Scand J Urol Nephrol26: 387-391, 1992

DECREASE IN RENAL FUNCTION FOLLOWING DECREASED FIBRINOGEN AND RAISED FIBRIN DEGRADATION PRODUCTS IN LUPUS

NEPHRITIS WITH NEPHROTIC SYNDROME

Yoichi Nagayama,' Hiroo Imura,' and Rie Muso'

From the '2nd Department and 23rd Department of internal Medicine, Kyoto University Hospital, Japan

(Submitted June 28, 1991. Accepted for publication December 20, 1991)

Abstract. To clarify the relationship between renal function and laboratory indicators of abnormal blood coagulation in lupus nephritis with nephrotic syn- drome, we studied 28 patients with this disease over the 11 years. Follow-up tests included serial determi- nation of plasma fibrinogen, serum fibrin degrada- tion products (FDP), serum creatinine and endo- genous creatinine clearance (Ccr) as well as other parameters. Either decreased fibrinogen, elevated FDP, or both were found in 13 cases. Taking as a criterion of decreased renal function an increase in serum creatinine above 0.2 mg/100 ml combined with a decrease in Ccr by more than 30% below the imme- diately preceding values, 11 of the above 13 patients showed a marked deterioration in renal function con- currently or within two weeks after the episodes of clotting disorder. Two other patients showed a less marked decrease in renal function. The 15 patients whose circulating fibrinogen and FDP remained nor- mal did not show deterioration in renal function. The difference in renal function decrease between the groups with and without abnormal hemocoagulation indicators is significant. Our preliminary results indi- cate that when fibrinogen and FDP indicate intravas- cular hypercoagulation deterioration in renal func- tion in patients with lupus nephritis is probable. Key words: lupus nephritis, nephrotic syndrome, plas- ma fibrinogen, serum fibrin degradation products, serum creatinine, endogenous creatinine clearance.

In patients with lupus nephritis or glomerulone- phritis (GN), the disease activity can be esti- mated roughly by histologic and histochemical studies on glomerular changes ( 14-1 6 ) com- bined with immunologic and serologic tests. Nevertheless, these methods for evaluating GN have certain limitations, since numerous fac- tors other than those described above may in- fluence glomerular lesions (1, 5).

Recently, several authors have reported that coagulation disorders are important in mediat-

ing glomerular injury in patients with lupus ne- phritis. These reports are based on direct or indirect observations that intraglomerular thrombosis and intrarenal platelet consumption contribute to glomerular sclerosis and to the progression of renal disease in many of these patients (2, 7, 11). Although the pathophysiolo- gy of intravascular coagulation has not been completely elucidated, it is clear that factors related to normal hemostasis are involved (19). Fibrinogen, other coagulation factors and plate- lets are consumed immediately after thrombo- sis develops. The fibrinolytic enzyme system is activated, and large amounts of fibrin-fibrino- gen degradation products (FDP) are produced (18).

To identify biochemical laboratory parame- ters that might predict glomerular damage and hence deteriorating renal function, we meas- ured circulating fibrinogen and FDP.

MATERIALS AND METHODS Patients We studied 28 patients (2 males and 26 females, aged 13 to 58 years, mean age 31 years, Table I ) with lupus nephritis who had proteinuria of more than 0.5 g/day. Renal biopsy was performed on all patients as part of the diagnostic evaluation at the beginning of the in- vestigation. All cases were positive for a minimum of four criteria for the diagnosis of systemic lupus ery- thematosus (SLE), as established by American Rheu- matism Association ( 1 7). These cases were followed from February 1976 through December 1989 (a mean period of 87 months).

Renal biopsy The biopsy specimens were fixed with neutral buff- ered formalin and processed to produce sections 3 Fm thick. The sections were stained with hematoxylin-

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388 Y. Nagayama et al.

Table I . ProJile of patients

Age (year) Renal histology"

11- 21- 31- 41- 51- - Class Class Class Class 20 30 40 50 60 F M IIB 111 IV V

Sex

Patient with decreased plasma fibrinogen and/or raised serum FDP 1 2 8 2 0 I1 2 3 2 6 2

Patient with normal plasma fibrinogen and serum FDP 1 8 4 1 1 15 0 6 2 2 5

World Health Organization classification of morphologic patterns of lupus nephritis is applied. Direct immunofluorescent antibody method was used to test fibrinogen deposition.

