Diseases of the Aging Kidney

John M. Starr, Latana A. Munang

Introduction

Older adults are particularly vulnerable to renal diseases as changes in the aging kidney diminish the capacity to respond to various physiologic and pathologic stresses. The diagnosis of renal disease in older people remains challenging and the causes are seldom as straightforward as in younger people. The cause is often multifactorial, and other concomitant nonrenal conditions such as diabetes and cardiovascular disease commonly complicate the clinical picture.

Diagnostic Problems in Older Adults

Atypical Presentation of Disease

The presentation of renal disease is often different in older adults (especially those who are frail) compared to younger people. They may have nonspecific symptoms that could be associated with a decline in their cognition or function or decreased mobility and falls, or they may be completely asymptomatic. Clinical examination findings can be hard to interpret. Decreased skin turgor and postural hypotension are common in older adults without necessarily signifying hypovolemia and dehydration. Leg edema is also common, particularly in those with reduced mobility, without necessarily indicating volume overload.

Measuring Renal Function

Although serum creatinine is most commonly used to detect renal dysfunction, it is an insensitive measure in older people because levels depend on age, sex, muscle mass, and diet. Renal disease is often undetected in older adults because their muscle mass is relatively lower and their serum creatinine levels can remain within the normal range until a significant proportion of renal function is lost.¹ Nevertheless, in the context of acute kidney injury, changes in serum creatinine levels remain the best marker of kidney function. In chronic kidney disease (CKD), however, the glomerular filtration rate (GFR) is the preferred indicator. This can be measured directly by the clearance of an endogenous or exogenous filtration marker, and in routine clinical practice, GFR is estimated from creatinine (eGFR_creat). Many laboratories now routinely report eGFR_creat in addition to the serum creatinine. However, estimation can be inaccurate and sources of error include race and ethnicity, as well as other factors more common in older people, such as a nonsteady state or acute illness, extremes of muscle mass and body size, diet and nutritional status, muscle wasting diseases, drugs that inhibit tubular secretion of creatinine (e.g., trimethoprim), extrarenal elimination of creatinine (including dialysis), large volume extracellular fluid loss, and inhibition of gut creatinase by some antibiotics. Errors can also occur as a result of interference with creatinine assays, for example by bilirubin, glucose, ketones, and certain drugs. All equations estimating GFR are less precise at higher GFR levels, compared to lower levels. Current guidelines²^,³ recommend using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation,⁴ which uses the same four variables as the Modification of Diet in Renal Disease (MDRD) equation.⁵ The CKD-EPI equation has been shown to have less bias and is more accurate compared to the MDRD, especially at higher GFRs.⁶ Cystatin C, a cysteine protease inhibitor freely filtered by the kidney, is an alternative serum marker of kidney function that is unaffected by age, sex, and muscle mass and approximates direct measurements of GFR more precisely. It is more sensitive in detecting early kidney dysfunction in older people and has been shown to be a strong prognostic indicator of death and cardiovascular disease.⁷ Guidelines now suggest estimating GFR using cystatin C in populations in whom more accurate estimation and improved risk stratification are required.²^,³

Collecting Urine Specimens

Obtaining a clean urine sample for analysis can be challenging, particularly in bedridden female patients or incontinent patients, but not impossible with good nursing care. The use of a Newcastle urine collection kit or similar equipment can be helpful. An early morning urine sample is preferable to exclude postural proteinuria. Occasionally catheterization may be necessary, but it should only be performed as a last resort because the procedure itself can cause infections.

Interpretation of Urine Examinations

In older people, urinalysis often shows increased numbers of leucocytes and epithelial cells, a result that does not necessarily indicate a pathologic condition. Mixed growth of organisms on culture is frequently a result of contamination, although mixed infections may occur in those with indwelling urinary catheters. Urinalysis may also reveal red cell casts, hematuria, or proteinuria because of intrinsic renal disease and should prompt further investigations and specialist input. Proteinuria should always be confirmed and quantified using laboratory albumin-to-creatinine ratio (ACR).

