| Abstract|| |
Since glomerulonephritis is a typical inflammation, we are approaching the time when inhibitors of the mediators of inflammation will be used to modify the course of nephritides. In this category are thromboxane synthetase inhibitors and thromboxane antagonists as well as anti-leukotriene and anti-platelet activating factor agents. Corticosteroids are often limited by their side effects. Other approaches include the use of heparins, endothelin antagonists and E prostaglandins. This article presents the background knowledge to these considerations.
Keywords: Glomerulonephritis, Inflammation, Proteinuria.
|How to cite this article:|
Wardle E N. Pharmacological Approach to Therapy of Glomerulonephritis. Saudi J Kidney Dis Transpl 1995;6:387-95
| Glomerulonephritis as an Inflammation|| |
Glomerulonephritis can be caused either by the deposition of circulating plasma immune complexes in the glomerular filters or much less commonly by reaction of an antibody with the glomerular basement membrane components as in Goodpasture's syndrome. In both situations there is accompanying complement activation, platelet aggregation and intra-capillary coagulation, attraction of pro-inflammatory phagocytic cells like the polymorphonuclear neutrophils (PMNs) and monocyte-macrophages as well as activation of intrinsic glomerular endothelial and mesangial cells. Details of involvement of cells and mediators in the glomeruli were assembled by Wardle in a review  .
How white cells accumulate at an inflammatory site is shown in [Figure - 1]. The process is mediated by the expression of Selection or CD11/CD18 adhesion molecules on white cells and the corresponding expression of E and P selections, and of binding molecules like ICAM-1 VCAM-1, on the endothelial cells of the post-capillary venules or in glomeruli along the length of the glomerular capillaries. Initial adhesion of white cells is promoted by local release of leukotriene B4 and platelet activating factor (PAF) and then there is slower induction of the adhesion molecules by the pro-inflammatory cytokines 11-1 beta and tumor necrosis factor alpha (TNFa). Furthermore, for adhesion to be effective the endothelial cell surface heparan sulphates must first be down-regulated  . The complex topic of adhesion molecules has been reviewed by Springer recently  .
In. most forms of glomerulonephritis, the PMNs are attracted into the glomeruli first, and often they disappear as monocyte-macrophages accumulate. The general rule about white cell activation is that it is mediated by the leukotrienes  , after triggering by C5a of complement, PAF and leukotriene B4, or cytokine interleukin-8. On the other hand, prostaglandins like PGE2 that is produced by cells of the glomeruli, or prostacyclin PGI2, from the vascular endothelial cells, will dampen activation of the various white cells, and also prevent the release of their cytokines. Transforming growth factor beta (TGFL) inhibits endothelial adhesiveness for PMNs  and thus, it helps limit the accumulation of white cells. Nitric oxide also has similar properties  .
| Proteinuria|| |
Permeability at sites of inflammation is caused by a combination of increased local blood flow caused by vasodilator prostaglandins and post-capillary venular constriction and an action on inter-endothelial cell junctions caused by peptidoleukotriene LTD4  . That LTD4 causes vascular permeability, has been shown by the use of an antagonist  . Additionally, complement activation, and release of white cell enzymes like cathepsin G and elastase  and formation by activated white cells of reactive oxygen species  will lead to damage to the components of the glomerular basement membrane (GBM) so that there is proteinuria, and even leakage of red cells. Leakage of albumin is facilitated greatly by the removal of negative charges from the heparan sulphates of the endothelial cells and from the GBM by means of heparanases that originate from platelets and white cells. Normally, albumin molecules are repulsed by the negative charges on the GBM. When those charges are reduced, albuminuria occurs; of course by this time the size of the pores in the GBM is also increased.
Increased leakage of plasma protein across the glomeruli occurs when there is vasoconstriction of the efferent arterioles of the glomeruli by agents like angiotensin II  , thromboxane A2  or leukotriene D4  or PAF  .
