glomerulosclerosis: are we any wiser?

Klin Wochenschr (1989) 67:876-881 Klinische

Wochen- schrift

© Springer-Verlag 1989

Glomerulosclerosis: Are We Any Wiser ?

A.M. El Nahas Sheffield Renal Unit, Northern General Hospital, Sheffield, UK

Summary. Chronic renal failure (CRF) is charac- terized histologically by progressive glomerulosclerosis (GS) and tubulo-interstitial scarring (TIS). Recently, research has focused on the study of the pathophysiology of GS. Most advances in this field have been derived from the study of various experimental models of CRF and GS in the rat. In this paper, I will review some of the concepts and hypotheses put forward to explain progressive GS and examine their relevance to glomerular scarring and CRF in humans.

Key words: Glomerulosclerosis (GS) - Glomerular hypertension - Glomerular hypertrophy" - System- ic hypertension

I. Role of Glomerular Hypertension in the Pathogenesis of Glomeruloselerosis

It has long been recognised that following an acute reduction in functional renal mass in the rat, the remnant kidney undergoes adaptive changes (Chanutin and Ferris 1932). These include compensatory renal growth (CRG) and hyperfunction. The glomeruli display adaptive hypertrophy as well as increase plasma flow and filtration rate (Hays- lett 1979). Following these early adaptive changes, proteinuria, hypertension, CRF and progressive GS take place (Morrison 1962; El Nahas etal. 1983). A few years ago, Brenner and his coworkers [1982] suggested that this experimental model of renal ablation in rats was representative of progressive CRF in humans. They postulated that the early adaptive glomerular haemodynamic changes initiate the subsequent development of GS in remnant glomeruli [Hostetter et al. 1981 a]. Using mi- cropunture techniques in the subtotally nephrecto-

mized Munich-Wistar rat, the observed that remnant glomeruli display a disproportionate afferent arteriolar vasodilatation [Hostetter et al. 1981@ This leads to an increase in single nephron glomerular filtration rate (SNGFR), plasma flow (Qa) and hydraulic pressure (Pgc). A similar pattern of glomerular hyperfiltration, hyperperfusion and hypertension has been described in rats with streptozotocin-induced diabetic nephropathy [Hostetter et al. 1981 b]. In favour of a role played by these haemodynamic alterations in the initiation of GS was the fact that a low protein diet (LPD) blunts these adaptive changes and prevents the development of GS in rats with remnant kidneys [Hostetter et al. 1981 a]. Over the next few years this exciting new hypothesis stimulated a considerable amount of research, some of which failed to support it. For instance, it became apparent that glomerular hyperfiltration and hyperperfusion were probably irrelevant to the initiation and progression of GS. Experimental nephropathies, such as the adriamycin nephrosis, have been described where early glomerular hyperfiltration and hyperperfusion took place yet GS failed to develop [O'Donnell et al. 1985]. Dietary and pharmacological interventions prevented GS without correcting these haemodynamic changes in rats following renal ablation. This is the case with the late introduction of a LPD [Nath et al. 1986], angiotensin converting enzyme (ACE) inhibitors [Anderson et al. 1985] and lipid lowering agents [Kasiske etal. 1988]. Further, some protective interventions such as heparin [Pur- kerson et al. 1988], thromboxane synthetase inhibition [Purkerson et al. 1985] and excercise training [Heifets et al. 1987] prevented GS in spite of an increased glomerular hyperfiltration. These observations shed considerable doubt on the role of glomerular hyperfiltration and hyperperfusion in the initiation of GS in rats with remnant kidneys.

