Progression of chronic renal disease

Progressive chronic renal disease is characterized histologically by the accumulation of extracellular matrix proteins within the renal interstitium and progressive tubular atrophy. A number of kidney diseases and their progression to end-stage renal failure are driven by the intercrine, autocrine, paracrine, and endocrine effects of angiotensin II. Growth factors appear to have an important role in the development and progression of diabetic nephropathy. Substantial evidence indicates that induction of transforming growth factor beta (TGF-beta) is mediated by high levels of glucose. TGF-beta is pivotal for the hypertrophy of mesangial and tubular cells. Other factors such as hypertension, protein glycation products, and other mediators may further amplify the synthesis of TGF-beta and/or the expression of its receptors in the diabetic state. Other cytokines, such as tumor necrosis factor alpha also contribute to the progression of chronic renal disease. The overall picture derived from several studies of chronic renal disease suggests that treatment of the progression of the renal fibrosis may require the use of several strategies to prevent the advent of end-stage renal disease.     

Factors predicting development of renal involvement in progressive systemic sclerosis

Renal involvement or "scleroderma renal crisis" developed in 60 patients with progressive systemic sclerosis evaluated at the University of Pittsburgh during the period from 1972 to 1982. Forty-seven of these patients had progressive systemic sclerosis with diffuse scleroderma, representing 18 percent of persons with progressive systemic sclerosis and diffuse scleroderma evaluated during this time period. Ten additional patients did not have truncal scleroderma but were suspected of having incompletely developed diffuse scleroderma. Only three patients were classified as having progressive systemic sclerosis with the CREST syndrome. Renal crisis was observed early in the course of the illness, a mean of 3.2 years after onset. During May and June, this complication developed in fewer patients than expected. Thirty-six patients who had diffuse scleroderma and renal involvement after their initial Pittsburgh evaluation were compared with 212 who had diffuse scleroderma without renal involvement during follow-up. The patients with renal involvement had a shorter mean disease duration at the time of their first evaluation (2.4 versus 4.2 years, p less than 0.05) and less frequently had digital pitting scars (29 versus 54 percent), but no other significant clinical, laboratory, or serologic differences were noted. Data available for 31 patients with renal involvement during the six months preceding the onset of renal disease were analyzed. Blood pressure, serum creatinine, urine protein and red blood cells, and plasma renin levels were similar in these patients and the 212 patients without renal involvement. More patients with renal involvement had anemia or clinical evidence of cardiac involvement during this period compared with the patients without renal involvement. During the 12-month period prior to renal involvement, seven of 16 (44 percent) patients with such involvement had an impressive increase in skin thickening on physical examination compared with only 23 of 180 (14 percent) patients without renal involvement at any time during their course. Thus, the subset of patients with diffuse scleroderma who show rapid progression of their skin thickening early in the illness with development of anemia, pericardial effusion, or congestive heart failure have a high risk of "scleroderma renal crisis."     

Renal protective effects of angiotensin-converting enzyme inhibition

Nephron loss is a common progression of a diverse range of kidney diseases. Recent experimental models of chronic renal disease have suggested that hemodynamic and nonhemodynamic mechanisms play key roles in progressive renal injury. Extensive renal ablation in the rat was followed by development of altered glomerular hemodynamics. Albuminuria and histologic damage leading to focal glomerulosclerosis were preceded by the development of increased glomerular pressures and were prevented by interventions such as severe dietary protein restriction and angiotensin-converting enzyme (ACE) inhibitor therapy. Both experimental interventions ameliorated glomerular hypertension. It was therefore concluded that these interventions ameliorated injury by glomerular hemodynamic effect. Similar findings were obtained in a rat model of type I diabetes mellitus induced by streptozotocin in which glomerular hemodynamic factors appeared important to the development of progressive renal disease. Recent studies have suggested that nonhemodynamic factors have important roles in the progression of glomerular injury. For example, although the predominant effects of ACE inhibitor therapy appear to be hemodynamically mediated, data are emerging which suggest that these agents may also influence growth/proliferation of glomerular cells. Because hyperplasia/hypertrophy may influence glomerular susceptibility to injury, this may also be a potential mechanism whereby ACE inhibitor therapy influences glomerular damage. In addition, a variety of studies have suggested that hyperlipidemia, which is frequent accompaniment of glomerular disease, is an important modulator of glomerular injury independent of glomerular hemodynamic effects. Coagulation factors, calcium phosphorus balance, as well as the genetic susceptibility of the glomerulus to injury, all appear to contribute to progressive nephron destruction.     

