Analele tiinifice ale Universitii Alexandru Ioan Cuza, Seciunea Genetic i Biologie Molecular, TOM XIV, 2013

EVALUATING THERAPEUTIC ANSWER THROUGH THE DETERMINATION OF BIOCHEMICAL PARAMETERS AT PATIENT SUFFERING PYELONEPHRITIS
ELENA TUTU 1, ELENA CIORNEA 1, GABRIELA DUMITRU 1*, SILVIA DUMITRACU 2
Keywords: pyelonephritis, biochemical parameters Abstract: Known as potentially severe disease, acute or chronic pyelonephritis requires early diagnosis and appropriate treatment administered promptly in order to prevent late sequel of renal parenchyma, as renal scarring, hypertension and renal failure. The purpose of the present study has been tracking trends in disease incidence by age, its analysis reported in the area of origin of the patient and the percentage distribution by type pyelonephritis (acute, chronic or exacerbated chronic pyelonephritis). Also to be confirmed laboratory diagnosis of the disease and its accurate staging in male and female patients were monitored biochemical indicators such as glucose and blood urea nitrogen, serum creatinine, uric acid, alkaline reserve, alanine-aminotransferase and aspartate-aminotransferase.

INTRODUCTION
The nephritic syndrome is a clinical-functional aspect that appears in certain general or kidney diseases and it is characterized from a clinical point of view by large edemas, sometimes generalizes, variable proteinuria, lipoproteinemia under 60 g/l, hyposerinemia, hyperlipidemia, hypercholesterolemia, and from a pathological and anatomical point of view, trough degenerative lesions of the basal glomerular membrane (Crciun and Grigore, 2004). The pyelonephritis are acute or chronic inflammations that affect the interstitial kidney tissue, their important being due to the large and increasing frequency of urinary infections, the most common cause of interstitial infections (Jan et al., 2008; Abbagani et al., 2010), their gravity (20-60% lead to chronic kidney insufficiency, 3 to 4 times more than glomerulonephritis), ore to the clinical tableau that is hard to recognize for a long time (70%). The disease is commonly found at women trough ascending infection and it is caused by constipation, breaking of the perineum, obstruction of the urinary paths or urological maneuvers (Domnioru, 1991; Trifan and Covic, 2003; Borundel, 2007). This work was carried out in order to establish of disease management strategies in concerned patients, the units of observation are laboratory biochemical analysis (uric acid, blood urea nitrogen, blood glucose, alkaline reserve, alanineaminotransferase and aspartate-aminotransferase. Moreover, were used the trend incidence analyzes based on parameters such as patient age, origin thereof and, at the same time, attempts an analysis of the share of periods and an examination of the relevance of deepening of the episodes under the chronicity of the disease.

MATERIALS AND METHODS

They were taken into this study a number of 31 patients from the Roman Municipal Hospital, both male and female, diagnosed with pyelonephritis. A series of biochemical parameters where determined such as: level of glucose in the blood, creatinine, uric acid, blood urea nitrogen, alkaline reserve and alanine-aminotransferase, respectively the aspartate-aminotransferase, using the automatic analyzer Hitachi 912 ISE.

RESULTS AND DISCUSSION From the total of 31 patients, 22 are female (70.96%), while the rest of 9 where male (29.04%), this being explained simply by the well-known fact that the interstitial nephrites, the infection reservoir being located in the digestive tract, and the most important germ is Escherichia coli, frequent colonizer of the saprophyte microbial colony that trough accidental maneuvers can go through the stages of generating an infection. At woman, this transmission is favored by the short urethra, by the sexual act, by transmitting mechanically germs into the urinary bladder by using spermicide contraceptives that kill alter the environment in the vagina, but also trough other maneuvers, while at man the ascending transmission is more rare due to a longer urethra, a lower

