Critical Reviews in Oncology/Hematology. 1992; 13:215-240 0 1992 Elsevier Science Publishers B.V. All rigths reserved. 1040-8428/92/$5.00

215

ONCHEM 00035

Evaluation

of nephrotoxicity

secondary to cytostatic agents

Gedske Daugaard and Ulrik Abildgaard Department

qf Oncology. Rigshospitalet. and Department of Hematology, Herlev Hospital, Copenhagen, Denmark (Accepted 16 July 1992)

Contents Introduction

II.

Blood urea nitrogen (BUN) .................................... A. Urea production ........................................ B. The influence of different factors on BUN ..................... C. Clinical utility of BUN determination .........................

217 211 217 217

III.

Serum creatinine . A. Creatinine production B. Analytical problems

217 218 219

...... .. ...... ...

.... . . .

Estimating creatinine clearance A. Variables affecting creatinine clearance estimates

V.

Measured creatinine clearance .. . A. Creatinine clearance versus glomerular filtration rate B. Effects of antineoplastic agents

221 221 222

VI.

Glomerular filtration rate A. Urinary clearance B. Inulin clearance C. Plasma clearance D. Simplified methods E. Comments .

223

Renal blood flow . . . . . . . . . . . . . . . . . . . . . . ............ . .. A. para-Amino hippurate clearance for evaluation of renal plasma flow B. Effects of antineoplastic agents .

226

The lithium clearance method ................................. A. Effects of antineoplastic agents ..............................

227

VIII.

IX.

X.

to:

.

IV.

VII.

Correspondence

216

.

I.

Proteinuria ............................................... A. Mechanisms of proteinuria .................................. B. Protein selectivity ......................................... C. Methods for measuring urinary proteins ....................... D. Effects of antineoplastic agents .............................. Measurement of low-molecular-weight proteins ..................... A. /I,-Microglobulin ......................................... B. Renal handling of j?,-microglobulin .......................... C. Retinol-binding protein ................................... D. Effects of antineoplastic agents ..............................

Gedske Daugaard, Wiedeweltsgade 31, DK-2100 Copenhagen, Denmark.

219 220

223 223 223 224 225

226 221

228 229

.

229 230 230 230

.

231 231 231 231 232

216 XI.

Measurement of renal enzymes in urine ................................... A. L-Alanine aminopeptidase (LAP) ..................................... B. N-Acetyl-p-o-glucosaminidase (NAG) ................................. C. Comparison of tubular markers ..................................... D. Effects of antineoplastic agents ......................................

232 232 232 233 233

XII.

Measurement of tubular antigens ....................................... A. Adenosine deaminase-binding protein (ABP) ............................

233 233

XIII.

Conclusions

234

. . . ..__..........................................._...

References................................................................

I. Introduction Many cancer patients receive antineoplastic agents during the cause of their illness, including drugs with a potential for significant nephrotoxicity. As many cancer patients are surviving for longer periods of time, cumulative and delayed nephrotoxic effects of antineoplastic therapy have been observed with increasing frequency. Also, as increasing numbers of cancer patients have been treated aggressively using higher dosages with a curative intent, nephrotoxicity has increased. Furthermore, current antineoplastic regimens often include several agents that have the potential for synergistic nephrotoxicity. The nephrotoxicity due to antineoplastic agents may be manifest as acute renal failure, chronic renal failure, or specific tubular dysfunction. Nephrotoxicity has been observed with alkylating agents, antimetabolites, antitumor antibiotics, and biological agents (Table 1). These antineoplastic agents may induce nephrotoxicity soon after initiation of therapy or only after long-term administration. The risk of nephrotoxicity varies with each agent. Table 1 summaraizes the risk of nephrotoxicity, time of onset, and type of functional impairment produced by each agent. The mechanism of the renal

234

side-effects of the single drugs has recently been reviewed [ 11. During evaluation of nephrotoxicity induced by cytostatic drugs it is very important to measure renal hemodynamic as well as the tubular functional variables, because renal blood flow (RBF), glomerular filtration rate (GFR), tubular reabsorption rates and urinary excretion rates are highly dependent variables. During changes in GFR, alterations will occur in the proximal reabsorption rates of sodium and water (the glomerular-tubular balance). Changes in tubular fluid reabsorption rates may conversely induce fluctuations in intratubular pressure and in the pressure in the Bowman’s space, thereby changing the transcapillary hydrostatic pressure gradient leading to changes in the GFR and filtration fraction. In the majority of the present literature concerning cancer patients, renal function is estimated by blood urea nitrogen, serum creatinine and creatinine clearance. Simple measurement of creatinine and/or urea plasma concentrations can be misleading when evaluating changes in glomerular filtration for several reasons, and the conditions and sources of error with these tests will be described in detail below. It is advised to use more sensitive tests for measuring glomerular filtration

TABLE 1 Antineoplastic

agents that produce nephrotoxicity

Alkylating agents

Antimetabolites

Antitumor antibiotics

Biologic agents

Cisplatin (la-I) High-dose carboplatin (3a-I) Ifosfamide (3~1)

High-dose methotrexate (la-I)

Mitomycin (I b-L)

Streptozotocin (la-I) Carmustine (BCNU) (3b-L) Lomustine (CCNU) (1b-L) Semustine (Methyl CCNU) (1b-L)

High-dose 6-thioguanine (3a-I)

Recombinant leucocyte A Interferon (3a-I) Corynebacterium parvum (3a-I) Deoxycoformycin (?)

Mithramycin (la-I) Doxorubicin (3a-I)

5-Azacytidine (3c-I)

(1) High risk; (2) intermediate risk; (3) low risk; (a) acute renal failure; (b) chronic renal failure; (c) specific tubular dysfunction; I, immediate nephrotoxicity; L, nephrotoxicity from long-term administration.

217

rate and these are described together with various tubular function tests. II. Blood urea nitrogen (BUN)

A relationship between plasma urea and renal function was recognized long before the development of the concept of clearance or of techniques to assess glomerular filtration rate (GFR) [2]. The factors influencing both the production of urea and its renal excretion, however, are considerably more complex and variable than those for inulin or even creatinine. As a result, urea clearance is rarely used today as a measure of renal function, but the blood urea nitrogen (BUN) concentration is still used by many, together with serum creatinine, as an index of glomerular function in routine clinical practice.

Ok’. 0

Plasma

.

.

xx) 4co creahnine

.

*

bco (umolll)

.

. ecn

.

.

.

1030

Fig. 1. Relation between plasma urea and plasma creatinine concentrations in 350 consecutive patients in whom the two measurements had been made on the same blood sample. (Reproduced with permission from British Medical Journal, Ref. 254.)

II. A. Urea production The major source of urea in normal individuals is metabolic breakdown of dietary proteins. In a person in nitrogen balance, the major fraction of the ingested protein is converted to urea and excreted by the kidney. Urea synthesis occurs almost exclusively in the liver, and the urea produced is distributed throughout total body water [3,4].

catabolism of protein during febrile illness [6], inhibition of anabolism by corticosteroids [7] or tetracycline therapy [8], ingestion of large quantities of protein, and absorption of blood from the gastrointestinal tract [9]. Raised BUN levels can also be observed after myocardial infarction [lo]. In these circumstances, the BUN concentration does not accurately reflect the prevailing filtration rate.