Development and progression of chronic renal disease: can it be prevented or attenuated?

Following its initiation, renal disease tends to progress relentlessly to end stage, necessitating dialysis or transplantation or causing death. Studies have shown that metabolic, hematologic and hemodynamic adaptations by the damaged kidney underlie the progressive nature of the disease. This review underscores the hemodynamic maladaptations and consequences and the evidence that suggests that glomerular hypertension is a necessary accompaniment to renal damage. The evidence reviewed indicates that high pressure develops in fragile glomerular capillaries after loss of a critical amount of renal mass and causes progressive sclerosis and destruction of remaining nephrons. This maladaptive renal response ensures progressive destruction in a variety of renal diseases including diabetes mellitus. Reduced protein intake and converting enzyme inhibitor therapy may prevent or attenuate the progression of these diseases.     

Renal effects of angiotensin converting enzyme inhibitors: Nondiabetic chronic renal disease

Summary Based on studies in the rat remnant kidney model, it has been proposed that glomerular hypertension is responsible for the progressive nature of chronic renal disease. In that model, therapy with angiotensin converting enzyme (ACE) inhibitors reduced glomerular pressures. As a result, glomerular injury was reduced and the rate of progression of renal disease was slowed. Thus, alterations in hemodynamics may play an important role in glomerular injury. However, it is now evident that a variety of metabolic and other factors affect the progression of renal disease. Moreover, recent studies suggest that ACE inhibitors may also have beneficial effects that are independent of alterations in glomerular pressure. In humans, the glomerular hemodynamic response to renal disease cannot be measured, and it is not known whether or under which conditions glomerular capillary pressure might be elevated. Treatment with ACE inhibitors safely lowers blood pressure without adversely affecting renal function in mots patients with nondiabetic chronic renal failure. Although proteinuria and the rate of progression of renal disease may decrease in some patients, these effects are inconsistently seen. Identification of the factors that modulate this variability in response to ACE inhibition may provide new insight into the pathogenesis and treatment of progressive renal disease in humans.     

Angiotensin II and progressive renal insufficiency

The inhibition of angiotensin II through angiotensin converting enzyme inhibitors or angiotensin receptor blockers has become the foundation of medical treatment of progressive chronic renal disease. Although these drugs provide a significant improvement over earlier treatments, they only slow the progression of renal disease, implying the need for additional drugs that could be combined with antiangiotensin treatment. Potentially valuable novel drug targets include downstream mediators of angiotensin II such as transforming growth factor-b, plasminogen activator inhibitor-1, and endothelin-1. In addition, recent evidence points to aldosterone as a major player in progressive renal disease, indicating that multiple points of the renin-angiotensin-aldosterone system might have to be targeted. This paper reviews the experimental and clinical evidence indicating that targeting these cytokines and hormones could provide additional benefits to antiangiotensin treatment in chronic renal disease.     

