Aspects of Renal-Pulmonary Pathogenic Replationships in Chronic Kidney Disease and Chronic Pulmonary Diseases – A Less-Known Connection GH. GLUHOVSCHI1,2, SILVIA VELCIOV2,3, LIGIA PETRICA2,3, CRISTINA GLUHOVSCHI3 1

Romanian Academy of Medical Sciences Emergency Clinical County Hospital, Timişoara, Romania 3 “V. Babeş” University of Medicine and Pharmacy Timişoara, Romania 2

The kidneys, as an integral part of the body, are in close functional relationship with other organs. Dysfunction of the relationship with one organ will affect the kidney. Chronic kidney disease (CKD) leads in time to alteration of the relationship of the kidney with other organs, sometimes with severe consequences. Thus, cardiovascular involvement in CKD leads to increased severity of CKD, with an increase in mortality rate. At present, the relationship between the kidney and the lung has been less studied. Many aspects of this relationship are still unknown. The objective of the present paper is to analyze the main situations of the alteration of the kidney-lung relationship in clinical pathology, with special reference to chronic kidney disease. The pulmonary-renal syndrome is at the forefront. This pathology – well known in practice – refers mainly to the kidney-lung relationship in vasculitis, systemic lupus erythematosus and Goodpasture’s syndrome. The relationship between the kidney and the lung is not limited to this syndrome. Many systemic diseases like sarcoidosis and amyloidosis alter the lung-kidney binomial. Likewise, the association in some patients of an important disorder primarily affecting the lung, such as silicosis, with concomitant renal involvement, highlights the relationship between the lungs and kidneys in clinical pathology. It is very important to know heart-kidney relationships via the lung in pulmonary arterial hypertension. In-depth knowledge of the patient with chronic kidney disease also requires thorough analysis of the lung-kidney relationship. This relationship is very evident in haemodialysed patients, taking into consideration that the pulmonary circulation is influenced by the dialysis membranes, in patients on peritoneal dialysis and especially in transplanted patients whose kidney-lung relationship has a favorable outcome. Although little dealt with, the relationship between the kidneys and the lungs requires more attention, as it can have important consequences, and appropriate therapy. Key words: chronic kidney disease, chronic pulmonary disease, pulmonary-renal syndrome.

The kidney is no longer regarded as an isolated organ. It is analyzed within the framework of the whole body. The relationship between the kidneys and other organs is under intense debate at present. The relationship between chronic kidney disease (CKD) and cardiovascular disorders takes central stage since cardiovascular diseases represent the main cause of mortality of CKD patients. Cerebral, especially vascular, involvement is also of paramount importance in CKD. The relationship between CKD and chronic pulmonary disorders has been less often addressed, although the lungs provide the necessary oxygen and the kidneys receive 1/5 of the blood flow, being important consumers of oxygen. The lungs, as well as the kidneys, play an important part in regulating the acid-base and hydro-electrolytic balance of the body. ROM. J. INTERN. MED., 2014, 52, 2, 68–77

Dysfunction of one of these organs will influence the functionality of the other. In acute diseases of these organs the lungkidney relationship is more evident and relatively better-known, but it has been approached less often in case of diseases with chronic evolution. Both the lungs and the kidneys are highly vascularized. An inflammatory disease of the vessels can impair both organs concomitantly. This is evident during auto-immune processes involving especially small and medium-sized vessels. The result is vasculitis. The combined involvement of lung and kidney vessels in vasculitis mediated through antineutrophil cytoplasmic antibodies (ANCAs) is a clear example that both organs (kidneys and lungs) participate together in these diseases. In fact, renal-pulmonary symptomatology is often dominant in the clinical picture.

2

Aspects of renal-pulmonary pathogenic relationships in CKD

This relationship is less clearly expressed in ANCA negative vasculitis. Autoimmune mechanisms that involve the vessels, producing vasculitis, are also present in other immune-mediated diseases. Systemic lupus erythematosus (SLE) sometimes causes vasculitis that involves the kidneys, producing – sometimes severe – glomerulonephritis (GN) associated with pulmonary involvement accompanied by hemorrhagic alveolitis. There are diseases that often affect the lungs and the kidneys sparing other organs. Thus, in Goodpasture’s syndrome, vascular involvement is limited to the lungs and the kidneys. The autoimmune mechanism acts by means of anti-glomerular basement membrane antibodies (anti-GBM antibodies). Anti-GBM antibodies are directed against elements in the GBM structure of the two organs rich in type IV collagen. External triggers uncover some epitopes not exposed to the circulatory system and trigger specific antibodies defined as anti-GBM antibodies. This disease seems to indicate a structural similarity of the two organs reflected in their pathology. Some general diseases that often impair the lungs can also affect the kidneys. In sarcoidosis and silicosis we have both pulmonary and kidney involvement. Generalized diseases, sometimes with pulmonary starting points, like amyloidosis associated with chronic lung suppuration, bronchiectasis or pulmonary abscesses, can affect the kidneys as well, causing important glomerular involvement, often associated with nephrotic syndrome. Pulmonary hypertension during CKD is another example. It represents a new interface between renal and cardiovascular diseases, with simultaneous pulmonary involvement. Simultaneous renal and pulmonary dysfunction in heart failure should not be forgotten. The relationship between CKD and chronic pulmonary disease is noticeable in patients on peritoneal dialysis, hemodialysis or in patients with transplants. The present article deals with some aspects of the relationship between CKD (sometimes with acute manifestations gone chronic) and chronic pulmonary disease. Many of these inter-relations are little known. The aim of the paper is to draw attention to them, hence the symbolic secondary title (“A Less-known Connection”).