II. B. The influence of different factors on BUN

II. C. Clinical utility of BUN determination

The BUN concentration is a less satisfactory measurement of GFR than serum creatinine because of two major factors: (1) urea clearance varies with the rate of urine flow; and (2) the plasma concentration of urea is related to nitrogen metabolism as well as renal function. Tubular reabsorption of urea varies from as little as 40% of the filtered load at high urine flow rates to as much as 70% during marked antidiuresis [5]. These reabsorptive rates correspond to urea clearance as low as 30% of the GFR during dehydration to as high as 60% of the GFR during high rates of urine flow. As a result, during antidiuresis, for example, in the moderately dehydrated patient, the BUN will be disproportionally elevated as compared to serum creatinine. By contrast, during marked diuresis, when the urea clearance is as high as 60% of the GFR, urea excretion is high and, as a result, the BUN falls. Alterations in nitrogen load also have a marked effect on the BUN concentration. For a given GFR, a large increase in the nitrogen load due either to increased breakdown of endogenous protein or to increased protein ingestion elevates the BUN. Large nitrogen loads occur in a variety of clinical settings, including excessive

It is apparent from the preceding that the BUN concentration is a poorer index of filtration rate than the serum creatinine and, as shown in Fig. 1, no useful relation could be observed between plasma urea and plasma creatinine in a large group of unselected patients. However, a BUN of 10 to 15 mg/dl almost always indicates normal glomerular function in a normal-sized adult ingesting an ad libitum protein diet. A BUN in the range of 50 to 150 mg/dl is beyond the level anticipated from variations in urine flow or nitrogen balance alone and implies impairment of glomerular filtration. It can be concluded that BUN is not a sensitive indicator of kidney function, and should not be used as a marker in patients undergoing antineoplastic treatment with nephrotoxic drugs. III. Serum creatinine

The parameter most often used to estimate renal function in clinical practice is the serum creatinine concentration. Unfortunately. serum creatinine concentration, when considered alone, is unsatisfactory as it is not directly related to glomerular filtration rate. Serum

218

Guarddim-acetic acid

Arginine Glycine

d

H2 H-C-NY COOH

NH~NH-PG(OHh N-W-CooH

(3)

a

Creatine &Hz

Ly Pbsphocreatine

01 0

t

t

1

20

40

60

1

80

C ,nu,,n, mlhmj

1

ioo

I

I

1

120

140

160

I 180

1.73 m2

Fig. 2. Serum creatinine levels vs. GFR in 171 patients with glomerular disease. The line (o-o) represents the hypothetical relationship between glomerular filtration rate and serum creatinine, assuming that creatinine is excreted solely by glomerular filtration. In this hypothetical case, the initial serum creatinine = 90 ~molil and GFR = 120 ml/min 1.73 m2, respectively. The broken line (- - -) represents the upper limit of normal serum creatinine (125 pmol/l). (Reproduced with permission from Kidney Int.. Ref. 73.)

creatinine concentration depends upon the balance between the production of creatinine and its excretion by the kidneys. Creatinine production is largely determined by muscle mass, which in turn is related to age, sex and weight, and it will therefore vary from patient to patient. In addition, serum creatinine concentration is related to glomerular filtration rate in a reciprocal fashion; when renal function is normal or only mildly impaired, small changes in serum creatinine represent large changes in glomerular filtration rate (Fig. 2). Even though GFR declines progressively in normal individuals after the age of 40, the normal value for serum creatinine concentration remains essentially the same as in young adults. This finding is apparently explained by a decline in creatinine production that roughly parallels the decline in GFR [1 l-131. III.A.

Creatinine production

Creatinine is formed from creatine and creatine phosphate (Fig 3). A ,further description of the, creatinine biosynthesis is given by Heymsfield et al. [14]. Most body creatine exists as creatine phosphate in muscle

Fig. 3. Principal pathway in creatinine metabolism. (1) Glycine amidinotransferase, (2) Guanidinoacetate methyltransferase, (3) Creatine kinase.

tissue; it serves as a rapidly available source of highenergy phosphate that may be converted to ATP. Once formed, creatinine distributes rapidly throughout the body. Its apparent volume of distribution is estimated to be 54% of the body weight, both in normal subjects and in subjects with renal failure [15,16]. Creatinine is normally produced in the body at a constant rate and eliminated at a rate that is proportional to serum creatinine. Under these conditions, serum creatinine is relatively constant at approximately 90 ,umolll (1.1 mg/dl) [ 11,131. A change in either the rate of production or the clearance of creatinine causes the serum creatinine to shift to a new steady-state level. The rate at which the shift from the old to the new level occurs depends only on the new half-life of creatinine [17], which is inversely related to its clearance (Creatinine clearance = 0.693 (volume of distribution)lt,,,). Therefore, a reduction in clearance of 50% would result in a doubling of the creatinine half-life to approximately 5 hours. Also serum creatinine would approach a new steady-state level that would be twice the original, and 3.3 half-lives, approximately 16.5 hours, would pass before the shift from the old to the new serum creatinine was 90% complete. If serum creatinine is to be used as a predictor of creatinine clearance, it is imperative that it be at steadystate for most of the methods described below.

219

III. B. Anal_vticalproblems

The analytical method used to measure creatinine is an important determinant. Both specific and nonspecific assay methods are available. The first, the Jaffe method, measures both creatinine and noncreatinine cromogens using a color reaction following deproteinization. The noncreatinine chromogens are found in plasma but not in urine and account for f&36% of total serum creatinine concentration [ 18,191. Alterations in the Jaffe method, such as the use of resorptive agents, dialysis steps, and rate-dependent modifications, have been proposed to better quantitate a ‘true creatinine’ concentration [ 18,20,21]. Various drugs and substances crossreact with the Jaffe method of creatinine analysis because of its low specificity. The interaction most widely described is with cephalosporin antibiotics [22-261. Especially cefoitin and cephalothin crossreact significantly to cause false elevations in creatinine at therapeutic concentrations. Therefore, measuring serum creatinine at least 2 hours after a dose of cefoxitin, or just prior to a dose, in patients with renal insufficiency is recommended [24]. The interaction is less significant in urine because samples are diluted (cefoxitin) and creatinine concentrations are higher than in serum. Other drug and substances that interfere with the Jaffe method of creatinine laboratory analysis include acetoacetate [27], bilirubin [28], acetohexamide (but not other sulfonylureas) [29], methyldopa [30], phenacemide [31], and furosemide [34. Drug interactions are not limited to the Jaffe method of creatinine analysis. An enzymatic method of measuring creatinine has been developed that does not crossreact with the noncreatinine chromogens [33]. However, soon after this analytical procedure gained widespread clinical use, the antifungal drug flucytosine was noted to cause significant increase in creatinine concentrations which were not found when cross analyzed via the Jaffe method [34,35]. This interference led to improvement in the assay that effectively eliminated the flucytosine interaction; however, patients receiving lidocaine demonstrated increases in serum creatinine of 15-37% over creatinine measured via the Jaffe reaction [36,37]. A lidocaine metabolite, N-ethylglycine, is thought to be the interfering substance. All commonly used methods, including the Jaffe reaction, autoanalyzer technique, and creatinine imidohydrolase assay suffer from a lack of precision within the normal range [38]. For example, in repeated measurements in individuals with GFR greater than 30 ml/min, the 95% confidence interval for serum creatinine level is + 22%, whereas it is + 13% in patients with GFR less

than 30 ml/min [39]. This shortcoming makes it more difficult to interpret alterations in creatinine values within the normal range, despite the fact that such alterations correspond to the largest absolute change in renal function. Serum creatinine concentration may be truly increased by blocking renal tubular secretion, but this does not reflect a decline in glomerular filtration. Trimethoprim and/or trimethoprim/sulfamethoxazole therapy has been demonstrated to result in a 1535% increase in serum creatinine concentrations due to an inhibition of tubular secretion [40,41]. The highest elevations occurred in patients with chronic renal failure because of the need to excrete a large amount of creatinine by the secretive process [41]. As with trimethoprim, cimetidine increases serum creatinine concentrations by approximately 15-25% [4244]. That this reflects a reduction in GFR has been refuted by studies using 5’Cr-EDTA and inulin showing that elevation in serum creatinine concentrations and reductions in measured creatinine clearance values occur without changes in GFR. Generally, cimetidine interaction is transient with an adaptive process overriding the competitive inhibition of tubular secretion. Finally, aspirin may also increase serum creatinine concentrations; although the mechanism is speculative, an inhibition of tubular secretion is probably involved [45]. IV. Estimating

creatinine clearance

To ascertain a more practical manner of estimating GFR, a number of investigators have proposed predicting creatinine clearance from serum creatinine concentrations [l 1,13,4649]. Originally, formulas relating serum creatinine to creatinine clearance were developed in small patient populations encompassing narrow age ranges. These formulas contained major deficiencies that prompted the development of a nomogram by Siersbzk-Nielsen and colleagues [ 13,461. Jelliffe and Jelliffe have proposed several formulas which have been refined to obtain a clinically practical equation [4749] (Fig. 4). In 1976, Cockcroft and Gault [ 1l] published perhaps the most widely used equation for estimating creatinine clearance (Fig. 4). Overall, these methods of estimating creatinine clearance are remarkably similar. The patient populations used to derive the formulas were well distributed according to age, serum creatinine concentrations, and creatinine clearance values. Numerous publications have evaluated the ability of these formulas to predict creatinine clearance. When the methods were tested by their authors a good correlation with measured values were demonstrated, an expected result when

