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Transient renal failure following intravenous methylprednisolone pulse therapy
CURRENT THERAPEUTIC RESEARCH VOL. 52, NO. 2, AUGUST1992
TRANSIENT RENAL FAILURE FOLLOWING INTRAVENOUS METHYLPREDNISOLONE PULSE THERAPY TAKANOBU SAKEMI, 1 SHOUICHI FUJIMOTO,2 SATORU FUJIMI,3 YOSHITAKA YAMAMOTO,2 TANENAO ETOH, 2 AND MASAYA YAMAGUCHI 1
~Department of Internal Medicine, Saga Medical School, Saga, 2First Department of Internal Medicine, Miyazaki Medical College, Miyazaki, and 3Kidney Center, Fukuoka Red Cross Hospital, Fukuoka, Japan
ABSTRACT The effect of i n t r a v e n o u s methylprednisolone (MP) pulse t h e r a p y o n r e n a l f u n c t i o n was studied i n 56 patients with r e n a l or collagen disease. We e x a m i n e d the correlation between the changes in serum crea t i n i n e , body weight, and u r i n a r y volume before a n d after pulse therapy a n d such other p a r a m e t e r s as s e r u m c r e a t i n i n e , total protein, a l b u m i n , a n d u r i n a r y sodium excretion. There was a significant corr e l a t i o n between the change in serum c r e a t i n i n e versus the change i n body weight (r = .648, P < 0.001), u r i n a r y volume (r -- -.557, P < 0.001), s e r u m c r e a t i n i n e (r -- .756, P < 0.001), s e r u m a l b u m i n (r --.421, P < 0.005), a n d u r i n a r y sodium (r = -.391, P < 0.05). We defined as deteriorated seven patients whose serum c r e a t i n i n e level rose more t h a n 0.5 mg/dl from baseline, 1.06 mg/dl on the average, after pulse therapy. I n two of the patients, the rise in s e r u m c r e a t i n i n e level was acutely reversed by i n d u c i n g diuresis by a d m i n i s t e r i n g a l b u m i n and furosemide. I n the other five, the s e r u m c r e a t i n i n e level fell spont a n e o u s l y to baseline level on d i s c o n t i n u a n c e of t r e a t m e n t . The deteriorated p a t i e n t s had more severe nephrosis a n d r e n a l i m p a i r m e n t versus the n o n d e t e r i o r a t e d patients. The findings indicate t h a t (1) the effect of MP pulse t h e r a p y on r e n a l f u n c t i o n depends o n the p a t i e n t ' s clinical state; a n d (2) the deterioration in r e n a l f u n c t i o n following such t h e r a p y m a y be more m a r k e d in those with more severe nephrosis a n d r e n a l f u n c t i o n a l i m p a i r m e n t at the outset. A n increase in sodium and water r e t e n t i o n d u r i n g MP therapy and associated r e n a l interstitial edema, which is proposed as a m e c h a n i s m for acute r e n a l failure in p a t i e n t s with m i n i m a l change nephrotic syndrome, m a y be responsible for the t r a n s i e n t r e n a l failure induced by M P therapy. INTRODUCTION
Intravenous methylprednisolone (MP) pulse therapy has been administered to treat various kidney diseases. Serious side effects during and after MP pulse therapy include cardiac arrythmias, 1-4 anaphylactoid reacAddress correspondence and reprint requests to: Takanobu Sakemi, Department of Internal Medicine, Saga Medical School, Nabeshima,Saga 849, Japan. Receivedfor publication on April 13, 1992. Printed in the U.S.A. Reproductionin whole or part is not permitted. 254
0011-393X/92/$3.50
T. SAKEMI ET AL.
tions, 5-7 and arterial thrombosis, s We previously reported the developm e n t of transient renal failure following MP pulse therapy. 9 Such renal deterioration was more m a r k e d in patients with initially more severe nephrosis and impairment of renal function. We speculated t h a t an increase in sodium and water retention was perhaps responsible. To investigate the relationship between MP therapy and changes in urinary sodium excretion, renal function, and other factors during treatment, we evaluated data on patients treated with MP. PATIENTS AND METHODS
Of a total of 77 patients with renal or collagen disease who had received MP pulse therapy at our hospitals between 1981 and 1990, data were analyzed on 56 (Table I). Their diagnoses included idiopathic nephrotic syndrome (34), systemic lupus erythematosus (SLE)(15), purpura nephritis (3), polyarteritis nodosa (PN)(2), and rapidly progressive glomerulonephritis (RPGN)(2). Three patients received two courses of MP pulse therapy and two patients received three courses. Thus a total of 63 (56 + 3 x 1 + 2 x 2) patients made up the study cohort. Renal biopsy was performed in 43 of the 56 patients; their renal pathology is summarized in Table I. Fifteen patients in whom serial data of urinary and serum sodium and creatinine were available comprised a subgroup for the analysis of daily Table I. Characteristics of 56 patients. No. of patients Age (yr) Male/female Laboratory data S-Cr (mg/dl) TP (gm/dl) Albumin (gm/dl) Urinary protein (gin/day) Renal pathology Idiopathic nephrotic syndrome MCN MGN MesPGN FGS No biopsy SLE DPLN No biopsy Purpura nephritis Polyarteritis nodosa Crescentic GN
56 35.5 -4- 16.4 33/23 1.25 _+ 0.86 5.1 _+ 1.1 2.7 __ 0.7 6.9 -- 8.4 16 7 4 3 4 6 9 3 2 2
S-Cr = serum creatinine; TP = serum total protein; MCN = minimal change nephrotic syndrome; MGN = membranous glomerulonephropathy; MesPGN = mesangial proliferative glomerulonephritis; FGS = focal glomerulosclerosis; DPLN = diffuse proliferative lupus nephritis; GN = glomerulonephritis.
