Features of Kidney Functions and Their Hormonal Regulation in Type 1 Diabetes Mellitus in the Context of Water and Water-Salt Load Tests

The dissertation is devoted to the study of kidney functions and their hormonal regulation in patients with type 1 diabetes mellitus using functional load tests — 1%-water, potassium water, and sodium water. The research was conducted at the Novosibirsk State Medical Academy and is aimed at detecting early, including preclinical, signs of diabetic nephropathy through the evaluation of hydrouretic and ionoureteric kidney function under conditions of functional loads.

The influence of excessive intake of water, potassium, and sodium on kidney functions and the levels of key hormones — cortisol, aldosterone, ACTH, TSH, T3, T4, parathyroid hormone, calcitonin, and C-peptide — is analyzed in the work. It has been established that in patients with type 1 diabetes mellitus without clinical-laboratory signs of kidney damage, impairments of water-salt metabolism and hormonal regulation of kidney function are already observed, which allows functional load tests to be regarded as a diagnostic instrument for the early detection of diabetic nephropathy.

Relevance of the Research:

Diabetes mellitus is one of the most prevalent endocrine diseases and constitutes an acute medico-social problem. Type 1 diabetes mellitus is widespread in all countries of the world. According to WHO (2001), the number of patients with this form of diabetes exceeds 12 million. In the Russian Federation, according to morbidity data, there are more than 2 million patients with diabetes mellitus, of whom approximately 300,000 suffer from the insulin-dependent form (Kutyrina I.M., 1995; Rakova N.G., 1998; Balabolkin M.I., 2000). According to the registry of the urban diabetological center of Novosibirsk as of 31.12.04, 20,447 patients with diabetes mellitus were registered (as of 31.12.03 — 19,906 persons), of whom 1,365 were patients with type 1 diabetes (6.7%), including 259 children and adolescents up to 17 years of age inclusive.

The prevalence of this disease is increasing from year to year, and the number of patients with severe vascular complications of diabetes mellitus is also growing, leading to early disability and mortality among patients. According to Dedov I.I. et al. (1998, 2000), Dedov I.I., Shestakova M.V. (2000), the prevalence of diabetes mellitus in developed countries amounts to 4–5%, while in developing countries it reaches 10–15%. The number of newly diagnosed cases increases by 5–7% annually, and every 10–15 years the number of patients with diabetes doubles (Shestakova M.V. et al., 2003, 2004). According to WHO experts' projections (2000), by 2030 every 15th–20th inhabitant of the planet will suffer from diabetes mellitus. The greatest threat to the lives of patients is diabetic kidney involvement — diabetic nephropathy, which develops already 10–15 years after the onset of diabetes mellitus and extremely rapidly leads to the development of chronic renal insufficiency (Diabetic Nephropathy, 1996; Balabolkin M.I., 2000; Sivous G.I. et al., 2003; Shestakov V.A. et al., 2001). Chronic renal insufficiency among diabetic patients is encountered 20 times more frequently than among the general population (Shestakova M.V. et al., 2000, 2003). The relevance of the problem of diabetic nephropathy and chronic renal insufficiency is confirmed by the progressive growth in the number of patients with diabetes mellitus among the structure of primary morbidity: in 30–50% of patients with type 1 diabetes mellitus, chronic renal insufficiency ultimately develops (Bondar I.A., Klimentov V.V., 2003), an increased need for replacement dialysis therapy, and an increase in financial costs for these types of treatment (Dunicheva O.V. et al., 2003).

The danger of diabetic nephropathy lies in the fact that, developing sufficiently slowly and gradually, it remains unnoticed for a long time. And only at the expressed (often terminal) stage of kidney damage do the patient manifest complaints associated with intoxication of the organism by nitrogenous waste products; however, at this stage, radical assistance to the patient is not always possible. Among all patients undergoing hemodialysis, 30% suffer from diabetes mellitus (Dedov I.I. et al., 2000). Hence arises the most important task — timely, as early as possible, diagnosis of diabetic nephropathy and the conduct of adequate pathogenetic therapy of this complication (Shestakova M.V., 1991; Rakov S.S. et al., 1994; Dedov I.I. et al., 2001; Shestakova M.V. et al., 2001, 2003).

