Korean J Intern Med > Volume 6(2); 1991 > Article
Hong, Yang, Lee, Ki, and Chung: The Urine Urokinase Concentration in End Stage Renal Disease with Acquired Renal Cyst

Abstract

To see whether there was any difference in the urine urokinase concentration between acquired cystic kidney disease (ACKD) group and control (non cyst) group in end stage renal disease patients (ESRD), we evaluated fifty ESRD patients who had been maintained on chronic hemodialysis for various period. The urine urokinase concentration was higher in the ACKD group (17.5±14.7 unit/ml, range 13.5–47.0 unit/ml, n=9) than the control group (4.1±3.4 unit/ml, range 0.5–12.0 unit/ml, n=36) (p<0.001), and polycyst group (2.6±1.8 unit/ml, range 1.0–5.1 unit/ml, n=5) (p<0.01).
But there was no difference between the control group and polycyst group. In the control group and the ACKD group, there was a direct relation between the dialysis duration and the urokinase concentration and the longer the dialysis duration, the higher the urine urokinase concentration (r squared=0.424, p=0.0001). The hemodialysis duration was longer in the ACKD group (42±17.0 months) than the control group (20.0±12.5 months) (p<0.005). These findings suggest that urokinase may be responsible for cystogenic degeneration in ESRD.

Key Words

Urine urokinase concentration; End Stage Renal Disease (ESRD); Acquired Cystic Kidney Disease (ACKD)

INTRODUCTION

It is generally accepted that acquired cystic kidney disease (ACKD) is a natural consequence of long standing end stage renal disease (ESRD) regardless of its underlying disease1). Recent reports about ACKD arouse clinician’s interest because it often lead to the complication of hemorrhage and it appear to increase the incidence of association with renal malignancy13). However, the mechanism leading to cyst formation in ESRD remain uncertain3,4). Urokinase is a serine protease cleave the peptide bond Arg-560-Val-561 of plasminogen to produce plasmin which is the main component of the fibrinolysis system5,6).
It is also known that urokinase plays an important role in extravascular fibrinolysis such as tissue remodeling, cell migration79) and degradation of the structural protein10,11). The urokinase production in the kidney is so great that the concentration in the urine is several times higher than in the plasma1214).
Recently, we reported15) that, as the renal mass decreases during the progression of ESRD, regardless of its underlying diseases, the remnant nephrons produce a larger amount of urokinase than the normal nephrons. With this result, if renal tubules were exposed to relatively high concentrations of urokinase, it might accelerate the cystogenic degenerative change of the renal tubules. This study was undertaken to see whether there is any difference in urine urokinase concentration between the ACKD group and non cyst (control) group in ESRD.

METHOD

1. Patients

Fiffy ESRD patients who had been maintained on chronic hemodialysis at Soonchunhyang university Chunan hospital for various periods of between 4 months and 70 months were chosen for this study. Causes for the underlying disease were various and ages ranged between 20 and 68 years old. The details of underlying diseases and sex distribution are summarized in Table 1.

2. Detection of Renal Cyst

Sonogram for the detection of renal cyst was performed by a radiologist (one of the authors of this study), using the 3.5 MHz linear and conex transducer (ALOKA SSD-270). Special attention was paid to rule out hydronephrosis and adult type polycystic kidney disease from ACKD.

3. Urokinase Activity

The urine urokinase activity was measured by a chromogenic peptide substrate, S-244416). 100 ul of urine, from 24 hours urine collection and standard urokinase in PBS were allowed to react with a defined amount of colorless substrate, S-2444 to release the colored p-nitroaniline which is measured spectrophotometrically at 405 nm. The absorbance was converted to urokinase activity (unit/ml) by the standard curve constructed from standard urokinase (product of Korean Green Cross CO.) in PBS.

4. Urokinase Concentration

It was derived from the following equation;
urokinase activity(unit/ml)×urine osmolarityplasma osmolarity
Our preliminary study showed that the urokinase activity was stable at room temperature for several weeks.

5. Statistics

Datas are expressed as mean±one standard daviation of mean. Difference of urine urokinase concentration, dialysis duration and urine volume between groups were evaluated by the Mann-Whitney U test (between 2 groups), through the software stativew 512+ (Brain power, calabasas, CA) operating on a Macintosh PC. Statistical significance was considered to be present if p<0.05.

