intravascular volume depletion), internal redistribution, decreased cardiac output, sepsis, and certain drugs (diuretics, ACE inhibitors) are responsible for the vast majority of cases of pre-renal ARF. In several series, intravascular volume depletion alone was found to account for more than half of the cases of pre-renal ARF in older adults. The slow response to sodium retention, the decreased urinary concentrating ability, and, most importantly, the impairment of thirst regulation, all characteristics of the older patient, contribute to this high incidence.
The use of drugs that alter intrarenal hemodynamics is a growing cause of pre-renal ARF in older adults. The rapid development of pre-renal ARF in a patient recently started on an ACE inhibitor should make the physician think about bilateral renal arterial stenosis. However, in one series, two thirds of the ACE inhibitor–related cases of ARF were found to have occurred in persons without renal arterial stenosis. Other factors that alter intrarenal hemodynamics include cardiac failure, concomitant use of NSAIDs (which inhibit prostaglandin production, an important regulator of kidney blood flow and GFR), diabetes mellitus, and volume depletion from any cause. (See the section on kidney diseases associated with NSAID use.)
It is important to distinguish between pre-renal ARF and ATN, which can develop in the more severe cases. In patients who are oliguric, a urinary osmolality > 500 mOsm/kg, a urinary sodium concentration of < 20 mEq/L, a urine-to-plasma creatinine ratio > 40, or a fractional excretion of sodium < 1% suggests pre-renal ARF. Generally, with pre-renal ARF the ratio of blood urea nitrogen to serum creatinine is > 20. These urinary indices are not always reliable in differentiating pre-renal ARF from other forms of ARF. Probably the most reliable indicator of the pre-renal state is the response to treatment with volume (salt and water) repletion, but, again, older patients may have a delayed response to volume expansion.
ATN can be either ischemic or nephrotoxic in origin. The causes of ischemic ATN are basically the same as those described in the preceding section as causes of pre-renal ARF, only more severe. In addition, surgical interventions, most notably cardiac surgery and repair of aortic aneurysms, as well as sepsis, account for most of the remaining cases in older adults. Hypotension during and after surgery, postoperative fluid loss, and arrhythmias may be important contributors. Measures to decrease the risk of ATN in the postoperative patient include careful attention to nutritional issues, avoidance of hypotension, prevention and treatment of postoperative infection, appropriate medication dosing, and hydration. (See also Perioperative Care.)
Most of the antibiotics effective in treating serious infections have been associated with nephrotoxic ATN. Age is a well-known risk factor for the development of aminoglycoside nephrotoxicity. Preexisting kidney disease and volume depletion may contribute to medication accumulation, leading to ATN. When it is necessary to use an aminoglycoside antibiotic in an older person, monitoring blood levels is essential.
Older adults also are at increased risk of developing radiocontrast-induced ARF. Although the non-ionic contrast dye has been reported in the literature to be less toxic to the kidneys, in practice, the risk of an acute renal insult is likely not significantly reduced. As mentioned earlier, it is best to avoid the use of intravenous contrast dye in any person with preexisting impairment of kidney function, multiple myeloma, vascular disease, intravascular volume depletion, or diabetes. Hydration before and after procedures employing use of contrast agents has been reported to be effective in reducing the incidence and severity of ARF in high-risk patients.
Clearly, when ARF develops, it needs to be dealt with promptly—but perhaps one of the most important roles of the clinician is preventing hospital-acquired ARF. With daily attention to changes in fluid intake, urine production, weight, and orthostatic blood-pressure measurements, the development of intravascular volume contraction in many older adults may be identified before significant symptoms develop. Another common cause of intravascular volume depletion is the order for “nothing by mouth” written in anticipation of a procedure, or the order for enemas written as a bowel preparation. When a procedure is delayed and maintenance intravenous fluids are not given, symptomatic intravascular volume depletion may develop in the frail older adult, with all the associated risks, including falls. (See also Perioperative Care.)