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colonization of the per urethral region - a much more dry area - and e presence of bactericide substances in the prostatic secretion. The sample was divided into five age groups, the highest incidence of pyelonephritis occurring in categories 61-70 years (32.25%), respectively, 71 - 80 years (41.93%), the opposite falling the people aged between 41-50 years, respectively, 81 - 90 years with a parity of 6.45 percent of all cases analyzed (fig. 1). The distribution is not random, due to the fact that at these patients the agents involved in the etiology of the diseases are those who have a high degree during the decade. Hence, the arterial hypertension, the kidney ischemia secondary to the arterial spasm, the capillary thrombosis, venulas, the inflammatory endarteritis, the vesico-urethral reflux, and the cicatricial modifications of the kidney tissue left after acute pyelonephritis episodes, the fibrosis from the kidney parenchyma, capable of leading to urinary obstruction, high blood pressure, kidney insufficiency, various immunological mechanisms developed in time at those who presented periods of acute chronicisation (persistence of the bacterial antigens in the kidneys, various auto-immune mechanisms alimented by the kidney anti-tissue anticorps), but also different problems of urine concentration, together with the various ways of the germs to resist to anybiothics are the main ways trough which the disease becomes chronic at older ages.
81 - 90 years 41 - 50 years 6,45% 6,45% 51 - 60 years 12,91%

71 - 80 years 41,93% 61 - 70 years 32,25%

Fig.1. Distribution by age The ratio of the patients with confirmed pyelonephritis is, as it can be seen in figure 2, to 3:1 in favor of the rural areas. Of the 31 patients, 22.58% where from the urban areas, while 77.42% where from the rural areas. This incidence shows the fact that the medium from which the patients came is statistically significant. There is a large influence of the life environment (from physical activities that can favor the bacteriuria and intense transpiration that can have a major impact in generating and maintenance different functions of the ionic homeostasis, the sanitary-preventive culture, the access to consultations and laboratory analysis, including financial motivations etc.).

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Analele tiinifice ale Universitii Alexandru Ioan Cuza, Seciunea Genetic i Biologie Molecular, TOM XIV, 2013

Urban area 22,58%

Rural area 77,42%

Fig.2. Distribution of cases by area of origin Data analysis regarding the repartition of patients on the type of affection (fig. 3) had shown the possibility to reveal that most of the patients had been cases of chronic acute pyelonephritis (51.62%). The larger share of this might suggest that only the acute episodes, with their dominant clinical manifestations are putting into alarm the patient. More over, one has to take into account the fact that data from the scientific literature shows that about 1/3 of the chronic pyelonephritis are not diagnosed during lifetime, being detect at about every 10-12 cases of necropsy (Sasu et al., 2010), while yearly, on a global scale, 1:1000 people become ill with chronic pyelonephritis. It cannot be ruled out that in this percent might also enter the affections with lesions specific to chronic glomerulonephritis (that can be seen only at the supplementary histochemical examinations, where advanced glomerular and tubular lesions might easily be spotted, with the apparition, on extended area, of the pseudo-tiroidisation microscopically aspect of the kidney parenchyma) or trough diverse tests if immunochemistry.
CP 16,13%

ECP 51,62% AP 32,25%

Fig.3. Percentage distribution by type of disease (CP = chronic pyelonephritis, AP = acute pyelonephritis, ECP = exacerbated chronic pyelonephritis) The infections of the urinary tract are common to persons with diabetes, and the associations between urinary infections with the high blood pressure (present, also, in diabetes), for more consecutive years, can lead to chronic pyelonephritis. The analysis of the concentration of sanguine glucoses on the patients lot shows that in the most cases of females, the glycemic level was in normal values (70-120 mg%) but at two cases, with very large values (329 mg% respectively 194 mg%) the hypothesis of a severe infection of the kidney parenchyma might be plausible (that

