notes by dr Claudio Italiano
Diabetic nephropathy in its evident clinical form is characterized by proteinuria with> 300 mg / 24 protein release, reduction of glomerular filtration and arterial hypertension. Diabetic nephropathy or glomerulosclerosis contributes to advanced chronic renal failure in the measure of about 15% of subjects per year in Italy, while in other countries in 30% of cases. The prevalence is 20-30% in patients with type 1 diabetes 10-20 years after onset, while in 10% of cases in patients with type 2 diabetes.
Clinically manifest diabetic nephropathy is preceded by a phase of incipient nephropathy characterized by the presence of microalbuminuria, defined as albumin excretion between 30 and 300 mg / 24. Patients with type 1 diabetes with microalbuminuria have a higher frequency of arterial hypertension with still normal glomerular filtration. With the appearance of proteinuria, the glomerular filtrate, however, begins to decay with a variable speed in different patients, which can reach up to 10-12 ml per year. This lesion, that is the nephropathy, microangiopatica, is almost always associated with retinopathy, but also with cardiopathies, such as left ventricular hypertrophy. Morbidity and mortality due to ischemic heart disease and other vascular complications are particularly high.
The diabetic manifestation does not involve the kidney only through glomerular involvement (the classical manifestation in this case is 1) nodular glomerulosclerosis or Kimmelstiel-Wilson disease), to be correlated with diabetic microangiopathy, ie lesions of small vessels related to suffering which is established in the alterations of metabolism. Most of the experts, however, impute the above phenomena to the glycation of some proteins essential for the integrity of the capillaries, glycation that would lead to the thickening of the basement membrane of the latter wall and a slowing of the internal blood flow, with logics negative repercussions on oxygenation and nourishment of the involved tissues.
Diabetic nephropathy also manifests itself in 2) damage to the structure of the
renal medulla (renal papillary necrosis) and finally 3) causes acute
pyelonephritis. Papillary necrosis is caused by a renal microangiopathy that
induces a phenomenon of ischemia with consequent necrosis of the papillary
structure, which already in physiological conditions does not receive a very
high quantity of blood (less than 10% of the blood that reaches the kidney).
The necrotic papilla often goes to detachment and manifests a condition
completely indistinguishable from renal colic. On the other hand, acute
pyelonephritis is an infectious condition of the renal parenchyma. In fact, the
diabetic has a much greater tendency of the non diabetic to develop a bacterial
infection in the urinary tract, both for the presence of glucose in the urine (present
only when the plasma glucose exceeds the renal threshold of 180-200 mg / dl) ,
which appears to be an excellent breeding ground for bacteria, both because it
is often found in diabetes an alteration in gastric and bladder emptying,
resulting in urinary stagnation and therefore greater tendency to infections.
Genetic alterations of PKCβII, endothelin and angiotensin play a fundamental
role in the pathogenesis of the disease. However, the main event of all the
pathogenesis is the hyperglycemia of diabetes, which will be expressed in the
diffuse nodular glomerulosclerosis (Kimmestiel-Wilson disease). The mechanism
that causes glomerular damage is of a metabolic nature: constant hyperglycaemia
involves a glucose load that is superabundant compared to the normal needs of
the glomerular cells and of the cells that make up the arteriolar walls; the
glucose excesses are therefore channeled towards alternative pathways (those
studied are the polyol pathway, the pathway of the exosamines, the non-enzymatic
glycation of proteins and the production of advanced glycation products or AGEs).
The final consequence is glucotoxicity at the level of vascular cells (such
glucose toxicity is also responsible for all microvascular complications of
diabetes: retinopathy, nephropathy and neuropathy). The glomerular modifications
are initially only functional (and therefore reversible) and then become
structural (irreversible).
The changes observed are of two orders: increased permeability (inability to
filter or change the quality of the ultrafiltrate); reduced glomerular perfusion
(ie reduction of the absolute amount of glomerular filtrate).
