mechanisms have been identified to explain the glomerular injury. Increases in kidney
plasma flow are associated with proteinuria and high protein intake. Inflammatory
cytokines may be responsible for fibrosis and kidney scarring, ultimately resulting in
Dyslipidemias are common in patients with CKD and often observed concurrently
with proteinuria. Increased low-density lipoprotein (LDL) cholesterol, total
cholesterol, and apolipoprotein B, as well as decreased high-density lipoprotein
(HDL) cholesterol, have been observed in patients with progressive kidney
15 Hypercholesterolemia has been associated with loss of kidney function in
patients with and without diabetes.
17,18 Accumulation of apolipoproteins in
glomerular mesangial cells contributes to cytokine production and infiltration of
macrophages and has been implicated in the progression of CKD, primarily in the
presence of previous kidney disease or other risk factors such as hypertension.
is thought to promote glomerular damage by initiating a series of cellular events in
mesangial cells and through oxidation to a more cytotoxic derivative once within
these cells. Although serum total cholesterol, triglycerides, and apolipoprotein B all
correlate with the rate of decline in eGFR, it is not clear that they directly increase
the rate of progression of kidney disease, particularly when present with concomitant
conditions that also cause kidney damage. Some evidence, however, suggests that
treatment of hypercholesterolemia with statin therapy in patients with CKD may
reduce proteinuria and progression of CKD.
Drug-Induced Causes of Chronic Kidney Disease
Analgesic nephropathy results from habitual ingestion of analgesics for many years.
Particularly, agents containing at least two antipyretic analgesics and usually caffeine
or codeine are commonly associated with the development of analgesic nephropathy.
It is a tubulointerstitial kidney disease characterized by renal papillary necrosis as a
primary lesion and chronic interstitial nephritis as a secondary lesion.
nephropathy is a slowly progressive disease, and the clinical signs and symptoms are
similar to the nonspecific presentation of CKD attributable to any other etiology.
Phenacetin, an acetaminophen prodrug, was the first agent to be identified as causing
Currently in the United States, most cases are caused by long-term use or misuse of
compound analgesics containing acetaminophen and aspirin along with caffeine or
codeine. Similar findings in terms of the effect on kidney function have also been
observed with chronic nonsteroidal antiinflammatory drug (NSAID) therapy.
uses of acetaminophen, aspirin, and NSAIDs have been associated with the
progression of kidney disease in CKD patients in a dose-dependent manner.
cumulative amount (at least 1–2 kg of acetaminophen), rather than the duration of
analgesic intake, is a primary risk factor for developing chronic analgesic
23,24 Thus, analgesics should be used with caution in the CKD
population, and chronic analgesic therapy should be discouraged. KDIGO guidelines
recommend discontinuation of NSAIDs in people with a GFR <60 mL/minute/1.73
Analgesic nephropathy is more prevalent in female patients, with a female to male
ratio of 5:1 to 7:1. The peak incidence occurs between the fourth and fifth decades of
20,24 Patients usually have a history or complaint of chronic pain syndromes.
Often, patients who develop analgesic nephropathy are dependent on analgesic
therapy and may exhibit psychiatric manifestations indicative of an addictive
behavior. At presentation, patients may have a reduced GFR and findings consistent
with CKD, such as elevated SCr, BUN, and proteinuria. However, during acute
necrosis, patients may experience flank pain, pyuria, and hematuria. As necrosis
progresses, cellular debris may cause ureteral obstruction. Kidney dysfunction is
damage is uncertain, but it is thought that because acetaminophen accumulates in the
renal medulla, its oxidative metabolite produced by the medullary cytochrome P-450
macromolecules, causing cellular necrosis. Although the reduced form of
glutathione in the medulla can prevent this process, agents that reduce medullary
glutathione content (e.g., aspirin) may promote kidney damage. This mechanism may
explain a lack of analgesic nephropathy associated with acetaminophen alone.
NSAIDs, which attenuate prostaglandin-mediated vasodilatation, may induce an
ischemic state within the renal medulla, leading to papillary necrosis.
Data on the chronic kidney effects of selective cyclooxygenase-2 (COX-2)
inhibitors are limited compared to traditional NSAIDs. A meta-analysis of 114
randomized, double blind clinical trials evaluated the adverse kidney events of
COX-2 inhibitors. The authors reported that, of the six agents evaluated, only
rofecoxib was associated with adverse kidney effects, defined as significant changes
in urea or creatinine levels, clinically diagnosed kidney disease, or kidney failure. In
contrast, celecoxib was associated with a lower risk of kidney dysfunction.
cohort study of 19,163 newly diagnosed CKD patients examined the association
between analgesic use and the risk of progression to ESRD. Among the COX-2
inhibitors, only rofecoxib use was significantly associated with an increased risk of
The long-term management of analgesic nephropathy is generally supportive and
primarily involves discontinuation of the offending agent and subsequent abstinence
from the use of NSAIDs and combination analgesics. If patients develop CKD or
ESRD, treatment of kidney disease-related comorbidities should be treated in the
same manner as those with kidney disease owing to any other cause. For patients
requiring analgesics, aspirin taken alone may be a reasonable alternative.