eosin and periodic acid-Shiff. The glomerular lesions were classified according to the World Health Organi- zation (WHO) (15). Another portion of the specimen was frozen and cut into 3 pm sections. These sections were stained directly with fluorescent monospecific antibodies to fibrinogen, immunoglobulins, and com- plement components (Zymed Lab., Burlingame, CA, USA), and examined with a fluorescence microscope (Nikon, Japan). The intensity of deposits in the glo- merulus was graded from 0 to 3 + . Laboratory testing Plasma fibrinogen levels were measured by the meth- od of Grannis (8), and values less than 205 mg/dl were considered depressed. Serum FDP titers were ana- lyzed by the method of Carvalho et al. (4), and were considered elevated when greater than 10 pg/ml. Platelet counts were determined using a Coulter counter (3). The normal platelet range was 130 to 4 0 0 x 109/l. Titers of serum and urinary creatinine and other biomolecules were determined using a Technicon SMAC biochemical analyzer (9). Endo- genous creatinine clearance (Ccr) was calculated on a 48 hour urine sample by the method of Hyde et al. (LO). The normal range of serum creatinine is 0.6 to 1.3 mg/100 ml, and that of Ccr over 70 mllmin. We considered renal function to have decreased if serum creatinine rose by more than 0.2 mgldl in a 2-week period, and if Ccr decreased simultaneously by more than 30% compared to the immediately preceding values.

Determinations were usually performed weekly while the patient was in the hospital, and monthly thereafter. In seriously ill patients the determinations were made every other day, yielding at least 26 deter- minations.

RESULTS Renal histology According to the WHO classification of glomer- ular histology, the 28 renal specimens that we

Scand J Urol Nephrol26

obtained at biopsy included 9 class IIB, 4 class 111, 8 class IV, and 7 class V (Table I). These classes correspond respectively to predomi- nantly mesangial hypercellularity, focal and segmental proliferative GN, diffuse prolifera- tive GN, and membranous GN. Deposition of fibrinogen in the glomerulus to a degree of 2 to 2 + , was observed in 18 of the 28 cases (Table I), and no fibrinogen deposition was observed in the other 10 cases. Microthrombi were not detected in the glomeruli in any patient.

Laboratory indicators of blood clotting Either a decrease in fibrinogen titer, an increase in FDP, or both were found in at least two determinations in 13 of the 28 patients studied (case 1-13, Table 11). Four of these patients (cases 1-4) had both a decrease in fibrinogen and an increase in FDP. All 13 also had one to five episodes of abnormal blood clotting, as defined above; the total number of episodes in the 13 cases was 26 (Table 11, Fig. 1). The epi- sodes of abnormal clotting varied in duration, in the degree of abnormality, in the combina- tion of parameters (fibrinogen and/or FDP) that were abnormal, and in the interval from renal biopsy. Serial liver function tests showed that these decrease in circulating fibrinogen were not due to impaired synthesis of the com- pound in the liver.

Reduction in renal function In relation to the 26 episodes of decreased fi- brinogen and/or raised FDP that we found in 13 cases, a clear decrease in renal function (as de-

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Renal function and clotting disorders 389

Deposition of fibrinogenb in glomerulus

1 2 1 6 2 1

9 3 0 2 1 0

fined above) was detected within two weeks in 17 episodes in 1 1 cases (Table 11). Six other episodes were followed by less severe reduction in renal function; the three remaining episodes

resulted in no detectable decrease in renal func- tion. In the 1 1 cases in which renal function decreased severely after abnormal blood clot- ting episodes, the maximum increase in creati- nine values were 0.2 to 4.8 mg/l00 ml (mean 1 . 1 9 mg/ 100 ml) and the levels of Ccr decreased by 30% to 82Y0, (mean 50.8 Yo) compared to the preceding levels (Table 11). Fig. 1 shows the changes of serum creatinine values and Ccr in relation to treatment and to the laboratory find- ings. In the remaining two cases of the 13 with decreased fibrinogen and/or raised FDP, serum creatinine rose by 0.2 mg/dl but Ccr decreased by 26 O/O and I6 %.