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changes in creatinine clearance (Ccr), urinary sodium (UNa), and the fractional excretion of sodium (FENa) following pulse therapy. We arbitrarily classified seven patients as "deteriorated" based on an increase in serum creatinine levels to more than 0.5 mg/dl from baseline following the pulse therapy. In general, we administered an oral prednisolone regimen in treating nephrotic patients with a minimal change lesion and lupus nephritis. Most of the idiopathic nephrotic patients having focal glomerulosclerosis, mesangial proliferative glomerulonephritis, or membranous nephropathy also received at least one course of conventional oral prednisolone therapy in the hope of inducing a remission. Furthermore, MP pulse therapy was administered to patients with the following characteristics: (1) active primary disease, (2) disease relapse with minimal change lesion, and (3) possible resistance to oral corticosteroid therapy because of poor absorption due to severe intestinal edema. Of the 21 patients excluded from analysis, three with PN and one with idiopathic RPGN developed progressive end stage renal failure and finally underwent dialysis treatment; seven having SLE and ten with idiopathic nephrotic syndrome had insufficient data for analysis. All patients received three consecutive-day pulses of i gm of MP in 500 ml of 5% dextrose infused over 60 minutes. Any patient who had received a diuretic or albumin or other medication during the course of MP therapy that could itself decrease renal function, were excluded from analysis. Throughout the study, patients received a diet containing a fixed level of sodium. Measurements of body weight (BW), serum creatinine (S-Cr), and sodium (S-Na) obtained on day 0 (first day of pulse therapy) served as pretherapy values, while those obtained on day 3 (fourth day of study) served as the posttherapy values. Urinary volume (UV) was measured daily for at least three days before and during pulse therapy. In ten patients with normal levels of S-Cr, we substituted the S-Cr values measured in the last week before pulse therapy as the control. Values of S-Cr and S-Na obtained on day 2 (third day of pulse therapy) in four cases and on day 4 in three cases were used as posttherapy values. Data on S-Cr and S-Na obtained after day 4 were excluded from analysis. Data on certain patients in whom the urinary sodium and/or creatinine concentration was monitored daily before and during pulse therapy were examined to analyze the daily changes in Ccr, UNa, and/or FENa. In 63 patients, we evaluated values of BW (52 patients), UV (52 patients), S-Cr (52 patients), and/or S-Na (42 patients) before and after pulse therapy. Values are expressed as the mean -+ SD. Unpaired and paired t tests were used for comparison of means, with P < 0.05 accepted as statistically significant.
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RESULTS
Table II shows the changes in serial Ccr, UNa, and F E N a before and during pulse therapy in 15 patients. In this subgroup, there was no significant change in Ccr following pulse therapy. U N a and F E N a decreased following pulse therapy, with the greatest reduction seen on day 1 (second day of pulse) from 103.5 +- 51.8 mEq/day to 42.3 +- 23.4 mEq/day, and from 0.59 -+ 0.31% to 0.27 -+ 0.14%, respectively (n = 15, paired t test). On day 3, U N a and F E N a returned to baseline levels (94.5 +- 82.5 mEq/L and 0.70 + 0.36%, respectively). In this subgroup, mean laboratory data before pulse therapy were as follows: total protein (TP) 5.5 +- 1.0 gm/dl, albumin 2.9 + 0.6 gm/dl, and S-Cr 1.00 -+ 0.3 mg/dl. Values for BW, S-Na, and S-Cr did not change significantly following pulse therapy (data not shown), but UV increased significantly from 3,905 -- 1,030 ml/72 hr to 4,704 -+ 1,297 ml/72 hr (P < 0.005). There was no significant correlation between the change in AS-Cr versus the change in ABW, AUV, UNa, TP, albumin, and S-Cr. Mean values of BW, UV, S-Cr, and S-Na before and after pulse therapy appear in Table III. BW did not significantly change after pulse therapy. However, both the UV (n = 52) and S-Cr (n = 52) increased significantly from 4,026 - 1,523 ml/72 hr to 4,456 -+ 1,641 ml/72 hr and from 1.25 +- 0.92 mg/dl to 1.42 -+ 1.31 mg/dl, respectively; S-Na (n = 45) decreased significantly from 140.4 -+ 2.8 mEq/L to 138.7 -+ 3.6 mEq/L. The correlation between AS-Cr and other laboratory parameters appears in Table IV. There were significant correlations between AS-Cr versus the change in ABW, AUV, S-Cr serum albumin, and day 1-UNa. For example, a significant correlation was observed between hS-Cr and ABW (r = .648, P < 0.001, Figure 1). There was a significant inverse correlation between S-Cr and AUV(r = - . 5 5 7 , P < 0.001, Figure 2) and between the change in AS-Cr and albumin (r = - .421, P < 0.005, Figure 3). There was a significant correlation between AS-Cr and S-Cr (r = .756, P < 0.001). Significant correlations between U N a on day 1 versus AS-Cr (r = -.391, P < 0.05), BW (r = - . 6 0 2 , P < 0.001), and albumin (r = .332, P < 0.05) were observed.