69

THE PULMONARY-RENAL SYNDROME

It represents a syndrome that associates diffuse alveolar hemorrhage with glomerulonephritis. These manifestations most often occur simultaneously. The pulmonary injury is represented mainly by small-vessel vasculitis involving arterioles, venules and capillaries. The renal lesion is also a small-vessel vasculitis. It presents as focal and segmental proliferative glomerulonephritis and frequently as glomerulonephritis with extra-capillary proliferation. The pulmonary-renal syndrome expresses most clearly a pathogenic relationship between the kidneys and the lungs that can be severe at the level of both organs. It is most frequently encountered in systemic diseases, such as vasculitis. Vascular lesions are also present in other systemic diseases like SLE and other connective tissue disorders. Some kidney diseases, like Goodpasture’s syndrome, associate renal vascular lesions with pulmonary injury. Some drugs can cause lesions of the vascular system, affecting renal and pulmonary small vessels. It is to be noted that this variety of diseases that involve simultaneously the kidneys and the lungs also presents various pathogenic mechanisms. The most important pathogenic mechanisms are represented by: – the presence of ANCAs in some vasculitides – immune mechanisms mediated by immune complexes present mainly in SLE. – anti-glomerular basement membrane antibodies as in Goodpasture’s syndrome Pathogenic mechanisms reflect the fact that in some diseases, pathology occurs at both renal and pulmonary level. In some of these diseases, as in vasculitis and in immune diseases of the connective tissue, the impairment is not limited to the lungs and the kidneys, whose lesions dominate the clinical picture, but it causes complex impairment of tissues and organs. In Goodpasture’s syndrome, the vascular injury seems to be much more limited, being present only in the kidneys and the lungs. Impairment of other organs is not clinically present, but in severe cases secondary manifestations occur, for example cardiovascular ones. The fact that the relationship between the lungs and the kidneys can be so complex – confined

70

Gh. Gluhovschi et al.

to the two organs or present systemically – indicates the existence of possible structural similarities of these two organs that require in-depth study and proper approaches. Pathogenic mechanisms that act in the relationship between the lungs and kidneys in the pulmonary-renal syndrome are auto-immune mechanisms. Structural alterations of one organ (either the lung or the kidney) related to infection or drugs can trigger the production of autoantibodies which cross-react with structures of the other organ. Some of the antigens are cryptic epitopes that become exposed secondary to infection or drugs. This is why therapy of these diseases is directed at auto-immune mechanisms: corticosteroids, immunosuppressive drugs, plasmapheresis. We will focus on reviewing diseases representative for the pulmonary-renal syndrome, with their pathogenic mechanisms and we will also mention other diseases. VASCULITIS

Vasculitis represents the main cause of the pulmonary-renal syndrome. Depending on the presence of ANCAs it can be defined as ANCApositive vasculitis and ANCA-negative vasculitis. ANCA-positive vasculitis is often associated with pulmonary manifestations while ANCA-negative vasculitis rarely presents this association. ANCA-positive vasculitis involved in the pulmonary-renal syndrome is represented by granulomatosis with polyangiitis (Wegener’s syndrome), microscopic polyangiitis and eosinophilic granulomatosis with polyangiitis (Churg-Strauss syndrome). In these vasculitides small vessels are affected secondary to the activity of neutrophils that cause inflammatory lesions at the levels of the arterioles, capillaries and venules. Monocytes also play an important part. Leukocytes (neutrophils and monocytes) are activated by ANCA-type antibodies. As a consequence of the activity of some inflammatory factors (cytokines) or of some microbial products, proteinase 3 or myeloperoxidase are expressed on the surface of leukocytes. The antibodies formed against these antigens lead to leukocyte activation with release of proteolytic enzymes, which induce vascular lesions. Some infections with germs like staphylococcus aureus, which can be located at the level of the nasal mucosa, can act at leukocyte level, probably by molecular mimicry, and activate a release of factors similar to ANCA.

3

In fact staphylococcus aureus can act by its antigens as a super-antigen activating Th17 cells, which intervene in autoimmune processes [1]. Alveolar capillaries and interstitial vessels are impaired at pulmonary level where destruction and necrosis occur. Renal vascular injury can show fibrinoid necrosis. Renal biopsy can reveal the presence of an interstitial granuloma. Vascular lesions allow access of monocytes into the filtration space, release of fibrin and infiltration of fibroblasts that causes extra-capillary proliferative glomerulonephritis. As a consequence of the lesions of pulmonary capillaries, hemoptysis occurs by extravasation of erythrocytes at the level of the alveoli. At kidney level, as a consequence of lesions of the glomerular capillaries hematuria and proteinuria occur and renal function is impaired. It is to be mentioned that at kidney level there is a paucity of immune deposits (immunoglobulins and complement). This is the reason why the lesion is defined as pauci-immune glomerulonephritis. THE IMMUNE-COMPLEX- MEDIATED PULMONARY-RENAL SYNDROME

This category includes systemic lupus erythematosus (SLE), other diseases of the connective tissue (rheumatoid arthritis, polymyositis or dermatomyositis, progressive systemic sclerosis). ANCA negative vasculitis, Henoch Schonlein Purpura, mixed cryoglobulinaemia, IgA nephropathy and Behçet’s disease are mediated by immune complexes [2]. PULMONARY-RENAL SYNDROME IN SLE