Infections of the Urinary Tract

Up to 25% of women and 10% of men aged older than 65 years have asymptomatic bacteriuria, which is defined as 100,000 or more colony-forming units/mL urine on two or more consecutive tests in the absence of any clinical symptoms. This figure rises to higher than 50% in women and higher than 35% in men older than 80 years.⁸ The prevalence is higher in individuals under institutionalized care, people with urinary catheters, and people with diabetes. Indwelling catheters result in bacteriuria in almost 100% of cases within 4 weeks and within 3 or 4 days in open drainage systems.⁹ Routine screening and treatment are not recommended, because unnecessary antibiotics result in more adverse effects and antimicrobial resistance without any clear benefits in mortality and morbidity.¹⁰ The only exceptions are those who are symptomatic or those about to undergo invasive urologic procedures such as transurethral resection of prostate.

Urinary tract infections (UTIs) occur when bacteria that colonize the superficial epithelium of the urinary tract breach this mucosal barrier. Once this barrier is breached, bacteria are able to invade bladder epithelial cells.¹¹ From this comes the recommendation for treating asymptomatic bacteriuria in patients undergoing invasive urologic procedures. Recurrent UTIs may occur because of susceptibility of the mucosal barrier, for example, in trauma secondary to urinary catheters, stones, or neoplasia or in people with problems clearing bacteria from bladder epithelial cells because of impaired immune response.

The diagnosis of UTI is based on clinical evaluation of symptoms and signs indicating breach of the mucosal barrier. Dysuria, urinary frequency, and hematuria significantly increase the likelihood of a UTI but may be absent in older patients; whereas vaginal discharge significantly reduces the probability.¹² UTI may also be associated with back pain, costovertebral angle tenderness,¹³ and urinary incontinence in women¹⁴ and therefore should be excluded in people who have these symptoms. Distinguishing asymptomatic bacteriuria from a clinically significant UTI may be difficult, particularly in those with cognitive impairment. A systematic review of the use of dipstick tests to diagnose or rule in UTI indicates that a positive result for either the leukocyte esterase or nitrite test showed the highest sensitivity and the lowest negative likelihood ratio.¹⁵ However, a study in younger women aged 16 to 50 years found that a 3-day course of trimethoprim reduced dysuria equally in those with and without positive nitrite tests on urinary dipstick even though the dipstick test reliably predicted who did and who did not have a UTI.¹⁶ It is unclear whether this is generalizable to older adults, but it raises the question of balancing symptomatic relief against potential promotion of antibiotic resistance. The problem of promoting antibiotic resistance also occurs with regard to management of recurrent UTIs. Some guidelines advise considering cranberry products to reduce the frequency of recurrent UTIs,¹⁷ although a recent systematic review suggests this may be less effective than previous studies indicate.¹⁸ Although this may be a useful first-line approach, the benefit for older age groups is less certain. Patients on warfarin should avoid taking cranberry products because of the risk of overanticoagulation, unless health benefits clearly outweigh the risks, in which case increased medical supervision and international normalized ratio (INR) monitoring should be considered.¹⁹ There is a paucity of evidence to support long-term antibiotic prophylaxis in older adults and attention to risk factors such as local hygiene, diabetic control and catheter use is more important.

Although mild uncomplicated lower UTI can be managed safely in the community, bacteremic urinary sepsis carries a significant mortality rate of 25% to 60%.²⁰ The most common causative organisms are Escherichia coli, Klebsiella, Pseudomonas, and Proteus. Several guidelines have been published with treatment recommendations.⁹^,¹⁷^,²¹ Uncomplicated symptomatic lower UTI in women should be treated empirically with 3 days of trimethoprim, nitrofurantoin, fosfomycin, or pivmecillinam. However, older people are at increased risk of toxicity with nitrofurantoin, and it is contraindicated in significant renal impairment (GFR < 60); therefore, it should be prescribed cautiously or avoided. Longer courses of antibiotics have not been found to be more effective than short courses in older women.²² A 3-day course of ciprofloxacin is equally effective,²³ but this antibiotic should not be used as a first-line treatment in older people, especially in hospital, because of its association with increased risk of the hypervirulent ribotype 027 Clostridium difficile–associated diarrhea.²⁴