220

Cockcroft and Gault Males:

Ccr

Females:

Ccr = 1.04 x (14o-age in years)x(wt in kg) ______________________----___ plasma creatinine fimol/l

Jelliffe

=

(11)

1.23 x (140-age in years)x(wt in kg) _____________________________ plasma creatinine fimol/l

IV. A. Variables affecting creatinine clearance estimates

(49) Ccr (ml/min/1.73 ml) = 98 - 0.8 (age - 20) _____________________ serum creatinine (For females, use 90% of predicted ccr)

Ccr = creatinine

A number of studies have tested the ability of creatinine clearance equations to accurately estimate renal function in ambulatory, nursing home, and hospitalized elderly patients [52-561. The error is consistently high, in the range of 9.5-20.0 ml/min for relative estimates of creatinine clearance of 17.5-90.1 ml/min. Caution is therefore warranted when using these equations in elderly patients.

clearance

Fig.4. Equations for the predictionofcreatinineclearance.

using the same patient population and laboratory facilities [11,48]. Independent investigators have found that formula estimates may correlate with, but only poorly predict actual measured values of GFR or creatinine clearance 150,511. In the study by Rolin et al. [51] a comparison of GFR predicted by the Cockcroft-Gault method to iothalamate GFR yielded a correlation coefficient of 0.84. However predicted GFR values were within & 10% of measured GFR less than 32% of the time, and were within f. 35% accuracy only 81% of the time. The mean error was small (3.1%) but the standard deviation was large (59.5%), suggesting a wide degree of scatter. The errors in this study were most often attributed to extremes of age, weight, body surface area, and serum creatinine. Of obvious importance is the ability of these equations to estimate creatinine clearance in the elderly. Because of the extreme variability of renal function in an older population, elderly patients may be more prone to concentration-dependent adverse drug reactions, when doses are not adjusted individually. The relationship between body size or weight and muscle mass becomes skewed as a patient ages, resulting in a reduction in the amount of creatinine produced per day [11,13]. The diminishing creatinine production would normally result in lower steady-state serum creatinine concentrations, but due to a decline in renal function these concentrations remain in the ‘normal’ range [12]. For this reason a serum creatinine concentration in an elderly patient is a poorer reflection of renal function than in younger patients.

The ability of serum creatinine to predict creatinine clearance is influenced by a variety of disease states and clinical conditions, as well as dietary intake, analytical variations, and drug interactions. Most equations relating serum creatinine to creatinine clearance assume serum creatinine concentrations are at steady-state. Therefore, these equations are inappropriate for patients with acute changes in renal functions. The equations also assume a ‘normal’ range of creatitine production within certain age groups. Those patients with substantial muscle wasting or large decreases in muscle tone produce less creatinine and demonstrate lower steady-state serum creatinine concentrations. Use of this low concentration in creatinine clearance equations results in an overestimation of renal function. Accurate estimation of renal function is therefore difficult in patients with spinal cord injuries [57], amputations, Cushing’s syndrome [58], muscular dystrophy [59], GuillainBarre syndrome [60] and rheumatoid arthritis [61]. Patients with severe liver disease also produce lower amounts of creatinine because of an inability to synthesize creatine [50,62,63]. In fact, in eight patients with liver disease, Hull et al. [50] describe high prediction errors using four commonly used creatinine clearance formulas. This overprediction was detectable at all ranges of renal function, with mean predicted creatinine clearance of 73.5 & 11.3 ml/min versus measured creatinine clearance of 46.3 -t 8.3 ml/min. Dietary intake potentially alters serum creatinine and the estimate of creatinine clearance. Ingestion of meat significantly increases these concentrations, apparently due to the conversion of meat creatine to creatinine, a process influenced by cooking duration and temperature [64]. High meat protein diets result in significantly higher serum creatinine concentrations and urinary creatinine excretion than do diets low in protein or meat [65]. Because vegetarians and protein- or protein-calory-malnourished patients demonstrate below-normal serum creatinine concentrations and daily urinary creatinine excretion [66-681, estimation of creatinine clearance tends to overpredict measured values. It should be noted that fasting individuals may have falsely elevated serum

221

creatinine levels when tested by the Jaffe method because of an increase in acetoacetate concentrations [69]. Also in patients receiving parenteral nutrition including amino acid solution an apparent increase of 69% in creatinine clearance can be observed [70]. The formulas overestimate creatinine clearance in obese and edematous patients. It is important to remember that the use of these formulas does not overcome inherent methodologic limitations in measurement of serum creatinine or in the accuracy of estimating GFR from creatinine clearance. V. Measured creatinine clearance The measurement of creatinine clearance as an estimate of GFR was introduced in the late 193Os, and is the most widely used method in clinical practice. The relationship between creatinine clearance and GFR is inexact, because creatinine is handled not only by glomerular filtration, but also by tubular secretion. A number of factors can give rise to erroneous measurements of creatinine clearance as mentioned in connection with serum creatinine and estimated creatinine clearance. A common problem rests with inaccuracies in the process of urine collection. Incomplete urine collection can result from misunderstanding by the patient or personnel of the timing directions or from incomplete emptying of the bladder at the start or end of the collection period. The latter problem can be overcome by bladder catheterization, but the potential risk of this procedure to the patient does not justify its routine use. Two approaches have been suggested to deal with errors of urine collection: (1) a l-hour timed urine collection carried out under close supervision by trained personnel; and (2) longer collection periods (such as 24 hours) in which small errors in collection at the beginning or end of the time will have less impact on the result. To further ensure accuracy, two (or more) clearances can be calculated and averaged or residual urine can be estimated by ultrasonography. Also water diuresis can reduce the sampling error. The l-hour technique has been largely abandoned because the extra effort and personnel required does not significantly improve the accuracy as compared to the 24-hour clearance. V.A. rate

Creutinine

clearance

versus glomerular

filtration

The ability of creatinine clearance to predict GFR or the extent to which creatinine clearance exceeds inulin clearance is a subject of considerable controversy. Methods of true creatinine measurement tends to yield

creatinine clearance estimates that exceeds true GFR in healthy individuals by as much as 15-30%, owing to the tubular secretion of creatinine [l&71.72]. Because the Jaffe method detects noncreatinine chromogens, true serum creatinine concentration are overestimated, thus yielding underestimates of creatinine clearance and a fictitious approximation of true GFR [21,71]. This has been cited as an argument for using creatinine clearance as an estimate of GFR. However, even when serum creatinine is measured by the total chromogen method, creatinine clearance in excess of inulin clearance has been determined [20]. Furthermore, as GFR decreases, creatinine clearance measurements may overestimate GFR by as much as 150-200% [ 195 1,721.This occurs in patients with glomerulopathic disease, such as diabetic nephropathy, glomerular sclerosis, and chronic glomerulonephritis, because of an unchanged tubular secretion of creatinine during reduction of filtration [73,74] (Fig. 4). Creatinine clearance also overpredicts renal function in patients with deficiencies in both filtration and secretion, where a larger component of creatinine is eliminated either metabolically or extrarenally. In one group of patients with chronic renal failure, 15.9-65.7% of the creatinine produced was eliminated extrarenally [ 151. Regardless of the etiology, with a progressive decrease in GFR, creatinine clearance by all methods tends to become proportionally higher than inulin clearance. Sequential creatinine clearance measurements are also often misleading as measures of progression in chronic renal failure [75]. The discrepancy between creatinine clearance and GFR has been illustrated in an article by Bauer et al. [19]. In 19 healthy men mean total chromogen derived creatinine clearance approximated inulin clearance, but creatinine clearance determined by true creatinine measurement overpredicted inulin clearance by an average of 14%. In 104 hypertensive patients, however, neither mean creatinine clearance determined by total chromogen or true creatinine methods approximated inulin clearance and the discrepancy became more pronounced as inulin clearance fell. Overprediction ranged from IO-21% in patients with normal to mild impairment (>70 ml/min/l.73 m’), to 62-87% in mild to moderate impairment (40-70 mUmin11.73 m2) and to 1277 141% in patients with moderate to severe impairment (~40 ml/min/l.73 m*) [ 191.These findings are consistent with those of others [20,73]. Furthermore, there appears to be no significant increase in serum creatinine until inulin clearance falls below 50 ml/min/1.73 m2. Therefore, a normal endogenous creatinine clearance can often mask a significant decline in GFR [19.20]. This may occur in up to 40% of patients with normal creat-