SLE is a systemic disease mediated by important immune mechanisms. Clinical manifesttations in SLE are complex. One of the most important is the renal one. This can be sometimes very severe, significantly influencing the outcome of the disease. Pulmonary-renal syndrome is a rare complication of SLE, associated with high mortality. Renal dysfunction that accompanies pulmonary-renal syndrome is also often severe. Immune mechanisms are present in SLE, with antibodies against many structures of the body. The main antigens are represented by DNA. Auto-antibodies are triggered against double stranded DNA, forming immune complexes. Their deposition

4

Aspects of renal-pulmonary pathogenic relationships in CKD

at kidney level is associated with the presence of serum complement, of cellular immunity mechanisms (B and T cells) and of numerous inflammatory mediators (cytokines, chemokines, etc.). Glomerulonephritis ensues, which sometimes has a severe evolution. Similar mechanisms produce vasculitis-like pulmonary lesions, causing alveolar hemorrhage, sometimes accompanied by hemoptysis. Hughson et al. found in patients with SLE immune complex-deposits at pulmonary and kidney level. The alterations produced by alveolar deposits are similar to renal ones. Hughson et al. mention that the pathogenesis of pulmonary lesions seems to be correlated with deposition of immune complexes and induction of apoptosis. After Hughson the pathogenesis of microvascular injury in kidney and lung is in relationship with these [3]. It is not known why clinically manifest pulmonary impairment is so rare, but we have to take into consideration that its association with renal impairment indicates a possible severe evolution. GOODPASTURE’S SYNDROME

Goodpasture’s syndrome is an autoimmune renal disease mediated by anti-glomerular basement membrane antibodies (anti-GBMs). They affect both the glomerular BM, causing GN, often with extra-capillary proliferation, and the pulmonary BM, presenting with alveolar hemorrhage followed by hemoptysis. Alterations of the BM are followed by the production of antibodies directed against the noncollagenous (NC-1) domain of alpha 3 chain of type IV collagen. High-concentrations of this type of collagen are present in glomerular and pulmonary BM. The presence of this collagen in both glomerular and pulmonary BM could explain the simultaneous impairment of the two basal membranes [4]. According to Chan et al. a “conformeropathy” could exist that refers to conformational alterations of the BM (conformational change) [5]. The immune inflammatory reaction is mediated by antibodies, with the participation of cellular immunity. The complement system also plays a part. This reaction is related to various factors that facilitate immune reactions. Thus, inhalation of organic solvents would allow exposure of cryptic antigens at capillary level, which are normally

71

hidden. Anti-GBM antibodies would react with these antigens. Viral infections could act in a similar fashion. Genetic predisposition could also facilitate such reactions. It is essential to know that fenestrations in glomerular capillaries allow access of circulating anti-GBM antibodies to the glomerular BM to which they get attached. Activation of the complement cascade allows access of neutrophils and monocytes to the fibrinogen spilled in Bowman’s space. Fibrinogen forms fibrin and associates with active monocytes. They generate crescents in the glomeruli. IL1 attracts fibroblasts in the interstitium which enhances crescent formation. Alveolar capillaries have no fenestrations and the endothelium could act as a barrier against antiGBM antibodies. When this barrier is disrupted, anti-GBM antibodies can cross-react with the pulmonary BM. RENAL INJURY IN SARCOIDOSIS, A SYSTEMIC DISEASE WITH PREDOMINANTLY PULMONARY INVOLVEMENT

Sacoidosis is a systemic disease of unknown etiology characterized by the formation of epitheloid cell granulomas in the organs involved [6]. Sarcoidosis mostly affects the lungs. It can be associated with cardiac, cutaneous, ophthalmologic, neurological, muscular-skeletal, gastrointestinal, and renal manifestations. The main lesion is produced by granuloma. In rare cases, sarcoidosis is not associated with pulmonary involvement. Involvement of one organ only is rare. The real incidence of the disease is not known. It was found more frequently in the USA and in Japan. Renal involvement in sarcoidosis varies highly in the literature. Acute cases are rare, chronic ones are more frequent. Bergner et al. estimate the incidence of renal involvement in chronic sarcoidosis to be 46% [7]. The etiology of sarcoidosis is still unknown. There are data that incriminate genetic factors. Familial clustering is mentioned, but no genetic marker of the disease was defined until present. Various infectious agents, mainly mycobacteria, are discussed as possible producers of the disease. Other incriminated germs are propionibacterium acne, viruses, etc. The fact that the disease can be transmitted via transplanted organs could argue in

72

Gh. Gluhovschi et al.