Although the older kidney is able to defend against changes in volume, the response to correction is delayed. Avoiding the simultaneous use of multiple medications that may interact also is of benefit. For example, in the treatment of heart failure, the combination of a diuretic and an ACE inhibitor together with an NSAID is a recipe for the potential development of renal insufficiency unless the patient is carefully monitored. When an older hospitalized patient is being treated by several physicians, it may be prudent to write orders for “no NSAIDs” when appropriate.
In one review of 259 kidney biopsies done for ARF on adults aged 60 and older (remembering that when the cause of ARF has been established by the history, physical examination, and laboratory data, a kidney biopsy is not done), the following diagnoses were made: pauci-immune crescentic GN (with or without arteritis) in 31% of the biopsy samples, acute interstitial nephritis (AIN) 19%, ATN with nephrotic syndrome 8%, atheroemboli 7%, ATN alone 7%, light chain cast nephropathy 6%, postinfectious GN 5.5%, antiglomerular membrane antibody nephritis 4%, and immunoglobulin A nephropathy or Henoch-Schönlein syndrome 4%.
Acute GN in older adults often presents with circulatory congestion that suggests heart failure, in contrast to the hypertension and edema seen in younger patients. This observation, together with low urinary sodium concentrations and high ratios of blood urea nitrogen to serum creatinine that suggests pre-renal ARF, results in the misdiagnosis of acute GN as heart failure.
Acute or subacute GN may be an immunologic consequence of a systemic disease, for example, lupus erythematosus, vasculitis, Wegener’s granulomatosis, mixed cryoglobulinemia, or a primary kidney disease of unknown cause, for example, crescentic GN with or without glomerular immune deposits. Other forms of proliferative GN include mesangioproliferative GN (including immunoglobulin A nephropathy), focal proliferative GN, crescentic GN (including antiglomerular basement membrane disease), and vasculitis. It is important to remember that acute postinfectious GN remains a common entity.
AIN is caused by a variety of agents and probably has no special implications for older adults except for the higher prevalence of NSAID-induced AIN, discussed below, and the fact that older adults tend to be on multiple medications.
Renal vascular causes of ARF are discussed below. Rhabdomyolysis with ARF is seen in the setting of acute immobilization, infectious diseases, stroke, hyperosmolar states, hyponatremia, and hypernatremia, and after falls associated with muscle trauma.
Urinary obstruction is one of the most common causes of ARF in older adults. It is an important diagnosis to make because it is usually reversible. Prostatic hypertrophy or carcinoma is the most common cause, but one should also consider retroperitoneal or pelvic neoplasia, such as lymphoma and carcinoma of the bladder, cervix, uterus, ovaries, or rectum. Another cause of post-renal obstruction may be a blocked indwelling Foley catheter.
Laboratory findings with obstructive ARF tend to be nonspecific, with high urinary sodiums and decreased osmolalities and a nondiagnostic urinalysis. The ratio of blood urea nitrogen to serum creatinine is usually increased. Ultrasonography is safe and readily available, and it has become the initial evaluation of choice in most settings. In most cases, but not all, the diagnosis of obstruction can be made on the basis of a dilated collecting system or large distended bladder.
Nearly half of both normotensive and hypertensive person aged 60 and over with evidence of atherosclerotic aortoiliac or peripheral vascular disease, or both, show some obstruction (> 50% narrowing) of the renal artery. In most of these patients, the obstruction goes unrecognized and is not clinically important. However, in some individuals, severe hypertension or progressive kidney disease, or both, may develop. Correction of stenosis may reverse these consequences. Therefore, any patient with suspected severe renal artery stenosis should have a diagnostic work-up. If a significant stenosis is found, the patient should be referred for evaluation for either percutaneous transluminal renal angioplasty or surgical revascularization of the renal artery. Clues suggesting hemodynamically significant renal artery stenosis include the new onset of severe hypertension, significant worsening of preexistent hypertension, failure to control hypertension on previously effective medications, repeated episodes of pulmonary edema, and renal insufficiency in the absence of urinary abnormalities or other known cause. The last may be most dramatic in patients started on ACE inhibitors. A vascular bruit may be heard in the mid-abdomen or flank.