Table II. Creatinine clearance (Ccr), u r i n a r y sodium (UNa), and fractional excretion of sodium (FENa) before and after pulse therapy (n = 15).
Ccr (ml/ml) UNa (mEq/day) FENa (%)
Day -1
Day 0
Day I
Day 2
79.1 +- 36.0 103.5 -+ 51.8 0.59 -+ 0.31
78.4 + 39.4 86.4 + 51.5t 0.50 -+ 0.31
77.0 +- 40.0 42.3 - 23.4* 0.27 -+ 0.14"
73.1 +- 34.1 57.1 -+ 36.6* 0.38 - 0.19~
* P < 0.005; tP < 0.05: significant vs day - 1.
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Table III. Bodyweight (BW), 72 hr-urine volume (72 hr-UV), serum creatinine (S-Cr), and serum sodium (S-Na) before and after pulse therapy. Before BW (kg) (n = 52) 72 hr-UV (ml) (n = 52) S-Cr (mg/dl) (n = 52) S-Na (mEq/L) (n = 45)
57.8 4,026 1.25 140.4
-+ 9.2 _+ 1,523 +_ 0.92 _+ 2.8
After 58.1 4,456 1.42 138.7
Change
-+ 9.2 _+ 1,641 _+ 1.31 _+ 3.6
0.3 429 0.17 -1.7
-+ 1.2 -+ 942 -+ 0.47 - 3.1
P value NS <0.005 <0.05 <0.005
NS = not significant.
Clinical details of the patients whose renal functions worsened after pulse therapy are shown in Table V. The m e a n serum creatinine level did not change significantly the week before pulse therapy (2.47 -+ 1.25 mg/dl versus 2.82 -+ 1.54 mg/dl), but increased significantly after three days of pulse therapy (2.82 -+ 1.54 mg/dl versus 3.88 -+ 2.17 mg/dl, P < 0.01) (Figure 4). BW increased significantly from 56.5 -+ 6.4 kg to 58.3 -+ 5.9 kg after pulse therapy (P < 0.01). The 72 hr-UV did not change significantly after pulse therapy, although it showed a tendency to decrease from 3,457 - 1,962 ml to 3,050 -+ 1,915 ml. In two patients (cases 41 and 42), a worsening of renal function as reflected by S-Cr levels was reversed by inducing forced diuresis by administering albumin (12.5 to 25 gm/day) and furosemide (up to 200 mg/day). These two patients have been described in detail in a previous report. 9 In the other five patients with deteriorated renal function, S-Cr returned spontaneously to baseline level by about day 10, as shown in Figure 4. Mean values of serum albumin and S-Cr in the 54 patients whose renal function did not deteriorate were 2.8 -+ 0.6 gm/dl and 1.06 -+ 0.47 mg/dl, respectively. Comparing the seven deteriorated with the 54 nondeteriorated patients, those who deteriorated showed a more severe hypoalbuminemia (2.0 + 0.4 gm/dl versus 2.8 -+ 0.6 gm/dl, P < 0.01) and a greater
Table IV. Correlationbetween Aserum creatinine (hS-Cr) and other factors.
AS-Cr vS: ABW AUV S-Cr Albumin Day 1-UNa Day 1-UNa vs: ABW Albumin
Coefficient of Correlation
P value
No. of Patients
0.648 - 0.557 0.756 - 0.421 0.391
<0.001 <0.001 <0.001 <0.005 <0.05
46 41 52 52 36
- 0.602 0.322
<0.001 <0.05
32 39
BW = body weight; UV = urinary volume; UNa = urinary sodium.
258
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impairment of S-Cr levels (2.82 -+ 1.54 mg/dl versus 1.06 + 0.47 mg/dl, P < 0.001, unpaired t test) as compared with the nondeteriorated patients. DISCUSSION
Of the 63 patients who received intravenous MP pulse therapy, seven were 3
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defined as having deteriorated on the basis of transient renal failure, showing an increase from baseline of more than 0.5 mg/dl in the serum creatinine level after treatment. There was a close association between MP therapy and the development of transient renal failure. Figure 4 shows the steep rise in serum creatinine levels following pulse therapy as compared with only a constant or gradual increase the week before pulse therapy. In two patients, the transient renal failure was rapidly reversed by administering albumin-furosemide. In the remaining five patients, the serum creatinine spontaneously returned to baseline. It is likely that the reversal of renal failure resulted from discontinuation of MP and/or t r e a t m e n t with albumin and furosemide rather than from the acute suppressive effect of MP on the disease itself. The direct effect of MP on renal function remains controversial, with a marked increase in glomerular filtration by MP being reported in some cases 1°'11 and the suppression of kidney function in others, z2 Our study shows that the effect of MP on renal function depends on the patient's initial clinical state. In the first 15 patients, mean values for BW, S-Cr, and Ccr did not change significantly after intravenous MP pulse therapy and there was no significant correlation between AS-Cr and other factors. However, in the total 63 patients including the first 15 patients, mean values for 72 hr-UV, S-Cr, and S-Na changed significantly after pulse therapy. The increase in UV and the decrease in S-Na appear to be due to the intravenous administration of 5% dextrose 500 ml during pulse therapy. The evidence that the change in S-Cr following pulse therapy is cor260