The evidence for treating UTI in men is less robust. Most infections are associated with prostatitis or instrumentation of the urinary tract. At least a 2-week course of quinolone therapy may be needed, although this has to be balanced against the C. difficile risk as noted in the previous paragraph. Catheter-associated UTI is a major problem in older people; it causes symptoms in 30% of patients, bacteremia in 4%, and a threefold increase in the risk of death in hospital.²⁵ Catheterization should therefore be avoided whenever possible; otherwise, the duration of catheterization should be minimal and the catheter system should remain closed. Alternatives to indwelling urinary catheters with lower risk of symptomatic infection should be considered in appropriate patients, such as suprapubic catheters, condom drainage systems, and intermittent catheterization.⁹ There is no convincing evidence for routine antibiotic prophylaxis in either short- or long-term catheterization or for catheter changes unless there is a history of catheter change–associated UTI or trauma. Symptomatic infections require broad-spectrum antibiotics based on local susceptibility patterns, which are then adjusted to culture results. A catheter change should be considered in those with long-term indwelling catheters before commencing antibiotics. There is some evidence to support the use of antimicrobial urinary catheters to prevent catheter-associated UTI in hospitalized patients²⁶; thus, the use of antimicrobial urinary catheters may be a useful adjunct to the general measures of avoiding catheter use whenever possible and providing careful catheter care when a catheter is necessary.

Pyelonephritis refers to infection of the upper urinary tract. This mostly occurs through ascending infection from the urethra and urinary bladder. Prostatic hypertrophy in men causes urinary obstruction, increasing susceptibility to infection. Immunocompromised and chronically ill patients, as well as those with renal calculi or any abnormality of the renal tract, are at a higher risk of complicated pyelonephritis. Clinical presentation ranges from mild illness to septic shock, often associated with fever, flank pain, and costovertebral tenderness as well as lower urinary tract symptoms. Older people may be completely asymptomatic and only diagnosed with chronic pyelonephritis when they are found to have renal failure. Prompt antibiotic treatment is important in acute pyelonephritis because of the high risk of bacteremia and complications such as intrarenal and perinephric abscess. Ciprofloxacin or co-amoxiclav is recommended as empirical treatment because of their good kidney penetration and the need to cover a broad spectrum of culprit pathogens. Hospitalization should be considered if the patient is unable to take fluids and medication or is showing signs of sepsis, or if there is no response to oral antibiotic treatment after 24 hours.¹⁷^,²¹

Acute Kidney Injury

Over recent years, the concept of acute renal failure has evolved to take into account mounting evidence that even a mild abrupt reduction in kidney function is linked to serious short- and long-term clinical outcomes, including increased mortality.²⁷^–²⁹ Acute kidney injury (AKI) encompasses the entire spectrum of the disease from a small decrease in function to requirement for renal replacement therapy (RRT).³⁰ It is a broad clinical syndrome that includes specific renal pathology such as acute glomerular and vasculitic renal diseases, nonspecific conditions such as ischemia and toxic injury, extrarenal pathology such as acute obstructive nephropathy, and functional impairment relative to physiologic demand without actual damage to the kidney.³¹ In this respect, AKI is similar to acute coronary syndrome or acute lung injury.

The most recent definition of AKI includes any of the following criteria:

• A rise in serum creatinine level of 26.5 µmol/L or higher within 48 hours

• A 50% or more rise in serum creatinine level, known or presumed to have occurred within the last 7 days

• Urine output 0.5 mL/kg/hr or less for more than 6 hours

AKI is common and occurs in more than 1 in 5 patients admitted to the hospital, with the majority managed outside an intensive care unit.³² Older people have the highest risk of AKI compared to other age groups because of more comorbid conditions, higher prevalence of CKD, polypharmacy, and structural, functional, and hemodynamic age-related changes affecting the ability of the kidney to withstand insults as well as cellular changes to renal tubular cells rendering them more vulnerable.³³ Outcomes for older patients with dialysis-requiring AKI are poor, with mortality rates of 31% to 80%.³⁴ In those who survive AKI, recovery rates are also significantly lower compared to younger patients, with patients older than 65 years 28% less likely to be dialysis independent.³⁵

With increasing stage of AKI severity (Table 81-1), the risk for death and need for RRT increases.²⁸^,²⁹ Nevertheless, AKI is potentially treatable if detected early by simply monitoring urine output and measuring serum creatinine. However, a recent inquiry into the deaths of patients who died with AKI in the United Kingdom found that only 50% received “good care,” with systemic failures identified in the prevention, recognition, and management of AKI and its complications, and lack of timely access to specialist services. It also found that 20% of postadmission AKI was both predictable and treatable and suggested that, unless attention is paid to providing the basics of good medical care and recognition of the acutely ill patient, the prevalence and outcome of AKI will not improve.³⁶

