Abstract
Background. This study aims to quantify the decrease in the reciprocal of serum creatinine during the two years prior to the start of dialysis and to identify the factors associated with the progression of renal disease. Methods. The study included 76 patients who were monitored for an average of 26.27 months. During the study 52 patients began dialysis treatments. The clinical and analytical variables were analyzed using the t-student test, ANOVA or the Kruskall-Wallis test. A multiple regression analysis was carried out with the decrease in the reciprocal of serum creatinine as the dependent variable. Results. There was a decrease between the mean value during the two years prior to dialysis, the mean value during the previous year and the value at the start of dialysis treatments of 0.29, 0.21 and 0.17 respectively. The nephropathy having the sharpest drop in the reciprocal of serum creatinine, expressed as a percentage of the initial value, was found to be nephroangiosclerosis (46.29%). A greater decline in the reciprocal of serum creatinine was exhibited by low albumin values and adjusted by means of different variables with LDL levels (p = 0.141). For different levels of haemoglobin, proteinuria and cholesterol, the drop in the reciprocal of serum creatinine was greater in patients having a diastolic blood pressure reading of 90 or greater. Conclusions. The decrease in the reciprocal of serum creatinine was associated with different variables in patients who required dialysis.
Introduction
Despite the progress that has been made in the field of chronic renal disease in the last two decades, it is considered to be an essentially progressive condition.Citation[[1]] This progression has nothing to do with the base disease, as is evidenced by the examination of the changes over time in the reciprocal of serum creatinine according to a linear model.Citation[[2]] Although the decline in renal function is linear and progressive, we still do not know why it differs from one patient to another.Citation[[3]], Citation[[4]]
The risk factors involved in the progression of renal disease must be determined by studying the variables which, acting individually or jointly, are involved in this process. This will make it possible for us to take action so as to delay or slow down the progression.Citation[[7]]
In a large number of patients, it is not possible to identify the factors influencing the progression. However, in most of the series published, the factors that predict progression with the greatest accuracy are arterial hypertension, proteinuria and changes in metabolism.Citation[[8]]
In order to achieve the effective prevention of terminal renal disease, we must implement a program for early detection in patients at risk of developing a progressive deterioration of the renal function and we must also monitor the pharmacological responses based primarily on an evaluation of the parameters of arterial hypertension and proteinuria.Citation[[10]], Citation[[11]]
The main strategies followed in the protection against kidney disease have been based on pharmacology, as a means of lowering blood pressure, and consequently, the levels of proteinuria, and on diet, to reduce the ingestion of proteins.Citation[[12]]
The purpose of this study is to quantify the drop in the reciprocal of serum creatinine during the two years prior to dialysis and to identify factors related to the progression of kidney disease. The use of the reciprocal of serum creatinine is advantageous in terms of creatinine clearance in that it does not require 24-h urine samples to be collected, which may involve error. Moreover, it allows for a greater number of creatinine measurements in patients, thus enabling us to calculate the progression of kidney failure over longer periods of time.
Subjects and Methods
From January 1998 to December 1999 76 patients were studied, with the average monitoring time being 26.27 months, and a median of 23.43, ranging between 0 and 173 months. A total of 52 of these patients began dialysis treatments and they were been monitored an average of 25.60 months prior to the start of dialysis, with a median of 23.43 and ranging from 3.93 to 120.56 months.
The following variables were studied in each patient: age, sex, type of nephropathy, systolic blood pressure, diastolic blood pressure, hematocrit, hemoglobin, leukocytes, platelets, iron, urea, creatinine, uric acid, sodium, potassium, bicarbonate, calcium, phosphorus, total proteins, albumin, cholesterol, triglycerides, HDL cholesterol, LDL cholesterol, glucose and 24-h proteinuria.
The analytical results were obtained by laboratory methods, the hematometry was performed using a Coulter hematological counter and the biochemical values were obtained by the conventional autoanalyzer method.