A.M. E1 Nahas: Glomerulosclerosis 877

Some of the experimental observations described above, while refuting a role for glomerular hyperfiltration/hyperperfusion, suggested that the increased glomerular capillary pressure (glomerular hypertension) was responsible for the initiation of GS. Early glomerular hypertension is a feature of a wide range of experimental nephropathies in the rat. These include the subtotal nephrectomy and diabetic nephropathy models, experimental glomerulonephritides as well as adriamycin induced nephrosis [Hostetter et al. 1981 a; Hostetter et al. 1981b; O'Donnell etal. 1985]. Therapeutic interventions, such as early and late dietary protein restrictions [Hostetter et al. 1981 a; Nath et al. 1986] and ACE inhibition [Anderson et al. 1985], reduce glomerular hypertension and prevent GS. However, in spite of these supportive observations, an exclusive role for glomerular hypertension in the initiation of GS is doubtful. Glomerular hypertension takes place early in the course of mild nephrotoxic nephritis [Maddox et al. 1975], Hey- man nephritis [Ichikawa et al. 1982] and adriamycin nephrosis [O'Donnell et al. 1985], yet none of these progress to significant GS and renal function is preserved. This is also the case with streptozotocin-induced diabetic nephropathy in rats where, in spite of severe glomerular hypertension, only mild glomerular sclerotic changes are observed at 18 months [Zatz et al. 1986]. Glomerulosclerosis can be prevented in rats with renal ablation by lipid lowering agents, such as clofibric acid, in the absence of a reduction of glomerular capillary pressure (Kasiske et al. 1988]. Finally, when Yos- hida et al. measured glomerular capillary pressure (Pgc) serially in individual remnant rat glomeruli, there was no correlation between the early rise in Pgc and the subsequent development of GS [Yos- hida et al. 1988a]. A similar dissociation between the two events was reported by the same group in the puromycin and adriamycin-induced models of nephrotic syndrome [Fogo et al. 1988]. These observations cast doubt on an exclusive role for glomerular hypertension in the initiation of GS in the rat. However, they don't exclude a contributing role for glomerular hypertension in concert with other factors, as will be discussed below.

The relevance of the concept of glomerular hyper filtration, hyperperfusion and hypertension in the development of GS in other species, including humans, is unknown. Rabbits develop a severe tubulo-interstitial nephropathy, with mild GS, following renal ablation [Eddy et al. 1986]. Dogs submitted to subtotal nephrectomy develop mild GS with no progressive renal functional loss [Bour- goignie et al. 1987]. Baboons examined 8 months

after subtotal nephrectomy display adaptive hyperperfusion and hyperfiltration but not GS [Bour- goignie et al. 1989]. Humans born with a reduced renal mass (unilateral renal agenesis) or a small number of glomeruli (oligomeganephronia) are said to have an increase incidence of GS [Kiprov et al. 1982]. Similarly, it has been claimed that males submitted to uninephrectomy are prone to develop GS and proteinuria [Zuchelli et al. 1983]. This was not confirmed by others [Kiprov et al. 1982] and seems of no functional significance. Live related kidney donors have been shown to develop proteinuria and hypertension many years after uninephrectomy [Hakim et al. 1984]. These observations are difficult to interpret in view of the genetic background of these donors. Renal function is also preserved in these individuals. In patients with chronic nephropathies, hypertrophy of the remnant glomeruli take place [Oliver 1950]. Glomeru- lar hyperfittration is observed early in the course of diabetic nephropathy [Hostetter et al. 1981b] and sickle cell disease [Etteldorf et al. 1955]. This is often followed in these patients by progressive renal failure and scarring. However, a causal asso- ciation between the two events is far from proven. In patients, therapeutic interventions known to reduce glomerular hypertension in the rat, decrease filtration fraction and proteinuria. This is the case of ACE inhibitors and LPD [Smith et al. 1989; E1 Nahas et al. 1984]. Whether this is related to a decrease in glomerular hypertension can only be speculative [Heeg et al. 1987]. In humans, as in experimental animals, the role of glomerular hypertension in the pathogenesis of GS remains to be defined.

