[ Diabetes Type 2 ]

Role of endothelin in chronic renal failure—developments in renal involvement

Summary The risk of a posttransplant recurrence of secondary glomerulonephritis (GN) is quite variable. We studied 15 cases of membranous glomerulonephritis (MG) in patients with diabetes mellitus focusing on the morphologic changes of the kidney. Find out below who they are, other conditions they have and drugs they take. Hypertension is a major factor driving the progression of CKD to ESKD. A 42-year-old woman with diabetes mellitus for 12 years, hypertensive for 6 years, hypothyroidism on treatment, with diabetic nephropathy and a baseline serum creatinine of 141.4 µmol/L (2.5 mg/dL) presented with a non-healing chronic trophic ulcer of the right sole. Histologically, in 13 cases the predominance of early glomerular alterations was characteristic, while in 9 cases the picture proved to be equivocal and accompanied by some degree of interstitial alterations. ESRD patients in Hawai’i have a two-fold higher prevalence of glomerulonephritis, compared with the general ESRD population in the United States.

As the prevalence of Streptococcus pyogenes disease in developed countries has declined, other causative pathogens are recognized more frequently. One patient had methicillin-sensitive S aureus infection. Increased serum IgA was noted in 75%. This is called nephrotic syndrome. While deleterious in some, it may contribute to recovery in other forms of renal diseases. During the course of chronic renal diseases, the intrarenal synthesis of ET-1 is remarkably up-regulated along with a modulation of ET receptor subtype expression, particularly at those sites affected by the pathological process. The treatment for glomerulonephritis depends on what is causing it.

Prognosis for these older patients is poor, with fewer than 25% recovering full renal function. Medications may also be ordered to suppress your immune system. epidermidis, which occurred in the absence of foreign body. The cause of IgA nephropathy is not known, although most people with the disease have abnormalities in their immune system. However, this raises the question on the mechanism of increased intrarenal ET-1 production and the mode of action in chronic renal diseases. In regards to the calcium phosphate product, two-thirds of the patients in all countries reporting data had values below the recommendation of 4.4 mmol2/L2. Renal involvement in the form of proteinuria or renal insufficiency is the most common manifestation.


(Do not take iron supplements without your doctor’s approval.) Steroid medication or immunosuppressive drugs may be prescribed for some patients. The outlook for chronic (ongoing) glomerulonephritis is more variable depending upon the type. In 36 cases electron microscopy was performed. There is a well recognized association between type 1 DM and autoimmune thyroid diseases [2]. In rats, renal mass reduction (5/6 nephrectomy; simulating the loss of functional nephrons) caused a time-dependent increase in proteinuria, which paralleled the up-regulation of intrarenal ET-1 mRNA expression [7]. Accordingly, in vitro exposure of proximal tubular epithelial cells to high-molecular-weight proteins such as albumin, IgG and transferrin elicits a dose-dependent production of ET-1, which is primarily released abluminally into the interstitial compartment, while only a minor portion is secreted luminally and thus appears in the urine [6]. It is present in urine only a result of a urinary tract infection.

Several conditions known to cause progressive glomerular injury have the ability to stimulate intraglomerular ET-1 expression. In streptozotocin-diabetic rats, glomerular ET-1 expression and urinary ET-1 excretion increase markedly [9]. Congenital proteinuria is caused by genetic mutations that disrupt key structural proteins in the slit diaphragm. ET-1 produced by glomerular cells may exert biological effect in an autocrine/paracrine manner on glomerular cells itself, or, via peritubular capillaries, on tubular and interstitial cells (see subsequently). Mesangial cell proliferation and expansion of extracellular matrix are a hallmark in chronic glomerular disease [10]. Interestingly, ET-1 stimulates mesangial cell proliferation and extracellular matrix production [10], thus likely contributing to glomerular pathobiology. In agreement, dual ET antagonism with bosentan prevents matrix deposition and glomerular basement membrane thickening in diabetic rats [11].

Increasing evidence suggests that the ET-1 system is also involved in glomerulosclerosis in hypertension. Several factors instrumental in hypertension, including oxidized LDL, shear stress, vasoconstrictors, reactive oxygen species, growth factors and others have the ability to increase ET-1 production by mesangial cells [10]. Indeed, uninephrectomized, spontaneously hypertensive rats showed increased intraglomerular ET-1 expression, which coincided with intense proteinuria, mesangial expansion and glomerulosclerosis [12]. Interestingly, angiotensin-converting enzyme (ACE) inhibition ameliorated proteinuria and reduced ET-1 expression [12], suggesting that ET-1 may at least partially mediate the detrimental effects of angiotensin II. Pro-inflammatory cytokines stimulate mesangial ET-1 production [10]. Accordingly, several experimental models of glomerulonephritis have demonstrated an increased glomerular abundance of ET-1 and ET receptors, which occurred in parallel with structural glomerular injury [13, 14]. Conversely, methylprednisolone treatment reduced both ET-1 expression and structural damage suggesting that ET-1 is involved in the inflammatory process.

Initial results in NZB/W F1 mice which develop glomerular lesions resembling human lupus nephritis indicate that bosentan treatment is effective, particularly when combined with COX-2 inhibition. Despite being known to reduce ET-1 expression and structural lesions in animal models [13, 14], high-dose corticosteroids may precipitate renal crisis in patients with systemic sclerosis [15, 16]. Thus, it may be difficult to separate causal and secondary effects in animals and to directly extrapolate experimental data to humans. The second major histomorphological alteration in progressive renal failure is tubulointerstitial inflammation and fibrosis. Increased tubulointerstitial ET-1 abundance may result from protein challenge of proximal tubular epithelial cells (mentioned earlier) and from ET-1 produced within glomeruli, reaching the tubulointerstitial compartment via peritubular capillaries originating from efferent arterioles. Locally released ET-1 may trigger renal injury by two mechanisms. First, ET-1 may cause constriction of peritubular capillaries with subsequent hypoxic injury of neighbouring proximal tubules based on their high metabolic demands.

Hypoxia, in turn, which is a major stimulus for ET-1 expression, may trigger ET-1 production in tubular epithelial cells, thereby potentially initiating a vicious circle. Secondly, ET-1 is not only a potent vasoconstrictor, but also promotes accumulation of inflammatory cells and extracellular matrix production. Accordingly, activation of nuclear factor (NF)-κB (which drives the expression of many pro-inflammatory cytokines) is prominent in proximal tubules and infiltrating mononuclear cells in rats with intense proteinuria, whereas ET antagonism reduces NF-κB activation, interstitial infiltration and renal lesions [17].

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