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inine clearance [20]. Overall, those investigations evaluating the ability of measured creatinine clearance by any method to estimate GFR conclude that at GFRs less than 90 ml/min, creatinine clearance tends to overestimate GFR [19-211. V.B. Effects of antineoplastic agents Patients undergoing antineoplastic treatment often face problems with emesis/starvation, muscle wasting and repeated infections. Therefore, these patients are not in steady-state and with regard to creatinine, this is one of the reasons for the discrepancy between studies using serum creatinine or creatinine clearance as estimates for GFR compared to studies using isotopic clearance measurements. Among the various nephrotoxic cytostatic agents, renal function after administration of cisplatin has been studied most extensively. Serum creatinine is often normal after treatment with one or more cycles of cisplatin in conventional doses (100 mg/m’ over l-5 day’s) [7679]. This is also the case in several studies where highdose cisplatin has been administrated (200 mg/m’ over 5 days) [80-821. In some of the studies serum creatinine increases during the first cycle of cisplatin containing treatment with a normalization after 2-4 weeks, without cumulative effect after subsequent doses [80,8 1,831 and with no significant difference in pre- and posttreatment creatinine levels. In a study by Catello et al. [84] serum creatinine increased progressively with repetitive courses, despite equal delivered doses. Creatinine clearance has been reported unchanged after 34 cycles of high-dose cisplatin [76,80] or decreased up to 40% after treatment with cisplatin in conventional doses [85]. In a study by Daugaard et al. [86] no correlation between creatinine clearance and “CrEDTA clearance could be observed during treatment with high-dose cisplatin. Actually serum creatinine decreased significantly during treatment, probably due to muscle wasting [86]. In contrast to studies using serum creatinine or creatinine clearance as an estimate of GFR, all studies using isotopic clearance methods find a significant decrease in GFR after different cisplatin containing regimens (froml2% to 40% depending on the dose delivered) and with a cumulative effect during the treatment period [8&91]. A comparison between measured and estimated creatinine clearance in patients treated with cisplatin, carboplatin and methotrexate showed some correlation between the two clearance measurements, but a wide scatter of the values, when compared to isotopic clearance [92,93].

Renal function is an important variable in patients treated with high-dose methotrexate since methotrexate is excreted largely unchanged in the urine [94] and any alteration in renal excretion of the drug could have significant effects on the blood concentration levels and myelosuppression. Doses are often modified according to serum creatinine level. Few studies have compared serum creatinine or creatinine clearance with inulin clearance. In a study by Abelson et al. [95], pre- and posttreatment inulin and creatinine clearance were measured in 4 patients treated with high-dose methotrexate and a great discrepancy between the decrease in renal function measured by inulin clearance and creatinine clearance could be observed. During treatment with nitrosourea a significant reduction in GFR is observed without elevation in BUN or serum creatinine. In patients treated with nitrosourea an early recognition of renal functional impairment is important, because a high percentage of patients with increasing BUN and serum creatinine progress rapidly to advanced uremia despite discontinuation of the drug [96,97]. Elevations in BUN and serum creatinine are late findings after treatment with streptozocin and sometimes do not occur despite the presence of other renal abnormalities [98]. During mitomycin treatment BUN, serum creatinine and creatinine clearance have never been compared with other measures of renal function, and severe decrease in renal function has not been established until serum creatinine has increased considerably. An increasing number of patients with different hematologic diseases are treated with cyclosporine A. Chronic deterioration of renal function in patients treated with cyclosporine A will not be apparent from slowly rising serum creatinine concentrations until the GFR has fallen below a value around 45 ml/min. Also both measured and estimated creatinine clearance shows a wide discrepancy from true GFR [99,100]. The above-mentioned data clearly show that the continued use of creatinine as a sole marker to monitor the GFR in patients treated with nephrotoxic agents is no longer justifiable in a research setting and suboptimal in many clinical settings. We urge that investigators looking at potentially nephrotoxic cytostatic agents and clinicians treating patients with some of these drugs make an extra effort to obtain meaningful determinations of GFR during such investigation or treatment. Only the finding of a reduced creatinine clearance or an elevated serum creatinine concentration is an almost certain indication that GFR is reduced. Similarly, a progressive decline in creatinine clearance or increase in serum creatinine level would indicate that GFR is pro-

223

gressively decreasing. Exceptions to this rule can be found in patients who are taking medications that inhibit tubular secretion of creatinine or in whom the measurement of serum creatinine is falsely elevated. VI. Glomerular filtration rate (GFR) Despite the well-recognized need to determine renal function when dosing a drug, there is considerable complexity, confusion, and controversy associated with the methods used to measure or estimate the glomerular filtration rate (GFR). To estimate GFR a substance must satisfy the following three conditions: (1) it must be freely filtered by the glomerulus; (2) it must not be secreted or reabsorbed; and (3) it must have a constant concentration during the period of measurement. Sevacid eral substances, including inulin, “Cr-edetic 9g”Tc-diethylenetriaminepentaacetic acid (EDTA), (DTPA) and sodium [i2’I]iodothalamate, largely fulfill these criteria. Inulin clearance is accepted as the standard and most accurate estimator of human GFR [18]. The rate of glomerular filtration is determined by three major factors: (1) the rate at which plasma flows through the glomerulus [loll; (2) the driving force for filtration, that is, the imbalance between the hydrostatic pressure gradient along the glomerulus favoring filtration (LIP,) and the oncotic pressure gradient retarding filtration (LIP,); and (3) the surface area and the permeability characteristics of the filtration membrane, collectively expressed as a single factor, Kp This relationship can be expressed by the equation: GFR=K@P,-dP,). VI. A. Urinary clearance

The concept of clearance is the cornerstone of our understanding of glomerular filtration. This concept rests on the self-evident proposition that the rate of excretion of any particular inert solute in the urine must be equal to the simultaneous rate of removal of that solute from the plasma. Thus if one measures the urinary excretory rate of a solute (i.e., urine concentration (v) times the urine flow rate (v) and divides that product by the concentration in plasma of the solute (P), one can calculate the volume of plasma completely cleared of that solute by the kidney during a given time period. Plasma clearance for any substance can be calculated by the following formula: Urine flow (ml/min) (V) x Concentration in urine (v) Concentration in plasma (P) This equation, however, says nothing regarding the

intrarenal handling of any particular substance. Substances that are only partially filtered or that are filtered and partially reabsorbed by the tubules have a clearance rate lower than the filtration rate. Substances that are both filtered and secreted by the tubules can have a clearance rate higher than the filtration rate. If the substance is filtered completely freely by the glomerulus and is neither reabsorbed nor secreted by the tubules, then and only then will the clearance rate be identical to the GFR. Thus to accurately evaluate the rate of glomerular filtration, it is necessary to measure the clearance rate of a substance that is completely filtered at the glomeruli and not reabsorbed, secreted or metabolized by the renal tubules. These demands are met by inulin. VI. B. Znulin clearance

Inulin, a polymer of fructose with a peak molecular radius (r,) of 15 A, possesses all of the characteristics of an ideal GFR marker and is therefore widely used in research laboratories. Because of a number of technical difficulties inherent in the assay of inulin concentration in urine and plasma, its utility in clinical practice is limited. The normal value for GFR, assessed by inulin clearance, is influenced by sex, age and body size; for men up to age 30 years, the normal value is 130+18 ml/mm/ 1.73 mZ (mean + SD) [102]. Thereafter, inulin clearance declines with advancing age by approximately 10 ml/ min per decade. Consequently, the normal inulin clearance for an 80-year-old man is approximately 80 ml/ miml.73 m2. The precise reason for the decline in GFR is unknown; however, aging is also accompanied by a decline in renal plasma flow and by development of glomerular sclerosis and arteriolar medial sclerosis [103-1051. Single-shot inulin clearance, which in principle is performed like an isotopic clearance, is presently under investigation. There seems to be a fairly good correlation with the classically performed inulin clearance [106,107]. VI. C. Plasma clearance