T. S A K E M I E T AL.
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related significantly with the value of both S-Cr and albumin indicates that the more severely nephrotic patients with a greater impairment of renal function tended to develop transient renal failure. This suggests that their nephrotic state m a y have contributed to the transient renal failure. Lowenstein and coworkers 13 reported the development of acute renal failure in patients with severe nephrotic syndrome associated with profound hypoalbuminemia averaging 1.5 gm/dl. In our seven patients who were classified as "deteriorated," marked hypoalbuminemia was characteristic; there was a significant correlation between renal deterioration and serum albumin level. There are clinical similarities between the renal failure seen in patients with severe nephrosis and the transient renal failure seen in our cases. In each case, acute renal failure occurred in the presence of severe nephrosis with clinical and laboratory evidence of an increased retention of water and sodium, as shown in Table V. In a previous report, 9 we speculated that the increase in sodium and water retention caused by the effect of a mineralocorticoid on the renal tubules to increase sodium reabsorption 14 may have been responsible for the transient renal failure observed following MP pulse therapy. In this study, we documented that both U N a and F E N a decreased following such pulse therapy even when the Ccr did not decline and that values returned to baseline following completion of pulse therapy (Table II). This indicates that the suppression of U N a is probably due to the mineralocorticoid effect of MP rather than to a reduction of glomerular filtration. There was a significant correlation between the suppression U N a (day 1-UNa) and ASCr. Moreover, the development of transient renal failure was correlated 262
T. SAKEMIET AL.
with a reduction in urine volume and a gain in body weight (Figures i and 2). This weight gain was well correlated with a reduction in urinary sodium excretion (Table IV). Such sodium and water retention was more marked in the hypoalbuminemic patients, evidenced by the finding of a significant correlation between the reduction in urinary sodium excretion (day 1-UNa) and serum albumin (Table IV). These findings suggest that a preexisting edematous state in nephrotic patients may be aggravated by the sodium and water retention resulting from the mineralocorticoid activity of MP. A worsening of the edema then induces transient renal failure, probably by triggering the same mechanisms of acute renal failure as seen in nephrosis. A renal factor other than the glomerular damage associated with the disease itself may have contributed to the deterioration of renal function during pulse therapy. Lowenstein and colleagues13 postulated that renal failure in the minimal change nephrotic syndrome may be due to a reversible alteration in glomerular hemodynamics related to fluid retention and an associated renal interstitial edema. The evidence that MP may induce transient renal failure in nephrotic patients indicates that renal interstitial edema may also be responsible for the deterioration of renal function following MP pulse therapy. In patients with normal kidney function, a transient reduction in glomerular filtration 12 and a suppression of urinary sodium excretion14 have been reported following pulse therapy. Although a suppressive effect of MP on urinary sodium excretion was observed in the patients with normal kidney function studied, the effect of MP on renal function appeared to be minimal even in patients who were nephrotic. Our study indicates that effects of MP on renal function and sodium retention probably depend on the patient's initial clinical status, including the severity of edema and impairment of renal function. The adverse effects of MP may be more pronounced in nephrotic patients having more severely impaired renal function at the outset of pulse therapy. References: 1. McDougal BA, Whittier FC, Cross DE. Sudden death after bolus steroid therapy for acute rejection. Transplant Proc 1976; 3:493. 2. Bocanegra TS, Castaneda MO, Espinoza LR, et al. Sudden death after methylprednisolone pulse therapy. Ann Intern Med 1981; 95:122. 3. Moses RE, McCormick A, Nickey W. Fatal arrhythmia after pulse methylprednisolone therapy. Ann Intern Med 1981; 95:781. 4. Fujimoto S, Kondoh H, Yamamoto Y, et al. Holter electrocardiogram monitoring in nephrotic patients during methylprednisolonepulse therapy. Am JNephro11990; 10:231. 5. Freedman MD, Schocket A, Chapel N, et al. Anaphylaxis after intravenous methylprednisolone administration. JAMA 1981; 245:607. 6. Rao KV, Andersen RC, O'Brien TJ. Successful renal transplantation in a patient with 263
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anaphylactic reaction to Solu-Medrol (methylprednisolone sodium succinate). A m J Med 1982; 72:161. 7. Thompson JF, Chalmeers DHK, Wood RFM, et al. Sudden death following high-dose intravenous methylprednisolone. Transplantation 1983; 36:594. 8. Murnaghan K, Vasmant D, Bensman A. Pulse methylprednisolone therapy in severe idiopathic childhood nephrotic syndrome. Acta Paediatr Scand 1984; 73:733. 9. Sakemi T, Yamaguchi M, Fujimi S, et al. Effects of the methylprednisolone pulse therapy on renal function. A m J Nephrol 1991; 11:48. 10. Baylis C, Brenner BM. Mechanism of the glucocorticoid-induced increase in glomerular filtration rate. A m J Physiol 1978; 234:F166. 11. deBermudez L, Hayslett JP. Effect of methylprednisolone on renal function and the zonal distribution of blood flow in the rat. Circ Res 1972; 31:44. 12. Popovtzer MM, Pinggera WF, Robinette J, et al. Acute renal response to large doses of intravenous prednisolone in kidney homograft recipients and in normal subjects. J Lab Clin Med 1971; 78:39. 13. Lowenstein J, Schacht RG, Baldwin DS. Renal failure in minimal change nephrotic syndrome. A m J Med 1981; 70:227. 14. Waller DG, Barrett DF, Polak A. Methylprednisolone pulses and urine electrolyte excretion. Arch Int Pharmacodyn 1988; 292:258.