The type of nephropathy was classified into the following sub-groups: diabetes, nephroangiosclerosis, glomerulonephritis, interstitial nephritis, and renal polycytosis, Wegener an unknown cause of kidney disease.
All patients were put on a restricted protein and low-sodium diet. Most patients were being treated for hypertension, consisting of an angiotensin conversion enzyme inhibitor in patients suffering from diabetic kidney disease and in cases of nondiabetic nephropathy with considerable proteinuria. The calcium phosphorus product was controlled by the addition of calcium carbonate, calcitriol and phosphorus chelates to the diet where necessary. Anemia was also treated with iron administered orally and/or subcutaneous erythropoietin in accordance with the criteria of <50 mg/dL ferropexia and <10 g/dL hemoglobin in cases with or without clinical symptomatology, respectively. Patients with dyslipemia were treated, where necessary, with HMG-CoA-reductase inhibitors.
Statistical Analysis
The values and decreases in the reciprocal of serum creatinine are expressed as the mean and standard deviation. A comparison of the decrease in the reciprocal of serum creatinine between the groups defined by the different variables was carried out using the Student t test, ANOVA or the Kruskall-Wallis test. The correlation of the different quantitative variables studied and the decline in the reciprocal of serum creatinine was determined by means of the Pearson correlation coefficient and its statistical significance. A multiple linear regression analysis was also performed using the decrease in the reciprocal of serum creatinine as the dependent variable with the co-variables being those found to be significantly associated with this decrease in the univariate analysis. This regression model was used on the baseline values and mean values during the two-year period prior to dialysis. The baseline value of the analytical results was considered to be the first value ascertained for each patient. A mean value was later calculated for the measurements taken during the two years prior to dialysis for each patient.
At the same time variables of clinical interest were stratified into different categories, analyzing the decline in the reciprocal of serum creatinine in each one. A variance analysis was performed to compare the different subgroups. Values of p<0.05 were considered to be statistically significant. The statistical tests were bilateral and the analysis was done using SPSS statistical software.
Results
The patients enrolled in this study were between 20 and 78 years of age. Thirty-three (63.5%) of the subjects were men and 19 (36.5%) were women.
The decrease in the reciprocal of serum creatinine between the mean value two years prior to dialysis, the mean value during the previous year, and the value at the start of dialysis was from 0.29 (SD 0.10) to 0.21 (SD 0.07) and to 0.17 (SD 0.15) respectively, which translates to a mean decrease of 0.13 (SD 0.13). presents the decreases in the reciprocal of serum creatinine according to sex and type of nephropathy. A comparison of males and females showed a drop of 35.22% and 31.17% respectively. The differences were not significant. Depending on the type of nephropathy, the greatest decrease in the reciprocal of serum creatinine, expressed as a percentage of the initial value, was found in patients with nephroangiosclerosis (46.29%), unknown cause of kidney disease (39.13%), renal polycytosis (30.79%) and interstitial nephritis (29.63), although no significant differences were found.
Table 1. Progression of renal failure according to sex and diagnosis
shows the baseline values and the mean values during the two years prior to dialysis pertaining to the variables that could potentially affect the diagnosis of renal disease. These values do not differ significantly except in the case of systolic and diastolic blood pressure, phosphorous, hematocrit, hemoglobin, leukocytes and triglycerides.
Table 2. Baseline values and mean values for 2 years of the biochemical parameters
shows the correlation between the decrease in the reciprocal of serum creatinine and the baseline and mean values in the two years prior to dialysis pertaining to the different variables. There is a negative correlation between the drop in the reciprocal of serum creatinine and the baseline reading of urea (r = −0.385) and albumin (r = −0.287). Also detected was a positive correlation with the baseline LDL (r = 0.676). Taking into account the mean value of the same variables during the two years prior to dialysis, we found a significant negative correlation between urea (r = −0.365), and albumin (−0.330) and a positive correlation with cholesterol (0.283) and a decrease in clearance.
