December 1994, Volume 44, Issue 12

Review Articles

Progression of Chronic Renal Disease - An Update

Iffat Yazdani  ( Institute of Urology and Transplantation, Dow Medical College, Karachi. )

Chronic renal disease once established usually pro­gresses to end singe renal failure even when the primary cause of the renal insufficiency is removed. This progression occurs in various clinical settings, including chronic renal allograft injury1, vesicoureteral reflux2, after recovery from bilateral renal cortical necrosis3, after drug discontinuation in some patients with analgesic nephropathy4, after initial recovery from post streptococcal glomerulonephritis5 or acute renal failure6, or as a consequence of a congenital reduction in nephron number, as in the case of oligemeganephronia7 or a congenital solitary kidney8. A reduction in the number of functioning nephrons (where GFR is reduced to one fifth of the normal) causes eventual failure of the remaining nephron units. Much stress has been placed on immunological factors that can lead to progressive deterioration of renal functions. There are different mechanisms that can lead to progression of the disease9 and these have been studied by various workers to halt the in-exorable decline of renal function with time. The histological yardstick to measure progressive renal disease is glomerulosclerosis9 and chronic tubulo-interstitial damage10. The interstitial damage is characterized by mononuclear inflammatory cell infiltration and intratubular cast formation that eventually results in tubule atrophy accompanied by interstitial fibrosis. Clinical studies have demonstrated that progressive glomemlar injury in humans is haemodynamically mediated. Adaptive alterations in glomerular haemodynamics include hyper filtration, hypertension, hyper perfusion and hypertro­phy. Dietary protein. hyperlipidaemia or systemic hyperten­sion play an ancillary role. The tubular factors which have a significant contributary role, are hypermetabolism in the remnant nephron, interstitial calcium deposition and in­creased ammonia genesis.

Glomerular Factors

Glomerular Hyperfiltration
In experimental models of renal disease, a critical reduction in renal mass has been found to cause hyper filtration and intraglomerular hypertension in the remnant nephrons. Two weeks after unin ephrectomy the GFR and kidney weight increased in proportion by average of 40%11. Micro puncture studies in rats show that there is an increase in glomerular capillary plasma flow rate (Qa) which results in a decrease in the vascular resistance in the afferent and efferent arterioles. The fall in resistance is greater in the afferent arteriole compared to the efferent and this gives rise to an increase in the glomemlarcapillary hydraulicpressure (Pge) 11,12. Qa and Pge account for the increase in single nephron glomerular filtration rate (SNGFR) measured in the remaining nephrons. Unilateral nephrectomy results in 40-50% increase in SNGFR11 while SNGFR more than double with more exten­sive, i.e. greaterthan7O% reduction in renal mass12. Even after one or two decades total GFR often averages approximately 70% of the prenephrectomy values despite the 50% reduction in renal mass. This indicates that the remaining kidney is hyper filtrating. Most studies have shown that with hyperfiltration the prevalence of hypertension and proteinuria also becomes a possibility13,14. On the contrary, some studies have failed to support causal relationship between intraglomerular hypertension and progression of renal disease. Rats treated with doxorubicin or pummycin amnino nucleoside have been shown to develop glomemlosclerosis despite normal or reduced GFR and pressures15. Fine16 proposed a new hypothesis of "glomerular tolerance”. He suggested that itis not the degree of hyper filtra­tion but the tolerance of the glomeruli to the haemodynamic stress that causes progressive renal injury. Quantitative differences in the threshold for injury may exist between intact and diseased nephrons of the same species and between intact nephrons of different species. If glomerular tolerance could be measured, it might prove useful in identifying patients with lowered threshold for injury who are likely to be more susceptible to the adverse effects of long term glomerular hypertension. No method for detecting or quantitating such a hypothetical threshold for injury has so far been evolved. Intra-renal renin and angiotensin II have been thought to play a key role in the progression of glomemloselerosis by causing efferent arteriolar constriction and raising the intra­glomerular capillary hydraulic pressure9. Angiotensin II also increases the trapping of macromolecules in the me­sangium17 and stimulates proximal tubular cell proliferation18. The beneficial effect of angiotensin II converting enzyme inhibitors on the progression of renal disease may be related to this mechanism. Of the glomemlar haemodynamic determinants of adaptive hyperfiltration, glomerular capillary hypertension probably plays the key role in the eventual structural injury.
Systemic hypertension
It may cause, as well as be a consequence of chronic renal disease. Previously it was thought that hypotension leads to glomerular sclerosis due to ischaemia where there was decreased glomenmlar perfusion resulting from renal vascular disease. More recent data has suggested that glomerular sclerosis could occur in the absence of arteriosclerotic disease and in many cases glomerular capillary hyperper fusion and hypertension could initiate glomemlar structural injury19. Systemic hypertension is not required for the development of glomerular capillary hyper filtration and hypertension. In diabetic rats a pathological reduction in afferent arteriolar resistance leads to an increase inglomemlarcapillary flow and allows a greater fraction of systemic blood pressure to be transmitted into the glomerular capillary network. This raises the glomerular capillary hydraulic pressure inspite of normal renal perfusion pressure20,21. Systemic blood pressure tends not to decline with protein rcstriction but glomerular injury is arrested22,16; this emphasizes the importance of glomerular than systemic haemodynamics. Studies have also shown that it is glomerular capillary hypertension rather than hyperfiltra­tion or hyperperfusion which is the critical detenninant of glomerular cell injury. Thus control of glomerular capillary pressure may concur renal protection even in the lace of the continued systemic hypertension. The factors that increase glomemlar capillary hydraulic pressure experimentally were: a high protein diet, dietary cholesterol supplementation27, admini­stration of glucocorticoids28, minerallocorticoids29,30 or erythropoitin31. There arc various studies %vhich defined the role of angiotensin converting enzymes inhibitors in not only control­ling blood pressure but also limiting proteinurea and slowing development of glomerular sclerosis in experimental models. ACE inhibitors normalized both systemic and glomerular capillary pressure32-37 and thereby they are most consistently beneficial in slowing progression of experimental renal disease. The role of calcium channel blocker5 is still under study and various studies have shown conflicting result of this family of drugs38-44. Several other drugs like a diuretic, vasodilator or centrally acting agent or a combination of the three have also been used though there have been very good control of blood pressure with the above drugs. Renal protection has been quite variabic with this regimen45. