Chronic renal failure:

Histological examination of an end-stage kidney provides little if any clue as to the identity of the original disease. This observation suggests that progression from the original insult to end-stage renal disease involves common mechanisms and a limited repertoire of morphological responses. Glomeruli become sclerotic with accumulation of large quantities of extracellular matrix. The periglomerular region and the renal interstitium both show fibrosis. The interstitium also shows evidence of chronic inflammation with infiltration by macrophages and lymphocytes. Tubules

mainly atrophic, although there are occasional hypertrophic tubules that are connected to the remaining functional glomeruli. Early investigations suggested that, after sufficient damage to total functional renal mass, a series of adaptive changes lead to progressive destruction of remaining nephrons, primarily through damage to glomeruli.l This "haemodynamic theory" states that compensatory glomerular hyperperfusion and hyperfiltration, together with glomerular hypertension, result in worsening proteinuria and progressive glomerular sclerosis. Early evidence in laboratory animal models of kidney disease showed that dietary protein restriction and reduction in systemic blood pressure prevented or slowed disease progression.’ This result could be explained by a reduction in glomerular hyperfiltration and glomerular hypertension.’ Rat models of renal disease have been adopted to explore mechanisms responsible for progression and to test the efficacy of various therapeutic interventions. Early studies confirmed that both dietary protein restriction and antihypertensive therapy slowed disease progression, as assessed morphologically and by measurements or renal function. Other "risk factors" or "progression promoters" were also clarified (table I). These influences will be examined from a scientific viewpoint in this article. Their clinical importance and the therapeutic interventions that can limit their damaging effects on the kidney will be assessed in the subsequent review on management.


mesangial expansion is not limited to the matrix but includes mesangial cell proliferation and accumulation of bonemarrow-derived macrophages.3 Proliferation of mesangial cells, accumulation of extracellular matrix, and infiltration by macrophages are interrelated. Several factors thought to be responsible for progression of glomerular disease affect mesangial cell turnover and extracellular matrix production and deposition. Some of these factors are produced by mesangial cells but many are also derived from macrophages.


Morphological characteristics Morphologically, progressive renal destruction involves major processes. Firstly, there "is obliteration of glomerular capillaries due to expansion of the mesangial region. This expansion involves accumulation of mesangial matrix, which is a complex extracellular material that includes type IV and V collagen, fibronectin, laminin, heparin sulphate, and chondroitin sulphate proteoglycans.2 In most experimental models of progressive renal disease, two


Systemic hypertension Glomerular Proteinuria


Hyperlipidaemia Dietary protein Dietary phosphate Intraglomerular coagulation Interstitial nephntis

The second morphological component of progressive renal destruction involves the extraglomerular interstitium.4 Careful morphometric studies of human kidney tissue have shown a striking correlation between the extent of renal dysfunction and the magnitude of tubulointerstitial disease.5,6 The main morphological expression of several disease processses, such as obstructive uropathy, analgesic abuse, and pyelonephritis, is in the tubulointerstitium. In these disorders, interstitial disease has a central role in loss of renal function. Whether tubulointerstitial abnormalities found in primary glomerular diseases are a secondary event due to ischaemic tubular injury from disruption of the peritubular blood supply following glomerular destruction, or whether there is a destructive process that attacks both the tubulointerstitium and the glomerulus, remains to be proven. Irrespective of whether these events are primary or secondary, the changes to the interstitium are similar to those in the glomerular mesangium; there is proliferation of interstitial fibroblasts, increased matrix deposition, and infiltration by macrophages and lymphocytes.

Molecular factors Several hormones, growth factors, cytokines, and

biologically active lipids influence mesangial and interstitial ADDRESS Division of Nephrology, Vanderbilt University Medical Center, Nashville, Tennessee 37232-2372, USA. Correspondence to Prof H R Jacobson, MD.



*Only sources and targets relevant to the kidney are listed

cell proliferation and extracellular matrix deposition. The data have largely come from in-vitro studies, but in-vivo results with immunohistochemistry, in-situ hybridisation, and transgenic animals have pointed to the pathophysiological importance of several of these compounds. I have chosen some of the more important factors for further discussion (table 11).