264
TRANSIENT RENAL FAILURE FOLLOWING INTRAVENOUS METHYLPREDNISOLONE PULSE THERAPY TAKANOBU SAKEMI, 1 SHOUICHI FUJIMOTO,2 SATORU FUJIMI,3 YOSHITAKA YAMAMOTO,2 TANENAO ETOH, 2 AND MASAYA YAMAGUCHI 1
~Department of Internal Medicine, Saga Medical School, Saga, 2First Department of Internal Medicine, Miyazaki Medical College, Miyazaki, and 3Kidney Center, Fukuoka Red Cross Hospital, Fukuoka, Japan
ABSTRACT The effect of i n t r a v e n o u s methylprednisolone (MP) pulse t h e r a p y o n r e n a l f u n c t i o n was studied i n 56 patients with r e n a l or collagen disease. We e x a m i n e d the correlation between the changes in serum crea t i n i n e , body weight, and u r i n a r y volume before a n d after pulse therapy a n d such other p a r a m e t e r s as s e r u m c r e a t i n i n e , total protein, a l b u m i n , a n d u r i n a r y sodium excretion. There was a significant corr e l a t i o n between the change in serum c r e a t i n i n e versus the change i n body weight (r = .648, P < 0.001), u r i n a r y volume (r -- -.557, P < 0.001), s e r u m c r e a t i n i n e (r -- .756, P < 0.001), s e r u m a l b u m i n (r --.421, P < 0.005), a n d u r i n a r y sodium (r = -.391, P < 0.05). We defined as deteriorated seven patients whose serum c r e a t i n i n e level rose more t h a n 0.5 mg/dl from baseline, 1.06 mg/dl on the average, after pulse therapy. I n two of the patients, the rise in s e r u m c r e a t i n i n e level was acutely reversed by i n d u c i n g diuresis by a d m i n i s t e r i n g a l b u m i n and furosemide. I n the other five, the s e r u m c r e a t i n i n e level fell spont a n e o u s l y to baseline level on d i s c o n t i n u a n c e of t r e a t m e n t . The deteriorated p a t i e n t s had more severe nephrosis a n d r e n a l i m p a i r m e n t versus the n o n d e t e r i o r a t e d patients. The findings indicate t h a t (1) the effect of MP pulse t h e r a p y on r e n a l f u n c t i o n depends o n the p a t i e n t ' s clinical state; a n d (2) the deterioration in r e n a l f u n c t i o n following such t h e r a p y m a y be more m a r k e d in those with more severe nephrosis a n d r e n a l f u n c t i o n a l i m p a i r m e n t at the outset. A n increase in sodium and water r e t e n t i o n d u r i n g MP therapy and associated r e n a l interstitial edema, which is proposed as a m e c h a n i s m for acute r e n a l failure in p a t i e n t s with m i n i m a l change nephrotic syndrome, m a y be responsible for the t r a n s i e n t r e n a l failure induced by M P therapy. INTRODUCTION
Intravenous methylprednisolone (MP) pulse therapy has been administered to treat various kidney diseases. Serious side effects during and after MP pulse therapy include cardiac arrythmias, 1-4 anaphylactoid reacAddress correspondence and reprint requests to: Takanobu Sakemi, Department of Internal Medicine, Saga Medical School, Nabeshima,Saga 849, Japan. Receivedfor publication on April 13, 1992. Printed in the U.S.A. Reproductionin whole or part is not permitted. 254
0011-393X/92/$3.50
T. SAKEMI ET AL.
tions, 5-7 and arterial thrombosis, s We previously reported the developm e n t of transient renal failure following MP pulse therapy. 9 Such renal deterioration was more m a r k e d in patients with initially more severe nephrosis and impairment of renal function. We speculated t h a t an increase in sodium and water retention was perhaps responsible. To investigate the relationship between MP therapy and changes in urinary sodium excretion, renal function, and other factors during treatment, we evaluated data on patients treated with MP. PATIENTS AND METHODS
Of a total of 77 patients with renal or collagen disease who had received MP pulse therapy at our hospitals between 1981 and 1990, data were analyzed on 56 (Table I). Their diagnoses included idiopathic nephrotic syndrome (34), systemic lupus erythematosus (SLE)(15), purpura nephritis (3), polyarteritis nodosa (PN)(2), and rapidly progressive glomerulonephritis (RPGN)(2). Three patients received two courses of MP pulse therapy and two patients received three courses. Thus a total of 63 (56 + 3 x 1 + 2 x 2) patients made up the study cohort. Renal biopsy was performed in 43 of the 56 patients; their renal pathology is summarized in Table I. Fifteen patients in whom serial data of urinary and serum sodium and creatinine were available comprised a subgroup for the analysis of daily Table I. Characteristics of 56 patients. No. of patients Age (yr) Male/female Laboratory data S-Cr (mg/dl) TP (gm/dl) Albumin (gm/dl) Urinary protein (gin/day) Renal pathology Idiopathic nephrotic syndrome MCN MGN MesPGN FGS No biopsy SLE DPLN No biopsy Purpura nephritis Polyarteritis nodosa Crescentic GN
56 35.5 -4- 16.4 33/23 1.25 _+ 0.86 5.1 _+ 1.1 2.7 __ 0.7 6.9 -- 8.4 16 7 4 3 4 6 9 3 2 2
S-Cr = serum creatinine; TP = serum total protein; MCN = minimal change nephrotic syndrome; MGN = membranous glomerulonephropathy; MesPGN = mesangial proliferative glomerulonephritis; FGS = focal glomerulosclerosis; DPLN = diffuse proliferative lupus nephritis; GN = glomerulonephritis.