Why kidneys fail in autosomal dominant polycystic kidney disease

The weight of evidence gathered from studies in humans with hereditary polycystic kidney disease (PKD)1 and PKD2 disorders, as well as from experimental animal models, indicates that cysts are primarily responsible for the decline in glomerular filtration rate that occurs fairly late in the course of the disease. The processes underlying this decline include anatomic disruption of glomerular filtration and urinary concentration mechanisms on a massive scale, coupled with compression and obstruction by cysts of adjacent nephrons in the cortex, medulla and papilla. Cysts prevent the drainage of urine from upstream tributaries, which leads to tubule atrophy and loss of functioning kidney parenchyma by mechanisms similar to those found in ureteral obstruction. Cyst-derived chemokines, cytokines and growth factors result in a progression to fibrosis that is comparable with the development of other progressive end-stage renal diseases. Treatment of renal cystic disorders early enough to prevent or reduce cyst formation or slow cyst growth, before the secondary changes become widespread, is a reasonable strategy to prolong the useful function of kidneys in patients with autosomal dominant polycystic kidney disease.     

Nierenmanifestationen bei rheumatischen Erkrankungen

Inflammatory rheumatic diseases other than systemic vasculitides and systemic lupus erythematosus are frequently associated with renal abnormalities, which are clinically less apparent due to the subtle course and the often only moderate impairment of renal function. These abnormalities include vascular, glomerular and tubulointerstitial changes. Renal manifestations in the course of rheumatoid arthritis influence the prognosis of the disease. Renal involvement due to AA amyloidosis following long-standing inflammatory joint disease can lead slowly, over years, to end-stage renal disease. A scleroderma renal crisis in the course of systemic sclerosis can potentially result in end-stage renal disease within days. The differential diagnosis of renal abnormalities in a rheumatic patient should include drug induced renal impairment as well as infection.     

Estrogens and progression of diabetic kidney damage

It is generally accepted that estrogens affect and modulate the development and progression of chronic kidney diseases (CKD) not related to diabetes. Clinical studies have indeed demonstrated that the severity and rate of progression of renal damage tends to be greater among men, compared with women. Experimental studies also support the notion that female sex is protective and male sex permissive, for the development of CKD in non-diabetics, through the opposing actions of estrogens and testosterone. However, when we consider diabetes-induced kidney damage, in the setting of either type 1 or type 2 diabetes, the contribution of gender to the progression of renal disease is somewhat uncertain. Previous studies on the effects of estrogens in the pathogenesis of progressive kidney damage have primarily focused on mesangial cells. More recently, data on the effects of estrogens on podocytes, the cell type whose role may include initiation of progressive diabetic renal disease, became available. The aim of this review will be to summarize the main clinical and experimental data on the effects of estrogens on the progression of diabetes-induced kidney injury. In particular, we will highlight the possible biological effects of estrogens on podocytes, especially considering those critical for the pathogenesis of diabetic kidney damage.     

Angiogenic cytokines in renovascular disease: do they have potential for therapeutic use?

Experimental and clinical studies suggest that the damage of the renal microvascular function and architecture may participate in the early steps of renal injury in chronic renal disease, irrespective of the cause. This supporting evidence has provided the impetus to targeting the renal microvasculature as an attempt to interfere with the progressive nature of the disease process. Chronic renovascular disease is often associated with renal microvascular dysfunction, damage, loss, and defective renal angiogenesis associated with progressive renal dysfunction and damage. It is possible that damage of the renal microvasculature in renovascular disease constitutes an initiating event for renal injury and contributes towards progressive and later on irreversible renal injury. Recent studies have suggested that protection of the renal microcirculation can slow or halt the progression of renal injury in this disease. This brief review will focus on the therapeutic potential and feasibility of using angiogenic cytokines to protect the kidney microvasculature in chronic renovascular disease. There is limited but provocative evidence showing that stimulation of vascular proliferation and repair using vascular endothelial growth factor or hepatocyte growth factor can slow the progression of renal damage, stabilize renal function, and protect the renal parenchyma. Such interventions may potentially constitute a sole strategy to preserve renal function and/or a co-adjuvant tool to improve the success of current therapeutic approaches in renovascular disease.     

Nutritional inhibition of genetically determined renal disease and autoimmunity with prolongation of life in kdkd mice.

