Recent Advance in the Treatment of Diabetic Nephropathy: Anticoagulant Therapy

Kazo Kaizu Kohei Uriu Osamu Hashimoto Sumiya Eto

Kidney Center (K K., K. U.) and The First Department of Internal

Medicine, School of Medicine (0. H., S. E.), University of Occupational and Environmental Health, Kitakyushu, Japan

Reprint requests to be sent to: Kazo Kaizu, Kidney Center, University of Occupational and Environmental Health, lseigaoka l-1, Yahatanishi-ku, Kitakyushu-shi, Fukuoka 807, Japan.

0 1991 Elsevier Science Publishing Co., Inc. 0891-6632/91/$3.50

INTRODUCTION

Diabetic nephropathy is one of the common secondary complications of diabetes.’ It has been shown that 40% of patients with insulin-de- pendent diabetes mellitus eventually develop nephropathy with in- creased proteinuria and decreased glomerular filtration rates.’ How- ever, the etiology of diabetic nephropathy and the cause of disease progression have not been well understood.

The aim of this study was to clarify the role of intraglomerular co- agulation and fibrinolysis in the progression of diabetic nephropathy and to examine the efficacy of anticoagulant therapy in patients with diabetic nephropathy.

PATIENTS AND METHODS

Forty-one diabetic patients were divided into two groups. Group I con- sisted of 21 patients with diabetic nephropathy, which was diagnosed by persistent proteinuria. Group II consisted of 20 patients with non- diabetic nephropathy. Although the HbA,, level was higher in group I than in group II, there was no difference in the fasting blood glucose between the two groups.

Heparin therapy was used for 10 patients with diabetic nephropathy who had a marked increase of urinary fibrinopeptide A (FPA), FDP-D, and FDP. Long-acting heparin calcium, 7500 U, was administered sub- cutaneously twice a day for 14 days. Blood and aliquots of 24-hour urine collections at 4°C were obtained 7 days before and 14 days after heparin administration. The renal function was measured before and after ther- apy. In order to examine the presence of intraglomerular coagulation and fibrinolysis, FPA and fibrinopeptide B,15-42 (FPB,l5-42) were mea- sured by radioimmunoassay3,4; FDP, by latex aggregation’; and FDP- E, by latex photometric immunoassay6 in both blood and urine.

RESULTS

Plasma concentrations of FPA and FPB,15-42 were higher in patients with diabetes mellitus than in normal subjects. Although plasma fi- brinogen concentration was significantly higher in group I than in group II, there were no differences in the blood levels of FDP, FPA, and FPB,15-42 between the two groups. Urinary FDP, FPA, and FPBB15-42 levels in group I were much higher than those in group II (Figure 1). Urinary levels of FDP, FPA, FDP-D, and FDP-E in patients with diabetic nephropathy were higher than those of patients with renal diseases. Urinary FPA levels showed a positive correlation to urinary protein lev- els and an inverse correlation to 24-hour creatinine clearance.

Urinary FDP, FPA, and FDP-D levels were measured after heparin was administered to IO patients with diabetic nephropathy. A marked re- duction of urinary FPA and FDP-D levels was observed in association with a reduction in urinary protein levels (Figure 2) and increases in serum albumin levels and total protein concentrations. The renal func- tion, however, did not change at all until 14 days after therapy.

92

ANTICOAGULANTS FOR DIABETIC NEPHROPATHY 93

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DISCUSSION FPA is a small peptide that is cleaved from fibrinogen by thrombin action. The determination of FPA itself indi- cates the presence of coagulation.3 Since FPB,15-42 is a peptide cleaved from fibrin II by plasmin action, FPB,15-42 indicates the presence of fibrinolysis. FDP, FDP-E, and FDP-D indicate the presence of fibrinolysisi fibrinogenolysis.

Although a hypercoagulable state with increased fi- brinolysis exists in diabetic patients,’ we did not find that the degrees of coagulation and fibrinolysis in patients with nephropathy were more prominent than those in pa- tients without nephropathy. However, it is still considered

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FIG. 2 The effects of heparin administration on urinary fibri- nopeptide A (FPA) in patients with diabetic nephropathy.

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FIG. 7 Urinary FDP (U-FDP), fibrinopeptide A (U-FPA), and fibrinopeptide B,15-42 (U-FPB, 75- 42) levels in group I (patients with diabetic ne-

phropathy) and group II (patients with nondi-

abetic nephropathy).

U-FP&l5-42

that the patients with microangiopathy such as nephro- pathy show a more severe hypercoagulable and fibri- nolytic state in circulating blood, since plasma fibrinogen levels are significantly higher.

The measurements of urinary FDP, FDP-D, FDP-E, and FPA could be valuable parameters for determining the presence of intrarenal coagulation and fibrinolysis. The degrees of coagulation and fibrinolysis in glomeruli might occur similarly, since there was a correlation be- tween urinary FPA and urinary FDP-E levels.

lntraglomerular coagulation might be one of the im- portant factors that induce the progression of renal dys- function. Anticoagulant therapy could become effective and probably improve the progression of renal dysfunc- tion in diabetic nephropathy when the patients are se- lected according to the sensitive parameters of coagu- lation and fibrinolysis in urine. This therapy is started early and is continued for several months until the urinary parameters decrease to the normal level.

Anticoagulant therapy by heparin should become a new treatment for patients with diabetic nephropathy in the macroproteinuric phase. It is necessary, however, to examine whether other anticoagulants, such as antiplate- let drugs, have such effects on intraglomerular coagu- lation, since OKY-046, a selective thromboxane AZ syn- thetase inhibitor,* did not show any effects on the inhibition of intraglomerular coagulation.

REFERENCES

Kimmelstiel P, Wilson C: Intercapillary lesions in glomeruli of kidney. Am J Pathol12:83, 1936. Mogensen CE, Christensen CK: Predicting diabetic nephro- pathv in insulin-dependent oatients. N Ena/./ Med311:89-93. i 9841 N&se1 HL, Younger LR, Wilner GD, Procupez T, Canfield RE, Butler VP Jr: Radioimmunoassav of human fibrinooeotide A. Proc Nat/ Acad Sci USA 68:235&2353, 1971. ’ ’ Tomura S, Oono Y, Kuriyama R, Takeuchi J: Plasma concen- trations of fibrinopeptide A and fibrinopeptide BP 15-42 in glomerulonephritis and the nephrotic syndrome. Arch intern Med 145:1033-1036, 1985.

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5. Samerano N, Ponati MB, Vermylen J: Detection of fibrinogen- related antigen in urine with latex techniques. Proceedings of the IVth International Congress of the Society of Throm- bosis and Haematostasis, Vienna, June 19-22, 1973.

6. Kaizu K, Morita E, Uriu K, et al: Coagulation and fibrinolysis of diabetic nephropathy in association with theview of urinary FDP-E measured by latex photometric immunoassay. J Dia- betic Complications 31257, 1990.

7. van de Loo Osterman J: Factor of the hemostatic system in diabetic patients. A survey of controlled studies. Haemostasis 16:386, 1986.

8. Kaizu K: Therapy diabetic nephropathy; advanced stage. Di- abetes frontier 11:4,525, 1990.