Interleukin-2 - Induced Renal Dysfunction in Cancer Patients Is Reversed by Low-Dose Dopamine Infusion

Bruno Memoli, MD, Luca De Nicola, MD, Carmelo Libetta, MD, Antonella Scial6, MD, Giulia Pacchiano, MD, Paolo Romano, MD, Giovanna Palmieri, MD,

Alessandro Morabito, MD, Rossella Lauria, MD, Giuseppe Conte, MD, and Vittorio E. Andreucci, MD

0 Recombinant interleukin-2 (rlL-2) is widely used in patients with advanced cancer to enhance killer cell functions. However, the main drawback of rlL-2 therapy is the frequent development of oliguric acute renal failure (ARF), presumably due to a vascular leak syndrome. The aim of this study was to evaluate the effect of low-dose dopamine infusion on this form of ARF. Nine patients with metastatic renal cancer and previous unilateral nephrectomy were treated with a continuous intravenous infusion of rlL-2 (3 x lo* Cetus units/m*/d) for 5 days (study A). After 1 week, all the patients repeated the same cycle, but wfth the addition of a continuous intravenous infusion of dopamine (2 ~g/minIkg body weight) that was started at the third day of treatment (study B). During study A, all patients showed a progressive (up to 34%) decrease of creatinine clearance. After rlL-2 withdrawal, these alter- ations persisted and were associated with a reduction in urinary output, sodium urinary excretion, and plasma protein. In study B, dopamine administration after renal function impairment (Aglomerular filtration rate = -44%) led to a prompt improvement of creatinine clearance. Creatlnine clearance showed a further significant enhance- ment after the withdrawal of both drugs, reaching a value within the baseline range on the third day of follow-up. Similarly, the decline in urinary output and sodium excretion during rlL-2 was promptly counteracted by dopamine; in addition, after withdrawal of rlL-2 and dopamine, plasma protein levels were normaliied. In conclusion, our data suggest that rll-2-induced ARF in cancer patients is due to renal hypoperfusion mainly caused by a reduction in oncotic pressure. Importantly, intravenous infusion of dopamine at low dosage is effective in reversing this form of renal impairment; such a therapeutic approach, while reducing recovery time, avoids dose reduction or discontinuation of rll-2 treatment. 0 1995 by the National Kidney Foundation, Inc.

INDEX WORDS: Interleukin-l; acute renal failure; dopamine; cancer patients.

R ECOMBINANT interleukin-2 (rIL-2) is used at a high dosage in patients with ad-

vanced melanoma or renal cancer to induce re- gression of the solid tumor and metastases.“6 Un- fortunately, the beneficial effects of rIL-2 immunotherapy are limited by side effects, such as the so-called vascular leak syndrome and de- velopment of renal dysfunction, more important in aging and in subjects with altered renal func- tion, that often lead physicians to discontinue or reduce rIL-2 doses.7-”

The vascular leak syndrome has been de- scribed in experimental studies as a primary in- crease in the vascular permeability with conse- quent shifting of proteinaceous intravascular fluid into the interstitium of many organs, hypo- albuminemia, and reduction of the intravascular volume.‘* Interleukin-2 may produce this syn- drome through direct effects on the integrity of blood vessels13; alternatively, lymphocytes acti- vated by rIL-2 may generate other cytokines, which in turn would increase vascular permeabil- ity.” In humans, the pathophysiology of rIL-2- induced renal dysfunction is still ill-defined; two groups have reported that rIL-2 therapy is associ- ated with declining renal function, oliguria, in-

tense tubular avidity for filtered sodium, fluid retention, increased plasma renin and aldoste- rone, and weight gain.14-16 Overall these alter- ations resemble a prerenal or functional form of acute renal failure (ARF). Since functional ARF is associated with an increase in renal vascular resistances that greatly accounts for renal hypo- perfusion,‘7 rIL-2-related renal impairment should be prevented or ameliorated by renal va- sodilators; to date, however, such a possibility has not been tested.

The current study was therefore designed with the aim of evaluating the effects of a continuous intravenous infusion of low-dose dopamine on the renal function in patients undergoing rIL-2

From the Departments of Nephrology and Oncology, Uni- versity Federico II of Naples; and the Department of Nephroi- ogy, Second University of Naples, Naples, Italy.