Transforming growth factor &bgr; This 25 kDa homodimer peptide is synthesised by several cell types, including macrophages and platelets.7 TGF-0 may also be synthesised by resident glomerular mesangial cells. This peptide acts as a bifunctional regulator of cell proliferation depending on the state of the target cell and the presence or absence of other growth-regulating factors. Most cells have receptors for TGF-(3, including all glomerular cell types and renal interstitial fibroblasts. TGF- 0 inhibits the proliferation of cultured mesangial cells, but stimulates the synthesis of collagen and fibronectin by these cells .7 While studies have shown that TGF-P stimulates proteoglycan synthesis in cultured glomerular mesangial cells, more recent in-vivo data support a pathogenetic role for increased glomerular expression of TGF-3 in renal disease.8

Glomeruli taken from rat kidneys 1 to 28 days after injection of antithymocyte serum (a model of mesangioproliferative glomerulonephritis) were found to synthesise proteoglycan in quantities up to 50 times the control rate. Fibronectin synthesis was also increased. Conditioned media from the glomerular cultures stimulated proteoglycan synthesis when added to normal cultured glomerular mesangial cells. This stimulatory activity was blocked by addition of antibodies to TG F - &bgr;. Furthermore, injection of TGF-(3 antibodies into laboratory animals with mesangioproliferative glomerulonephritis significantly retarded disease expression as measured by mesangial proliferation and matrix accumulation.9 Taken together, these studies point to a central role for TGF-P in the expansion of the extracellular matrix in glomerular disease. Insulin-like growth factor-I IGF-I is synthesised in the liver and its circulating concentration is controlled mainly by growth hormone. However, the principal cells of the collecting duct, several types of fibroblasts, and mesangial cells also synthesise this peptide. In addition, mesangial cells, endothelial cells, proximal tubule cells, and interstitial fibroblasts have receptors for IGF-1. Although IGF-I is mitogenic for cultured mesangial cells, overproduction of IGF-I in


transgenic animals is associated with a hypertrophic3 response leading to both enlarged kidneys and glomeruli. In the absence of any other insult to the kidneys, IGF-I alone is insufficient for progressive morphological and functional renal damage. IGF-I may have an important role in the hypertrophic response of residual glomeruli after subtotal renal mass ablation.to Dietary protein restriction, which is known to retard the progression of renal disease in both laboratory animals and man, is associated with significant reductions in plasma concentrations of IGF-1. Since glomerular hypertrophy may be a risk factor for glomerular sclerosis, there may be a pathogenetic role for IGF-I as either an endocrine or an autocrine glomerular growth factor. IGF-I might promote disease progression. Platelet- derived growth factor This potent mitogen released from a granules of platelets is also produced in monocytes, macrophages, and endothelial cells including renal microvascular (probably glomerular) endothelial cells.l2 PDGF is mitogenic for mesangial cells, smooth muscle cells, and interstitial fibroblasts.7 Indeed, increased immunostaining for PDGF receptors has been shown in glomeruli of chronically rejecting kidney transplants. 13 PDGF could be an important autocrine factor in the proliferative component of chronic progressive glomerular injury. PDGF also increases collagen synthesis in cell types such as renal epithelial cells. Cellular proliferation and increased matrix synthesis in response to growth factors and cytokines are central to the process of disease progression. Glomerular hypertrophy may be important in the progression of renal disease.14 Morphometric analyses of kidney biopsy specimens from patients with minimal-change disease or focal glomerular sclerosis showed that the latter had substantially larger glomeruli than the former.t5 Similar correlations between glomerular size and the risk of progression have been described in patients with type I diabetes, obesity, and chronic reflux nephropathy.14 However, in all these disorders only a correlation between glomerular size and the tendency for progression has been shown. The hypothesis remains that the same factors that are responsible for glomerular hypertrophy will, over time, lead to progressive glomerular sclerosis and shrinkage. An experiment of nature that supports this theory is oligomeganephronia. This disease is associated with a striking reduction in the number of nephrons. The glomeruli of the existing enlarged nephrons develop severe focal glomerular sclerosis.16

Risk factors

Systemic and glomerular hypertension Proteinuria and glomerulosclerosis develop in genetically hypertensive rats in the absence of underlying renal disease. There is strong evidence to suggest that hypertension superimposed on underlying renal disease worsens both renal function and histological deterioration. This conclusion has been drawn from studies in laboratory animals that become hypertensive because of subtotal renal ablation, nephrotoxic serum nephritis, immune-complex nephritis, or diabetic nephropathy. Until recently, the adverse impact of systemic hypertension on renal structure and function was thought to be mediated through vasoconstriction and arteriolar nephrosclerosis. However, evidence from rat models shows that systemic hypertension