II. Role of Glomerular Hypertrophy in the Pathogenesis of Glomerulosclerosis

Ichikawa and his coworkers observed a strong correlation between the size of the remnant glomeruli and the degree of GS [Yoshida et al. 1988b]. They claimed that glomerular hypertrophy, rather than hypertension, played a role in the initiation of glomerular scarring. Some experimental observations support this concept. For instance, in rats with a unilateral uretero-peritoneal urine diversion, the contralateral kidney displays glomerular hypertension. Yet, GS fails to take place in the absence of CRG in this model [Ichikawa et al. 1988]. PVG/C rats are resistant to the development of age-related and nephrectomy-induced GS [Grond et al. 1986]. This may be attributed to the smaller

878 A.M. El Nahas: Glomerulosclerosis

size of glomeruli from PVG/c rats when compared to strains prone to GS [Grond et al. 1986]. The absence of significant glomerular hypertrophy after contralateral nephrectomy in this strain, may also underly their resistance to GS in spite of nor- mal adaptive glomerular haemodynamic changes. Whilst these observations may suggest an important role for glomerular size in the susceptibility to develop GS, it is unlikely that glomerular hypertrophy alone is sufficient to initiate it. Rats with diabetic nephropathy have marked glomerular hypertrophy, yet GS is mild and functionally insigni- ficant [Zatz et al. 1986]. Rats following 40% renal ablation develop more GS than those submitted to uninephrectomy (50% ablation). This in spite of less compensatory glomerular hypertrophy in the former compared to the latter [Meyer and Rennke 1988]. Fries et al. [1988] suggested that synergism between glomerular hypertrophy and hypertension is necessary for the induction of GS in rats. Glomerular hypertrophy and GS develop in 4/5th nephrectomized rats with adriamycin nephrosis. In the absence of a reduction in renal mass, these rats develop comparable glomerular hypertension but minimal GS. These authors suggested that according to the Laplace's Law (tension=pressure x radius), a high glomerular pressure would be more damaging to hypertrophied glomeruli as the result of higher tension generated and transmitted to the capillary wall. Such assumption may reconcile many experimental observations that previously seemed conflicting. For instance, when Yoshida et al. [1988] failed to detect a correlation between glomerular capillary pressure and GS in remnant rat glomeruli, they observed a strong correlation between glomerular size and scarring. This may imply that a correlation exists in this model between glomerular capillary tension and the development of GS.

The relevance of the concept of glomerular hypertrophy to the pathogenesis of GS in humans is unknown. However, indirect observations on the susceptibility of humans to progressive CRF al- lows some speculation. Females seem in general less prone to progressive CRF than males. This is the case in chronic glomerulonephritides such as idiopathic membranous and mesangial IgA nephropathies [Davison et al. 1984; Zeier et al. 1988]. Females have smaller kidneys than males. It is therefore possible that the smaller glomerular size of females with chronic nephropathies underlies their reduced susceptibility to progressive CRF. This may also explain racial differences in suscep- tiblity to the development of hypertensive nephros- clerosis [Rostand et al. 1989].

HI. Role of Systemic Hypertension in the Pathogenesis of Glomerulosclerosis

The onset of systemic hypertension is an important factor in the development and progression of CRF in experimental animals and humans with chronic nephropathies [Baldwin and Neugarten 1986]. In the rats with experimental nephropathies, significant GS seldom takes place in the absence of systemic hypertension. In Heyman nephritis [Okuda et al. 1984] or adriamycin nephrosis [Fries et al. 1988], the superimposition of hypertension leads to progressive disease and GS. A preponderant role for systemic hypertension in the initiation of GS explains many of the discrepancies highlighted in previous sections. For instance, the resistance of rats with streptozotocin-induced diabetes to develop GS in spite of glomerular hypertrophy and hypertension is likely to be due to the absence of significant hypertension in this model. The fact that rats with 40% renal ablation are more prone to GS than those with more extensive (50%) resec- tion can be explained by the presence of systemic hypertension in the former and its absence in the latter [Meyer and Rennke 1988]. The development of GS in subtotally nephrectomized rats with adriamycin nephrosis coincides with the onset of systemic hypertension [Fries et al. 1988]. Systemic hypertension may therefore be synergistic with glomerular hypertension and hypertrophy in the initiation of GS in rats. In patients with chronic renal disorders, systemic hypertension often precedes the onset of CRF [Baldwin and Neugarten, 1986]. It indicates a poor prognosis as it accelerates the decline in renal function. Its control is one of the few interventions known to slow the progression of CRF in man [Bergstr6m et al. 1987].