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requires the urgent batching of the levels of glycosylated hemoglobin and of the immune mechanisms of the host), while in the case when the level of the blood glucose level is correlated with high levels of glycosylated hemoglobin and with much diminished immune mechanisms, it might be taken into account a possible emphysematous pyelonephritis and an adequate treatment should be made (fig. 4).
350 300 250 200 150 100 50 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 Patients

140 120 100 80 60 40 20 0 1 2 3 4 5 6 7 8 9 Patients

mg/dl

Fig.4. The concentration of glucose in the blood of female sex patients diagnosed with pyelonephritis

Fig.5. The glucose concentration in the blood of male sex patients diagnosed with pyelonephritis

In the blood of the male patients we can see that the level of glucose is situated, at all patients, in normal levels, excepting number 1 and number 5, with values of the blood glucose level at 126 mg% and 125 mg%, that might be due to a diet that is rich in carbohydrates or due to a lower physical activity (fig. 5). In other words, at the basis of the acute, interstitial or chronic acute nephrites in the case of the studied patients are not the high values of blood level glucose, capable of leading in time to the alteration of the sanguine kidney vessels that constitute one of the basis of kidney deficiencies. Moreover it can be taken into account the fact that in general, males are more active, the burning at the level of the carbohydrates substrate being more intense than those of the females, given the existence of a much more developed somatic musculature. Based on this data, we can consider that the sanguine glucose level might be an insignificant biomarker at the male patients with pyelonephritis, regardless of their age. Taking into account the fact that most of the creatinine is eliminated through urine, the determination of the serum creatinine is very important for diagnosing the kidney function and for the quick signalization of the evolution of kidney diseases. In the acute interstitial nephritis, the serum creatinine like the sanguine urea does not constitute defining parameters for these affections, because is concentrated mostly on the function of cleansing the metabolic product, being specific for the so-called nitrogen syndrome retention. Most patients from our lot had shown values of creatinine situated in the normal limits (0.5 - 1.2 mg/dl), the exceptions, preset at three from the 22 female patients showing a chronic pyelonephritis or an association of this affection with a glomerulonephritis, while a level grown three times at one of the females (4.81 mg/dl) of this parameter shows the existence of a potential uroproietic syndrome (the syndrome of local inflammation), a possible immuno-deprivation, an altering of the function of the septic organ and a transit towards an acute episode of kidney insufficiency (fig. 6). This hypothesis is confirmed by the fact that for this patient, the sanguine urea has in its turn very high values (almost the double of normal value - 91 mg %). Moreover, it is well known the fact an in order for the value of serum creatinine to rise from 1mg/dl to 2mg/dl, it is necessary a loss of 50% of the kidney function, a fact

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m g/dl

Analele tiinifice ale Universitii Alexandru Ioan Cuza, Seciunea Genetic i Biologie Molecular, TOM XIV, 2013

that shows the gravity of the case. The other two cases situated above the normal limit (1.97 mg/dl and 1.6 mg/dl) show a possible renal lithiasis. At the rest of the females, the rest of the values where normal, so we can conclude that these have efficient homeostatic mechanisms for eliminating creatinine trough urine, a fact that might indicate that the kidney sanguine flux and the rate of glomerular filtering are normal.
5 4,5 4 3,5 3 mg/dl 2,5 2 1,5 1 0,5 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 Patients

1,2 1 0,8 m g /d l 0,6 0,4 0,2 0 1 2 3 4 5 6 7 8 9 Patients

Fig.6. The concentration of creatinine in the blood of female sex patients diagnosed with pyelonephritis

Fig.7. The concentration of creatinine in the blood of male sex patients diagnosed with pyelonephritis

Like in the case of glucose blood level, the level of creatinine at the 9 male patients had been found to be in the normal limits, a situation that can be explained by the fact that the level of glomerular filtering is normal, while the nitrogen retention does not take place at men, a fact that describes, indirectly, the well regulated homeostatic mechanisms at this level, but also the fact that the gravity of the pyelonephritis is minor, being well known the fact that for a doubling of the quantity of creatinine in blood, it is necessary loss of 50% of the glomerular filtering capacity (fig. 7).
100 90 80 70 60 mg% 50 40 30 20 10 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 Patients