favour of an infectious etiology. Another hypothesis is the autoimmune hypothesis. Delayed type hypersensitivity mechanisms could be involved. The granulomatous reaction is considered a dominant element. Baughman considers that sarcoidosis could be related to a particular immune mechanism associated with genetic factors. This could be a reaction to antigens, mainly infectious ones. The immune reaction could be a long-term one, although a further presence of the antigen is no longer noticed. Anti-TNF antibodies were also incriminated [8]. Sarcoidosis can be observed during patients treated with etanercept. Abnormalities of vitamin D3 metabolism are also found in the cells composing the granulomatous lesions. Consequently, hypercalcemia occurs. It is due to an excess of 25 (OH) Vitamin D conversion to 1.25 (OH) Vit D by a process of action of macrophage 1 hydroxylase in granulomas. Hypercalcaemia can be followed by hypercalciuria with nephrocalcinosis. This can be associated with renal lithiasis which, in its turn, can be associated with obstruction of the excretory system. Sarcoidosis with renal involvement can also be associated with high blood pressure, whose mechanism has not been clarified yet. The main renal manifestations in sarcoidosis are represented by granulomatous interstitial nephritis and by manifestations secondary to disorders of calcium metabolism frequently associated with calcemic nephropathy. In children, kidney-located sarcoidosis presents mainly with granulomatous interstitial nephritis. Coutant et al. report 11 cases of granulomatous interstitial nephritis [9]. Renal and pulmonary localisations of sarcoidosis are frequently associated. In this situation both pulmonary and renal involvement are the expression of one and a single disease, with corresponding evolution of each organ. The fact that both organs are impaired at the same time indicates their combined participation to the disease within the same pathogenic mechanism and it expresses the relationship of the two organs in sarcoidosis. It should be mentioned that sarcoidosis cases were reported with renal impairment without pulmonary involvement and cases of pulmonary impairment without renal involvement, which explains the complexity of renal participation. Renal failure is a rare complication of renal sarcoidosis. It is due to granulomatous interstitial

5

nephritis associated with calcium metabolism disorders. An association of pulmonary and renal involvement is not to be found in all cases [10]. Sometimes it is difficult to diagnose sarcoid granulomatous nephritis that occurs under the form of isolated acute kidney injury [11]. Renal involvement in sarcoidosis, a systemic disease in which the pulmonary lesion is predominant raises the question of the concomitant participation of the two organs in a disease with generally systemic character, indicating that injury could occur by a common pathogenic mechanism. The fact that the kidney-lung association is not present in all cases could plead for a characteristic specific reaction of the two affected organs. EXPOSURE TO SILICA DUST – PULMONARY AND RENAL INVOLVEMENT

Important groups of people are exposed during their professional activity to silica. This is released under dust-form in the environment and the air and it reaches the body via the respiratory system. Part of the silica dust will be deposited in the lungs and a small part will reach the kidneys via the circulation. In case of long-term exposure, the silica dust will accumulate at lung level and it will have a noxious influence. This is due to the toxic activity of the silica and to the immune reactions it triggers. Silica can also cause nephrotoxic effects at kidney level. At the same time, the presence of silica in the body triggers autoimmune phenomena, being thus incriminated in the production of autoimmune diseases, like SLE or scleroderma. Autoimmune mechanisms can cause renal dysfunction that augments the lesions produced by nephrotoxicity. Pulmonary and renal lesions can be associated in patients exposed to silica dust as an occupational noxious agent. Under exposure to silica dust pulmonary lesions progress towards a clinically manifest disease defined as silicosis. Pulmonary involvement in silicosis can be associated with cor pulmonale and with important respiratory failure. According to Ghahramani, exposure to silica dust can be associated with the following diseases with renal involvement: tubulointerstitial disease, immune-mediated multi-system disease, chronic kidney disease and end-stage renal disease [12].

6

Aspects of renal-pulmonary pathogenic relationships in CKD

Exposure to silica dust primarily affects miners, mainly those working in coal mines, but also those working in other categories of mines, for example gold mines. Other exposed activities are represented by work in stone pits, in blasting workshops, in the ceramics industry, in glass processing, etc. Exposure to that kind of activities is long-term, it lasts for several years. Pulmonary silicosis has various forms (micronodular, macro-nodular). The dominant element is pulmonary fibrosis. It is sometimes associated with pulmonary tuberculosis. Cor pulmonale appears progressively and it is accompanied by chronic respiratory failure. Silica nephropathy manifestations can be a consequence of silica nephrotoxicity or of autoimmune phenomena triggered or accelerated by exposure to silica dust. These manifestations will have various aspects, tubulointerstitial disease, caused by direct toxic action, or glomerular/ vascular involvement in the context of autoimmune phenomena related to the immune reaction to the presence of silica in the body. A study conducted by Trifan et al., analysing 2 groups of persons with occupational exposure to silica dust – one in gold mines, the other in coal mines – found microalbuminuria in 34% patients of the first group and in 19% of the second group. The prevalence of eGFR < 60 ml/min was 18% in the first group and 10% in the second. The two groups of miners under study presented chronic pulmonary diseases, mainly chronic obstructive pulmonary disease. Some of them also had silicosis (68% in the first group and 30% in the second) [13]. The presence of CKD in occupationallyexposed-to- silica-dust miners correlated with the duration of exposure, that is the length of their mining activity. Vupputuri et al. reported that exposure to silica dust is associated with increased risk for CKD, related to the duration of exposure to silica dust [14]. End-stage renal disease (ESRD) was reported by several studies with occupational exposure to silica dust: – in 4626 silica-exposed persons in the sand industry [15] – in a group of 2412 miners in South-Dakota, USA gold mines [16] – in 2980 male ceramic workers in Civito Castelara, Italy [17].