Recent advances in our understanding of hypertensive induced GS has derive from the study of experimental models of systemic hypertension in rats [Baldwin and Neugarten 1986]. In these, the development of GS is variable. Okamoto spontaneously hypertensive, stroke-prone and milan hypertensive rats are resistant to the development of GS in spite of severe systemic hypertension. On the other hand, in Dahl S and DOCA-Salt hypertensive rats GS is extensive. Hill and Heptinstall [1968] suggested that the development of GS in hypertensive rats depends on the transmission of systemic hypertension to the glomeruli. In hypertensive rats resistant to GS, the glomeruli are protected from systemic hypertension through afferent arteriolar vasoconstriction [Brandis et al. 1986]. Those prone to GS have glomeruli with inadequate autoregulation exposing the glomeruli through af-

A.M. E1 Nahas: Glomertflosclerosis 879

ferent arteriolar vasodilatation to the transmission of systemic pressure [Olson et al. 1986]. Dahl S rats have a reduced number of presumably large glomeruli [Baldwin and Neugarten 1986]. This may explain their poor autoregulation and susceptibility to GS. A Similar loss of glomerular autoregulation is believed to expose the glomeruli of rats with a reduced renal mass to systemic hypertension [Bi- dani et al. 1987]. This leads to glomerular hypertension and GS. In favour of such concept, Dwor- kin and coworkers observed that interventions leading to loss of glomerular autoregulation initiate GS in otherwise resistant hypertensive rats. This is the case when spontaneously hypertensive rats (SHR) are uninephrectomized [Dworkin et al. 1986]. On the other hand, therapeutic interventions known to restore autoregulation, such as a low protein diet (LPD), prevent the progression of GS in otherwise prone rats such as uninephrectomized SHR and DOCA-Salt hypertensive rats [Dworkin et al. 1984, 1986]. A LPD also restores autoregulation in hypertensive rats with remnant kidneys and prevents progressive CRF and GS [Bidani et al. 1987].

The concept of loss of glomerular autoregulation following a reduction in functional renal mass leading to the transmission of systemic hypertension to the glomeruli may explain the difference incidence of GS in hypertensive individuals. Cau- casians with essential hypertension, like SHR, may be protected from progressive GS through periph- eral and glomerular vasoconstriction. Elderly and black hypertensive patients are more prone to a progressive decline in renal function [Rostand et al. 1989]. Those, like Dahl S rats, may have a reduced number of glomeruli making them more susceptible to hypertensive GS. Finally, patients with chronic renal disorders and a reduced number of functioning glomeruli, would also be more prone to accelerated GS. This seems to be the case as the degree of vascular and glomerular sclerosis induced by hypertension in these patients exceeds that observed in patients with a similar degree of essential hypertension [Baldwin and Neugarten 1986].

A Unifying Concept of Glomerulosclerosis ?