Received September 14, 1994; accepted in revised form March 7, 1995.

Address reprint requests to Bruno Memoli, MD, Cattedra di Nefrologia, Facoltd di Medicina e Chirurgia, Universitd “Federico II” di Napoli, Via S. Pansini 5, Edijcio 5, 80131

Napoli, Italy. 0 1995 by the National Kidney Foundation, Inc. 0272-6386/95/26014?004$3.00/0

American Journal of Kidney Diseases, Vol26, No 1 (July), 1995: pp 27-33 27

28 MEMOLI ET AL

therapy. Indeed, dopamine at low dosage, while not having systemic effects, does increase renal blood flow and urinary sodium excretion by stim- ulating specific intrarenal dopaminergic recep- tors.18 Previous studies by our group have dem- onstrated protective effects of low doses of dopamine in some forms of functional ARF, such as diuretic-induced volume depletion and acute cyclosporine nephrotoxicity. In both conditions, low-dose dopamine restored normal glomerular filtration rate (GFR) and urinary output by de- termining a decrease of renal vascular resistances and proximal tubular sodium reabsorption.‘9*2o

MATERIALS AND METHODS

Patients Nine patients (eight men and one woman with a mean

age of 55.22 ? 6.36 years) who underwent uninephrectomy because of metastatic renal carcinoma in which standard ther- apy (chemotherapy and/or radiation therapy) had failed, were included in our study. Written informed consent was obtained from all patients.

All patients had histologically documented evidence of metastatic, bidimensionally measurable cancer with a pcrfor- mance score of 0, 1, or 2 on the Eastern Cooperative Oncol- ogy Group.” Patients with brain metastasis or other primary neoplasms, or with renal disease other than neoplasia, were excluded from the protocol. No patient received antineoplas- tic therapy during the 30 days prior to rIL-2 infusion.

Experimental Design The same group of patients underwent two cycles of rIL-

2 treatment: with (study B) and without (study A) intravenous dopamine infusion.

Study A. According to the West schedule, which has been found to be associated with less toxic effects in comparison with bolus-dose therapy,zz.23 all patients, after basal measure- ments were obtained in the first 3 days of the study, underwent a continuous 24-hour infusion via an electric pump (Phar- macia, Deltec, St Paul, MO) of rIL-2 at a dose of 3 million Cetus units/m*/d (18 million IU/m2/d; EuroCents B.V., Am- sterdam, The Netherlands) for 5 days. The patients were stud- ied for 3 days after drug withdrawal (follow-up period).

Study B. The second phase of our protocol was performed 1 week after the last day of the follow-up period of study A. Patients repeated the same cycle with the addition of a continuous intravenous infusion of dopamine (2 @mm/kg body weight) that was started on the third day of treatment.

To control hemodynamic instability, volume expanders (saline or albumin) were administered in the same amount in both studies (NaCl 0.9% 500 mL/d and albumin 20% 20 g! d) to each patient during both studies. Indomethacin (50 mg/ d) was used to alleviate chills and malaise during rIL-2 ther- apy in all patients during both phases of the study.

Body weight, blood arterial pressure, heart rate, and urine volume were measured daily throughout the study. Blood urea nitrogen, serum and urine creatinine, plasma total pro-

tein, hematocrit, sodium and potassium in serum and urine, and proteinuria also were assessed daily using standard tech- niques described in previous reports.‘9~20 Mean arterial pres- sure was calculated as the sum of the diastolic arterial pres- sure plus one third of the difference between systolic and diastolic arterial pressures.

Twenty-four hour creatinine clearance was used as GPR index to monitor the variation of filtration rate day-by-day throughout the 11 days of the study. Creatinine clearance was calculated according to the standard clearance formula (C = U x V/P) and was adjusted to.a body area of 1.73 m2. The fractional excretion of Na+ was calculated as Na+ clearance/ creatinine clearance X 100. The oncotic pressure (A) was calculated using the following equation: rr = aC + bC*, where C is the plasma protein concentration and coefficients a = 1.629 and b = 0.294 have been derived by least chi-squared analysis of the quadratic relationship between plasma oncotic pressure and C.”