50 45 40 35 30 m g% 25 20 15 10 5 0 1 2 3 4 5 6 7 8 9 Patients

Fig.8. The concentration of urea blood in female sex patients diagnosed with pyelonephritis

Fig. 9.The concentration of urea in the blood of male sex patients diagnosed with pyelonephritis

Like the creatinine, the sanguine urea might have values situated in normal limits (15-50 mg %) in acute, simple pyelonephritis. From the total of 22 female patients studied, a quarter (6) had shown high values of this parameter, situated above the normal limits (fig. 8). The excessive concentration (91 mg%) of plasmatic urea, depending on the renal perfusion, leads into the conclusion that the rate of glomerular filtering had been altered and the patients, diagnosed with exacerbated chronic pyelonephritis, having also a high level of creatinine, might have developed a

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kidney insufficiency. Because not the interdependence of the urea to the protein degradations, the urea is more of a prognosis factor then a diagnostic for the kidney affections in the case of this person. The other females had values situated until the limit of 60 mg%, with a single exception (the patient with number 6 - 68 mg%, diagnosed in her turn with acute chronic pyelonephritis). Taking into account the fact that the share between the urea/creatinine and the fact that the values of both parameters are inversely proportional with the rate of glomerular filtering, we can conclude that, at most patients, the nitrogen state (reflected by the high values of the report) can be attributed to the kidney and post-kidney nature, confirming thus the medical diagnosis. Even if it is considered that, being un-absorbed at the level of the kidney tube, the creatinine might better reflect the kidney dysfunction, when it is seconded by the high level of uremia; both show a high degree of injury to the kidney function, indicating precisely the diagnosis. From the analysis of graphical data, we can easily observe which patients had a reserve prognosis and which have a good one, conditioned however by a series of dietetic, preventive and drug-curative measures. The analysis for the data regarding the level of uremia in blood, as has been made in the case of each 9 male patients from the lot (fig. 9), orients the attention, just like in the case of glucose blood level and serum creatinine, towards the values situated in normal limits (15-50 mg%) in acute, chronic, or chronic acute pyelonephritis, confirming again the fact that the rate of glomerular filtration at all patients taken into account was not affected by the presence of interstitial nephrites, indicating, in the same time, the fact that the level of the blood urea is a good factor for prognosis in this disease.
9 8 7 6 mg/dl

9 8 7 6 m g /d l 5 4 3 2 1 0
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 Patients

5 4 3 2 1 0

9 Patients

Fig.10. The concentration of uric acid in the blood of female sex patients diagnosed with pyelonephritis

Fig.11. The concentration of uric acid in the blood of male sex patients diagnosed with pyelonephritis

The results obtained from dosing the uric acid in female patients from the studied lot reflect values situated above the normal physiological values (2.5 - 5 mg %). Used especially in order to establish the lithiasic uric nature of pyelonephritis, the concentration of uric acid from figure 10 discovers the substratum of the inflammatory processes of acute pyelonephritis, at a large part of the female patients (from the 22 females diagnosed with pyelonephritis, 13 had high values of uric acid in the blood - the maximum level where found at patient number 9 - 8.5 mg% with ECP and the smallest - 6.28 mg % with CP, while two of them barely went over the superior normal limit - 5.24 mg% at patient number 11 and 5.25 mg % at patient number 18, both with ECP). At the last two, the analysis indicate either the fact that the substratum of the acute pyelonephritis was not a lithiasic one, either that the curative treatment had been successful.

