Tubular dysfunction in patients with rheumatoid arthritis

Many uses of certain groups of drugs for therapeutic purposes (NSAIDs, drugs that modify disease activity (DMRADs and immunosuppressive cytotoxic drugs), may have a specifi c nephrotoxic effect. The given dose is often not suitable for the patient’s condition, it can cause side effects, ie it can lead to reduction of the kidney function, as a result of accumulation in the kidneys’ cells. This is usually found in long-term therapy as in Rheumatoid arthritis.


Introduction
Microalbuminuria is used as a marker for glomerular damage and urinary excretion of N-Acetyl--D-glucosaminidase (NAG) as an indicator of proximal tubular damage. These tests indicate that, there is no specifi c indicator, tracer, marker, which detects nephrotoxicity that occurs in the course of the therapy.
Many uses of certain groups of drugs for therapeutic purposes (NSAIDs, drugs that modify disease activity (DMRADs and immunosuppressive cytotoxic drugs), may have a specifi c nephrotoxic effect. The given dose is often not suitable for the patient's condition, it can cause side effects, ie it can lead to reduction of the kidney function, as a result of accumulation in the kidneys' cells. This is usually found in long-term therapy as in Rheumatoid arthritis.

Urinary enzymes to assess nephrotoxicity
Albumin in urine, (Microalbuminuria). Albumin (molecular weight of 66 KDa) is the most important protein in plasma, as well in urine. Approximately 30% of the protein in the urine belongs to it and presents a good indicator for assessing the change in glomerular permeability. Urinary albumin excretion has a high individual variability and depends on physical activity or food variations [1,2].  All participants voluntarily took part in this study, so that the criteria to do it are met.

Clinical assessment with disease activity score (DAS 28) index
Clinical assessment was made by sub specialist in the given area Disease Activity Score (DAS 28) index [16][17][18].
Score below 3.2 qualifi es the disease as low active. DAS 28 indexes range from 0 to 10.

Statistical analysis
Two arithmetic means is testing of the differences between i.e. the corresponding proportions, the Student t-test is used, when comparing the mean values of the given number of parameters between two groups, such as Wilcoxon-matched test for independent samples. predictivity and sensitivity for negative and negative tests of the examined markers is determined with tests for sensitivity and specifi city. Statistically signifi cant is the P value of between 0.05 and 0.1 is considered. Statistical package Statistica 7.0 is used for data preceding.

Results
Between NAG and microalbuminuria, Pearson's analysis of 2 test showed that there was correlation, which was moderate (r=0.21) in the four samples tested during the period of 8 weeks in patient's group treated only with Etoricoxib, while there was statistically signifi cant correlation (r=0.28) between increase in NAG and microalbuminuria values in the four samples in the period of 8 weeks in the group Diklofenak ( Figure 1).
There is signifi cance of the differences in the two groups in the group of treated with Etoricoxib, where the value mean of the microalbuminuria was (0.46 ± 0.37), while in the patients group treated with Diclofenac was (0.56 ± 0.41). This explains why Etoricoxib gives almost identical value to microalbuminuria in relation to Diclofenac.
Group of patients treated with Etoricoxib in relation to the distribution of patients according to the values of NAG in the four groups, it was concluded that the values of NAG were registered in 4 patients in the 3 rd week, when the mean value of NAG urinary induction was highest (1.12 ± 0.13).
It was concluded that NAG values were registered in 6 patients in the 3rd week, when the mean value of NAG urinary induction was highest (1.41 ± 0.31). Analyzing patient's distributions according to NAG values in the four probes in the group of patients treated only with Diclofenac.

Discussion
Approaches for the assessment of nephrotoxicity of drugs are possible only with drugs or medications that have a dominant proximal tubular excretion, such as Methotrexate, Etoricoxib, Diclofenac, Acetaminophen and gold salts. This approach for the assessment of nephrotoxicity of drugs is not possible with other medications or drugs from the baseline which are used in the treatment of RA, such as resorhin, sulfazalazine and lefl unomide, due to predominantly hepatic excretion. For these preparations there are no literarature data on the occurrence of proximal tubular dysfunction.
Methotrexate in the low-dose regimen is the most commonly used drug from the DMARDs group, while from the NSAIL group the most commonly used drug is Diclofenum (Diklofenak R ), as well as Etoricoxib (Arcoxia R ).
In the non-treated RA primarily is damaged tubular and to a very small extent the glomerular apparatus [19]. Signifi cant increase in the activity is due to changes in cellular synthesis and not always the enzymuria may result in lytic or necrotic processes.
Etoricohib does not cause signifi cant damage to the renal proximal tubules in the most of monitored patients. The nephrotoxicity during the use of Diclofenac is greater in relation to Etoricohib. Diclofenac is discretely more potent NAG inductor in relation to Etoricohib. These observations correspond with other authors [20,21].
Early detection of increased NAG enzymuria or occurrence of microalbuminuria before exposure to drugs may be used for prediction of possible toxicity associated with renal impairment.
There was not any change in clinical fi ndings of renal function in relation to degradation products of nitrogen metabolism (serum creatine, urea / serum, GFR) during the follow-up.

Conclusion
Enzymura detected with urinary NAG, together with degradation product with urinary creatinine excretion may be considered as a complementary diagnostic tool.