TABLE 81-1

Staging of Acute Kidney Injury

Stage	Serum Creatinine	Urine Output
1	1.5-1.9 times baseline OR ≥26.5 µmol/L increase	<0.5 mL/kg/hr for 6-12 hours
2	2.0-2.9 times baseline	<0.5 mL/kg/hr for ≥12 hours
3	3.0 times baseline OR Increase in serum creatinine to ≥353.6 µmol/L OR Initiation or RRT	<0.3 mL/kg/hr for ≥24 hours OR Anuria for ≥12 hours

AKI is a feature of many severe illnesses and often occurs as a result of multiple insults. The risk of developing AKI is determined by the balance between the susceptibility of the kidneys to injury and impairment versus the exposure to insults. Susceptibility factors include nonmodifiable characteristics such as older age, female gender, and black race. Other susceptibility factors that are more common in older people include hypovolemia, neurologic or cognitive impairment limiting access to fluids, a previous history of AKI, symptoms of urologic obstruction or conditions that may cause urologic obstruction, acute and chronic comorbidities (such as anemia, CKD, diabetes, cancer, and chronic heart, lung, and liver diseases), and treatment of these conditions with potentially nephrotoxic drugs. The type, severity, duration, and number of insults are also important. These include any critical illness, sepsis, shock, burns, trauma, major surgery, radiocontrast agents, and nephrotoxins, including drugs and certain poisons. The interaction among these factors allows a degree of risk assessment in some individuals that may help prevent AKI, for example, before surgical interventions, radiocontrast administration, and nephrotoxic drugs, therefore helping clinicians identify patients who require closer monitoring and more supportive measures.

The causes of AKI have traditionally been divided into three categories: prerenal, intrinsic, and postrenal. There is substantial overlap between these categories, particularly the first two, and causes are often multifactorial in older adults.

Prerenal Acute Kidney Injury

Prerenal AKI is an appropriate physiologic response to renal hypoperfusion, which may occur as a result of true hypovolemia caused by dehydration, blood loss, vomiting, or diarrhea, or functional hypovolemia in sepsis, cardiac failure, or decompensated liver cirrhosis. Older people are particularly prone to volume depletion because of impairments in renal concentrating ability, thirst sensation, mobility and cognition limiting access to fluids, and the use of drugs such as diuretics, nonsteroidal antiinflammatory drugs (NSAIDs), angiotensin-converting enzyme (ACE) inhibitors, or angiotensin II receptor blockers (ARBs). Drugs that interfere with autoregulation of renal blood flow can cause AKI in preexisting renal disease or hypoperfused kidneys. ACE inhibitors and ARBs can also cause hemodynamically mediated AKI in patients with renal artery stenosis in a solitary kidney or bilateral renal artery stenosis.³⁷

Intrinsic Kidney Injury

Intrinsic AKI involves structural injury to renal cells, most commonly acute tubular injury. Unfortunately, many causes of acute tubular injury are iatrogenic in nature, through diagnostic procedures, therapeutic interventions, or nephrotoxic medications. The most common drugs causing hospital-acquired renal failure are aminoglycoside antibiotics.³⁸ They are directly toxic to renal tubules; therefore, serum levels should be closely monitored.

Drugs can also cause acute tubulointerstitial nephritis, a pertinent problem considering the prevalence of polypharmacy among older people. A thorough drug history of current and recent medications is therefore crucial, including any over-the-counter preparations. Common culprits include NSAIDs, diuretics, allopurinol, proton pump inhibitors, and antimicrobials such as penicillin, ciprofloxacin, and aciclovir. A rash, fever, and arthralgia may also suggest acute interstitial nephritis. Stopping the offending drug should improve renal function, but corticosteroids are often used to help recovery by diminishing the inflammatory process.

Contrast-induced AKI (CI-AKI) is a growing problem, accounting for 11% of AKI in hospitals.³⁸ The rise in serum creatinine level generally occurs 2 to 5 days after exposure to contrast medium. The risk is fourfold higher in patients with preexisting renal disease and diabetes, and contrast osmolality and volume are also directly correlated to nephrotoxicity.³⁹ Regional hypoperfusion causing hypoxia and direct tubular toxicity are mechanisms thought to be involved, but the underlying pathophysiologic process is still poorly understood. The most recent guidelines³¹^,⁴⁰ recommend offering intravenous volume expansion with either isotonic sodium bicarbonate or 0.9% sodium chloride to patients at increased risk of CI-AKI. Other prophylactic measures using antioxidants such as N-acetylcysteine or ascorbic acid may be beneficial, but current evidence is still inconclusive. Contrast media should therefore be avoided if at all possible but, if used, should involve the lowest volume of iso-osmolar contrast and other potentially nephrotoxic medications should be temporarily stopped.