73

The study of Rapiti found that ESRD was more frequent in silicosis patients, which could plead for an acute toxic effect at both lung and kidney level [17]. Other authors, like Steenland, do not consider that silicosis patients present an increased risk of developing ESRD [15]. Genetic susceptibility also plays a role, as well as the type of sand people are exposed to. According to Parks et al., the silica dust acts as a non-specific adjuvant in autoimmune reactions promoting and accelerating autoimmune diseases. These could be related to genetic or environmental factors [8]. Autoimmune diseases associated with silicosis are Wegener’s granulomatosis, ANCA-associated small vessel vasculitis and polyarteritis nodosa [12]. Another association of renal dysfunction with silicosis was reported in patients with SLE and rheumatoid arthritis. The association of renal involvement in silicosis, either by direct nephrotoxic effect, or by autoimmune mechanisms, argues in favour of a nephrotoxic and autoimmune action of silica dust both on the lungs and kidneys and suggests that some pathogenic mechanisms in silicosis might concomitantly affect the lungs and the kidneys. RENAL AMYLOIDOSIS AND PULMONARY DISEASES

Amyloidosis is a disease that can involve the lung and the kidneys simultaneously. It is caused by the deposition of fibrillar insoluble proteins in various organs. As a consequence of this deposition in various organs, disorders and, in severe cases, organ failure occurs. Amyloidosis is most often systemic. Localised amyloidosis is described in rare cases. Hereditary amyloidosis is another form of the disease. Renal involvement is frequent in amyloidosis. It can lead to chronic renal failure that requires renal replacement therapy. Renal amyloidosis is sometimes related to pulmonary diseases: often suppurative chronic pulmonary infections and bronchiectasis, lung abscesses with chronic evolution. Pulmonary tuberculosis can also be the cause of amyloidosis with renal impairment. More rarely, amyloidosis can be caused by pleural empyema with chronic evolution. At the basis of secondary amyloidosis with renal localisation, lies the deposition of an acute-phase inflammatory protein, namely the acute phase reactant serum amyloid A (SAA) [19].

74

Gh. Gluhovschi et al.

This protein is produced by the liver under the action of some stimuli, after an infection with chronic evolution. Thus, a chronic lung infection can lead to amyloidosis with renal localisation. Among stimulating factors, pro-inflammatory cytokines IL1, IL 8, TNF alpha are of foremost importance [20]. This secondary amyloidosis is also defined as AA amyloidosis. It could have a preference for the kidneys [19]. A type of amyloidosis that affects concomitantly the lungs and the kidneys is caused by leukocyte chemotactic factor 2 (LECT 2). Thus, Khalighi reports a case of pulmonary-renal syndrome produced by this factor [21]. Tuberculosis was considered the main cause of pulmonary amyloidosis. Modern chemotherapy for tuberculosis reduced the number of cases of amyloidosis [22]. Dixit et al. mentioned that renal amyloidosis can also be present in patients with pulmonary tuberculosis with long-term evolution, even when correctly treated [20]. Amyloidosis secondary to bronchiectasis was reported in association with renal amyloidosis [23]. Pulmonary fibrillar deposits appear under three forms: tracheobronchial, nodular pulmonary and alveolar septal [24]. No particular relationship with a possible renal localisation was reported. The relationship between the infectious focus and renal amyloidosis is relevant when the therapeutic control of a pulmonary focus leads to improvement of renal impairment. Lowenstein et al. reported the favorable evolution of a patient with nephrotic syndrome under antibiotic treatment of the pulmonary focus [25]. Castellano et al. also reported remission of a patient with nephrotic syndrome after tuberculostatic treatment [26]. PULMONARY ARTERIAL HYPERTENSION – EXPRESSION OF THE RELATIONSHIP BETWEEN CHRONIC KIDNEY DISEASE, AND THE PULMONARY AND CARDIOVASCULAR APPARATUS

Pulmonary arterial hypertension can occur as such, being a rare disease in which immune processes intervene. Pulmonary arterial hypertension (PAH) can also occur as a secondary manifestation during CKD, after this disease has impaired the heart. It is caused by left ventricular disorders under the influence of precipitating factors.

7

It is common knowledge that there is important and frequent cardiovascular involvement in CKD. In fact this cardiovascular pathology represents the main cause of mortality in CKD. High blood pressure and atherosclerotic coronary disease account for the largest part of cardiovascular diseases. Left ventricle dysfunction will influence the pulmonary circulation, causing pulmonary hypertension. Later, it will also influence the right heart, being often associated with tricuspid valve insufficiency. PAH in the early stages of CKD presents mild clinical manifestations. It becomes more frequent in the pre-dialysis phase. PAH appears very often in hemodialysed patients and in patients on peritoneal dialysis. Bolignano et al. consider that the prevalence of PAH is between 9-39% in CKD patients, 18.868.8% in hemodialysed patients and 0-42% in patients on peritoneal dialysis [27]. From a clinical point of view, PAH is frequently asymptomatic in the early stages and it becomes clinically manifest in the advanced stages of CKD, especially in End Stage Renal Disease. Initially, dominant clinical manifestations are represented by dyspnoea and fatigue, followed later on by symptoms of right ventricle dysfunction. PAH can present with severe clinical manifestations of which acute lung oedema is the most important. By association with coronary disease and other risk factors PAH can lead to global heart failure. Diagnosis is suggested by clinical manifestations. It can be specified using invasive methods, such as right-sided cardiac catheterization with assessment of mean pulmonary artery pressure and pulmonary vascular resistance. At present, non-invasive methods are preferred. Doppler ultrasound is used to assess PAH. The heart-kidney relationship in case of PAH is accompanied by unfavourable evolution of predialysis CKD, because of diminished renal irrigation. Shah et al. report that the association of CKD with PAH is expressed by high values of serum creatinine associated with hemodynamic alterations and high mortality risk [28]. The main factor causing PAH is a dysfunction of the left ventricle. Insufficiently therapy-controlled hypertension, severe post-infarction coronary disease and inefficient control of hydroelectrolytic balance with volume overload are aggravating factors.