RESULTS

Out of fifty patients, nine patients have ACKD, five patients had polycystic renal disease (underlying disease of ESRD) and there was no cyst in thirty six patients (control group). The cyst (ACKD) was single in six cases, unilateral in eight cases and the diameter was less than 2 cm in ten cases (Table 2).
The duration of hemodialysis was 42.2±17.0 month (range 19–70 months) in the ACKD group, 39.0±10.3 months (range 24–54 months) in the polycyst group, and 20.0±12.5 months (range 4–53 months) in the control group. It was longer in ACKD group than the control group (p<0.005).
The 24 hour urine volume was 181±131 ml (range 50–400 ml) in the ACKD group, 450±250 ml (range 100–800 ml) in the polycyst group, and 697±472 ml (range 100–1,500 ml) in the control group. It was smaller in ACKD group than contro group (p<0.001) and polycyst group (p<0.05).
The urine osmolality was 323.3±59.1 mOsm/L (range 250–429 mOsm/L) in ACKD group, 311.2±53.1 mOsm/L (range 237–520 mOsm/L) in control group, 366.3±70.6 mOsm/L (range 286–419 mOsm/L) in polycyst group. There was no difference of urine osmolality between groups.
The urine urokinase concentration was 17.5±14.7 unit/ml (range 3.5–47 unit/ml) in the ACKD group, 2.6±1.8 unit/ml (range 1.0–5.1 unit/ml) in the polycyst group and 4.1±3.4 unit/ml (range 0.5–12.0 unit/ml) in the control group. It was higher in the ACKD group than the polycyst group (p<0.01) and control group (p<0.001), but there was no difference between the control group and polycyst group (Fig. 1).
The urine urokinase concentration showed a direct relation with hemodialysis duration and the longer the dialysis duration, the higher the urine urokinase concentration (r squared=0.424, p=0.0001) (Fig. 2).

DISCUSSION

Three hypotheses which exist for the mechanism of cyst formaiton in adult polycystic kidney disease17) may be applid to ACKD; 1) tubular obstuction due to epithelial hyperplasia with subsequent elevated transmural pressure leading to tubular dilatation; 2) increased tubular basement membrane compliance with tubular dilatation at normal transmural pressure leading to tubular dilatation; 3) increased radial growth of epithelial cells and basement membrane due to an unknown stimulus, resulting in dilatation in parts of the tubules.
There have been many reports supporting these hypothesis in ACKD1825), but non are coinclusive. Ishikawa et al26) reported two cases of ACKD which regressed after renal transplation; one recurred when the graft failed. This finding support a role for the uremic milieu or hemodialysis in the genesis of acquired cystic disease.
But there is good evidence that tubule obstruction could occur in ACKD, by epithelial hyperplasia19), intraluminal casts1), calcium oxalate deposits27) or tubular atrophy and associated interstitial fibrosis1). Whether tubule basement membrane compliance is increased in ACKD is unknown. If the increased compliance of basement membrane were the important factor for cystic degeneration in ACKD, possible factos suggested in literature, are hyperfiltration in remnant nephrons28), acute and chronic renal ischemia3), compensatory renal growth factor3), abnormal hormone level3), uremic toxin and some exogenous substance introduced by hemodialysis procedure18,20,29,30).
Urinary plasminogen activator is principally urokinase which is not filtered but is mainly produced in tubular epithelial cells31) and act on its main substrate plasminogen to produce plasmin. Considering that urokinase play an important role in tissue remodeling, cell migration79), and structural protein destruction10,11) and ACKD arises from renal tubule of ESRD, the urokinase concentration in the tubule might be a cystogenic factor in some situation. The urokinase production was reported to decrease in ESRD32,33). Recently we found15) that as the GFR decreases, total urokinase in urine decreases, but the total urokinase divided by GFR (total u-PA/Ccr) increases abruptly when the GFR falls below 25L/day. This finding suggests that as the renal mass decrease, remnant nephron produce larger amount of urokinase than do normal nephron.
Even in ESRD, as long as urine formation is continued, there may be functioning nephrons on the way to functional loss. The deterioration of renal function will reach the point at which urine volume will be zero due to complete renal loss. We believe that this is the reasoin for decreased urine volume and longer duration of dialysis in ACKD group in our study. During this period, the tubules face a higher concentration of urokinase than the tubules of normal nephrons, and the longer the duration of ESRD (hemodialysis), the higher the expected urokinase concentration.
Our results show that the ACKD group had a higher concentration of urokinase and longer duration of hemodialysis than the control group.
With this concept, transformation of the control group into the ACKD group after some period of dialysis during which, remnant nephron produces much more urokinase is expected. Higher urokinase concentration in the ACKD group might be a result rather than a cause of ACKD. But there was no difference in the between the polycyst group and control group. This finding suggests that the increased urine urokinase concentration in the ESRD is rather the cause of ACKD than the result of ACKD.