Acetaminophen as a single agent may be safe, although habitual use can contribute to
progression of kidney disease as well as to liver toxicity.
chronic analgesic therapy should use the lowest dose to control pain, avoid
combination products when possible, and maintain adequate hydration.
Lithium use has been associated with alterations in kidney function secondary to
acute functional and histologic changes and has been associated with the
development of chronic pathologic changes to the kidneys (e.g., chronic interstitial
nephritis). The role of lithium as a causative agent in the development of CKD has
been suggested in a variety of epidemiologic, clinical, and histopathologic studies.
The concentrating ability within the kidney and GFR have been shown to decline
26 Lithium-induced chronic renal disease has a slow
progression (average latency between onset of lithium use and ESRD is 20 years) in
which the rate of progression is related to the duration of lithium therapy.
Patients with lithium nephropathy are generally asymptomatic. They typically
present with an insidious decline in renal function over the course of many years, and
proteinuria is usually absent or minimal.
25 Women are generally at greater risk than
In patients taking chronic lithium therapy, close monitoring of serum lithium
concentrations is advised, and regular measurements of SCr should be obtained to
detect changes in kidney function. Higher lithium concentrations are associated with
26 Current clinical practice guidelines recommend monitoring
SCr every 2 to 3 months during the first 6 months of chronic lithium therapy,
followed by yearly measurements thereafter.
If patients develop CKD or ESRD,
management of kidney disease–related comorbidities should be treated in the same
manner as those with kidney disease owing to any other cause. The decision to
discontinue lithium and to initiate another mood stabilizer should be a mutual
decision made by the psychiatrist, the nephrologist, and the patient. The diuretic
amiloride has been suggested to reduce lithium-induced renal adverse effects.
QUANTIFYING GLOMERULAR FILTRATION RATE
One of the most widely used clinical measures to determine baseline kidney function
and monitor progression of kidney disease with time is eGFR. The ideal marker of
eGFR should be a nontoxic substance that is freely filtered at the glomerulus and not
secreted, reabsorbed, or metabolized by the kidney. Inulin and exogenous radioactive
51CrEDTA, have been used to assess GFR
because they meet these criteria; however, they are not readily available to
clinicians, require intravenous (IV) administration, and are costly.
Creatinine is an endogenous substance that is produced at a relatively constant rate
by nonenzymatic hydrolysis of muscle stores of the amino acid derivatives creatine
and phosphocreatine. Under steady-state conditions, the urinary excretion of
creatinine equals the creatinine production rate, and the SCr concentration remains
relatively stable. Creatinine is excreted primarily by glomerular filtration—thus,
creatinine clearance (CrCl) has been used as a reasonable surrogate for eGFR. There
are limitations to consider when using methods to assess eGFR that incorporate
creatinine. Creatinine is eliminated not only through glomerular filtration but also by
tubular secretion. Consequently, the CrCl overestimates the true GFR by 10% to
20%. As nephron function declines, tubular secretion of creatinine contributes more
substantially to overall elimination such that CrCl overestimates true GFR.
Extrarenal elimination of creatinine in the gastrointestinal (GI) tract may also lead to
27 As a result of these processes, disease progression
may be underestimated. Commonly used drugs also need to be taken into
consideration when interpreting SCr values. For example, trimethoprim can inhibit
the secretion of creatinine, and increase SCr and decrease CrCl without affecting
GFR. On the other hand, cimetidine has been administered to block tubular secretion
of creatinine before measurement of CrCl for a more accurate assessment of GFR.
SCr alone is used clinically as an index of kidney function; however, multiple
limitations to this practice exist. In the initial stages of kidney disease, SCr may
remain within the normal range. Consequently, SCr may be relatively insensitive in
detecting early kidney disease and is not accurate for estimating the progression of
the disease. Because generation of creatinine is proportional to total muscle mass, it
is affected by diet (notably by the ingestion of meats), age, and sex. Generally,
muscle mass declines with age and is lower in women. Thus, a SCr that is in the
upper limit of normal (e.g., 1.2 mg/dL) for a young male athlete is likely to be
associated with a high CrCl, whereas the same SCr in a 70-year-old woman could
indicate compromised kidney function.
Use of SCr to assess kidney function in patients with liver disease may also lead to
28 This may be attributed to decreased production of creatine
(the precvursor of creatinine) by the liver or increased tubular secretion of creatinine
by the kidney. Also, substantial variation is seen in the calibration of SCr among
laboratories that can result in differences in measured SCr. The National Kidney
Disease Education Program Laboratory Working Group initiated the creatinine
standardization program to improve and normalize SCr results, reduce
interlaboratory variability, and enable more accurate eGFR determinations.