The plasma clearance of any tracer, including a filtration marker, can be measured under steady-state conditions during continuous i.v. infusion (without urine sampling), or from the rate of disappearance from plasma following i.v. bolus injection (the ‘single shot’ technique). The single-shot technique is the simplest way to measure plasma clearance; thus

224

Clearance =

injected dose area under the plasma concentration curve

extrapolation

t

0

Fig. 5. Determination

clearance

=

of renal plasma clearance by the single injection technique without urine sampling.

injected dose area under plasma concentration

curve

Because it is not possible to measure the entire plasma concentration curve, extrapolation to infinity is necessary (Fig. 5). This is usually accomplished by monoexponential extrapolation of the final measured part of the plasma curve. The rational basis for such a procedure is the experimental fact that biological indicator curves do end monoexponentially [ 1081.After complete resolution of the plasma curve into monoexponential functions (e.g., by the peeling-off technique starting with the apparently final monoexponential function), the total area is calculated as the sum of areas under each of these. Another approach is to determine the area under the recorded part of the plasma curve by planimetry or by numerical integration using a computer, whereas the remaining area is calculated as the area under the final monoexponential function from the time of last blood sampling until infinity [109]. The time needed for this extrapolation to be valid is 4-5 hours in a patient with normal to moderately decreased renal function, whereas it is too short at lower levels. Also in patients with severe oedema or ascites a recording period of this length is too short. To minimize the error prolongation of the sampling period with decreasing renal function, up to 24 hours at predicted clearance values less than 15-20 ml/ min, have been recommended by some authors [110radio-iodinated iothalamate and 1131. “Cr-EDTA, 99”Tc-DTPA are handled very similarly to each other and to inulin, and have been extensively investigated for the measurement of GFR. The chief advantage of these compounds is that the measurement of radioisotopes in serum and urine is easier and more accurate than measurement of inulin. The clearance of each of these compounds provides a better approximation of inulin clearance over a wide range of renal function than does creatinine clearance (Fig. 6). In general, the urinary

clearance of 99”Tc-DTPA [I 14,115], “Cr-EDTA [1151181 and iothalamate [ 1191 are less than the urinary clearance of inulin, although their plasma clearance have generally been greater [115,120,121]. Urinary 99”Tc-DTPA and “Cr-EDTA clearance have generally been less than their simultaneous plasma clearances [ 115,122,123]. Although this suggests extrarenal uptake or tubular reabsorption, neither has been proved. 99mTcDTPA plasma clearance has generally correlated well with the plasma clearance of “Cr-EDTA [115,124126] and iothalamate [114,127], although some commercial preparations of W”Tc-DTPA have given lower values [ 124,127], probably as a result of instability [ 1281 or protein binding in plasma [ 126,129]. The non-ionic contrast agent iohexol (normally used for clinical urography), has recently been introduced as a marker of GFR. The plasma elimination of iohexol seems to be closely correlated to “Cr-EDTA [130-1321 VI. D. Simpl$ed methods Determination of the area under the entire plasma curve necessitates drawing of many blood samples during a time period of several hours starting a few minutes after intravenous injection of the indicator. These inherent requirements make the use of total plasma clearance measurement less suitable for routine assessment of GFR, and explain why numerous simplified versions have been proposed over the years. Most simplifications concern shortening of the time of recording and minimizing the number of blood samples with determination of a plasma clearance either according to a two-pool mode1 [133] from the first part of the plasma curve or to a one-pool model [134] from the final monoexponential part, the so-called final slope clearance. The precision of such simplified single injection methods is high - in the order of 5% determined as

225

c I

240 -

': Li-

,

,

,

DTPA ,

vs. cm”,,” ,

,

,

,

N = 45 r = 0.969

N = 171 r = 0.831

80

, 0

20

40

60

80

100

120

140

160

I

I

1

I

1

20

40

60

80

100

,

,

120 140

,

160

C ,n,,,,n, ml’min/ 1.73 m2

Fig. 6. Individual clearances of 99mTc-DTPA(left panel) and creatinine (right panel) are plotted as a function of simultaneous inulin clearance (GFR). The unbroken line is the line of identity. (Reproduced with permission from Kidney Int., Ref. 73.)

the total day-to-day variation of clearance in patients with stable renal function [135-1391. The necessary number of blood samples used for a final slope clearance determination (i.e., Refs. 24) can be reduced to a single blood sample by the most simple variant of the single injection technique introduced by Fisher and Veal1 [140]. They found a very close relation between GFR higher than 30 ml/min and the plasma concentration of “Cr-EDTA (normalized with respect to injected dose) 3, 4 and 5 hours after injection. The single sample technique has since been evaluated [1411441and refined by incorporating the distribution space of the indicator substance used [145,146] (Fig. 7). It is generally agreed that the reliability of the estimate depends on the time of blood sampling, level of GFR and how exactly the distribution space of indicator can be predicted in the individual patient. The single sample technique has a reliability in the order of 3-5 ml/min at GFR levels higher than 30 ml/min using a blood sample drawn, respectively, in the periods of 3-4 hours in adults and 90-l 20 min in children [ 1471after the injection. The method has recently been extended to cover clearance values greater than 15 ml/min [148]. The plasma clearance of 51Cr-EDTA in patients with estimated clearance values below 21 ml/min can be determined with adequate precision by one plasma sample drawn at 24 hours after injection of the tracer [149].

VI. E. Comments A high degree of correlation bettween isotopic clearance and inulin clearance has been found by several investigators. Whenever a reliable estimate of GFR is needed, isotopic clearance measurement should be applied. “Cr-EDTA clearance is probably the most extensively studied method and in patients without severe renal failure, edema or ascites, the single sample clearance method will be adequate in most clinical situations. In patients with edema or ascites a urinary clearance is needed. Specific comments related to measurement of GFR during antineoplastic treatment can be found during the discussion of creatinine clearance. During treatment with carboplatin, measurement of GFR are needed to calculate the correct dose [150]. The radiation dose is often a matter of discussion, when other estimates of GFR are preferred rather than isotopic clearance investigations. The radiation dose of “Cr-EDTA used in most studies is equal to 3-4 MBq for a 70-kg man (Table 2), which is an equivalent dose to the body of 0.006 millisiverts. This is in the category I of the WHO recommended categories, i.e., within the variation of natural radiation. It is equivalent to 1112th of the radiation dose of a chest X-ray and is one hundredth of the background radiation dose received by an

226

EDTA

.c E 1 E

SO-

i3 E

100.

50.

I

100 Cl ml 1 min

50 (referencemethod

I

100

)

Fig.7. Plasma clearance of “Cr-EDTA after a single injection determined by five single-sample methods (A-E) and one five sample method (F) compared to the simultaneously measured total plasma clearance by use of 13 plasma samples (n=44). The solid line is the line of identity. (A=Russel, 180 min [255], B=Groth, 210 min [144], C=Jacobsson, 300 min [146], D=Tauxe, 120, 150 or 240 min [256], E=Christensen, 240 min [257], F=Brochner-Mortensen, 180, 210, 240, 270 and 300 min [39]. (Reproduced with permission from Clin Physiol, Ref. 258.)

individual living in London for 1 year [151]. Thus, although inulin is safer, the dose of radiation used to measure GFR using 51Cr-EDTA is very small. VII. Renal blood flow

VKA. para-Amino hippurate clearance for evaluation of renal plasma flow If a tracer is taken up exclusively by the kidney with an arterio-venous extraction fraction over the kidney (EF) of lOO%, then the plasma clearance of the tracer equals the renal plasma flow (RPF). Since no such compound exists, a suboptimal compound, such as paraamino hippurate (PAH) with an extraction fraction of

about 87%, is used. To acknowledge this discrepancy, the term effective renal plasma flow (ERPF) is conventionally used. Thus, ERPF =

RPF .EF

RPF is commonly estimated by the classic clearance technique: The disappearance of an indicator substance from blood passing through the kidney equals the subsequent appearance of the indicator in the urine. On the assumption that the indicator is neither synthetized nor metabolized in the kidney, then RPF = (I’&,) / (A,,- V,) where V,, is the urine flow rate; C, is the concentration