Fig. 1
Urine urokinase concentration in ACKD group, control group and polycystic group. It is higher in the ACKD group than the control group and The polycystic group.
kjim-6-2-64-3f1.gif
Fig. 2
Scattergram showing the correlation between dialysis duration and urine urokinase concentration. The longer the dialysis duration the higher the urine urokinase concentration (p=0.0001)
kjim-6-2-64-3f2.gif
Table 1
Underlying Diseases and Sex Distribution of the Cases
Underlying dz Male Female Total No.
CGN 6 4 10
Hypertension 2 2
DM 4 2 6
Cystic dz 4 1 5
Unknown 11 16 27

Total No. 27 23 50
Table 2
Characteristics of the Cyst in ACKD
2cm > 2cm <
Unilateral
 Single 4 1
 Multiple 2
Bilateral
 Single
 Multiple 2 0

Total No. 8 1

REFERENCES

1. Gehrig JJ, Gottheiner TI, Swenson RS. Acquired cystic disease of end stage kidney. Am J Med 79:609–6201985.
crossref pmid
2. Basile JJ, Mccullough DL, Harrison LH, Dyer RB. End stage renal disease associated with acquired cystic disease and neoplasia. The J of Urology 140:938–9431988.
crossref
3. Grantham JJ, Levine E. Acquired cystic disease; Replacing one kidney disease with another. Kidney Int 28:99–1051985.
crossref pmid
4. Avner ED. Renal cystic disease. Insights from recent experimental investigation. Nephron 48:89–931988.
crossref pmid
5. Summaria L, Arzadon L, Bernabe P, Robbin SKC. The activation of plasminogen to plasmin by urokinase in the presence of the plasmin inhibitor trasylol. J Biol Chem 250:3988–39951975.

6. Violand BN, Castellino FJ. Mechanism of the urokinase catalysed activation of human plasminogen. J Biol Chem 251:3906–39121976.
pmid
7. Kluft C. Studies on fibrinolytic system in human plasma. Thromb Haemost 41:365–3831979.
crossref pmid
8. Nishino N, Aoki K, Kokura Y, Sakaguchi S, Takada Y, Takada A. The urokinase type of plasminogen activator in cancer of digestive tracts. Thromb Research 50:527–5351988.
crossref
9. Takahashi K, Ikeo K, Gojobori T, Tanifuji M. Local function of urokinase receptor at the adhesion contact sites of a metastatic tumor cell. Thromb Research Supplement X:55–611990.
crossref
10. Knudsen BS, Silverstein RL, Leung LLK, Harpel PC, nachman RL. Binding of plaminogen to extracellular matrix. J Biol Chem 261:10765–711986.
pmid
11. Marder VM, Sherry S. Thrombolytic therapy: current status. NEJM 318:1512–15201988.
crossref pmid
12. Stump DC, Thienpont M, Collen D. Urokinase related proteins in human urine. The Journal of Biological Chemistry 261:1267–12731986.
pmid
13. Huber K, Kirchheimer J, Binder BR. Characterization of a specific anti human urokinase antibody: Development of a sensitive radioimmunoassay for urokinase antigen. J Lab Clin Med 103:684–6941984.
pmid
14. Shimada H, Takashima E, Soma M, Murakami M, Maeda Y, Kasakura S, Takada A, Takada Y. Source of increased plaminogen activator during pregnancy and purperium. Thromb Reearch 54:91–981989.
crossref
15. Hong SY, Yang DH. Urinary plasminogen activator activity in progressive renal failure. Korean J Inter Med 5:58–621990.
crossref pmid pmc
16. Fiberger P, Kanos M, Eriksson E. The use of chromogenic peptide substrates in fibrinolytic research and clinical practice. In Davidson JF, Nilsson IM, Astedt B (eds). Progress in fibrinolysis 5:212–2221981;Edinburgh, Churchill Livingstone.