is transmitted to the single glomerulus in such a way as to lead to hyperperfusion and increased glomerular capillary pressure. Intraglomerular haemodynamics are probably similar to those found in other models of disease progression where systemic blood pressure is minimally or slightly increased but glomerular perfusion and glomerular capillary pressure are increased.17 The reduction of glomerular injury associated with antihypertensive therapy in many of these experimental models supports this view.17 Despite the beneficial effects of antihypertensive treatment on the progression of renal disease in animal studies, we still do not know in molecular or cellular terms how "haemodynamic damage" occurs. The glomerular hypertrophy found in many of these animal models predicts (by Laplace’s law) that the tension on the glomerular capillary wall can increase by up to 500%. This mechanical stimulation can initiate biological responses that affect cell shape, cell division, and cellular biochemistry, including the synthesis of extracellular matrix.18 Glomerular endothelial, epithelial, and mesangial cells are probably altered by the physical changes of glomerular hypertension and hyperfiltration. An additional mechanical effect of glomerular hypertension and hyperperfusion may cause actual damage to endothelial cells. This damage is likely to result in activation of platelets and intraglomerular coagulation with resultant exposure of nearby cells to numerous potent mitogens and modifiers of matrix synthesis such as PDGF and TGF-M. Intraglomerular thrombin generation can also contribute to this process since thrombin activation of endothelial receptors leads to the release of several factors, including PDG F.12 Separation of the relative contributions of altered and glomerular intraglomerular haemodynamics to disease the hypertrophy progression seen when hypertension is superimposed on underlying renal disease is not yet possible because the strategies for preventing






calcium-channel blocker, both inhibit glomerular hypertrophy. However, ACE inhibitors substantially decrease glomerular capillary pressure, while calcium-channel blockade has a much smaller effect on these variables. 19 Calcium-channel blockers may, however, inhibit atherogenesis, platelet aggregation, and the formation of reactive-oxygen species within the kidney. 19




Proteinuria Most experimental evidence on progressive renal injury from studies of subtotal renal mass ablation and streptozotocin-induced diabetes, which show altered glomerular permselectivity very early in their course. Proteinuria precedes both light and electron microscopic evidence of mesangial or epithelial cell damage.2o Intervention that limits disease progression, such as antihypertensive therapy and reduction in dietary protein intake, also significantly decreases proteinuria in these models. Thus, is proteinuria a marker of or a contributor to glomerular damage? Those who favour a contributory effect of proteinuria suggest that the increased quantities and types of protein that pass through the abnormal filtration barrier are injurious to both glomerular epithelial and proximal tubule cells. In addition, proteinuria in quantities sufficient to saturate the reabsorptive capacity of the proximal tubule may lead to cast formation in the distal nephron and with interstitial damage subsequent epithelial inflammation.2° Support for this hypothesis can be found in



the model of puromycin nephrosis in which the degree of tubulointerstitial damage correlates with the degree of proteinuria.2° Another possible mechanism for proteinuriainduced damage is the associated secondary hyperlipidaemia that may be a risk factor by itself. Several studies have shown that proteinuria is associated with increased trapping of macromolecules in the mesangium. Whether there is a direct correlation between this trapping and proteinuria is uncertain since the capillary lumen is not separated from the mesangium by basement membrane. The increased of circulating access macromolecules to the mesangial region may be a stimulus for mesangial cell proliferation and increased matrix synthesis .21 Manoeuvres that decrease proteinuria, such as low-protein diets or antihypertensive treatment, lead to a decreased accumulation of macromolecules in the mesangial


/Vy/?e///t/ae/7?/a animal species, increased dietary cholesterol mild produces glomerulosclerosis and proteinuria but not progressive glomerular injury. However, similar treatment in laboratory animal models of renal disease exacerbates progressive nephron destruction.2’ Lipid-lowering drugs limit glomerular injury.21 The specific lipid or lipoprotein responsible for this effect has not been identified. In the obese Zucker rat with spontaneous hyperlipidaemia, an increase in mesangial cell number and mesangial matrix occurs very early. These early lesions regress after treatment with lipid-lowering agents.21 The mesangium of these animals also has greater numbers of macrophages. Hypercholesterolaemia may increase the adherence of monocytes to endothelial cells and promote their migration to the subendothelial space. In addition, macrophages can be activated by low-density lipoprotein (LDL) to release biologically active eicosanoids and several peptide factors that are described in table 11.21 Oxidised LDL may also contribute to progressive renal damage since it is cytotoxic to cultured mesangial cells.21 Preliminary evidence supports a pathogenetic role for oxidised LDL in glomerular injury, and suggests that probucol, a lipid-lowering agent that is also an antioxidant, exerts a protective effect in vivo, which is independent of any significant change in circulating cholesterol .21 Although unrelated to hypercholesterolaemia, dietary manipulation of fatty acid intake also modifies the progression of renal disease. Diets low in linoleic acid, a precursor of arachidonic acid, augment deterioration of renal function in subtotal nephrectomised laboratory animals.22 These studies suggest a beneficial effect of certain arachidonate metabolites, presumably prostaglandins. Diets low in essential fatty acids are protective in several models of experimental renal disease, especially those associated with severe inflammation. Essential fatty acid deficiency may prevent the homing of macrophages to both the mesangium and the renal interstitium.22 In