[Figure - 2] shows typical physiological measurements of glomerular hemodynamics in rats in the acute stage of anti-GBM nephritis, in comparison with measurements in normal animals. Details of the procedure are given by Blantz, et al  . A detailed description of the findings in nephritis has been given by Badr 
The hemodynamic features of the acute nephritic stage are explained by the vasoconstrictor effects of leukotrienes C4-D4, acting along with angiotensin II and thromboxane A2. When the chronic phase is reached, the arterioles dilate in response to prostaglandins PGE1 and PGI2 and so the renal blood flow increases, although the vasconstrictor action of thromboxane A2 goes on. One will understand that in the normal circulation there is a prostaglandin/ thromboxane A2 balance. At all times in nephritis the glomerular ultrafiltration coefficient, the Kf, is reduced  . The Kf can be restored by the use of the leukotriene C4/D4 antagonist .
This pathophysiological knowledge is required for understanding the mechanism of proteinuria, as in [Table - 1]. Proteinuria is determined by raised glomerular capillary hydrostatic pressure and increased glomerular permeability.
| Phospholipid Derived Mediators|| |
All cell membranes are formed of a bilayer of phospholipids. At position 2 of each phospholipid is the 20 carbon atom, 4 unsaturated bond, arachidonic acid (C20:4, n-6)  . From arachidonic acid the body can synthesize the 20 carbon atom derivatives "eicosanoids" namely the prostaglandins, the thromboxanes and the leukotrienes. The other agent PAF-acether is a direct derivative of phospholipid  .
| The Prostaglandins|| |
The E and I prostaglandins cause vasodilatation of arterioles and capillaries, and generally they inhibit platelet aggregation. Yet, PGE2 that is so much involved in nephritis can enhance platelet aggregation  . Significantly, it facilitates proteinuria  . PGE2 also relaxes the mesangial cells thereby increasing the GFR. PGE2 is also known for its "cytoprotection" of tissues, and its ability to suppress local production of cytokines and growth factors , . The one prostaglandin that is different is PGF2 alpha, for it causes vasoconstriction and it can enhance proliferation of mesangial cells  . Its action is thus similar to thromboxane A2 (TxA2).
| Thromboxane A2|| |
In many pathological situations TxA2 acts as a powerful vasoconstrictor and as an agent that causes platelet aggregation. One will find this in pulmonary hypertension of diverse etiologies. In the renal circulation TxA2 lowers blood flow and the GFR  and it causes proteinuria  . Thromboxanes mediate tubuloglomerular feedback within the kidneys  , and also they mediate the renal effects of angiotensin II  . It is of note that the intra-renal action of thromboxane induces salt retention  . Even more significant in the context of nephritis is the fact that thromboxanes help mesangial cell proliferation, and they promote formation of new extracelllar matrix proteins that will eventually account for glomerulosclerosis  . Thus, deposition of collagen and fibronectin around mesangial cells is promoted. So, we see that preventing thromboxane action should be a prime aim in the therapy of the nephritides. When we consider that TxA2 is involved in all of the glomerulopathies  , the importance of this approach is evident.
| Platelet Activating Factor (PAF)|| |
This mediator is 1-0 alkyl-2 acetyl- snglycerol 3 phosphorylcholine. One will observe that like the phospholipids, its structure is based on the glycerol molecule  . In the kidneys, PAF causes a reduction of renal blood flow  and reduction of the GFR by causing mesangial cell contraction, and it causes vascular permeability and proteinuria. It is known to be involved in nephritis  .
| The Leukotrienes|| |
There are two main forms. Leukotriene B4 is a chemotactic agent for white cells and it activates them. In this role it is helped by PAF. Secondly, there are the peptidoleukotrienes LTC4-LTD4-LTE4  . As has been emphasized, LTC4-LTD4 cause vasoconstriction of the efferent arterioles of the glomeruli and they increase vascular permeability and hence cause proteinuria , .
Evidence that leukotrienes are important in causing cellular proliferation in nephritis, as well as, in activating white cells, comes from studies using the 5 lipoxygenase inhibitor MK 886  . Zuckerman, et al have shown how a leukotriene synthetase inhibitor (lipoxygenase inhibitor) arrests mesangial cell proliferation  .