8

Aspects of renal-pulmonary pathogenic relationships in CKD

Diabetes mellitus, especially by metabolic disturbances associated with coronary disease, is also a risk factor. According to Bolignano et al. pre-existing connective tissue diseases, associated infections, hematological and hepatic diseases play an important role in causing PAH in CKD patients. Bolignano et al. considers that they intervene in influencing the microvascular tone in the lung [27]. Hemodialysis influences PAH via the presence of an arterio-venous fistula that influences cardiac output and via the presence of the dialysis membranes. Activation of neutrophils takes place at their level, followed by their pulmonary sequestration with perturbation of the pulmonary microcirculation [29, 30]. The membranes recently used in haemodialysis diminish the abovementioned effects. Interruption of the functionality of the arteriovenous fistula diminishes PAH [31]. Other risk factors also intervene in causing or worsening PAH – sleep apnoea, endothelial dysfunction [32, 33], increased stiffness of the pulmonary artery partly because of disorders of phosphorus-calcium metabolism, with arterial calcification [34]. Disturbances in NO production are also reported with excess production of asymmetric dimethylarginine (ADMA), an inhibitor of NO synthase [33]. The CKD-heart relationship is also important from the point of view of pulmonary impairment, namely PAH, which is an aggravating factor accompanied by an important mortality rate. Appropriate treatment of PAH is mandatory. Renal transplantation plays an important part as it brings about regression of PAH. CKD STAGE V – DIALYSED PATIENTS AND PATIENTS WITH RENAL TRANSPLANTS

Lung congestion is frequent in ESRD and represents a risk factor for these patients. Haemodialysed patients can present both acute and chronic pulmonary diseases. Fairshter mentions diseases like interstitial fibrosis, pleural fibrosis, calcifications, pulmonary amyloidosis, granulomatous lung disease, and, in some cases, pulmonary artery atherosclerosis (rare), and lung cancer (35).

75

Some hemodialysed patients present nospecific bronchial hyper-reactivity (Ferrer et al.). Ferrer considers that subclinical interstitial oedema could be involved in lung functional impairment in hemodialysed patients [36]. Another functional renal disorder noticed in other hemodialysed patients consists of restrictive ventilation disturbance with perturbation of tests indicative of small airway disease obstruction [37]. It is worth mentioning that recent assessments of hemodialysed patients’ lung by means of bioimpedance, ultrasound, found pulmonary involvement consisting of lung congestion. These explorations could detect lung alterations that need correction. Zoccali et al. define lung congestion as a hidden threat in end-stage kidney disease [38]. Enia et al. report pulmonary congestion in peritoneal dialysis patients [39]. Patients with chronic obstructive pulmonary disease (smokers) have increased risk of kidney transplantation (Kent et al.) [40]. In transplanted CKD patients various pulmonary abnormalities, pulmonary calcifications, fibrosis and hemosiderosis have been identified. They are present in patients with poor transplantation, but absent in patients with successful renal transplantation. One can conclude that dialysed patients can present chronic pulmonary involvement that can influence life quality. Pulmonary changes have favourable evolution after renal transplantation. CONCLUSIONS

The lungs and the kidneys present many functional similarities in the way they regulate body homeostasis. Kidney and lung pathology identifies the existence of a relationship between CKD and chronic pulmonary diseases. The best known is the pulmonary-renal syndrome. The kidney-lung relationship includes other diseases with systemic manifestations, like sarcoidosis, amyloidosis, silicosis, etc. The framework of the pulmonary-renal syndrome has to be enlarged and chronic pulmonary disease has to be regarded as an important partner of the kidney in CKD.

Rinichiul, ca parte integrantă a întregului organism, se află în strânsă legătură funcţională cu celelalte organe. O disfuncţie a relaţiei cu un organ atrage şi suferinţa rinichiului.

76

Gh. Gluhovschi et al.

9

Boala cronică de rinichi (BCR) duce în timp la perturbarea relaţiei rinichiului cu alte organe cu consecinţe uneori severe. Afectarea cardiovasculară din BCR duce la agravarea BCR cu numeroase cauze de deces. În prezent, relaţia dintre BCR şi plămân, respectiv cu afecţiunile pulmonare, este mult mai puţin abordată. Numeroasele sale aspecte rămân puţin cunoscute. Lucrarea de faţă are ca obiectiv principal situaţii din patologia clinică a perturbării relaţiei dintre rinichi şi plămân cu referire în principal la BCR. În prim plan se situează sindromul pulmonar-renal, o patologie mai bine cunoscută în practică, care se referă în principal la relaţia dintre rinichi şi plămân în vasculite, lupusul eritematos sistemic (LES) şi sindromul Goodpasture. Relaţia dintre rinichi şi plămân nu se limitează la acest sindrom. Multe boli cu afectare sistemică ca sarcoidoza şi amiloidoza afectează binomul plămânrinichi. De asemenea, asocierea unei afecţiuni importante care interesează în primul rând plămânul, ca silicoza, concomitent cu afectarea renală la unii bolnavi aduce în discuţie relaţia în patologie dintre plămân şi rinichi. Este foarte importantă cunoaşterea relaţiei cord rinichi prin intermediul plămânului în cadrul hipertensiunii arteriale pulmonare. Cunoaşterea bolnavului cu BCR impune şi o analiză atentă a relaţiei plămân-rinichi. De altfel, această relaţie trebuie cunoscută şi la bolnavii hemodializaţi având în vedere că circulaţia pulmonară este influenţată şi de membranele de dializă, la bolnavii cu dializă peritoneală şi, în special, la bolnavii transplantaţi la care relaţia rinichi-plămân are o evoluţie favorabilă. Deşi puţin abordată, relaţia dintre rinichi şi patologia pulmonară necesită a fi privită cu un interes mai mare deorece implicarea ei în patologie poate avea consecinţe importante impunând o terapie adecvată. Corresponding author: Professor Gheorghe Gluhovschi Calea Alexandru Ioan Cuza, No. 8, Ap. 16 300088 Timişoara, Romania E-mail: [email protected] REFERENCES 1.