The presence of systemic hypertension may initiate GS in chronic experimental nephropathies through an increase in glomerular capillary pressure. For any such level of glomerular hypertension, hypertrophied remnant glomeruli would be subjected to a higher degree of capillary wall tension. Thus, experimental animals or humans with a genetically

determined or acquired reduction in number of glomeruli would be more susceptible to hypertensive GS. Such hypertension-induced increase glomerular tension would lead to damage to the glomerular endothelial lining and increase transuda- tion of plasma macromolecules into the mesan- gium [Rennke 1986]. Glomerular endothelial damage is likely to initiate a progressive scarring pro- cess that bears strong similarities to atherosclerosis [El Nahas 1987; Diamond and Karnovsky 1988]. In both, platelet aggregation takes place and leads to the formation of vascular thrombosis [Rennke 1986]. Monocytes infiltrate scarred glomeruli and foam cells are formed [Grond et al. 1980]. Mesan- gial cells proliferate in a fashion comparable to that of smooth muscle cells in arterial walls. Col- lagenous extracellular matrix expansion takes place within scarred glomeruli as in atheromatous arteries. The glomerular capillary wall is infiltrated by proteinaceous material and lipids [Rennke 1986; Grond et al. 1980]. Finally, both GS and atherosclerosis are accelerated by the presence of systemic hypertension. Progressive GS leads to the obliteration of the glomerular capillaries, their ob- solescence and fibrosis. End stage renal failure e n s u e s .

Therapeutic Implications

The assumption that systemic hypertension is synergistic with glomerular hypertension and hypertrophy in initiating GS is likely to have important therapeutic implications. The reduction of either systemic hypertension or glomerular capillary wall tension (size or pressure) should suffice to prevent the development of severe GS. This seems to be the case in experimental animals.

In rats with CRF following renal ablation, the control of systemic hypertension can account for some of the therapeutic effect of a wide range of therapies. This is the case with anti-hypertensive, anti-platelet and lipid lowering agents as well as thromboxane inhibitors and anticoagulants [Klahr et al. 1986]. A reduction of systemic hypertension concommitantly with the prevention of GS in these rats is also observed upon feeding a diet high in linoleic acid [Heifets et al. 1988]. Some interventions are equally protective in these rats in the absence of a reduction of systemic hypertension. This is the case of low protein and low phosphate diets. However, both these interventions increase glomerular afferent arteriolar tone, restore glomerular autoregulation and prevent the transmission of systemic hypertension to remnant glomeruli in rats [Bidani et al. 1987; Harris et al. 1988]. LPD is lik-

880 A.M. E1 Nahas: Glomerulosclerosis

ely to further reduce gtomerular capillary tension through the prevention of glomerular hypertrophy. The protective effect of ACE inhibitors in rats with CRF may be due to their reduction of systemic hypertension as well as glomerular capillary pressure [Anderson et at. 1986]. This may account for the therapeutic advantage of these agents over con- ventional antihypertensive agents in rats with CRF [Anderson et al. 1986]. The calcium antagonist Ni- fedipine, on the other hand, reduces systemic hypertension and gtomerular hypertrophy without affecting glomerular hypertension in rats with CRF [Dworkin et al. 1988]. Thus, it is also likely to prevent GS through a reduction of glomerutar capillary wall tension. At the later stages of experimental GS, prevention of progressive glomerular scarring follows similar lines to that of the prevention of progressive atherosclerosis. The prevention of glomerular microthrombosis and reduction of hyperlipidemia are beneficial [Klahr et al. 1986; Kasiske et al. 1988].

The control of systemic hypertension slows the progression of CRF in humans [Bergstr6m et al. 1987]. Whether some antihypertensive agents have therapeutic advantages over others remains to be determined. ACE inhibitors and calcium antogon- ists seem promising. The role of other dietary and pharmacological interventions aimed to slow CRF is currently under clinical investigation.

Conclusions

Many hypotheses have been put foward over the last few years to explain the progressive nature of CRF and GS. These need not be mutually exclusive. Close analysis indicates that they are comple- mentary as they take us step by step towards a better understanding of the pathophysiology of CRF. They have led to advances in the prevention of progressive CRF and GS in the rat. It is now hoped that humans don't prove too different from rats and may benefit from such progress.

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AM E1 Nahas, M.D. Department of Renal Medicine Northern General Hospital Herries Road Sheffield, $5 7AU United Kingdom

glomerulosclerosis: are we any wiser?

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