255
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changes in creatinine clearance (Ccr), urinary sodium (UNa), and the fractional excretion of sodium (FENa) following pulse therapy. We arbitrarily classified seven patients as "deteriorated" based on an increase in serum creatinine levels to more than 0.5 mg/dl from baseline following the pulse therapy. In general, we administered an oral prednisolone regimen in treating nephrotic patients with a minimal change lesion and lupus nephritis. Most of the idiopathic nephrotic patients having focal glomerulosclerosis, mesangial proliferative glomerulonephritis, or membranous nephropathy also received at least one course of conventional oral prednisolone therapy in the hope of inducing a remission. Furthermore, MP pulse therapy was administered to patients with the following characteristics: (1) active primary disease, (2) disease relapse with minimal change lesion, and (3) possible resistance to oral corticosteroid therapy because of poor absorption due to severe intestinal edema. Of the 21 patients excluded from analysis, three with PN and one with idiopathic RPGN developed progressive end stage renal failure and finally underwent dialysis treatment; seven having SLE and ten with idiopathic nephrotic syndrome had insufficient data for analysis. All patients received three consecutive-day pulses of i gm of MP in 500 ml of 5% dextrose infused over 60 minutes. Any patient who had received a diuretic or albumin or other medication during the course of MP therapy that could itself decrease renal function, were excluded from analysis. Throughout the study, patients received a diet containing a fixed level of sodium. Measurements of body weight (BW), serum creatinine (S-Cr), and sodium (S-Na) obtained on day 0 (first day of pulse therapy) served as pretherapy values, while those obtained on day 3 (fourth day of study) served as the posttherapy values. Urinary volume (UV) was measured daily for at least three days before and during pulse therapy. In ten patients with normal levels of S-Cr, we substituted the S-Cr values measured in the last week before pulse therapy as the control. Values of S-Cr and S-Na obtained on day 2 (third day of pulse therapy) in four cases and on day 4 in three cases were used as posttherapy values. Data on S-Cr and S-Na obtained after day 4 were excluded from analysis. Data on certain patients in whom the urinary sodium and/or creatinine concentration was monitored daily before and during pulse therapy were examined to analyze the daily changes in Ccr, UNa, and/or FENa. In 63 patients, we evaluated values of BW (52 patients), UV (52 patients), S-Cr (52 patients), and/or S-Na (42 patients) before and after pulse therapy. Values are expressed as the mean -+ SD. Unpaired and paired t tests were used for comparison of means, with P < 0.05 accepted as statistically significant.
256
T. SAKEMI ET A L
RESULTS
Table II shows the changes in serial Ccr, UNa, and F E N a before and during pulse therapy in 15 patients. In this subgroup, there was no significant change in Ccr following pulse therapy. U N a and F E N a decreased following pulse therapy, with the greatest reduction seen on day 1 (second day of pulse) from 103.5 +- 51.8 mEq/day to 42.3 +- 23.4 mEq/day, and from 0.59 -+ 0.31% to 0.27 -+ 0.14%, respectively (n = 15, paired t test). On day 3, U N a and F E N a returned to baseline levels (94.5 +- 82.5 mEq/L and 0.70 + 0.36%, respectively). In this subgroup, mean laboratory data before pulse therapy were as follows: total protein (TP) 5.5 +- 1.0 gm/dl, albumin 2.9 + 0.6 gm/dl, and S-Cr 1.00 -+ 0.3 mg/dl. Values for BW, S-Na, and S-Cr did not change significantly following pulse therapy (data not shown), but UV increased significantly from 3,905 -- 1,030 ml/72 hr to 4,704 -+ 1,297 ml/72 hr (P < 0.005). There was no significant correlation between the change in AS-Cr versus the change in ABW, AUV, UNa, TP, albumin, and S-Cr. Mean values of BW, UV, S-Cr, and S-Na before and after pulse therapy appear in Table III. BW did not significantly change after pulse therapy. However, both the UV (n = 52) and S-Cr (n = 52) increased significantly from 4,026 - 1,523 ml/72 hr to 4,456 -+ 1,641 ml/72 hr and from 1.25 +- 0.92 mg/dl to 1.42 -+ 1.31 mg/dl, respectively; S-Na (n = 45) decreased significantly from 140.4 -+ 2.8 mEq/L to 138.7 -+ 3.6 mEq/L. The correlation between AS-Cr and other laboratory parameters appears in Table IV. There were significant correlations between AS-Cr versus the change in ABW, AUV, S-Cr serum albumin, and day 1-UNa. For example, a significant correlation was observed between hS-Cr and ABW (r = .648, P < 0.001, Figure 1). There was a significant inverse correlation between S-Cr and AUV(r = - . 5 5 7 , P < 0.001, Figure 2) and between the change in AS-Cr and albumin (r = - .421, P < 0.005, Figure 3). There was a significant correlation between AS-Cr and S-Cr (r = .756, P < 0.001). Significant correlations between U N a on day 1 versus AS-Cr (r = -.391, P < 0.05), BW (r = - . 6 0 2 , P < 0.001), and albumin (r = .332, P < 0.05) were observed.
Table II. Creatinine clearance (Ccr), u r i n a r y sodium (UNa), and fractional excretion of sodium (FENa) before and after pulse therapy (n = 15).