Dietary protein and dietary phosphate Dietary protein restriction retards the progression of renal disease in virtually every experimental animal model tested.23 Suggested mechanisms for this protective effect include: beneficial changes in glomerular haemodynamics (reduction in hyperfiltration and glomerular capillary pressure); reduction in glomerular eicosanoid production; reduction in proteinuria due to a protective effect on

glomerular perm selectivity ; reduction in hyperlipidaemia; reduction in circulating, and possibly intrarenal, IGF- I; and prevention of glomerular hypertrophy. The relative contribution of each factor is uncertain but the benefit is probably multifactorial. Dietary phosphate restriction in both rats and dogs with subtotal renal ablation slows progression of chronic renal failure.24.25 However, confirmation of this observation in patients has proven elusive because of difficulty in separating phosphate restriction from dietary protein restriction and vice versa. Laboratory animal studies suggest a role for calcium and phosphorus precipitation in multiple intrarenal compartments including the tubular lumen, parenchymal cell cytoplasm, and renal interstitium. The intracellular calcium intoxication that follows will lead to disorders in cell function and eventually cell death with resultant interstitial inflammation and subsequent fibrosis .24 Although calcium and phosphate precipitation may exacerbate glomerular injury in experimental models of renal disease, the main morphological changes occur in the tubulointerstitial areas. 24,25

Intraglomerular coagulation Inhibition of platelet aggregation with thromboxane synthetase inhibitors or prevention of intravascular coagulation with heparin or warfarin, protects residual nephron structure and function in subtotally nephrectomised rats.26 However, the beneficial effect of heparin may be independent of its anticoagulant properties since a derivative that does not affect clotting is also protective. Furthermore, heparin suppresses proliferation of mesangial cells in culture and decreases mesangial cell matrix synthesis.26 The beneficial effects of inhibiting platelet aggregation could be partly due to limiting the release of PDGF and other proliferation-inducing factors. Since thrombin activates endothelial cells to produce PDGF, prevention of thrombin formation would also be expected to be protective. Interstitial nephritis The final risk factor for disease progression is tubulointerstitial injury. As discussed earlier, several experimental models and naturally occurring human forms of renal disease mainly involve the tubulointerstitial region. The role for either simultaneous or subsequent tubulointerstitial disease is less well understood. Several hypotheses have been raised to explain the tubulointerstitial injury in kidneys with glomerular pathology.27 One possible mechanism involves loss of tolerance to either a shared or a cross-reacting antigen in the glomerulus. Such an event could lead to autoimmune destruction of the tubular epithelial or interstitial cell. A second mechanism could involve induction of nephritogenic antigens in the tubulointerstitial area. Such a process could be enhanced by expression of MHC class II antigens on the surfaces of tubular epithelial cells. A third mechanism could be a spillover of immune deposits and their associated activated complement components and inflammatory mediators from the glomerulus to the tubulointerstitium, presumably through lymphatics as well as the postglomerular circulation.28 Whatever the mechanism proves to be, the expected result would be infiltration of the tubulointerstitium with acute inflammatory cells, macrophages, and T cells. Through the actions of cytokines


and growth factors, epithelial and interstitial cell changes would ultimately lead to the tubulointerstitial lesions that are part of the end-stage kidney.

was supported by USPHS NIDDK grants: #DK37097, and I wish to thank Ms Judy Hurst for her assistance in the preparation of this manuscript and my collaborators in the Vanderbilt Kidney and Urologic Disease Center for their support.

This work


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et al. Glomerular hypertrophy in change disease predicts subsequent progression to focal glomerular sclerosis. Kidney Int 1990; 38: 115-23. 16. Elfenbein IB, Baluarte HJ, Gruskin AB. Renal hypoplasia with oligomeganephronia. Arch Pathol 1974; 97: 143-49. 17. Baldwin DS, Neugarten J. Hypertension and renal diseases. Am J Kid


Fogo A, Hawkins EP, Berry PL, minimal

Nephron adaptation to renal injury or ablation. Am J Physiol 1985; 249: F324-37. 2. Abrahamson DR. Structure and development of the glomerular capillary wall and basement membrane. Am J Physiol 1987; 253: F783-94. 3. Striker LJ, Peten EP, Elliot SJ, Doi T, Striker GE. Biology of disease: mesangial cell turnover: effect of heparin and peptide growth factors. 1. Brenner BM.