CARTIN-CEBA R, PEIKERT T, SPEKS U. Pathogenesis of ANCA-associated vasculitis. Rheum Dis. Clin. North. Am. 2010, 36, 3, 463-477. 2. McCABE C, JONES Q, NIKOLOPOULOU A, WATHEN C, LUQMANI R. Pulmonary-renal syndromes: An update for respiratoy physicians. Respiratory medicine. 2011, 105, 1413-1421. 3. HUGHSON MD, HE Z, HENEGER J, MCMURRAY R. Alveolar hemorrhage and renal microangiopathy in systemic lupus erythematosus immune complex small vascular injury with apoptosis. Arch Pathol Lab Med 2001, 125, 475-483. 4. DEMMACCO F, BATTAGLIA S, GESUALDO L, RACANELLI V. Goodpasture’s disease:a report of ten cases and a review of literature. Autoimmune Rev.2013, 12, 11, 1101-1108. 5. 5CHAN AL, LOUIE S, LESLIE KO, JUAREZ MM, ALBERTSON TE. Cutting edge issues in Goodpasture’s disease. Clin.Rev Alergy Immunol.2011, 41, 2, 151-162. 6. IKEDA A, NAGAI S, KITAICKI M, HAYASHI M, HAMADA K, SHIGEMATSU M, NAGAO T, IZUMI T, Sarcoidosis with granulomatous interstitial nephritis. Report of three cases. Internal Medicine. 2001, 40, 241-245. 7. BERGNER R, HOFFMANN M, WALDHERR R, UPPENKAMP M. Frequency of kidney disease in chronic sarcoidosis. Sarcoidosis Vasc. Diffuse Lung Dis. 2003, 20, 126-132. 8. BAUGHMAN RP. A concise review of pulmonary sarcoidosis. Am. J. Resp. Crit. Care Med. 2011, 183, 5, 573-581. 9. COUTANT R, LEROY B, NIAUDET P, LOIRAT E, DOMMERGUES JP, ANDRE JL, BACULAR D, BENSMAN A. Renal granulomatous sarcoidosis in childhood: a report of 11 cases and review of the literature. Eur. J. Pediatr. 1999, 158, 2,154-159. 10. SADEH BH, SQUALLI Z, AL HAMANY Z, BENAMAR L, BAYAHIA R, OUZEDDOUN N. Renal failure in sarcoidosis. Rev. Pneumol. Clin. 2011, 67, 6, 324-326. 11. LE BESNERAIS M, FRANÇOIS A, LEROY F, JANVRESSE A, LEVESQUE H, MARIE I. Renal sarcoidosis: a series of five patients. Rev Med Interne. 2011, 32, 1, 3-8. PubMed. 12. GHAHRMANI N. Silica nephropathy.www.theijoem.comp.2010, vol. 1, no. 8, 108-114.