Table 3. Correlation coefficient of the decrease in the reciprocal of serum creatinine with baseline values and mean values for 2 years of the biochemical parameters
After fitting a multiple linear regression model () for the different variables showing a significant correlation with the decrease in the reciprocal of serum creatinine in the univariate analysis, we found that on fitting the baseline values, the variable closest to statistical significance was LDL (p = 0.141).
Table 4. Multiple regression model adjusted to fit the baseline or mean values of certain factors related to progression
The stratified analysis of the different variables and the decreases in the reciprocal of serum creatinine in the different categories are shown in . This table shows a greater decrease in the reciprocal of serum creatinine for low values of albumin. For different levels of hemoglobin, proteinuria and cholesterol, the drop in the reciprocal of serum creatinine was greater in patients with a diastolic blood pressure of 90 or over. In patients having albumin levels over 3.5, the decrease in reciprocal of serum creatinine was greater in patients with a diastolic blood pressure of 90 or over.
Table 5. Decrease in the reciprocal of serum creatinine during the 2 years prior to dialysis according to the combination of different parameters
Discussion
The progression of renal disease has correlated consistently with clinical and analytical parameters, which are the subject of most of the studies on renal protection.Citation[[3]], Citation[[4]] It is essential to determine these predictive risk factors in order to be able to develop adequate therapeutical methods that will allow us to act on these mediators and stop or slow the progression.Citation[[5]], Citation[[6]]
The parameters that have traditionally been analyzed are the base disease, high blood pressure, anemia, hypoalbuminemia, dyslipemia and proteinuria.Citation[[7]]
On the basis of the results of our study, there was no correlation between the base disease and the decrease in the reciprocal of serum creatinine.Citation[[8]]
In keeping with other studies on progression, we found a correlation between the decrease in the reciprocal of serum creatinine and the variables of albumin, hypertension, proteinuria and cholesterol.Citation[[9]]
A diastolic blood pressure of 90 or over correlated with a greater decrease in the reciprocal of serum creatinine. Systemic hypertension has long been known as a risk factor in the progression of renal disease. This hypertension is transmitted to the glomerular capillary. Glomerular hypertension is one of the factors causing the permeability to increase leading to proteinuria and speeding up the process of glomerulosclerosis.Citation[[10]], Citation[[11]]
The reciprocal of serum creatinine also decreased sharply when the levels of plasmatic albumin were under 3.5. This decline in plasmatic albumin, which is detected in end-stage renal disease, is due to malnutrition, inflammation and dilution, present at this stage of the disease. They correlate with a greater morbidity-mortality in the patients when they have come to the point of requiring dialysis.Citation[[12]] For this reason there is a growing concern with improving the nutritional parameters in patients in the predialysis stages.Citation[[13]]
This study did not find a significant correlation between proteinuria and the decrease in the reciprocal of serum creatinine, although it did highlight a correlation when it was studied in association with other variables. Patients with levels of proteinuria of over 3 g, hypoalbuminemia and a blood pressure reading of over 90 mm of mercury showed a greater decrease in the reciprocal of serum creatinine. As we mentioned earlier in our discussion of the diastolic hypertension variable, proteinuria has long been recognized as a risk factor in progression.Citation[[14]] The filtration of proteins and their tubular reabsorption contribute to glomerulosclerosis and tubulointerstitial fibrosis. Fortunately we now have the tools to be able to induce the lowering of diastolic blood pressure and proteinuria by means of medication that inhibits angiotensin II, either in the form of the classical conversion enzyme inhibitors or the more up-to-date angiotensin receptor antagonists.Citation[[15]], Citation[[16]]
The variable with the highest correlation in our study was LDL cholesterol. Experimental studies have demonstrated that the low-density lipoprotein (LDL) stimulates the proliferation of glomerular and tubular cells as well as the proliferation of the extracapillary matrix, which contributes to fibrosis.Citation[[17]] There are, however, no studies confirming that a reduction in hyperlipidemia will slow the progression of renal disease, but it has been seen to reduce proteinuria, which is a known cause of progression. Since this is the progression factor that has received the least amount of attention in studies, and moreover, has resulted in controversial findings in different articles, we believe that steps must be taken to obtain a better lipid profile in order to be able to confirm the relation between dyslipemia and the progression of renal disease.