Cholesterol embolism can occur following vascular procedures such as cardiac surgery, angiography, angioplasty, and stenting. It can also occur following thrombolysis and anticoagulation. Showers of small cholesterol crystals break off from atherosclerotic plaques and occlude arterioles or larger vessels. It can affect almost any organ in the body, including the kidney, and can be difficult to recognize. Malignant hypertension, mesenteric and cutaneous ischemia, and encephalopathy may be more prominent than the associated AKI. Symptoms and signs usually manifest weeks to months after the procedure. True incidence is unknown but is higher in older adults and predominantly affects males.⁴¹

Acute tubular necrosis can also be caused by endogenous renal insults. In rhabdomyolysis, skeletal muscle breaks down, releasing its contents and causing myoglobinuria, accounting for 7% to 10% of cases of AKI.⁴² This is caused by muscle injury from direct trauma, metabolic disorders, prolonged exercise, or seizures, as well as medications such as statins and neuroleptics. Up to a third of rhabdomyolysis patients will develop AKI,⁴² and this is important to exclude in older people who have sustained a stroke or a fall with a prolonged lie.

Multiple myeloma is another condition mostly affecting older adults, of whom approximately 50% will develop renal failure.⁴³ This is mediated through the direct toxic effects of light chains to renal tubules or intratubular obstruction by their casts. The associated hypercalcemia and hyperuricemia may also give rise to intratubular crystals. Renal failure is reversible in approximately half of these cases, and this is associated with better long-term survival.

About two thirds of cases of acute tubular necrosis are caused by renal ischemia-reperfusion injury,⁴⁴ making prerenal AKI and ischemic acute tubular necrosis part of the same continuum. The most common cause is sepsis, particularly with multiple organ failure. There is also increasing evidence suggesting sepsis-associated AKI is an inflammatory event.⁴⁵ Postoperative acute tubular necrosis may also occur, often with prerenal causes.

Glomerulonephritis refers to immune-mediated conditions causing inflammation in the kidney, usually classified according to their histologic appearances. Previously thought to be rare in older people, it is now recognized to be a frequent finding as increasing numbers of renal biopsies are performed in this patient group. Rapidly progressive or crescentic glomerulonephritis is more common in older than younger patients.⁴⁶ The clinical features depend on the underlying cause, which include antibodies to the glomerular basement membrane, connective tissue diseases, infections, and systemic vasculitides (Table 81-2). Prompt diagnosis and treatment are essential to prevent irreversible loss of renal function. Blood, protein, or red cell casts found on urinalysis are useful clues. A full history and examination will often narrow down the differential diagnosis.

TABLE 81-2

Common Causes of Crescentic Glomerulonephritis and Associated Clinical Features

Causes	Clinical Features
Anti–glomerular basement membrane (GBM) antibody	Goodpasture syndrome—hemoptysis and pulmonary hemorrhage Anti-GBM disease—renal involvement only
Immune complex–mediated disease	Connective tissue diseases Systemic lupus erythematosus—fever, malaise, myalgia, Raynaud phenomenon, hypertension, edema, frothy urine Essential mixed cryoglobulinemia—peripheral neuropathy, arthralgia, skin purpura Henoch-Schönlein purpura—skin purpura, arthritis, abdominal pain, gastrointestinal hemorrhage Infection-associated causes Poststreptococcal infection—edema, hypertension, hematuria Endocarditis—fever, sweats, weight loss Glomerular disease IgA nephropathy—frank hematuria, hypertension Membranoproliferative nephropathy—hypertension, edema
Antineutrophil cytoplasmic antibody (ANCA)–associated systemic vasculitis	Wegener granulomatosis—nasal and upper airway symptoms, pulmonary nodules and infiltrates, c-ANCA positive Microscopic polyangiitis—general malaise, weight loss, cutaneous lesions, p-ANCA positive Churg-Strauss syndrome—late-onset asthma, eosinophilia, gastrointestinal upset, peripheral neuropathy, p-ANCA positive
Others	Malignancies: solid organ carcinomas and lymphoma Drugs: penicillamine, hydralazine