Other studies demonstrate a similar importance of leukotrienes for white cell activation and circulatory changes in the glomeruli in renal transplant rejection  .
| The HETE (Hydroxy Eicosatrienoic Acid) Molecules|| |
A HETE molecule is a hydroxy eicosatrienoic acid that arises from the 5 lipoxygenase pathway. There are several of them and their actions are complex  . Our main consideration is that they are vasoconstrictors that aid proteinuria  .
| The Lipoxins|| |
As described recently by Badr, early in nephritis, one will see infiltrating PMNs at a time when the 5 lipoxygenase pathway is producing large amounts of leukotrienes, both LTB4 and the peptidoleukotrienes LTC4-LTD4  . Then, macrophages come in and via the 15 lipoxygenase pathyway they form 15 (S) HETE. This molecule is a precursor of lipoxin A4, whose production then increases over days and weeks. Since lipoxin A4 is a vasodilator which counteracts the actions of leukotrienes, it constitutes a counter inflammatory mediator. Lipoxin A4 then prevents chemotaxis of PMNs and so its formation helps to explain the disappearance of PMNs after the acute phase of nephritis.
| The Role of Endothelins|| |
Endothelins are released from endothelial cells or mesangial cells and from epithelial cells by the action of cytokines and angiotensin II. They are known for their vasoconstrictor potential, and they can cause profound reduction of renal blood flow and glomerular filtration. ET-1 contracts the mesangial cells so that there is reduction of the glomerular filtration surface area. The glomerular ultrafiltration coefficient Kf is thereby reduced  .
Endothelins are mitogens for endothelial cells  and it is probable that their action contributes to mesangial matrix formation because they release platelet derived growth factor (PDGF). Indeed, we know that endothelin gene expression is increased in models of glomerulosclerosis  . Furthermore, an endothelin receptor antagonist has been shown to reduce the progression of lupus nephritis in NZB/W Fl mice  .
| Nitric Oxide|| |
As endothelium derived relaxing factor, nitric oxide is a vasodilator which helps maintain glomerular blood flow  . By causing elevation of intracellular cyclic GMP, nitric oxide offsets vasoconstrictor influences as well as the tendency of thromboxanes to cause extracellular matrix deposition in chronically inflamed glomeruli. Nitric oxide arises also from inflammatory cells like macrophages and the mesangial cells  .
Unfortunately, although nitric oxide has these protective actions, it can exacerbate acute and chronic inflammation  . Tissue injury that results from the deposition of immune complexes is actually facilitated by nitric oxide  . Inhibitors of nitric oxide benefit the autoimmune glomerulonephritis of MRL-1pr mice. Yet, nitric oxide inhibition would not be recommended in man because that reduces salt excretion by the kidneys.
| The Therapy of Nephritis|| |
1. Use of Corticosteroids
Steroids are used to treat minimal change nephrosis and SLE nephritis because they cause lymphocytolysis. Via the activation of specific endonucleases, they lead to programmed cell death (apoptosis) of those cells.
There are several important anti-inflammatory effects of steroids [Table - 2]. All this means that a trial of their use should be used in other types of nephritis. Yet, one realises that really they are best used in combination with other immunosuppressive agents because high dosage steroids alone cause so many side-effects.
The beneficial effects of steroids only last for the duration of usage. However, there is effective inhibition of cytokine release when they are administered on an alternate day basis. Most of the effects of steroids are mediated by means of intranuclear events  , although they also promote synthesis of cell membrane "lipocortin" which is the inhibitor of phospholipase A2  . In this way, the ability of steroids to stop the synthesis of PAF and of the leukotrienes is explained.
| Reducing Proteinuria|| |
Non-steroidal anti-inflammatory drugs can be used to reduce heavy proteinuria, which they do by inhibiting the production of PGE2/PGI2, so that there is constriction of the afferent arterioles of the kidneys. They can cause adverse side effects. Thus, there is the possibility of causing allergic interstitial nephritis or even acute renal failure. Hence, for the purpose of lessening proteinuria, one would be better advised to try the ACE inhibitors  . Their action is mediated by dilatation of the efferent arterioles. Yet, there are patients who cannot tolerate the ACE inhibitors.