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Researchers show that the osmotic diuresis in the residual nephrons is one of the factors that condition the relative growth of the renal uric acid excretion at patients suffering from acute pyelonephritis, the rise of uric acid in blood signaling it rapid deterioration (Moist et al., 2000). The lot of female patients that presented values of this sanguine parameters situated in normal limits, are rather not characterized by an kidney acidification defect, as it is well known that in most cases of pyelonephritis with this defect have at its origin the destructions of the kidney distal tubes caused by a high degree of metabolic acidosis, supported by high concentrations of urates (Ranabir et al., 2012). The graphical representations of the dosing of uric acid in the blood of the male patients suffering from pyelonephritis shows at 7 out of 9 patients levels that are much above the medium values of uric acid blood level, suggesting maybe a lithiasic substrate of the disease, a fact that might not be surprising considering the fact that man are large meat consumers (fig. 11). The hypothesis is suggested by the just under the limit concentrations of the alkaline reserves in the blood, that show a certain acidification of the blood, connected in a vicious circle, among others, with the presence of some calculi of uric nature at the level of kidney parenchyma that support the acutisation of interstitial nephritis, through their inflated substratum used by microorganisms (Boix et al., 2007; Sakhaee et al., 2011).
25

30 25 20

20

15

m E q /l
10 5 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 Patients

mEq/l

15 10 5 0 1 2 3 4 5 6 7 8 9 Patients

Fig.12. The values reported for the alkaline reserve in female sex patients diagnosed with pyelonephritis

Fig.13. The values reported for the alkaline reserve in male sex patients diagnosed with pyelonephritis

The limits of normal values of the total quantity of bicarbonates in blood (the alkaline reserve) are, according to the used laboratory methodology, between 24 - 27mEq/l. The analysis of the data obtained from the lot of female patients diagnosed with pyelonephritis of different kind, represented in figure 12, had been seen a predominance of the cases showing a normal level, a fact that means the bicarbonate is neutralized by the acids resulting from the cell metabolisms, being thus no excess of bicarbonates that trough elimination, could create an alkaline urine. However, 6 female patients have diminished values, beyond the normal limits, that confirm a possible shift in the acid-basal equilibrium into metabolic acidosis, that is capable of supporting the substratum on which pyelonephritis evolves. According to figure 13, that depicts the values of alkaline reserves at male patients suffering of pyelonephritis, only 2 out of 9 patients had shown somewhat higher levels of alkaline reserve, suggesting a minor alkalinisation of the urine (25 mEg/l at patient number 4, respectively 26.25 mEg/l at patient number nine). However, the other patients had shown the acid-basal equilibrium shifted towards acid, because of a lower neutralization capacity of the acids resulting from cell metabolism, due to lower sanguine bicarbonate levels.

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Thus, it is confirmed the post-kidney (lithiasic) nature of the pyelonephritis in the male patients, the mechanism at the level of the kidney tubes favoring urine acidification, as it is shown in the data from previous researches, the levels necessary to counterbalance these being below the normal (Moe et al. 2002, Sakhaee et al. 2002).
60 120 50 100

40

80

U/L

30

U/L

60

20

40

10

20

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 Patients

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 Patients

Fig.14. Alanine-aminotransferase activity in female sex patients diagnosed with pyelonephritis

Fig.15. Aspartate-aminotransferase activity in female sex patients diagnosed with pyelonephritis