References
- Mitch W.E., Buffington G., Lemann J., Walser M. Progression of chronic renal failure: a simple method of estimation. Lancet 1976; 2: 1326–1331
- Rutherford W.E., Blonding J., Miller J.P., Grunwalt A.S., Vavra J.D. Chronic progressive renal disease. Rate of change of serum creatinine concentration. Kidney Int. 1977; 11: 62–70
- Klarh S., Schreiner G., Ichikawa I. The progression of renal disease. N. England J. Med. 1988; 318: 1657–1666
- Jacobson H.R., Klahr S. Chronic renal failure: pathophysiology and management. Lancet 1991; 333: 419–423
- Klarh S. Mechanisms of progression of chronic renal damage. J. Nephrology 1999; 12: 53–62
- Grupo Italiano di Studi Epidemiolodici in Nefrologia (GISEN). Renal function and requirement for dialysis nephropathy patients on long-term ramipril: Rein follow-up trial. The Lancet 1998; 352: 1252–1256
- Mazouz H., Kacso I., Ghazali A., El Esper N., Morinieri P, Makdassi R., Hardy P., Westeel P.F., Achard J.M., Pruna A., Fournier A. Risk factors of renal failure progression two years prior to dialysis. Clinical Nephrology 1999; 51: 355–366
- Lun˘o J., García Vinuesa S., Gómez Campdera S., Lorenzo I., Rodríguez P., Dall'Anesse C., Rodríguez A., Valderrabano F. Factores predictivos en la progresión de la enfermedad renal. Nefrologia XIX 1999; 523–531
- Ruggenenti P., Perna A., Gherardi G., Garini G., Zoccali C., Salvadori M., Scolari F., Schena F.P., Remuzzi G. Renoprotective properties of ACE-inhibition in nondiabetic nephropathies with nonnephrotic proteinuria. The Lancet 1999; 354: 559–364
- Hannedouche T., Albooze G., Chauveau P., Lacour B., Jungers P. Effects of blood pressure and antihypertensive treatment on progression of advanced chronic renal failure. Am. J. Kidney Dis. 1993; 21(suppl 2)131–137
- Preston R.A., Fernandez L. Managing hypertension in patients with kidney disease implications for preservation of renal function. Am. J. Therapy 1998; 5: 355–362
- Hunscker L.G., Adler S., Caggiula A., England B.K., Greene T., Kusek J.W., Rogers N.L., Teschan P.E. Predictors of the progression of renal disease in the modification of diet in renal disease study. Kidney Int. 1997; 51: 1908–1919
- Pereira B.J.G. Optimization of pre-ESRD care: the key to improve dialysis outcomes. Kidney Int. 2000; 57: 351–365
- Peterson J.C., Adler S., Burkart L.M., Greene T., Hebbert L.A., Hunsicker L.G., King A.J., Klahr S., Massry S.G., Seifter J.L. Blood pressure control, proteinuria and the progression of renal disease. The modification of diet in renal disease study. Ann. Int. Med. 1995; 123: 754–762
- Fabris B., Candido R., Armini L., Fischeti F., Calci M., Bardelli M., Fazio M., Campanacci L., Carreta R. Control of glomerular hyperfiltration and renal hypertrophy by an angiotensin converting enzyme inhibitor prevents the progression of renal damage in hypertensive diabetic rats. J. Hypertension 1999; 17: 1925–1931
- Bakris G.L., Weir M.R. Angiotensin-converting enzyme inhibitor associated elevations in serum creatinine: is this a cause for concern?. Arch. Int. Med. 2000; 13: 685–693
- Samuelsson O., Mulec H., Knight Gibson C., Attman P.Q., Kron R., Larsson R., Weis H., Wedel H., Alaupovic P. Lipoprotein abnormalities are associated with increase rate of progression of human chronic renal insufficiency. Nephrol. Dial. Transplant. 1997; 12: 1908–1915