Many nephrologists use small dose of aspirin (75 mg per day) in order to stop thromboxane synthesis, as one might use in the prevention of pre-eclampsia. The hope is to arrest proliferation of mesangial cells and the development of glomerulosclerosis. To date there is little evidence that this objective is achieved. In fact, aspirin 75 mg per day is best combined with dipyridamole 100 mg thrice daily for its anti-oxidant effect. We know that dipyridamole prevents formation of leukotrienes and reduces proteinuria  . An anti-oxidant drug that has received too little attention is Probucol. This is effective for the prevention of atherosclerosis in animals  . Probucol stops the action of lipoxygenases. It can be used to prevent focal glomerulosclerosis  . Probucol could be useful in the prevention of diabetic nephropathy  . Certainly, it can be used when patients cannot tolerate the ACE inhibitors. The drug pentoxifylline (Trental) reduces proteinuria in insulin dependent and non-insulin dependent diabetics  . By increasing red cell deformability it may reduce glomerular hydraulic pressure. Since pentoxifylline is a phosphodiesterase inhibitor like aminophylline that potentiates the action of cyclic AMP in cells, it can also inhibit platelets and the activation of leucocytes. So it might confer additional advantage in nephritides.
| Anti-PAF Agents or Anti-leukotrienes|| |
A role of PAF in experimental renal injury is well established  . Steroids will suppress the production of PAF and of the leukotrienes. Furthermore, specific antagonists for both PAF and the leukotrienes are now available. The only information about their application is in experimental renal disease , . It has been shown that a PAF receptor antagonist can help preserve the remaining nephrons in damaged kidneys  .
| Thromboxane Antagonism|| |
Inhibitors of thromboxane synthetase [Figure - 3] and antagonists for thromboxane receptors are now available  . Many experimental studies attest to their efficacy in the control of proteinuria and lessening of nephritis and subsequent glomerulosclerosis  . Thromboxane synthetase inhibition prolongs the survival of mice with lupus nephritis  .
Reports of the use of these agents in man are limited. Ideally one should use a thromboxane synthetase inhibitor and a thromboxane receptor antagonist in combination. One will expect lowering blood pressure and marked lessening of proteinuria. They have been used in minimal change nephrosis and in SLE nephritis and for diabetic nephropathy. The agent Ridogrel appears promising in this regard  .
| Vasculitis with Nephritis|| |
One will know of the prednisolone plus cyclophosphamide regimens for vasculitides  . Monthly intravenous pulse cyclophosphamide is certainly effective for various serious nephropathies  .
One can use dapsone for Henoch-Schonlein syndrome  , since dapsone stops neutrophil damage to tissues. Dapsone 100 mg per day in combination with pentoxifylline 400 mg thrice daily is good for serious vasculitides  . Another useful approach is intravenous PGE1 therapy  . PGE1 can be infused daily on a long term basis  . Its action is to inhibit the activation of platelets, polymorphs and lymphocytes, and to reduce proteinuria  . It is of particular note that PGE1 will inhibit the Th-1 lymphocytes  that direct the delayed hypersensitivity reaction involving activated macrophages which is the basis of progressive forms of nephritis , . With all vasculitides one must bear in mind that the cause could be a drug allergy  .
| Other Consideration: Preventing Renal Fibrosis|| |
Cyclosporin can be used for nephritides, but in view of the possibility of decline of renal function  that decision should be made by an expert. Certainly it can be used to good effect for lupus nephritis.
Heparins have a respectable record in the treatment of experimental nephritides  and they can be used in acute nephritis, SLE nephritis and rapidly progressive nephritides as well as for more chronic cases  . Nowadays we might prefer to use low MW heparins. Heparin suppresses the proliferation of mesangial cells  . Significantly heparin has been shown to suppress the release of endothelins (ET-1) and to promote moderate nitric oxide for-mation by endothelium  . Preservation of nitric oxide opposes the potential of thromoboxanes for causing glomerular and interstitial fibrosis.
The ACE inhibitors have the potential for reducing renal fibrosis, and this benefit will accrue if they are used for treating any hypertension associated with nephritis. They stop angiotension II exerting its profibrotic influence. Also, by potentiation of bradykinin they facilitate the beneficial effects of nitric oxide.
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E Nigel Wardle
21, Common Road, North Leigh, Oxford OX8 6RD, England
[Figure - 1], [Figure - 2], [Figure - 3]
[Table - 1], [Table - 2]