The glutamic-pyruvic transaminase is one of the enzymes commonly found in the kidney, but also one of the most valuable markers used in diagnosing infections in the kidney apparatus, when it value are beyond normal (31/U/L). The results from the laboratory analysis, graphically shown, show that a number of four female patients had values over the normal sanguine level of alanine-aminotransferase (fig. 14). The data from the literature stipulate the fact that the activity of this enzyme might grow in emphysematous pyelonephritis (Prkain et al., 2001), a rare kidney infection, of necrotic nature, found commonly at those suffering from diabetes, and the obtained results require, at the female patients with a normal glucose blood level, a supplementary test of glucose tolerance, for an eventual invalidation of the diagnosis, or, in the event of confirmation, to take the necessary curative measures. Other data from the literature signal also in acute pyelonephritis anomalies at the sanguine level of alanine-aminotransferase, characteristic to the acute period of interstitial nephrites, tending towards normalization, once the patient enters convalescence (Campos et al., 2009). In the meantime, it cannot be excluded that the level of this enzymes might be due to eventual diseases that induce immunodeficiency (hepatitis, even dormant, unobserved or toxic ones), or to the presence in the immediate antecedents of curative hepatotoxic treatments (such as ceftriaxone from the group of cephalosporin), as it was shown by some researches (Suankratay et al., 2008). The seric levels of glutamic-oxalacetic transaminase did not have a different behavior at the level of samples, compared to those of the glutamic-piruvic transaminase, a level of 8 female patients showing higher values of this enzyme, beyond the maximum normal limit (31 U/L). At a closer look (fig. 15) one can see the levels three time higher at patient number 3 - 102 U/L, 84 U/L at patient 12 and over two times higher at patient 22 (74 U/L). Analyzing the diagnosis one can clearly see that the female patients showing higher serum levels of aspartate-aminotransferase where in the acute phases of interstitial nephrites, either in an acute pyelonephritis or in a chronic, acute one. The only exception, patient 22 had a diagnosis of interstitial chronic nephritis. Taking into account the data from previous researchers that say the fact that aspartate-aminotransferase is, together with the alanine-aminotransferase a biochemical marker for about 24% of patients found

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in acute phases of interstitial nephrites, we can suppose that both enzymes characterize certain processes related to the acute stage of the disease, that require further investigations in order to explain how the liver interacts with the metabolic cycle of the disease.
60 50 40 U/L 30 20 10 0 1 2 3 4 5 6 7 8 9 Patients

90 80 70 60 50 U/L 40 30 20 10 0 1 2 3 4 5 6 7 8 9 Patients

Fig.16. Alanine-aminotransferase activity in the blood of male sex patients diagnosed with pyelonephritis

Fig.17 Aspartate-aminotransferase activity in the blood of male sex patients diagnosed with pyelonephritis

In regard to the activity of the glutamic-pyruvic transaminases and to the glutamic-oxalicacetic transaminase at male patients, it can be said that, unlike the case of females, the measure in which the aspartate-aminotransferase can be considered a marker in pyelonephritis is negligible unlike alanine-aminotransferase that at only 2 out of 9 patients presented values located in the normal limits (31 U/L), while at some patients the serum levels where almost double (59 U/L at patient 5 and 58 U/L at patient 1), at the rest of man the serum levels of glutamic-pyruvic transaminase being until 40 U/L (fig. 16 -17). The same patients with high levels of aminotransferase had shown, in the case of aspartate-aminotransferase (TGO), levels almost three times above the normal limit (84 U/L and 85 U/L), while the rest of the patients had normal values of both enzymes in their blood. It cannot be excluded that in the interpretation of these results, both enzymes might not have a significant value for diagnosing interstitial nephrites, but can signal an eventual immunodeprivation at patients 1 and 5, due to a possible viral hepatitis, or a depression of the hepatic functions due to hepatotoxic drugs or due to a chronic alcoholism, case in which are recommended not only supplementary tests for confirming this diagnostics, but also the urging of specific curative treatments, considering the fact that the liver is, together with the kidney, the main detoxifying organism in the human body. CONCLUSIONS Disease distribution by age, by sex and area of origin was found to have statistical value in the present study, the units can be regarded as defining the parameters characterizing pyelonephritis. It was also established, one statistical relevance of acute disease, its chronicity, but also of the occurrence of the crisis flares in context by term evolution of pyelonephritis. The blood glucose level was not found to be an essential biomarker laboratory diagnosis of pyelonephritis in contrast with the blood urea, the level of uric acid, the serum creatinine and the alkaline reserve.

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Significance of aspartate-aminotransferase and alanine-aminotransferase was statistically correlated with processes that characterize the acute stage of pyelonephritis. REFERENCES
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