227 TABLE 2 Absorbed radiation doses from renal radiopharmaceuticals Compound or test

“Cr-EDTA 99mTc-DTPA ‘23101H ?OIH Intravenous urography

Usual activity given

Absorbed dose (mrad)

(mCi)

(MBq)

Kidney

Gonad

Whole body

0.1 10 1.5 0.5

4 400 60 20

40 380 3&1000* 50-10.000* 400

6 140 23 30 800

0.2 100 12 8

*In a well-functioning obstructed kidney. MBq = megabecquerel.

of the indicator in the urine, and A, and V,, are the concentrations of the indicator in the arterial and renal venous blood. In daily practice V,,is set to zero, and Ab equals the concentration of the indicator in a peripheral vein. Thus, during normal conditions ERPF is calculated as V,,C,,IA,. PAH seems to be the tracer with the highest EF, and ERPF is in other words synonymous with hippuran (or PAH) clearance. Other methods for measuring total renal plasma flow are invasive and traumatic and are only used in the experimental laboratory. A decrease in the PAH clearance after administration of a drug might be due to either a reduction in RPF or a decrease in the extraction fraction of PAH as a result of an impaired tubular secretion of PAH in proximal tubules [ 152,153]. Substances which compete with PAH for transport on the tubular level will also reduce the extraction fraction of PAH [154]. Thus, clearance of PAH cannot be considered a reliable measure of RPF, unless the exact extraction fraction of PAH is known and this requires a catheter in the renal vein. In an experimental study on clearance markers for renal plasma flow it was demonstrated that during a low concentration level of PAH, the extraction fraction of PAH was not constant. The extraction fraction of PAH was significantly lower during glucose administration. The reason why glucose infusion decreased the extraction fraction of PAH is not known, but the phenomenon is certainly a disadvantage for the use of PAH clearance as a plasma flow marker in studies using glucose infusion to induce water diuresis. In the same study tetraethylammonium (TEA) was tested in the anesthetized rat. This compound is transported by the organic cation system, and has previously been suggested as RPF marker in rats and rabbits in certain experimental situations [155,156]. The extraction fraction of TEA was slightly higher (92% vs. 88%) however, for both indicators a fixed value of extraction fraction shold not be used without considerations.

VII...

Effects

of antineoplastic

agents

Any state which alters proximal tubular function, such as disease or therapy with cytostatic drugs, may reduce hippuran and PAH extraction fraction to levels that invalidate their use for measuring RPF. It has been shown in several studies that the extraction fraction of PAH is not a constant parameter, but can be influenced by changes in renal blood flow [ 1571,GFR [ 1581,uremia [ 1591, glucose infusion [ 1601, administration of anionic drugs like furosemide [161], and administration of cisplatin [ 1621. Despite many reservations with the PAH clearance for estimation of renal plasma flow the method is still used in many studies, but as a marker for ‘renal function’ without distinguishing between renal plasma flow and tubular function [163.164]. If a cytostatic agent has a selective toxic effect on the tubules without affecting the renal blood flow and filtration, then the extraction fraction of PAH decreases together with the excretion rate of PAH. Therefore, if measurement of the extraction fraction of PAH is not performed at the same time, erroneously low values of ERPF will be obtained. Since hippuran (PAH and ortho-iodo hippurate (IOH)) extraction efficiency is unstable during different experimental conditions and during treatment with cytostatic drugs and many other drugs, e.g., ACE-I [165] and cyclosporine [ 1661, hippuran clearance is unreliable as a marker of RPF. Use of the first-pass approach with other markers [ 1671 or the gamma-camara techniques may lead to more reliable results. VIII. The lithium clearance method

In 1968 the lithium clearance method was introduced as a method to estimate quantitatively sodium and water delivery from the pars recta of the proximal tubules into the descending limb of the loop of Henle [168-1701. Estimates of tubular function were until the

228

1970s assessed by very indirect and inaccurate methods such as the renal clearance of phosphate, calcium, uric acid, and maximal free water clearances - methods which did not allow quantitative estimation of proximal tubular reabsorption rates of sodium and water. The lithium clearance method is an atraumatic noninvasive method, which is simple to perform and which can be repeated multiple times in the same subject. This method has obvious advantages over the conventional micropuncture methods, which only determine tubular functional parameters in one nephron of a heterogeneous system in operated, anaesthetized rats. However, little is known about the mechanisms of transepithelial transport of the lithium ion itself, and much evidence is circumstantial about the assumption that lithium is reabsorbed beyond the proximal tubules. Despite of many indirect evidences, it may still be questioned whether small changes in lithium clearance purely reflect changes in proximal tubule sodium handling. The lithium clearance method rests on the following assumptions: (1) lithium has no influence on renal function; (2) it is freely filtered through the glomerulus membrane; (3) it is reabsorbed in parallel with sodium and water along the entire proximal tubule; (4) it is not reabsorbed in measurable amounts beyond the pars rectae of the proximal tubule; and (5) it is not secreted in the entire nephron. As to point 1: there is no evidence that 300 mg of lithium-carbonate as a single dose has any tubular effect inducing diuresis or natriuresis. As to point 2: since the lithium ion does not bind to plasma proteins it can be filtered freely across the glomerular membrane. As to points 3 and 4: In recent years the renal clearance of lithium has been used extensively in animal studies as well as in clinical studies to assess proximal tubular function [171]. Recent evidence in animals has cast doubt on the main assumption that filtered lithium ions are reabsorbed in the proximal tubules in roughly the same proportion as sodium and water and that no lithium ions are reabsorbed more distally. These main assumptions have been extensively studied in rats and man [168,169,171-1761. Suggestive evidence has been given that no detectable lithium reabsorption occurs in the ascending limb of the loop of Henle, the distal convolute tubules and the collecting ducts. Only during severe sodium depletion in rats, a significant distal reabsorption of lithium has been observed to occur. Amiloride is able to abolish such distal lithium reabsorption without having any detectable effect on the proximal tubular reabsorption rates [ 175,176]. As to point 5: there is no evidence in the literature that lithium is secreted in the nephron. Some studies have shown that the proximal tubular fluid to plasma Li concentration ratio is greater than

unity, and that some lithium might be reabsorbed in distal parts of the nephron by frusemide- and amiloridesensitive mechanisms [ 176,177]. The major problems with regard to interpretation of the lithium clearance method in man are that the lithium clearance is significantly lower in salt-depleted than in salt-repleted states, and that loop diuretics cause increase in lithium clearance regardless of salt intake, although the increase is greater when dietary salt intake is restricted [178,179]. If loop-diuretics have an inhibitory effect on carbonic anhydrase activity in proximal tubules, then the lithium clearance method in man might be justified. Despite many experimental studies distal lithium reabsorption has only been shown in salt-depleted rats, and this distal lithium reabsorption has been inhibited by amiloride. Recent studies suggests that up to 10% of filtered lithium might be reabsorbed in the loop of Henle [ 178,180]. However, these studies are not able to distinguish between pars recta and the loop of Henle. Thus, although the validity of the lithium clearance as a selective proximal marker has certain limitations, accumulating evidence suggests that the amount of lithium which might be reabsorbed in Henle’s loop is negligible. The lithium clearance method is performed in human studies by giving 300 mg of lithium-carbonate (about 8 meq lithium) orally approximately 12 hours before a clearance session. On account of the large volume of distribution and relatively slow elimination of lithium, the concentration of lithium is stable about 0.1-0.2 mmol/l, and is declining by 3 to 6% per hour during the clearance period. The lithium may itself cause significant functional changes in tubular cell functions at higher dosages [181,182] inducing increased diuresis and natriuresis. Since patients during treatment with cytostatic drugs are candidates for dehydration and salt-depletion, it is very important that clearance investigations with the lithium clearance method in such patients are preceded by rehydration eliminating any possibility of salt-depletion.