Although SCr can provide a rough estimate of kidney function, other markers of early
kidney damage, such as proteinuria, should also be evaluated in patients at risk for
Several equations have been developed to calculate CrCl or eGFR.
The Cockcroft–Gault (CG) equation (Eq. 28-1). has been the most commonly used
method to estimate kidney function for drug dosing, which provides an estimate CrCl
in patients with stable renal function
where age is in years, IBW is ideal body weight in kg (male IBW = 50 + [2.3 ×
height >60 inches]; female IBW = 45 + [2.3 × height >60 inches]), and SCr is the
serum creatinine concentration (mg/dL). For women, the CG equation is multiplied
by 0.85 to account for decreased muscle mass.
The CG equation should not be used to estimate GFR in patients with rapidly
changing SCr concentrations because it was derived from normal, healthy subjects
with stable kidney function. The CG equation is also inaccurate in populations that
have low muscle mass—such as elderly, obese, or cachectic patients.
is used in children (Eq. 28-2):
where k is dependent on age (infant [1–52 weeks] k = 0.45; child [1–13 years] k =
55; adolescent male k = 0.7; and adolescent female k = 0.55), and SCr is the serum
creatinine concentration (mg/dL).
The most commonly used method for kidney function assessment is the prediction
equation developed using data from the Modification of Diet in Renal Disease
(MDRD) study, a multicenter trial that evaluated the effects of dietary protein
restriction and BP control on progression of kidney disease. This equation, referred
to as the MDRD equation, was derived using GFR measured directly by urinary
clearance of a radiolabeled marker (
I-iothalamate) as opposed to creatinine, and
included a relatively large and diverse population (>500 white and black individuals
with varying degrees of kidney disease) for derivation and validation of the equation.
where SCr is the serum creatinine concentration (mg/dL), age is in years, BUN is the
blood urea nitrogen concentration (mg/dL), and Alb is the serum albumin
An abbreviated version was developed and is referred to as the four-variable
where SCr is the serum creatinine concentration (mg/dL) and age is in years.
Subsequently, this equation was reexpressed in 2005 for use with a standardized SCr
assay enabling consistent results across clinical laboratories to improve accuracy in
eGFR determinations (Eq. 28-5).
where SCr is the serum creatinine concentration (mg/dL) and age is in years. The
National Kidney Disease Education Program recommends this equation for
laboratories using a creatinine method that has its calibration standardized by isotope
The MDRD equation was found to be biased and imprecise at higher GFRs with
the potential of misidentifying patients with high GFR as having poor kidney
1,33 The Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI)
research group established by the National Institute of Diabetes and Digestive and
Kidney Diseases pooled studies of different populations to develop and validate a
new estimating equation for GFR that is more complex, but uses the same variables
1,34 The CKD-EPI equation was found to be more accurate
than the MDRD equation, especially at high GFRs and across a wider range of body
An important point is that the results from the MDRD and CG equations are not
interchangeable. That is, the MDRD equations are used to quantify GFR, to detect or
stage the degree of CKD, and to follow progression. The CG equation is most
commonly used to evaluate the appropriate doses of drugs that are eliminated by the
(see Chapter 31, Dosing of Drugs in Renal Failure).
Cystatin C is another endogenous marker of kidney function that is freely filtered at
the glomerulus. Subsequently, it is reabsorbed and catabolized by proximal tubular
epithelial cells. Unlike SCr, cystatin C is not influenced by gender, age, body mass,
and nutritional status. Several equations based on serum cystatin C levels either
alone or in combination with SCr and other demographic variables have been
1,35 The KDIGO guidelines suggest the use of a Cystatin C–based equation
test for confirmatory testing of GFR when eGFR based on SCr is less accurate.
Normally, proteins are not filtered at the glomerulus because of their relatively large
molecular size. Thus, only trace amounts of protein are present in the urine in patients
without kidney disease. However, with glomerular damage, proteinuria is commonly
observed and may precede elevations in SCr. The amount of protein present in the
urine has been shown to be a predictor of kidney disease progression. As a result,
protein excretion should be monitored in patients at risk for kidney disease as well as
those with existing kidney disease at routine checkups.
Proteinuria is defined as a total protein excretion rate >200 mcg/minute or >300
mg/24 hour (referred to as albuminuria; if albumin is the only protein measured).
Measurement of total protein includes quantification of albumin plus other proteins,
such as low molecular weight globulins and apoproteins. Assessment of albuminuria
is a better indicator of early kidney disease because it is primarily indicative of
glomerular damage as opposed to total protein, which is not specific for glomerular
damage. Other tests, including urinalysis (UA), radiographic procedures, and biopsy,
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