17. Grantham JJ. Polycystic kidney disease: a predominance of giant nephrons. Am J Physiol 244:F3–F101983.
crossref pmid
18. Evan AP, Gardner KD. Nephron obstruction in nordihydro guaiaretic acid induced renal cystic disease. Kidney Int 15:7–191979.
crossref pmid
19. Evan AP, Gardner KD, Bernstein J. Polypoid and papillary epithelial hyperplasia: a potential cause of ductal obstruction in adult polycystic disease. Kidney Int 16:743–7501979.
crossref pmid
20. Gardner KD, Solomon S, Fitzgerrel WW, Evan AP. Function and structure in the diphenylamine exposed kidney. J Clin Invest 57:796–8061976.
crossref pmid pmc
21. Dobyan DC, Hill D, Lewis T, Bulger RE. Cyst formation in rat kidney induced by cis-platinum administration. Lab Invest 45:260–2681981.
pmid
22. Carone FA, Rowland RG, Perlman SG, Ganote CE. The pathogenesis of drug induced renal cystic disease. Kidney Int 5:411–4121974.
crossref pmid
23. Hostetter TH, Olson JL, Rennke GH, Venkatachealam MA, Brenner BM. Hyperfiltration in remnant nephrons: a potentially adverse response to renal ablation. Am J Physiol 241:F85–931981.
crossref pmid
24. Preus HG. Compensatory renal growth symposium; an introduction. Kidney Int 23:571–5741983.
crossref
25. Mcmanus JFA, Hughson MD, Hennigar GR, Fitts CT, Rajagopulan PR, William SAV. Dialysis enhances renal epithelial proliferation. Arch Pathol Lab Med 104:192–1951980.
pmid
26. Ishikawa I, Yuri T, Kitada H, Sinoda H, Slinoda A. Regression of acquired cystic disease of the kidney after successful fenal transplantatin. Am J Nephrol 3:310–3141983.
crossref pmid
27. Heiji O, Hiroko O, Takashi O, Kazuhiko K, Yukinori O. Acquired renal cyst in five-sixths nephrectomized rats; the role of oxalate deposits in renal tubules and a renotropic factor. Nephron 51:393–3981989.
crossref pmid
28. Kanwar YS, Carone FA. Reversible changes of tubular cell and basement membrane in drug induced renal cystic disease. Kidney Int 26:35–431984.
crossref pmid
29. Thomas JO, Cox AJ, Deeds F. Kidney cyst produced by diphenylamine. Stanford Med Bull 15:90–931957.
pmid
30. Carone FA, Stolarczyk J, Krumlovsky FA, Perlidan SG, Roberts TH, Rowland RG. The nature of a drug induced renal concentrating defect in rats. Lab Invest 31:658–6641974.
pmid
31. Angles-Cano E, Rondean E, Delarur F. Identification and cellular localization of plasminogen activators from human glomeruli. Thrombosis and Haemostasis 54:688–6921985.
crossref pmid
32. Asbeck F, Sistig E, Renner E, Sieberth G, Vandeloo J. Urokinase excretion in chronic renal disease of different histological type. Clin Nephrol 1:46–501973.
pmid
33. Vreeken J, Boomgaard J, Deggeller K. Urokinase excretion in patients with renal disease. Acta Med Scand 180:153–1581966.
crossref pmid

Editorial Office
101-2501, Lotte Castle President, 109 Mapo-daero, Mapo-gu, Seoul 04146, Korea
Tel: +82-2-2271-6792    Fax: +82-2-790-0993    E-mail: kaim@kams.or.kr                

Copyright © 2024 by Korean Association of Internal Medicine.

Close layer
prev next