Occlusive arterial disease can cause either acute or chronic kidney failure with or without changes in the urinalysis and urinary sediment. Renal arterial embolization or thrombosis may occur in patients with acute myocardial infarction, chronic atrial fibrillation, and subacute bacterial endocarditis. Symptoms vary from a slowly progressive, clinically silent event to severe acute flank pain and tenderness, hematuria, hypertension, fever, nausea, and vomiting. Serum lactic dehydrogenase concentrations increase dramatically after 1 to 2 days and remain elevated for a week or more.
Renal cholesterol embolization may occur after vascular manipulation (ie, aortic surgery or angiography) or in association with anticoagulation or thrombolytics. Although less common, cholesterol emboli may also occur spontaneously. The usual course is a progressive kidney disease and worsening hypertension, but it can be acute with a vasculitic picture, including oliguria or anuria, fever, eosinophilia, eosinophiluria, hypocomplementemia, and embolization to other organs, including the extremities (digital infarctions). Hints to this diagnosis include livedo reticularis and cholesterol emboli on a dilated funduscopic examination (which should be performed on every patient when this diagnosis is suspected). The urinalysis is usually unremarkable, although hematuria and mild proteinuria may be seen. If the diagnosis remains unclear or other diagnoses exist as valid possibilities (radiocontrast nephropathy, endocarditis with left-sided emboli, vasculitis, thrombotic emboli), a definitive diagnosis may be made on visualization of cholesterol crystals on a biopsy of the skin or kidney.
NSAIDs are widely consumed by older adults because of their effectiveness in relieving pain in a variety of common chronic musculoskeletal disorders. Older persons are more predisposed than younger adults to the adverse effects of NSAIDs on the kidneys because of the age-associated decline in kidney function, the increased prevalence of such comorbid conditions as heart failure, hypertension, cirrhosis, and CKD, and the high use of concomitant drugs that affect kidney function (eg, diuretics, antihypertensives). It should be possible to use these drugs safely in older adults and maintain a low risk-to-benefit ratio, as those who are at risk for NSAID-induced kidney disease can be identified and monitored.
As mentioned above, NSAIDs may alter intrarenal hemodynamics and decrease GFR. NSAIDs may induce a variety of acute and chronic renal lesions. AIN can follow the use of nearly all NSAIDs. The typical clinical picture includes the nephrotic syndrome with acute renal insufficiency in a patient who has been on NSAIDs for months. An increase in eosinophils in blood or urine, or both, with NSAID-induced AIN is not nearly as common as in AIN due to penicillin and other agents. The kidney abnormalities usually improve after discontinuation of the medication, with or without corticosteroid therapy, but chronic renal insufficiency and even ESRD may occur. The AIN results primarily from a delayed hypersensitivity response to NSAIDs, and the nephrotic syndrome results from changes in glomerular permeability mediated by prostaglandins and other hormones. Less commonly, nephrotic syndrome may occur without AIN; rarely, an immune complex glomerulopathy is observed. Patients taking NSAIDs for months or years may develop papillary necrosis, chronic interstitial nephritis, and even ESRD. Case-control studies show that patients at increased risk are older men with chronic heart disease and kidney hypoperfusion. Impaired medullary circulation and direct toxicity due to a drug metabolite appear to play a critical role in inducing interstitial fibrosis, which can be facilitated by a sustained production of some growth factors and cytokines. The newer COX-2 inhibitors may also be injurious to the kidneys.
An examination of kidney biopsy results in older adults with chronic kidney failure showed that the most common histologic findings are hypertensive nephrosclerosis, focal segmental glomerulosclerosis, interstitial nephritis, and amyloidosis. Again, in persons with chronic kidney failure where a cause is clear from the history and physical examination (eg, diabetes mellitus), no biopsy would be necessary.
There are several points to be made with regard to chronic renal insufficiency in the older adult. First, although chronic elevation of serum creatinine represents a loss of kidney function that likely will not be recovered, defining the underlying pathology may help to prevent further decline in function. Second, the degree of kidney failure may be much greater than indicated by the serum creatinine, so that cognitive difficulties may develop at lower-than-expected serum creatinine levels. Third, although this area needs considerable research, some data suggest that erythropoietin serum levels do not change with age. Data also suggest that anemia secondary to erythropoietin deficiency may occur with more mild cases of renal insufficiency than previously thought. Preventing a further decline in kidney function or the development of “acute or chronic” kidney failure is critical. This requires careful attention to medication dosing, measurement of serum blood levels of medications when available, and avoidance of medications known to accumulate in renal insufficiency, including magnesium-containing compounds and meperidine. In addition, the older adult with renal insufficiency is even less able than the healthy older adult to defend against physiologic stress, including a free water load, salt challenge, or acidosis; this should be taken into consideration during acute illness. Lastly, as detailed below, early referral to a nephrologist and pre-ESRD care is very important.