VIII. A. Effects of antineoplastic agents The lithium clearance method has been used in experimental and human studies in order to elucidate the effect of cisplatinum on kidney function [183-l 871. Immediately after administration of cisplatin to dogs a significant increase in lithium clearance was observed while GFR and renal blood flow (measured by electromagnetic flowmeter) remained essentially unchanged. The increase in lithium clearance indicates an increased fluid delivery from the proximal straight segment and a decrease in proximal reabsorption rates, strongly sug-

229

gesting that cisplatin-induced nephrotoxicity is initiated by a proximal tubular functional impairment. The lithium clearance method was also used in studies on the effect of c&platinum on kidney function in man [183,187]. In a group of low-dose cisplatin-treated patients with malignant germ cell tumors, lithium clearance did not change, neither during nor after treatment. However, in a high-dose cisplatin group a significant decrease in absolute as well as in fracional proximal reabsorption rates occurred as indicated by changes in GFR and lithium clearance. These changes could be observed at least 6 months after termination of treatment. These observations in humans are in accordance with the data obtained in dogs and correspond to the ultrastural changes in both proximal and distal tubules observed in renal biopsies obtained from patients treated with cisplatin [188,189]. Despite the fact that direct studies on tubular lithium handling are required before the lithium clearance method can be appreciated fully, the method can be a precious tool in the hands of the investigator conscious of the above-mentioned limitations. IX. Proteinuria

Proteinuria is one of the most common and easily detectable signs of renal disease. Protein is normally found in the urine with a 24-hour urine protein excretion of up to 150 mg in helathy adults [190]. In children, this rate varies with age, with body surface, and between individuals. For practical purposes, it has been suggested that values of urinary protein greater than 100 mg per day in children less than 10 years of age should be viewed as abnormal [ 1911. In normal urine, 60% of the proteins are normal plasma proteins, and the remaining 40% originate from the kidney and the urogenital tract [ 190,192]. Thirtytwo different plasma proteins have been detected in the urine, with albumin being the predominant protein, comprising about 40% of all urinary proteins [193]. Immunoglobulin G is the next most prevalent protein, accounting for 5 to 10% of the urinary total proteins, followed by the immunoglobulin light chain, representing an additional 5%. Other plasma proteins, together representing 5% of the total urinary proteins, are /Imicroglobulin, transferrin, parathyroid hormone, insulin, ceruloplasmin, haptoglobin and a number of enzymes such as amylase, ribonuclease, lysozyme and kallikrein [192-1941. Three proteins that are known to be derived from the kidney are Tamm-Horsfall mucoprotein, urokinase and secretory IgA. Tamm-Horsfall protein is a mucoprotein (M, 7 000 000) that can aggregate to form polymers up

to M, 100 000 000 [195,196]. It makes up almost all of the remaining 40% of the total urinary proteins and is derived from Henle’s loop, distal tubule and collecting duct. Tamm-Horsfall protein also makes up the matrix of casts [197]. IX. A. Mechanisms

ofproteinuria

Under normal circumstances, the glomerular capillary wall acts as a selective size and charge barrier, allowing only small molecules (for example inulin) free access across the glomerular capillary while becoming increasingly restrictive to substances of increasing size or negative charge. Hence, small-molecular-weight proteins pass through the glomerular barrier easily; largemolecular-weight proteins such as IgM do not normally pass through the glomerular capillary wall; and the passage of intermediate-size proteins (such as albumin) is restricted. The proteins that are filtered across the glomerular selective barrier are almost totally reabsorbed and catabolized by the proximal tubular cells. Abnormal proteinuria with increased amounts of urinary protein can result from (1) defects in glomerular wall permeability with an increase in filtered proteins; (2) inadequate tubular reabsorption of normal amounts of filtered proteins; or (3) elevated concentrations of normal or abnormal plasma proteins leading to an increased filtration load. In most kidney diseases characterized by increased protein excretion, albumin makes up 60 to 90% of the urinary protein [198-2001 (Fig. 8). The excretion of low-molecular-weight proteins usually remains minimal [201]. The preponderance of evidence indicates that an increase in loss of protein across the glomerular wall is the major disturbance responsible. Although increased filtration of protein appears to be the major factor leading to proteinuria, the specific defect in the capillary wall that are responsible for the protein loss are not well defined. Data in humans with various forms of glomerulonephritis support the concept that the glomerular capillary wall is leaky in these disorders. In the case of tubular proteinuria disease processes that affect only the proximal tubule with normal glomerular selectivity will lead to tubular proteinuria. where low-molecular-weight proteins will predominate µglobulin and lysozyme), and the amount of proteins does not exceed 2 g of protein per day. A typical pattern of urinary proteins in patients with tubular proteinuria is shown in Fig. 8. An increase in the concentration of plasma proteins, particularly small-molecular-weight proteins can lead to increased amounts of filtered proteins that exceed the proximal tubules’ reabsorptive capacity, resulting in

230

1

b

a, a, Abumin

SERUM (Normal) Ld

JRINE

: Norma\

cules, such as IgG, range from less than 10% to greater than 60% of the clearance rate of albumin or transferrin, a protein similar in size to albumin. Patients with a clearance ratio of IgG/albumin (or transferrin) of less than 0.10 are considered to have only a modest increase in glomerular permeability and are defined as having a ‘highly selective’ pattern of protein excretion; conversely, those patients in whom the clearance ratio is 0.5 or greater are considered to have a relatively porous filter and are defined as having a poor selective pattern. Studies of the pattern of protein have shown that the majority of patients with glomerular proteinuria have a non-selective pattern [207].

“Glomerular” Protetnurta ,_I

“Tubular” Protelnurla

“Overproduction”Proteinuna

Fig. 8. Electrophoretic patterns of normal serum, normal urine, and urines with three types of abnormal protein excretion. The electrophoresis pattern shown for overproduction proteinuria is taken from a patient with multiple myeloma. (Reproduced with permission from Ref. 259.)

proteinuria. Clinical examples include multiple myeloma (immunoglobulin light chains), mono- and myelocytic leukemia (lysozyme), and myoglobinuria secondary to tissue damage [190,202,203]. The interpretation of increased excretion of light chains and lysozyme poses a problem, namely, to distinguish between hyperexcretion secondary to tubular disease on the one hand and to overproduction of the protein on the other. In the case of light chains, a slight increase in excretion and a finding of a mixture of both kappa and lambda fragments points to a primary tubular defect, whereas high levels of excretion (greater than 500 mg/day) and the presence of only a single type of light chain points to accelerated synthesis [204]. Another kind of proteinuria is the so-called ‘functional’ proteinuria, which is a transient phenomenon subsequent to exercise, fever and emotional stress [205,206].

IX. C. Methods for measuring urinary proteins Urine is most often screened by dipstick test. When testing for proteinuria, the color of the dye is dependent almost entirely on the protein concentration. When proteins are present in the urine, they bind to the indicator dye, inducing a calorimetric reaction. Various proteins bind with different affinities to the indicator, with albumin having the greatest affinity. Hence, the dipstick test is more sensitive to albumin and may give falsely low levels for other proteins such as immunoglobulin light chains [208]. False-positive results can occur with highly alkaline (pH>7.0) urine, where the dye may indicate trace amounts of protein in the absence of proteinuria. Also, contamination with bacteria, blood, quaternary ammonium compounds, and the skin cleaner chlorhexidine will give false-positive readings [209,2 lo]. Most hospital laboratories use a tubidometric method whereby a reagent such as sulfosalicylic acid, trichloroacetic acid, or heat causes denaturation of urinary proteins, resulting in precipitation. The precipitation methods detects all proteins equally well. Falsepositive results can occur if the urine contains tolbutamide, radiocontrast agents, or high levels of cephalosporin, penicillin or sulfonamide derivatives [211]. Use of specific antisera to individual proteins has allowed accurate determination of the urinary concentration of these proteins. A number of tests that utilize the antibody’s ability to recognize a specific antigen include radioimmunoassay, radial immunodiffusion, immunoelectrophoresis, enzyme-linked immunosorbent assay (ELISA) and immunonephelometry. IX. D. Effects of antineoplastic drugs

1X.B. Protein selectivity In patients with proteinuria secondary to a wide variety of renal diseases, the clearance rates of large mole-

Analysis of proteinuria can in most cases be used to differentiate between glomerular and tubular damage (Fig. 8). During treatment with the nephrotoxic anti-