Striking inhibition of development of renal disease and prolongation of lifespan have been achieved in kdkd mice by restricting their daily food intake. Restricting protein intake alone did not prolong life nor did it inhibit development of kidney disease. The kdkd nephronophthisis, although very different histologically from the renal disease of B/W mice, may also have immunological components. Like the immunologically based renal disease of B/W mice, renal disease in kdkd mice is decreased or eliminated histologically by dietary restriction, which inhibits development of autoimmunity directed toward the erythrocytes of these mice. Further analysis will be needed to elucidate the cause of progressive renal disease in both the kdkd and B/W models and to permit understanding of the profound influence of restriction of food intake on development and progression of these very different renal diseases.     

Nierenmanifestationen bei rheumatischen Erkrankungen

Inflammatory rheumatic diseases other than systemic vasculitides and systemic lupus erythematosus are frequently associated with renal abnormalities, which are clinically less apparent due to their subtle course and impairment of renal function that is often only moderate. These diseases encompass vascular, glomerular, and tubulointerstitial changes. Necrotizing glomerulonephritis in the course of rheumatoid vasculitis influences the prognosis of rheumatoid arthritis. Renal involvement due to AA amyloidosis following long-standing inflammatory joint disease can lead within years to end-stage renal disease, and scleroderma renal crisis in the course of systemic sclerosis can evolve within only days to this outcome. The differential diagnosis of renal abnormalities in a rheumatic patient should include drug-induced renal impairment as well as infection.     

Can the progression of chronic renal failure be delayed?

Chronic renal failure does not only involve the risk for the patient of becoming dependent on hemodialysis, but also increases the risk of premature death due to cardiovascular events. In most renal diseases, progressive chronic loss of renal function develops once a critical extent of renal damage has occurred, independent of the course of the underlying renal disease. The key factors driving the progressive loss of renal function are, apart from the underlying nephrological disease, arterial hypertension and diabetes mellitus. The loss of renal function is also promoted by other factors, such as increased intake of dietary proteins, chronic inflammation, smoking, and anemia. With the help of a multimodal therapeutic concept, the progression of chronic renal failure can be delayed effectively. This approach comprises strict blood pressure control with a target blood pressure of 130/80 mmHg in patients with micro-albuminuria and of 120/75 mmHg in patients with proteinuria of >1 g/d. The preferred drugs for the treatment of hypertension are ACE inhibitors and angiotensin receptor blockers. In diabetics with renal insufficiency, target HbA1c levels below 7% are to be aimed for. Dietary protein intake should be restricted to 0.8-1 g/kg body weight/d. Additional therapeutic targets include nicotine abstinence, early treatment of renal anemia, weight reduction, and, if indicated, lipid-lowering therapy.     

Aldosterone blockade: an emerging strategy for abrogating progressive renal disease

In recent years, there has been a striking paradigm shift with respect to our understanding of the widespread effects of aldosterone. Whereas the role of angiotensin II in mediating progressive renal disease and heart failure has been documented extensively, more recent evidence has implicated aldosterone as an important pathogenetic factor in addition to angiotensin II in the development of these diseases. The focus of this review is aldosterone and progressive renal dysfunction. The extensive preclinical and clinical evidence supporting the efficacy of aldosterone blockade in abrogating proteinuria is summarized. The frequency and clinical importance of aldosterone “escape” is reviewed. Therapeutic considerations to reduce the incidence of hyperkalemia with aldosterone blockade are discussed. The studies reviewed have several important clinical implications for considering new treatment algorithms for patients with incipient nephropathy. Because full doses of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers attenuate but do not abrogate progression of renal dysfunction, add-on aldosterone blockade therapy may constitute a rational therapeutic strategy for retarding progression of renal disease.     

What Are New Avenues for Renal Protection,in Addition to RAAS Inhibition?