Early referral of older adults with evidence of kidney disease to a nephrologist is important. In general, when the serum creatinine is greater than or equal to 1.5 mg/dL, patients should be referred for a nephrology consultation. There is currently a national effort to improve pre-ESRD care. National guidelines have been established by the Kidney Disease Outcomes Quality Initiative (KDOQI). The goal of the nephrology consultation is to determine the type of kidney disease, to define any associated comorbid conditions, and to assess the severity of renal dysfunction and any associated risk factors. A plan should be developed to address specific therapies for CKD and associated complications, maximize GFR, treat comorbid conditions, prevent cardiac disease, and, when indicated, begin planning for replacement therapy. In addition, data suggest that beginning dialysis early in older adults may improve clinical outcomes and patient survival; early referral contributes to this positive outcome.
With regard to blood-pressure control, in patients with CKD the goal blood pressure is less than 130/80 mm Hg. High blood pressure is both a cause and consequence of CKD. Poorly controlled blood pressure may accelerate a decline in kidney function and exacerbate underlying cardiovascular disease. Whenever tolerated, an ACE inhibitor or angiotensin receptor blocker (ARB) should be used together with a diuretic. Attention to life-style change, including weight control, smoking, and an adherence to a low-salt diet, is also very important.
Anemia (normocytic, normochromic) is associated with CKD and is usually secondary to either decreased production of erythropoietin (EPO) or possibly inhibitors of erythropoiesis. However, before this diagnosis is made other common causes of anemia need to be excluded. All patients should have peripheral blood smear, screening for fecal occult blood, serum B12, and iron studies. If folate deficiency is suspected, a red blood cell folate should be measured. After other causes for anemia are excluded, a patient may be considered for EPO therapy. The goal hematocrit/hemoglobin is 33–36/11–12 to reduce the risk of heart disease, cognitive dysfunction, higher hospitalization rates, and increased mortality.
Individuals with CKD (GFR less than 60 mL/min) are at risk for alterations in calcium-phosphate metabolism that place them at risk for underling bone disease. The histiologic types of bone disease vary in different clinical setting. There are several therapies available that need to be individualized, again, depending on bone histology and clinical setting. All patients should have a serum phosphate, calcium, and parathyroid hormone measurement done before referral to a nephrologist.
Individuals with CKD are also at risk for metabolic acidosis and loss of bone mineral. The national guidelines include recommendations that the serum CO2 be greater than 22 mEq/L to protect bone loss.
It is important for older adults with a GFR less than 60mL/min to have a consultation with an expert in nutrition. The U.S. Multicenter Modification of Diet in Renal Disease Study has shown a benefit of a low-protein diet (0.7 g/kg of body weight) to those with a CrCl < 55 mL/min/L in slowing the progression of chronic kidney failure. However, the benefits must be weighed against the nutritional consequences, as this study showed there were also small declines in various indices of nutritional status (protein-calorie malnutrition). It is important for the clinical team, including a nephrologist and dietitian, to determine what is best given each patient’s individual nutritional needs. Again, these goals in pre-ESRD care are developed by a team effort between the patient’s primary care physician and a consulting nephrologist.
A 1999 report from the U.S. Renal Data System indicates that in 1997 more than half of all patients on chronic dialysis were aged 65 years or older. Diabetes mellitus, hypertension, GN, and obstructive nephropathy are the most common causes of ESRD in this group. The increased number of older adults started on dialysis has occurred for two reasons. First, there is increased referral and acceptance of older adults, especially those with serious comorbid conditions. Second, the increased survival rates of other competing diseases, such as coronary artery disease or diabetes, increase the chances that a person will survive to develop ESRD.