Statistical Analysis All values are reported as mean + SEM. The statistical

significance of differences between baseline and treatment values was examined by ANOVA for repeated measurements. The level of statistical significance was defined as P < 0.05.

RESULTS

Interleukin-2 therapy was associated with a significant decrease of the two major diameters of measurable lesion in two patients; the disease did not progress in four patients, while three pa- tients were unresponsive to therapy. No patient required early discontinuation of immunotreat- ment.

The administration of i-IL-2 (study A) induced a progressive decline of renal function, the decre- ment of creatinine clearance persisting in the re- covery phase after i-IL-2 withdrawal (Fig 1A). The decreasing GFR was associated with a pro- gressive and parallel increase in serum creatinine (Fig 2) and a decrease in absolute urinary sodium excretion (Table 1). Figures 3 and 4 show the modifications of urinary output and fractional urinary sodium excretion (FENa), respectively: a significant reduction of both parameters was demonstrated during i-IL-2 therapy. Interestingly, the renal functional changes were associated with a significant decrease in plasma proteins and on- cotic pressure that persisted after discontinuing rIL-2 infusion (Table 1).

Dopamine was started on the third day of the second 5day cycle of rIL-2 therapy (study B). Despite the earlier (second v third day of therapy) and greater (-44% v -34%) GFR impairment observed during this second rIL-2 cycle, a

29 DOPAMINE IN IL-2 NEPHROTOXICITY

rll-2

F 20- 9 8 lo-

o- , , , , , , , , , ( -012345676.

DAYS

rlL-2 rll-2 + D B + + + 110 -I

ElOO- - - -

g 90

- -

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5 20-

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0 I I I I I I I I I I -012345676-

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Fig 1. (A) Changes of creatinine clearance during continuous intravenous infusion of rlL-2 and in the first 3 days after drug wfthdrawal in cancer patients. (B) Effect of dopamine (0) infusion on the rll-2-induced changes of creatinine clearance in the same group of patients. All data are expressed as mean values ? SEM. Ranges are within the dashed line above and below the mean. ‘P < 0.05 versus baseline (day 0).

prompt improvement of renal function followed dopamine infusion, as demonstrated by a numeri- cal increase of creatinine clearance (Fig 1B) and a reduction of serum creatinine (Fig 2). Creati- nine clearance showed a further significant en- hancement after the withdrawal of both drugs, reaching a value within baseline range on the third day of follow-up. Similarly, the decline in urinary output and fractional excretion of sodium

THERAPY

0; I 1 I I I I I I I 0 1 2 3 4 5 6 7 0

DAYS

Fig 2. Effect of rfL-2 (sofii circles) and rlL-2 + do- pamlne (D, open circles) on serum creatinine in cancer pathts. Dopamine was infused on days 3,4, and 5 of therapy. A5 data are expressed as mean values ? SEM. ‘P < 0.05 versus baseline (day 0).

during i-IL-2 was promptly counteracted by dopa- mine administration (Figs 3 and 4). As shown in Table 2, the concentration of plasma proteins and the values of oncotic pressure decreased during rIL-2 therapy, and it remained low after adding dopamine infusion; however, in contrast to study A, in which only i-IL-2 was infused, plasma pro- teins concentrations and oncotic pressures re- turned to basal conditions after drug’ withdrawal.

No significant change in either blood pressure or body weight was observed in the two phases of the study. No patient developed proteinuria greater than 300 mg/24 hr in either study.

DISCUSSION

In the present study, patients receiving rIL-2 alone showed a rapid and progressive decrease of GFR associated with a decline in urinary out- put and a very low urinary sodium excretion; these changes resembled a form of prerenal or functional ARF.