231

neoplastic agents known at present, tubular proteinuria is common. Proteinuria is present after cisplatin administration in some studies [79,8X$212,213] and absent in others [78] despite equal dose intensity. One of the reasons for this discrepancy is probably different intervals between the cisplatin administration and the time of urine collection. Proteinuria, or as it is in most cases, albuminuria, slowly reaches a peak between 3 and 9 days after cisplatin administration [79,86,212] depending on the dose regimen. Between cycles of cisplatin treatment, proteinuria predominantly of glomerular origin, can be observed [86,213]. Proteinuria has also developed in several cases after streptozocin and ifosfamide treatment [98,214]. X. Measurement of low-molecular-weight proteins X. A. /I,-Microglobulin &Microglobulin (B2-M) is a low-molecular-weight protein of M, 11.800, and, as a component of the HLA class I antigens, it is partially bound to the cell surface and partially dissolved in body fluids. &M can be measured in plasma, serum, urine and other human fluids like saliva, cerebrospinal and pleural fluids. It is usually measured by radioimmunoassay or enzymelinked immunosorbent assay (ELISA). Normal serum values are 1.1 to 2.7 mg/l and the normal excretion is ~370 pug/24 hours. /&-M is unstable at room temperature, and in urine with pH6.0, RBP and /?*-M concentrations were well correlated. If a renal threshold exists for both RBP and/$-M, the urinary excretion of RBP and p,-M is probably only diagnostically significant as a specific index of proximal tubular impairment when the glomerular filtration rate is only slightly or not at all decreased. After tobramycin administration an initial increase in RBP and /3,-M was observed, whereas the increase in NAG excretion appeared somewhat later, probably reflecting a progress in tubular damage during the course of aminoglycoside therapy [242]. XI. D. Effects of antineoplastic agents A peak increase in NAG and alanine aminopeptidase are often observed within l-2 days after cisplatin ad-

ministration [76,183,212,243]. The patients show a great variation of the enzyme excretion patterns in response to cisplatin administration [243], and increased excretion of enzymes is often observed without concomittant increase in serum creatinine [76,79,243,244]. In cases where serum creatinine does increase, this is often preceded by an increase in tubular enzymes. The same cyclic pattern as that observed for&M can also be observed for urinary enzymes. Often a normalization is observed before the subsequent course [183,244], but the opposite has also been observed [212] together with a cumulative effect during treatment periods. Excretion of urinary enzymes has been used to evaluate the tubular nephrotoxicity of cisplatin vs. cisplatin analogs and cisplatin+ifosfamide [79,245]. Increased urinary excretion of phosphorus, glucose and amino acids is often observed after treatment with streptozocin [98,246], increased magnesium, potassium and sodium excretion after treatment with cisplatin [183], polyuria, glucosuria, changes in urinary pH and phosphorus after 5-azacytidine [247] and similar changes can be observed after administration of ifosfamide [248,249]. The tubular toxicity of a drug would probably in most cases be detected by the above-mentioned low-molecular-weight proteins or tubular enzymes. but a further description of the tubular function can be obtained by measuring the excretion rate of different components reabsorbed by the tubule. Tubular enzymes (and low-molecular-weight proteins) can be used in the screening for tubular toxicity, especially in those patients where urinary excretion of enzymes has been measured before and during treatment. The severity and long-term renal toxicity cannot be predicted by measuring urinary enzymes. XII. Measurement of tubular antigens XII. A. Adenosine deaminase-binding protein (ABP) A monoclonal antibody-based assay for ABP, a proximal tubular antigen present on the brush border of the proximal tubular epithelial cells, has been introduced, and evaluated in a number of clinical situations [2502521. Low levels of ABP (less than 0.1 A.U.) appear in the urine of normal individuals. Patients with biopsyproven glomerular disease have only low levels of ABP in their urine (less than 0.2 A.U.). In contrast, patients with acute renal failure secondary to a variety of causes of proximal tubular injury (contrast-induced renal failure, myoglobinuria secondary to rhabdomyolysis, or acute tubular necrosis secondary to hypotension) all

234

have significant increases in the level of ABP in their urine. ABP release appears to occur promptly concomittant with an acute tubular injury, with the level rising before serum creatinine. Conversely, ABP levels return towards normal with cessation of proximal tubular injury, often before falls in the serum creatinine level occur. Cyclosporine toxicity is associated with elevation in urinary ABP levels [250,251], and preliminary studies suggest that the ABP assay may also be helpful in screening and monitoring potential nephrotoxicity in patients receiving cisplatin and other antineoplastic drugs [253]. Should monoclonal antibody-based assay specific for other portions of the nephron become available, the diagnostic worth of urinary disease markers will be enhanced. Not only could they provide a useful guide to the differential diagnosis of acute renal injury, but also provide a dynamic measure of the extent and activity of the process. XIII. Conclusions Although the number of nephrotoxicants is large and rapidly expanding, the basic pathway by which they exert their toxic effect are few in number. The selective vulnerability of specific cells of the kidney, for example, proximal tubular cells, to certain drugs and xenobiotics is a predictable consequence of the unique transport and/or metabolic profile of such cells that results in the generation and/or accumulation of the offending toxicant. At the present time huge gaps exist in our knowledge of the ultimate toxic species of many agents, the specific targets of the toxicant and how the interaction of the toxicant with its target eventuates in cellular injury or death. Nephrotoxicity due to antineoplastic agents is a frequent cause of acute renal failure and other renal obnormalities in the cancer patient. A decrease in the incidence of this complication can be attained with an increased awareness of (1) the nephrotoxic potential of offending antineoplastic agents; (2) the nephrotoxic dosage of these agents; (3) appropriate prophylactic measures; and (4) the clinical settings that predispose to nephrotoxicity. Early diagnosis of nephrotoxicity is clearly dependent on the sensitivity of the applied methods for detecting a decrease in renal function. Sensitive methods should be used whenever simple screening methods have yielded abnormal results, or when the drugs investigated are expected to present a major risk of renal toxicity, either because they are chemically or pharmacologically related to known nephrotoxic agents, or be-

cause they are accumulated in the kidneys to an unusual extent. Creatinine, as discussed above, is not an ideal filtration marker. Because of tubular secretion, creatinine clearance exceeds GFR. However, the usual clinical measurement (made with the Jaffe reaction) underestimates the creatinine clearance. Consequently, the similarity of the usual clinical measurement of creatinine clearance to the GFR in normal individuals reflects a fortuitous balance of opposing effects of tubular secretion and measurement error. Most importantly, these effects are unrelated and are influenced differently by numerous variables, including the level of renal function and various drugs. Inulin clearance or one of the more simple isotopic clearance methods should be preferred whenever a decrease in glomerular filtration rate is expected. The criticism is sometimes raised that urinary enzymes are in fact ‘too sensitive’ in that elevations are sometimes present in the absence of other measurable abnormalities. This may reflect the ability of the kidney to recover rapidly from damage but the insensitivity of other tests of renal function should be borne in mind. However, low-molecular-weight protein and tubular enzymes can be used for screening purposes whenever drug influence of the proximal tubular function is expected. Neither low-molecular-weight proteins nor tubular enzymes has been of any value in determining the severity or the long-term renal toxicity after treatment with nephrotoxic antineoplastic agents. The lithium clearance method might be a more sensitive measure of the long-term toxicity, but further evaluation of this method during treatment with nephrotoxic drugs is needed. Several other renal function tests, than those mentioned in the present review, are available. It is likely that most antineoplastic agents with a direct toxic action on the kidney should be detected by using the above-mentioned methods of detection. As our understanding of specific molecular mechanisms mediating toxicity expands, it should be possible to device strategies for protecting the kidney from a major cause of injury. Reviewer This paper was reviewed by Samuel Waxman, M.D., Mount Sinai Hospital, New York, NY, USA. Biographies Gedske Daugaard received her MD from the University of Copenhagen. She did clinical and research fellowships at Rigshospitalet, Copenhagen. She obtained a DMSc degree in

235 1989 at the University of Copenhagen. Her current appointment is senior registrar at the Department of Hematology, University Hospital of Herlev, Denmark. Ulrik Abildguard received his MD from the University of Copenhagen. He did clinical and research fellowships at the Department of Cardiology, Gentofte University Hospital, Copenhagen. His current appointment is consultant at Department of Cardiology, Gentofte University Hospital. He obtained his DMSc degree in 1989 at the University of Copenhagen, Denmark.

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