The results of studies looking at life satisfaction and functional status in older adults on dialysis have varied. One prospective cohort study found that life satisfaction of older adults on dialysis and those in the control group did not differ significantly at 3 years. For some older adults living alone or in isolation, time spent on dialysis was a time to interact both with their “neighbors” on dialysis and with nursing staff; in a sense, this becomes their social life. It is also clear that rehabilitation (occupational and physical therapy) is important in slowing the loss of function in the dialysis patient. The choice of hemodialysis or peritoneal dialysis (chronic ambulatory peritoneal dialysis) depends on the patient’s wishes and overall condition, the physician’s expertise, and available resources. Neither method offers any advantage in survival rates when patients with similar risk factors are compared.
An alternative therapy for ESRD in older adults is kidney transplantation. The results have improved because of better patient selection, improved perioperative care, and the use of safer, more effective immunosuppression. Despite improved survival, kidney transplantation in persons aged 65 years and over remains uncommon and controversial, largely because of a reluctance to allocate a scarce resource (the donor kidney) to an older adult with a limited life expectancy. As older adults have a senescent immune system, they may require less aggressive immunotherapy.
One report comparing older adults with a kidney transplant with those on dialysis (matched by age, underlying diagnosis leading to ESRD, and number of comorbid conditions) showed that after adjusting for known prognostic factors, the transplant patients had a much better (twofold) survival probability than did the patients on dialysis. The 5-year survival rates were 81% and 51% for transplant and dialysis patients, respectively. In addition, a study comparing graft survival in patients aged 18 to 59 with that in patients 60 years and older found that in the absence of risk factors (pretransplant history of nonskin cancer, vascular disease, or being an active smoker), the survival rates were similar. These findings will have important implications in the future for the management of ESRD patients aged 60 years and older.
■ Brown WW, ed. Aging and the kidney. Adv Renal Replacement Ther. 2000;7(1):1–92.
The entire issue is dedicated to the aging kidney. It includes articles on a broad range of issues, including the biology of renal aging, hypertension, diabetes mellitus, kidney replacement therapy, and ethical issues in aging and renal disease, as well as information on healthy aging and disease prevention.
■ Johnson DW, Herzig K, Purdie D, et al. A comparison of the effects of dialysis and renal transplantation on the survival of older uremic patients. Transplantation. 2000;69(5):794–799.
The purpose of this clinical study was to evaluate survival for transplant versus dialysis in persons aged 60 years and older in Australia. Sixty-seven patients were randomized to kidney transplant and 107 to dialysis. The two groups were matched for age, gender, body mass index, cause of renal disease, comorbidity, and dialysis duration. The authors conclude that kidney transplantation confers a significant survival advantage over dialysis in patients who are rigorously screened for kidney transplantation.
■ Levey AS, Coresh J, Balk E, et al. National Kidney Foundation practice guidelines for chronic kidney disease: evaluation, classification and stratification. Ann Intern Med. 2003;139(2):137–147.
This paper reviews the current criteria for classification of chronic kidney disease and summarizes current recommendations on early diagnosis of kidney disease in older adults.
■ Loos C, Briancon S, Frimat L, et al. Effect of end-stage renal disease on the quality of life of older adults. J Am Geriatr Soc. 2003;51(2):229–233.
This is a controlled cross-sectional study to assess the quality of life of older adults on dialysis. The authors conclude that in in older patients with a planned initiation for dialysis, the impact of end-stage renal disease on quality of life is no different from the impact of other diseases but that in patients with unplanned dialysis, the quality of life is impaired.
■ Luckey AE, Parsa CJ. Fluid and electrolytes the elderly. Arch Surg. 2003;138(10):1055–1060.
This is a comprehensive review of the common electrolytes abnormalities experienced by older adults.
■ Wolfson M. Nutrition in elderly dialysis patients. Semin Dial. 2002;15(2):113–115.
This article discusses the special challenges posed by the aging process, including concurrent illness, mobility, and cognitive dysfunction, that may impact nutrition in the growing number of older patients on dialysis.
Catherine Lee Kelleher, MD
Robert Dean Lindeman, MD