Ccr (ml/ml) UNa (mEq/day) FENa (%)
Day -1
Day 0
Day I
Day 2
79.1 +- 36.0 103.5 -+ 51.8 0.59 -+ 0.31
78.4 + 39.4 86.4 + 51.5t 0.50 -+ 0.31
77.0 +- 40.0 42.3 - 23.4* 0.27 -+ 0.14"
73.1 +- 34.1 57.1 -+ 36.6* 0.38 - 0.19~
* P < 0.005; tP < 0.05: significant vs day - 1.
257
RENAL FAILURE
Table III. Bodyweight (BW), 72 hr-urine volume (72 hr-UV), serum creatinine (S-Cr), and serum sodium (S-Na) before and after pulse therapy. Before BW (kg) (n = 52) 72 hr-UV (ml) (n = 52) S-Cr (mg/dl) (n = 52) S-Na (mEq/L) (n = 45)
57.8 4,026 1.25 140.4
-+ 9.2 _+ 1,523 +_ 0.92 _+ 2.8
After 58.1 4,456 1.42 138.7
Change
-+ 9.2 _+ 1,641 _+ 1.31 _+ 3.6
0.3 429 0.17 -1.7
-+ 1.2 -+ 942 -+ 0.47 - 3.1
P value NS <0.005 <0.05 <0.005
NS = not significant.
Clinical details of the patients whose renal functions worsened after pulse therapy are shown in Table V. The m e a n serum creatinine level did not change significantly the week before pulse therapy (2.47 -+ 1.25 mg/dl versus 2.82 -+ 1.54 mg/dl), but increased significantly after three days of pulse therapy (2.82 -+ 1.54 mg/dl versus 3.88 -+ 2.17 mg/dl, P < 0.01) (Figure 4). BW increased significantly from 56.5 -+ 6.4 kg to 58.3 -+ 5.9 kg after pulse therapy (P < 0.01). The 72 hr-UV did not change significantly after pulse therapy, although it showed a tendency to decrease from 3,457 - 1,962 ml to 3,050 -+ 1,915 ml. In two patients (cases 41 and 42), a worsening of renal function as reflected by S-Cr levels was reversed by inducing forced diuresis by administering albumin (12.5 to 25 gm/day) and furosemide (up to 200 mg/day). These two patients have been described in detail in a previous report. 9 In the other five patients with deteriorated renal function, S-Cr returned spontaneously to baseline level by about day 10, as shown in Figure 4. Mean values of serum albumin and S-Cr in the 54 patients whose renal function did not deteriorate were 2.8 -+ 0.6 gm/dl and 1.06 -+ 0.47 mg/dl, respectively. Comparing the seven deteriorated with the 54 nondeteriorated patients, those who deteriorated showed a more severe hypoalbuminemia (2.0 + 0.4 gm/dl versus 2.8 -+ 0.6 gm/dl, P < 0.01) and a greater
Table IV. Correlationbetween Aserum creatinine (hS-Cr) and other factors.
AS-Cr vS: ABW AUV S-Cr Albumin Day 1-UNa Day 1-UNa vs: ABW Albumin
Coefficient of Correlation
P value
No. of Patients
0.648 - 0.557 0.756 - 0.421 0.391
<0.001 <0.001 <0.001 <0.005 <0.05
46 41 52 52 36
- 0.602 0.322
<0.001 <0.05
32 39
BW = body weight; UV = urinary volume; UNa = urinary sodium.
258
T. SAKEMIET At.
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impairment of S-Cr levels (2.82 -+ 1.54 mg/dl versus 1.06 + 0.47 mg/dl, P < 0.001, unpaired t test) as compared with the nondeteriorated patients. DISCUSSION
Of the 63 patients who received intravenous MP pulse therapy, seven were 3
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RENAL FAILURE
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defined as having deteriorated on the basis of transient renal failure, showing an increase from baseline of more than 0.5 mg/dl in the serum creatinine level after treatment. There was a close association between MP therapy and the development of transient renal failure. Figure 4 shows the steep rise in serum creatinine levels following pulse therapy as compared with only a constant or gradual increase the week before pulse therapy. In two patients, the transient renal failure was rapidly reversed by administering albumin-furosemide. In the remaining five patients, the serum creatinine spontaneously returned to baseline. It is likely that the reversal of renal failure resulted from discontinuation of MP and/or t r e a t m e n t with albumin and furosemide rather than from the acute suppressive effect of MP on the disease itself. The direct effect of MP on renal function remains controversial, with a marked increase in glomerular filtration by MP being reported in some cases 1°'11 and the suppression of kidney function in others, z2 Our study shows that the effect of MP on renal function depends on the patient's initial clinical state. In the first 15 patients, mean values for BW, S-Cr, and Ccr did not change significantly after intravenous MP pulse therapy and there was no significant correlation between AS-Cr and other factors. However, in the total 63 patients including the first 15 patients, mean values for 72 hr-UV, S-Cr, and S-Na changed significantly after pulse therapy. The increase in UV and the decrease in S-Na appear to be due to the intravenous administration of 5% dextrose 500 ml during pulse therapy. The evidence that the change in S-Cr following pulse therapy is cor260
T. S A K E M I E T AL.
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RENAL
FAILURE
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Figure 4. Time course of serum creatinine levels before and after pulse therapy in the deteriorated group (n = 7).