10

Aspects of renal-pulmonary pathogenic relationships in CKD

77

13. TRIFAN E, VELCIOV S, MATES A, GLUHOVSCHI C. Evaluation of the renal function in persons with occupational exposure to silica dust (Gold and coal mines). J. Exp. Med Surg. Res/Cerc. Exp. Med. Chir. 2011, VIII, 2, 83-89. 14. VUPPUTURI S, PARKS C, NYLANDER LA, OWEN-SMITH A, HOGAN SL, SANDLER DP. Occupational silica exposure and chronic kidney disease. Renal Failure 2012, 34, 1, 40-46. 15. STEENLAND K, ROSEMAN V, SOCIE E, VALIANTE D. Silicosis and end stage renal disease. Scand. J. Work. Eviron Health. 2002, 28, 6, 439-442. 16. CALVERT GM, STEENLAND K, PALU S. End-stage renal disease among silica-exposed gold miners. A new method for assessing incidence among epidemiologic cohort. JAMA 1997, 277, 15, 1219-1223. 17. RAPITI E, SPERATI A, MICELI M, FORASTIERE F, DILALLO D, CAVARIANI F, GOLDSMITH DE, PERUCCI CA. End stage renal disease among ceramic workers exposed to silica. Occup. Environ. Med 1999, 56, 8, 559-561. 18. PARKS CG, CONRAD K, COOPER GS. Occupational exposure to crystalline silica and autoimmune disease. Environ Health Perspect. 1999, 107, suppl 5, 793-802. 19. KHALIGHI MA, WALLACE D, PALMA-DIEA MF. Amyloid nephropathy. Clin. Kidney J. 2014, 7, 2, 97-106. 20. DIXIT R, GUPTA R, DOVE L, PRASAD N, SHARMA S. Clinical profile of patients having pulmonary tuberculosis and renal amyloidosis. Lung India 2009, 26, 2, 41-45. 21. KHALIGHI MA, YUE A, HWANG MT, WALLACE WD. Leucocyte chemotactic factor 2 (LECT2). Amyloidosis presenting as pulmonary renal syndrome (a case report and review of the literature). Clin Kidney J. 2013, 6, 16, 618-62. 22. KRISHNAMURTHY S, SAMANTA D, YADAV S. Renal amyloidosis secondary to childhood tuberculosis: a report of two cases. J Postgrad Med. 2009, 55, 2:121-123. 23. AKCAY S, AKMAN B, OZDEMIR H, EYUBOGLU FA, KARACAN O, OZDEMIR N. Bronchiectasis-related amyloidosis as a cause of chronic failure. Ren Fail 2002, 24, 6, 815-823. 24. WIEIRA IG, MARCHIORI F, ZANETTI G, GABRAL RF, TAKAYASSU TC, SPILBERG G, BATISTA RR. Pulmonary amiloidosis with calcified nodules and masses-a six year computed tomography. Cases Journal 2009, 2, 6540 doi 10, 4076/17571626-2-6540. 25. LOWENSTEIN L, GALLO G. Remission of the nephritic syndrome in renal amyloidosis. N. Engl. J. Med 1970; 282, 128-132. 26. CASTELLANO I, GOMEZ-MAARTINO JR, HERNANDEZ MT, NOVILLO R, COVARSI A. Remission of nephrotic syndrome caused by renal amyloidosis secondary to pulmonary tuberculosis after tuberculostatic treatment. Nephrologia 2001, 21, 1, 88-91. 27. BOLIGNANO D, RASTELLI S, AGARWAL R, FLISER D, MASSY Z, ORTIZ A, WIECEK A, MARTINEZ-CASTELAO A, COVIC A, GOLDSMITH D, SULEYMANIAR G, LINDHOLM B, PARATI G, SICARI R, GARGANIS L, MALLAMACI F, LONDON G, ZOCCALI C. Pulmonary hypertension in CKD. Am. J Kidney Dis. 2013, 61, 4, 614-622. 28. SHAH SJ, THENAPPAN T, RICH S, TIAN L, ARCHER SL, GOMBERG-MAITLAND M. Association of serum creatinine with abnormal hemodynamics and mortality in pulmonary arterial hypertension. Circulation. 2008, 19, 2475-2483. 29. YIGLA M, NAKHOUL F, SABAGH A. Pulmonary hypertension in patients with end-stage renal disease. Chest 2003, 123, 1577-1582. 30. ABASSI Z, NAKHOUL F, KANKIN E, REISNER SA, YIGLA M. Pulmonary hypertension in chronic dialysis patients with arteriovenous fistula pathogenesis and therapeutic perspective. Curr Opin Nephrol Hypertension 2006, 15, 353-360. 31. CLARKSON MR, GIBLIN L, BROWN A, LITTLE D, DONOHOE J. Reversal of pulmonary hypertension after ligation of a brachiocephalic arteriovenous fistula. Am J. Kidney Dis. 2002, 40. c8 PubMED. 32. GIAID A, SALEH D. Reduced expression of endothelial nitric oxide synthase in the lungs of patients with pulmonary hypertension. N. Engl J. Med. 1995, 333, 214-221. 33. ZOCCALI, C. The endothelium as a target in renal diseases. J. Nephrol. 2007, 20, 12, 39-44. 34. NITTA K, AKIBA T, UCHIDA K et al. The progression of vascular calcification and serum osteoproterigin levels in patients on long-term hemodialysis. Am. J. Kidney Dis 2003, 42, 303-309. 35. FAIRSHTER RH, VAZIRI ND, MIRAHMADI MK. Lung pathology in chronic hemodialysis patients. Int J Artif Organs. 1982 Mar; 5(2):97-100. 36. FERRER A, ROCA J, RODRIGEZ-ROISIN R, LOPEZ-PEDRET J, REVERT I. Bronchial reactivity in patients with chronic renal failure undergoing haemodialysis. Eur Resp J. 1990, 3, 4, 387-391. 37. MAHMOUD BL, ABDULKADER A, EL-SHARKAWY MM, KHALIL HH. Assessment of pulmonary functions in chronic renal failure patients with different haemodialysis regimen. J. Egypt Soc Parasitol. 2004, 34, 3, 1025-1040. 38. ZOCCALI C, PUNTORIERI E, MALLAMACI F. Lung congestion as a hidden threat in end stage kidney disease:a call to action. Nephrol. Dial. Transplant. 2013, 28, 11, 2657-2660. 39. ENIA G, TRIPEPI R, PANUCCIO V, TORINO C, GAROZZO M, BATTAGLIA GG, ZOCCALI C. Pulmonary congestion and physical functioning in peritoneal dialysis patients. Perit Dial Int. 2012, 32, 5, 531-516. 40. KENT BD, ELTAYEB EE, WOODMAN A, MUTWALI A, NGUYEN HT, STOCK AG. The impact of chronic obstructive pulmonary and smoking on mortality and kidney transplantation in end-stage kidney disease. Am. J. Nephrol. 2012, 36, 3, 287-295. Received May 25, 2014