Diabetic nephropathy is the leading cause of end-stage renal disease, with both the incidence and prevalence continuing to increase worldwide. Current treatments include optimization of glycemic and blood pressure control by targeting the renin-angiotensin-aldosterone system (RAAS) with angiotensin-converting enzyme (ACE) inhibitors and/or angiotensin II receptor blockers. More innovative strategies are needed to prevent and treat this disease. New agents and approaches have recently been described that have the potential to delay the progression of diabetic kidney disease and minimize the growing burden of end-stage renal disease. Possible targets include the formation of advanced glycation end products (AGEs) and the AGE receptor, increased oxidative stress and inflammation, protein kinase C, endothelin receptors, growth factors and cytokines, the vitamin D receptor, Rho-associated kinases, and the renal sympathetic system. This article reviews these recent developments as potential therapeutic interventions that may prevent this disease, with targets generally beyond the RAAS.     

Trophic factors and cytokines in early diabetic glomerulopathy

The intent of this review is to focus on recent advances in the understanding of the factors responsible for the progressive pathologic features of diabetic kidney disease, with special attention to various growth factors and cytokines that appear to be important in this process. In addition, emphasis is centered on relatively early stages of the disease, because animal models have been most helpful to date in understanding this stage of the disease process. Although tubulointerstitial changes are of critical importance in the progression of diabetic nephropathy, especially in the evolution to end-stage renal disease, there is a general consensus that glomerular pathology occurs first. Therefore, attention is limited to factors that may be important in the development of early diabetic glomerulopathy, including transforming growth factor-beta (TGF-beta), insulin-like growth factor (IGF)-I, vascular endothelial growth factor (VEGF)-A, and connective tissue growth factor (CTGF).     

Kann man die Progression der chronischen Niereninsuffizienz verzögern?

Chronic renal failure does not only involve the risk for the patient of becoming dependent on hemodialysis, but also increases the risk of premature death due to cardiovascular events. In most renal diseases, progressive chronic loss of renal function develops once a critical extent of renal damage has occurred, independent of the course of the underlying renal disease. The key factors driving the progressive loss of renal function are, apart from the underlying nephrological disease, arterial hypertension and diabetes mellitus. The loss of renal function is also promoted by other factors, such as increased intake of dietary proteins, chronic inflammation, smoking, and anemia. With the help of a multimodal therapeutic concept, the progression of chronic renal failure can be delayed effectively. This approach comprises strict blood pressure control with a target blood pressure of 130/80 mmHg in patients with micro-albuminuria and of 120/75 mmHg in patients with proteinuria of >1 g/d. The preferred drugs for the treatment of hypertension are ACE inhibitors and angiotensin receptor blockers. In diabetics with renal insufficiency, target Hb_A1c levels below 7% are to be aimed for. Dietary protein intake should be restricted to 0.8–1 g/kg body weight/d. Additional therapeutic targets include nicotine abstinence, early treatment of renal anemia, weight reduction, and, if indicated, lipid-lowering therapy.     

Scleroderma and pregnancy. New case and review of the literature

A new case of the rare association of scleroderma and pregnancy is reported. The pregnancy was complicated by renal failure in the last month of gestation which was initially well controlled by anti-hypertensive therapy but then suddenly progressed to pre eclampsia with signs of foetal distress necessitating emergency caesarian section. A moderately hypotrophic child was delivered. The mother progressively recovered; diuresis and blood pressure returned to normal and the proteinuria disappeared. In the light of previously reported cases and of recent advances in our knowledge of scleroderma, especially scleroderma renal disease, the authors discuss their attitude to the management of women with scleroderma wishing to become pregnant. They review the role and place of renal biopsy in the detection of subclinical renal lesions due to the scleroderma, the presence of which would be a decisive factor in assessing the risks of pregnancy. Scleroderma renal disease is, in fact, a major contraindication to pregnancy because of the very poor foetal prognosis and the risk of maternal death due to a lethal progression of renal failure.