Initial changes in podocytes are observed and loss of their ability to
collaborate with the filtration barrier: therefore, increased permeability of
the filtration barrier is observed. In the ultrafiltrate, molecules with a low
molecular weight like albumin (normally unfiltered) will appear first and we
will talk about selective proteinuria; with the progression of podocyte lesions,
an increasingly frank and non-selective proteinuria will appear (with
ultrafiltration of proteins with an increasing molecular weight). In addition to
the "selective" and "non-selective" classification, it is preferable to describe
the conditions such as microalbuminuria and macroalbuminuria (defined according
to the amount of albumin contained in the 24H urine).
Parallel to the podocyte lesion, microvascular damage occurs with thickening of
the glomerular basement membrane (consequent to the glycation of proteins, with
reduction of the turn-over of the fundamental structures that guarantee
filtration). The net result is a reduction of negative electrical charges on the
membrane surface, which favors the passage of albumin (negatively charged
protein) into the urine. The strong participation of TGF-β and VEGF also favors
the permeabilization of vascular endothelium, with a further increase in
proteinuria.
There is a marked hyalinosis, as well as an arteriosclerosis of afferent and efferent arterioles; interstitial fibrosis and tubular atrophy may be present. Only the expansion of the mesangial matrix seems to be related to the evolution towards terminal renal failure.
Diabetic nephropathy (proliferation of mesangial cells and expansion of the matrix) Diabetic nephropathy (proliferation of mesangial cells and expansion of the matrix) Diabetic nephropathy (proliferation of mesangial cells and expansion of the matrix)
Diabetic nephropathy begins with glomerular hyperfiltration (increase in glomerular filtration rate); the glomerular filtration rate is normalized with the onset of early renal damage and mild hypertension that worsens over time. Microalbuminuria then appears, that is, urinary excretion of albumin in a range of 30-300 mg / day. At these concentrations, urinary albumin is defined as microalbuminuria because it can not be detected by routine urine analysis with dipstick, which typically requires> 300 mg / day. Microalbuminuria progresses to macroalbuminuria (proteinuria> 300 mg / day in a variable time, usually over the course of years.The appearance of nephrotic syndrome (proteinuria ≥ 3 g / day) precedes the end stage of renal disease, on average, of about 3-5 years, but this range is very variable.
In all patients at diagnosis of diabetes and for a year as a screening requires a urinalysis with research of proteinuria (it is also good with Albustix). The demonstration of proteinuria has diagnostic value for a clinically manifested nephropathy. Then the quantitative evaluation of proterinuria and the measurement of renal function parameters, ie the creatinine, the creatinine clearance, ie the capacity of the kidney to purify the body from the nitrogenous waste, must be carried out, the expression of power and health of the kidney. If proteins are indosable, then it is good to request a fineness exam, which is microalbuminuria; in addition, the albumin / creatinine ratio in a random urine sample, better in the morning is another useful investigation; or the search for albuminuria in 24 hours.
Also in this case, the optimal control of glycometabolic decompensation is the
basis of the treatment of diabetic nephropathy and can reduce the risk of
developing glomerular damage and therefore microalbuminuria by 39%; if vice
versa "attacks" the diabetic disease with insulin therapy, then the success will
be in 54% of the cases. According to data from the UKPDS, a study on diabetic
patients who has made the history of medicine, diabetes control is the basis for
success in controlling nephropathy. Hypertension control; it is implemented
employing drugs like ace-inhibitors; in general, ramiprilat is preferred or,
according to the on-target study, telmisartaN; indeed, other sartans have also
shown excellent control of proteinuria and have implemented protection in the
renal glomerulus, for example irbesartan, at a dosage of 150 and 300 mg / day;
the more controlled the pressure and the better the protective effect on the
kidney, there is a consensus in this case about the objectives to be achieved
and that is, that the diabetic must keep his pressure lower than a non-diabetic
subject; the ideal values are certainly <130 mmHg for systolic and <85mmHg for
diastolic. Indeed, a strict control of hypertension is the basis of success for
the prevention of cerebrovascular accidents, stroke, myocardial ischemia and, of
course, damage on the eye and kidney.
Diet, it is advisable not to exceed on the contribution of proteins that must be
of 0.8 g / die per kg weight, that is for a subject of 70 kg of weight 0.8 x 70
= 56 g / day; in case of reduction of the filtrate it can be further reduced to
0.6 g / kg; today, however, there are conflicting studies on these aspects.
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