Lab Invest 1991; 64: 446-56. G, Neilson EG. Molecular mechanisms of tubulointerstitial hypertrophy and hyperplasia. Kidney Int 1991; 39: 401-20. 5. Bohle A, Bader R, Grund KE, Mackensen S, Tolon M. Correlations between renal interstitium and level of serum creatinine: morphometric investigations of biopsies in perimembranous glomerulonephritis. Virchows Arch (A) 1977; 373: 14-22. 6. Bohle A, Bader R, Grund KE, Mackensen S, Neunhoffer J. Serum creatinine concentration and renal interstitial volume: analysis of correlations in endocapillary (acute) glomerulonephritis. Virchows Arch (A) 1977; 375: 87-96. 7. Segal R, Fine FG. Polypeptide growth factors and the kidney. Kidney Int 1989; 36: S2-10. 8. Okuda S, Languino LR, Ruoslahti E, Border WA. Elevated expression of transforming growth factor-&bgr; and proteoglycan production in experimental glomerulonephritis: possible role in expansion of the mesangial extracellular matrix. J Clin Invest 1990; 86: 453-62. 9. Border WA, Okuda S, Landuino LR, Sporn MB, Ruoslahti E. Suppression of experimental glomerulonephritis by antiserum against transforming growth factor &bgr;-1. Nature 1990; 346: 371-74. 10. Fagin JA, Melmed S. Relative increase in insulin-like growth factor I messenger ribonucleic acid levels in compensatory renal hypertrophy. Endocrinology 1987; 120: 718-24. 4. Wolf

Dis 1987; 10: 186-91. 18. Watson PA. Function follows form: generation of intracellular signals by cell deformation. FASEB J 1991; 5: 2013-19. 19. Dworkin LD. Effects of calcium channel blockers on experimental glomerular injury. J Am Soc Nephrol 1990; 1: S21-27. 20. Remuzzi G, Bertani T. Editorial review: is glomerulosclerosis a consequence of altered glomerular permeability to macromolecules? Kidney Int 1990; 38: 384-94. 21. Keane WF, Mulcahy WS, Kasiske BL, Kim Y, O’Donnell MP. Hyperlipidemia and progressive renal disease. Kidney Int 1991; 39: S41-48. 22. Klahr S, Harris K. Role of dietary lipids and renal eicosanoids on the progression of renal disease. Kidney Int 1989; 36: S27-31. 23. Diamond JR. Brief review: effects of dietary interventions on glomerular pathophysiology. Am J Physiol 1990; 27: F1-8. 24. Lau K. Nephrology forum: phosphate excess and progressive renal failure: the precipitation-calcification hypothesis. Kidney Int 1989; 36: 918-37. 25. Brown SA, Crowell WA, Barsanti JA, White JV, Finco DR. Beneficial effects of dietary mineral restriction in dogs with marked reduction of functional renal mass. J Am Soc Nephrol 1991; 1: 1169-79. 26. Klahr S, Schreiner G, Ichikawa I. The progression of renal disease. N Engl J Med 1988; 318: 1657-66. 27. Yee J, Kuncio GS, Neilson EG. Tubulointerstitial injury following glomerulonephritis. Semin Nephrol 1991; 11: 361-66.

Chronic renal failure: management

An increased serum urea or creatinine concentration indicates impaired renal function. Identification of the cause of the renal insufficiency, as well as secondary factors contributing to it, will help classify the condition as acute or chronic. Although acute and chronic renal disease states do not have mutually exclusive causes, the diagnosis of chronic renal disease can be established, firstly, by assessment of the extent and severity of the disease-eg, diabetes or glomerulonephritis-that underlies renal damage and, secondly, by showing the constant presence and progressive nature of the renal impairment. In kidney diseases characterised by irreversible injury, once a critical amount of functional renal loss has taken place, progression to end-stage disease seems common, even if the initiating event or condition is resolved or eradicated. Moreover, of the cause of chronic renal failure, several irrespective intercurrent events (table i) may accelerate the rate of loss of renal function. These events may lead to either a transient or a permanent loss of renal function. The importance of such intercurrent events cannot be overemphasised because their detection and correction may slow the progression of renal insufficiency and delay the need for renal replacement


Clinical assessment

progression of chronic renal failure is best assessed by sequential measurements of glomerular filtration rate (GFR) with exogenous markers such as inulin, 1251iothalamate, 9

Chronic renal failure: pathophysiology.

419 SCIENCE & PRACTICE Chronic renal failure: Histological examination of an end-stage kidney provides little if any clue as to the identity of the...
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