In recent years, it has become known that already after the manifestation of diabetes, structurally functional changes are detected in the kidneys that are not captured by routine diagnostic methods. At the same time, it is precisely at the initial stages of nephropathy development that one can count on the effectiveness of pathogenetic methods of treatment (angiotensin-converting enzyme inhibitors, low-protein diet, etc.), whereas the appearance of proteinuria and elevated arterial pressure — the first clinical signs of diabetic nephropathy — indicates expressed and irreversible changes in the kidneys (Zhukovsky M.A., 1994; Kutyrina N.M., 1995; Balabolkin M.I., 2000; Shestakova M.V. et al., 2001). In this connection, the relevant task is the study and introduction into clinical practice of new methods for the early diagnosis of diabetic nephropathy (Ryabov S.I. et al., 1979; Bondar I.A., Klimentov V.V., 1995). Meanwhile, at present, the frequency of clinically established diagnosis of diabetic nephropathy ranges, according to various authors, from 6% to 54%. This means that the hidden preclinical period of the disease, which already has its morphological equivalent, often remains outside the view of clinicians for a long time (Basharova N.G. et al., 1994).

Such low indicators of diabetic nephropathy diagnosis at the preclinical stage are associated with insufficient knowledge of the pathogenesis of the development of angiopathies in diabetes mellitus as a whole, and nephropathy in particular. To this day, little is known about how the excretion and reabsorption of sodium and potassium ions, urea nitrogen, and creatinine are disrupted. There are also no data on changes in the hormonal regulation of kidney functions in response to the development of diabetic kidney damage, especially at early preclinical stages. An important role is played by the kidneys in the preservation of water-salt homeostasis; however, changes in water-salt metabolism in diabetes mellitus and its complicating nephropathy have been studied to an entirely insufficient extent up to the present time.

It is also unclear what role in the progression of diabetic nephropathy are played by the endocrine-metabolic changes accompanying diabetes mellitus, changes in the system of arterial blood pressure regulation, hormonal shifts, and so on. There are experimental data obtained in animals with alloxan diabetes indicating that in the formation of impaired diuretic response to water loading, an important role is played not only by morphological changes but also by functional interrelationships in neuroendocrine regulation, with amplification of the tone of the sympathoadrenal system (Belikova F.S., 1966).

It appears necessary to evaluate kidney function at the stage when it has not yet been affected by the pathological process, there are no signs of nephropathy, and the kidney responds to inadequate conditions of the internal environment in the patient's organism. It is probable that the time has come for the differentiation of two concepts — nephropathy and altered kidney response when its functional capacity is still normal. The question deserves discussion as to whether kidney function is impaired during the "preclinical" (hidden) period of diabetic nephropathy or whether a normal, still healthy kidney adequately responds to the increased glucose load and only gradually, thereafter, develops impairment of its function. Consequently, in the evaluation of clinical data, it is important to distinguish impaired kidney function from the response to changed conditions in the organism that cause alteration in kidney function, as well as to evaluate the features of the state of the water-salt metabolism regulation system (Natochin Yu.V., 2002; Fedorova E.Yu., 2004).

All of this makes relevant not only the development of methods for early diagnosis and prevention, but also pathogenetically grounded, stable compensation of diabetes mellitus itself and all accompanying vascular complications of this disease, which would contribute to a reduction in the risk of disability and mortality among patients with this pathology and to an improvement in the quality of life of patients with diabetes (DCCT, Research Group, 1993). It is necessary to evaluate the interrelationships between water-excretory and ion-excretory kidney functions, the regulation of water-salt metabolism by neuroendocrine mechanisms under conditions of load tests at early stages of the disease, when structural changes in the kidneys are presumed to be absent.