related significantly with the value of both S-Cr and albumin indicates that the more severely nephrotic patients with a greater impairment of renal function tended to develop transient renal failure. This suggests that their nephrotic state m a y have contributed to the transient renal failure. Lowenstein and coworkers 13 reported the development of acute renal failure in patients with severe nephrotic syndrome associated with profound hypoalbuminemia averaging 1.5 gm/dl. In our seven patients who were classified as "deteriorated," marked hypoalbuminemia was characteristic; there was a significant correlation between renal deterioration and serum albumin level. There are clinical similarities between the renal failure seen in patients with severe nephrosis and the transient renal failure seen in our cases. In each case, acute renal failure occurred in the presence of severe nephrosis with clinical and laboratory evidence of an increased retention of water and sodium, as shown in Table V. In a previous report, 9 we speculated that the increase in sodium and water retention caused by the effect of a mineralocorticoid on the renal tubules to increase sodium reabsorption 14 may have been responsible for the transient renal failure observed following MP pulse therapy. In this study, we documented that both U N a and F E N a decreased following such pulse therapy even when the Ccr did not decline and that values returned to baseline following completion of pulse therapy (Table II). This indicates that the suppression of U N a is probably due to the mineralocorticoid effect of MP rather than to a reduction of glomerular filtration. There was a significant correlation between the suppression U N a (day 1-UNa) and ASCr. Moreover, the development of transient renal failure was correlated 262
T. SAKEMIET AL.
with a reduction in urine volume and a gain in body weight (Figures i and 2). This weight gain was well correlated with a reduction in urinary sodium excretion (Table IV). Such sodium and water retention was more marked in the hypoalbuminemic patients, evidenced by the finding of a significant correlation between the reduction in urinary sodium excretion (day 1-UNa) and serum albumin (Table IV). These findings suggest that a preexisting edematous state in nephrotic patients may be aggravated by the sodium and water retention resulting from the mineralocorticoid activity of MP. A worsening of the edema then induces transient renal failure, probably by triggering the same mechanisms of acute renal failure as seen in nephrosis. A renal factor other than the glomerular damage associated with the disease itself may have contributed to the deterioration of renal function during pulse therapy. Lowenstein and colleagues13 postulated that renal failure in the minimal change nephrotic syndrome may be due to a reversible alteration in glomerular hemodynamics related to fluid retention and an associated renal interstitial edema. The evidence that MP may induce transient renal failure in nephrotic patients indicates that renal interstitial edema may also be responsible for the deterioration of renal function following MP pulse therapy. In patients with normal kidney function, a transient reduction in glomerular filtration 12 and a suppression of urinary sodium excretion14 have been reported following pulse therapy. Although a suppressive effect of MP on urinary sodium excretion was observed in the patients with normal kidney function studied, the effect of MP on renal function appeared to be minimal even in patients who were nephrotic. Our study indicates that effects of MP on renal function and sodium retention probably depend on the patient's initial clinical status, including the severity of edema and impairment of renal function. The adverse effects of MP may be more pronounced in nephrotic patients having more severely impaired renal function at the outset of pulse therapy. References: 1. McDougal BA, Whittier FC, Cross DE. Sudden death after bolus steroid therapy for acute rejection. Transplant Proc 1976; 3:493. 2. Bocanegra TS, Castaneda MO, Espinoza LR, et al. Sudden death after methylprednisolone pulse therapy. Ann Intern Med 1981; 95:122. 3. Moses RE, McCormick A, Nickey W. Fatal arrhythmia after pulse methylprednisolone therapy. Ann Intern Med 1981; 95:781. 4. Fujimoto S, Kondoh H, Yamamoto Y, et al. Holter electrocardiogram monitoring in nephrotic patients during methylprednisolonepulse therapy. Am JNephro11990; 10:231. 5. Freedman MD, Schocket A, Chapel N, et al. Anaphylaxis after intravenous methylprednisolone administration. JAMA 1981; 245:607. 6. Rao KV, Andersen RC, O'Brien TJ. Successful renal transplantation in a patient with 263
RENALFAILURE
anaphylactic reaction to Solu-Medrol (methylprednisolone sodium succinate). A m J Med 1982; 72:161. 7. Thompson JF, Chalmeers DHK, Wood RFM, et al. Sudden death following high-dose intravenous methylprednisolone. Transplantation 1983; 36:594. 8. Murnaghan K, Vasmant D, Bensman A. Pulse methylprednisolone therapy in severe idiopathic childhood nephrotic syndrome. Acta Paediatr Scand 1984; 73:733. 9. Sakemi T, Yamaguchi M, Fujimi S, et al. Effects of the methylprednisolone pulse therapy on renal function. A m J Nephrol 1991; 11:48. 10. Baylis C, Brenner BM. Mechanism of the glucocorticoid-induced increase in glomerular filtration rate. A m J Physiol 1978; 234:F166. 11. deBermudez L, Hayslett JP. Effect of methylprednisolone on renal function and the zonal distribution of blood flow in the rat. Circ Res 1972; 31:44. 12. Popovtzer MM, Pinggera WF, Robinette J, et al. Acute renal response to large doses of intravenous prednisolone in kidney homograft recipients and in normal subjects. J Lab Clin Med 1971; 78:39. 13. Lowenstein J, Schacht RG, Baldwin DS. Renal failure in minimal change nephrotic syndrome. A m J Med 1981; 70:227. 14. Waller DG, Barrett DF, Polak A. Methylprednisolone pulses and urine electrolyte excretion. Arch Int Pharmacodyn 1988; 292:258.
264