In 15 cases that showed neither a decrease in fibrinogen nor an increase in FDP, neither an increase in serum creatinine above 0.2 mg/dl nor a decrease in Ccr by more than 29% com- pared with the preceding levels was found in

Table 11. Episodes of abnormal clotting indicators in clinical course FDP = fibrin degradation products, Ccr=endogenous creatinine clearance, N = normal value

Decrease in renal No. of Abnormal data Time of function at episode episodes episode

Case Age of abnormal Fibrinogen FDP (week after) Creatinine Ccr no. Sex data (mg1100 ml) (pg/ml) (renal biopsy) (mg/100 ml) (Yo)

I 40 F

2 35 M

3 31F

4 37 F

5 34 F

6 21 F

7 35 F 8 19 F 9 24 F

10 40 F I 1 32 M 12 43 F 13 41 F

3

4

5

3

2

2

1 1 1 1 1 1 1

162-190 155-1 90 165-185 N 157 187 124-199 I90 I20 N 150 107-199 N 131-195 197 1 5 1-1 96 188 166-1 86 161-177 176-185 177-188 143-186 187-1 90 N N N

N 18-19 12-336 13-5 1 N N 22-1 10 N N 12-56 15 N 12-25 N N N N N N N N N N 16-33 18-30 15-3 I

1 6

13 1 7

12 14 3 6 9

25 27

2 15 29 2

I 1 8

17 18 5

19 7

27 12 3

+2.5 +0.6 +4.6 +0.6 + 0.4 + 2.2 f 4 . 8 +0.2 +0.7 +0.2 + 0.4 +0.6 ? O + 0.2 +0.1 +0.5 ? O 20 +0.3 +0.2 f0.2 f0.2 +0.2 + 1.0 + 0.4 +0.2

- 82 - 30 - 59 -41 - 28 - 65 - 62 - 20 - 55 - 37 -25 - 59 - 43 - 26 -25 - 48 ? O ? O - 46 - 48 - 30 - 16 -31 - 68 -41 -41

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390 Y, Nagayama et al.

0 1 2 3 4 5 6 1 Fig. 1. Clinical course of case 3 (31 year old woman). Laboratory data of anti-DNA antibody (D---4), he- molytic activity of complement (CH50, n-. -n), serum creatinine (G-G), endogenous creatinine clearance (Ccr, U), plasma fibrinogen (A---A), serum fibrin-fibrinogen degradation products (FDP,

any case in any of the fortnightly determina- tions.

DISCUSSION Glomerular deposition of fibrinogen in lupus nephritis is reported to correlate with the clini- cal manifestations and chronicity of the disease ( 1 3). On the other hand, it has been stated that serum and urinary FDP concentrations are con- sistently elevated in active forms of GN (6, 12). In our patients, renal function (as defined above) was decreased in 11 of the 13 patients who had decreased fibrinogen and/or raised FDP. In contrast, there was no decrease in renal

8 9 10 11 12 13 14 15 week A- - -A), and platelet count (-) are shown in relation to the doses of prednisolone. The patient received only prednisolone at this period. Arrow in the figure indicates point of decreased fibrinogen an- d/or raised FDP.

function in the 15 patients with normal fibrino- gen and FDP levels. The difference in renal function between the two groups is significant (x2=20.9, p<O.OOl). Our results therefore indi- cate that when both fibrinogen (an index of hemostasis) and FDP (an index of blood coagu- lation) point to intravascular hypercoagulation, in a patient with lupus nephritis and nephrotic syndrome, there is a strong chance that renal function is reduced. The glomerular deposition of fibrinogen that we found at renal biopsy in almost all (12 of 13) of our patients with de- creased fibrinogen and/or raised FDP suggests the presence of intraglomerular thrombosis in such cases.

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Renal function and clotting disorders 391

Active thrombosis may cause an elevation in the serum FDP titers (19). Seven of our patients had elevated serum FDP with or without de- creased fibrinogen. All 7 also had reduced renal function, whereas only 5 of the 21 patients with normal circulating FDP had reduced renal function ( 9 2 1 =23.8%). T h e difference is sig- nificant (x2= 12.4, p<O.OOl). Elevated serum FDP therefore apparently is another useful lab- oratory parameter for predicting deterioration of renal function in patients with lupus nephri- tis with nephrotic syndrome.

It is reported that in many cases of diffuse proliferative G N , glomerular thrombosis devel- ops (2, 11) and platelet consumption is in- creased (7). Of our eight patients with class IV lupus nephritis (predominantly diffuse prolif- erative glomerular lesions), six (75 O/o) had de- creased fibrinogen and/or raised FDP. In the 20 patients with lupus of class IIB, I11 or V (i.e., predominantly mesangial hypercellularity, fo- cal and segmental proliferative G N , and mem- branous GN, respectively) 7 (35%) had abnor- mal coagulation parameters. Patients with dif- fuse proliferative GN thus seems more prone to intravascular hypercoagulability than patients with other histologic types of G N .

ACKNOWLEDGEMENTS We are grateful to Boldface Editors Inc. for assistance in preparation of the manuscript.

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