A distinctive feature of the development of microvascular lesions in diabetes is their prolonged preclinical period, which, without doubt, dictates the necessity of optimizing dispensary observation of this contingent of patients in order to detect complications at the preclinical stage at an early stage and to prescribe timely treatment. Today this becomes especially relevant, since medicinal preparations have appeared that are capable of pathogenetically affecting the processes of development of complications and, consequently, there exists a real possibility of halting their progression and, in certain cases, subjecting them to reverse development.

In connection with the above, the following goal of the research has been formulated:

Goal of the Research:

To study kidney functions and their hormonal regulation in patients with type 1 diabetes mellitus using 1%-water and water-salt load tests.

Tasks of the Research:

1. To study renal responses in patients with type 1 diabetes mellitus in response to the application of: a) 1%-water load; b) potassium water load; c) sodium water load.

2. To evaluate blood hormone levels (cortisol, aldosterone, ACTH, TSH, T3, T4, parathyroid hormone, calcitonin, C-peptide) in patients with type 1 diabetes mellitus under conditions of excessive intake of water, potassium, and sodium into the organism;

3. To establish correlation relationships between hormonal changes and kidney functions under conditions of load tests.

Scientific Novelty.

By means of functional load tests (1%-water, potassium water, and sodium water), evidence of impairment of hydrouretic and ionoureteric kidney functions in patients with type 1 diabetes mellitus has been obtained for the first time. It has been demonstrated that in this case, the degree of manifestation of changes depends on the type of load and on the clinical stage of kidney complications in these patients. It has been established for the first time that in patients with type 1 diabetes mellitus without clinical-laboratory signs of kidney damage, an excessive, compared with the control, hydro- and ionuresis is observed in response to loads. However, in the dynamics of the reaction, monotonicity and a more prolonged latent period for achieving maximum changes in the principal indicators of kidney functions are manifested.

It is expedient to consider excessive hydro- and ionuresis, as well as a more prolonged latent period of response to load tests in patients without signs of nephropathy, as initial structurally functional changes of specific kidney damage in type 1 diabetes mellitus.

In patients with diabetic nephropathy, renal responses to water-salt loads are characterized by lower efficiency in the excretion of water, ions, creatinine, and urea, and by a reduction in the principal kidney processes — glomerular filtration and tubular reabsorption.

In the group of patients with diabetes mellitus without signs of diabetic nephropathy, an inadequate elevation of TSH and aldosterone levels in response to water load has been demonstrated. The response to the potassium water test in these same patients is characterized, on the contrary, by the absence of a TSH response, but by an excessive elevation of aldosterone level. In response to sodium water load, a dishormonal reaction is revealed with respect to TSH — a significant increase in its concentration in response to the load, as well as an insufficient decrease in aldosterone and an excessive decrease in cortisol titer. In the group of patients with diabetic nephropathy, the opposite changes are observed: an excessive decrease in aldosterone and an insufficient decrease in cortisol.

Weakened correlation relationships between the principal indicators of ionoureteric kidney function and counter-regulatory hormones in the dynamics of development of diabetic nephropathy have been identified, which testifies to a disruption of hormonal regulation of kidney functions under specific kidney damage.

Practical Significance.

The work has obtained a rationale for the application, for diagnostic purposes, of functional water and water-salt load tests in patients with diabetes mellitus in order to detect early signs of diabetic kidney damage.

The results obtained indicate that the application of any of the load tests allows the detection of deviations of kidney functions from control indicators in patients with type 1 diabetes mellitus depending on the duration of the disease. The propositions put forward for defense.

1. The earliest changes at the preclinical stage of diabetic nephropathy, in addition to generally accepted criteria, are impairments of hydrouretic and ionoureteric kidney functions, detectable by means of functional water-salt load tests.

2. In patients with type 1 diabetes mellitus, even at the preclinical stage of kidney damage, a disruption of hormonal regulation of kidney functions is observed. In the dynamics of development of diabetic nephropathy, weakened correlation relationships are noted between changes in the concentrations of counter-regulatory hormones and ion excretion by the kidneys.