The present work cannot provide conclusive data on the pathophysiology of rIL-2-induced ARF since renal plasma flow was not measured. Indeed, as expected on the basis of our clinical experience, filtration rate markedly decreased during rIL-2 infusion to values of approximately 40 mL/min (with wide scatter), and it is well recognized that in such a condition, para-amino- hippurate (PAH) clearance is not a valid index

30 MEMOLI ET AL

Table 1. Plasma Concentration of Total Protein, Oncotic Pressure, and Urinary Sodium Excretion in Basal Conditions, During and After lnterleukin 2 Infusion (Study A)

rlL-2 Therapy Follow-up

Days 0 1 2 3 4 5 6 7 0

TP WV 7.07 6.50 6.46 6.36’ 6.12 6.20 6.06 6.07’ 6.18 + 0.19 + 0.17 2 0.13 ” 0.16 + 0.11 4 0.14 ? 0.15 + 0.18 2 0.17

s (mm Hg) 26.22 24.02 22.87 22.54’ 21.01’ 21.48 20.78’ 20.81’ 21.44 + 1.1 2 0.78 k 0.81 5 0.89 ? 0.61 k 0.76 2 0.77 + 0.82 % 0.92

UNaV (mmol/min) 0.139 0.074 0.052' 0.035 0.026 0.016* 0.019 0.020* 0.044'

2 0.021 k 0.031 2 0.018 k 0.013 2 0.014 * 0.009 2 0.011 2 0.012 2 0.035

NOTE. All data are expressed as mean values 2 SEM. Abbreviations: TP, total protein; S, oncotic pressure: UNaV, urinary sodium excretion. * P < 0.05 v baseline.

of renal plasma flow unless patients undergo re- nal vein catheterization. Such a procedure was ethically impossible in our very ill patients.

However, the data obtained in the current study strongly suggest that hypoperfusion is the main cause of rIL-2-induced ARF in humans. In fact, ARF was associated with a marked and earlier reduction of plasma proteins from approx- imately 7.0 to 6.0 g/dL, likely caused by the augmented permeability of blood vessels due to rIL-2. This implies a significant decrease in on- cotic pressure (from 26.22 to 20.78 mm Hg). It

THERAPY

2500 -I 1

- 2000 -

s

g 1500 -

ii 5 o 1000 -

s

g 500 -

3 01 .

I I I I I I I I I 0 1 2 3 4 5 6 7 0

DAYS

Fig 3. Effect of rlL-2 (solid circles) and rlL-2 + do- pamine (D, open circles) on daily urinary output in can- cer patients. Dopamine was infused on days 3,4, and 5 of therapy. All data are expressed as mean values t SEM. ‘f < 0.05 versus baseline (day 0).

is interesting that in the first 2 days of follow-up, no improvement in plasma proteins was observed and the constant hypoprotidemia was paralleled by protracted renal dysfunction and antinatriure- sis, suggesting that, even after rIL-2 withdrawal, functional ARF persists if intravascular volume is not restored.

This hypothesis is further supported by the observation in study B that low-dose dopamine infusion was able to counteract all the rIL-2- induced renal changes; interestingly, the protec-

1.8,

1.8 {

1.4 -

1.2 -

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THERAPY

0: l t l l

I ! r I I I I I I

0 1 2 3 4 5 6 7 8 Days

Fig 4. Effect of rlL-2 (solid circles) and rlL-2 + do- pamine (D, open circles) on fracthal urinary excre- tion of sodium (FENa) in carbser path& Dopamine was infused on days 3,4, and 5 of therapy. All data are expressed as mean values 5 SEM. ‘P < 0.05 versus baseline (day 0).

DOPAMINE IN IL-2 NEPHROTOXICITY 31

Table 2. Plasma Concentration of Total Protein, Oncotic Pressure, and Urinary Sodium Excretion in Basal Conditions, During riL-2 and rlL-2 + Dopamine Infusion, and After Withdrawal of Both Drugs (Study B)

rlL-2 rlL-2 + D Follow-up

Days 0 1 2 3 4 5 6 7 a

TP WW 7.12 6.45 6.15 6.17* 6.16 6.29* 6.46 6.75 6.62 k 0.19 2 0.15 2 0.14 ? 0.13 2 0.18 t 0.17 2 0.20 t 0.16 ‘- 0.13

li (mm Hg) 26.50 22.74 21.14 21.35 21.31* 21.74 22.99 24.15 23.70 2 0.89 2 0.94 2 0.86 2 0.70 r+_ 0.97 k 0.96 t 1.08 2 0.87 2 0.73

UNaV (mmol/min) 0.135 0.042 0.022 0.046 0.058 0.087 0.124 0.104 0.118

2 0.033 t 0.016 ? 0.008 2 0.024 t 0.012 + 0.017 2 0.028 2 0.016 !I 0.018

NOTE. All data are expressed as mean values 2 SEM. Abbreviations: TP, total protein; 7~, oncotic pressure; UNaV, urinary sodium excretion; D, dopamine. l P < 0.05 v baseline.

tive effects of dopamine took place even though the renal impairment was earlier and greater, probably due to an increased susceptibility to the rIL-2 nephrotoxic effects after the first cycle. Functional ARF is characterized by overproduc- tion of vasoconstrictive substances, due to hypo- volemia itself, that contributes to the decrement in (3Fj317.25; the administration of vasodilating doses of dopamine can counteract such hemody- namic changes.*’ It is notable that we recently demonstrated that the early phase of functional ARF induced by salt depletion in humans is con- sistently associated with renal vasoconstriction dependent on the activation of the sympathetic nervous and renin-angiotensin systems.*’ In that study, we found that low-dose dopamine infusion resulted in effectively increasing renal plasma flow and re-established a normal GFR without any volume restoration. A similar renal vasodi- lating effect of dopamine also may be hypothe- sized in this form of functional ARF.

It is noteworthy that dopamine also exerted the beneficial effect by increasing natriuresis. Indeed, dopamine restored urinary sodium excre- tion to pre-m-2 therapy values; in addition, fol- lowing rIL-2 withdrawal, an immediate increase in plasma protein concentration was noted. Since patients received the same amount of exogenous albumin in both studies A and B and no change in proteinuria occurred, it is reasonable to hy- pothesize that the increment in plasma protein was dependent on the primary dopamine-related increase of natriuresis (over 100%) with a conse-

quent concentrating effect on plasma proteins and an increase in oncotic pressure. The restored oncotic pressure likely allowed a refilling of the intravascular volume that improved renal hemo- dynamics, as mirrored by the re-establishment of basal creatinine clearance during the follow-up period.

We cannot exclude that the low doses of indo- methacin administered to our patients may have played a minor additional role in the pathophysi- ology of rIL-2-induced renal hypoperfusion, secondary to prostaglandin synthesis inhibition. The effectiveness of dopamine in improving re- nal function after rIL-2, however, seemed to not be blunted by this anti-inflammatory drug.

The observed protective effects of low-dose dopamine are of clinical relevance; development of ARF, in fact, is a main cause of discontinua- tion of rIL-2 therapy. Moreover, it is important to note that we did not observe any reduction in the therapeutic effectiveness of rIL-2 secondary to intravenous dopamine, nor has this finding been reported in the literature.

Of note, the rIL-2-induced nephrotoxicity in our patients was milder than that first described by Rosenberg and colleagues’,*; indeed, these in- vestigators observed a high incidence of severe hypotension and anuria. Such a different toxicity probably is related to the diverse treatment schedule. In the original series, in fact, very high doses of m-2 were given as bolus therapy’,*; in contrast, we used the West schedule, which consists of a continuous intravenous infusion of

32 MEMOLI ET AL

lower doses of rIL-2, which are similarly effec- tive but which have less toxic effects.22*23

In contrast to the present results, Mercatello and colleagues recently suggested that vasocon- strictor agents may be useful in this clinical con- dition.27V28 These investigators demonstrated preservation of renal plasma flow and a solitary decrease in GFR in rIL-2-treated patients; they therefore concluded that the isolated reduction in GFR presumably was due to a greater decrease in efferent than in afferent arteriole resistance.** However, the patients in that study were given oral misoprostol (200 mg every 8 hours), which is a potent renal vasodilator,2gV30 as prophylaxis against gastrointestinal bleeding; therefore, it is conceivable that the prostaglandin analogue actu- ally may have blunted the rIL-2 effects on renal plasma flow.

In conclusion, our data suggest that rIL-2- induced ARF is due to renal hypoperfusion mainly caused by decreasing oncotic pressure. It is important to note that low-dose dopamine infusion is demonstrated to reverse this form of renal impairment; such a therapeutic approach, while reducing recovery time, avoids dose reduc- tion or discontinuation of IL-2 therapy.

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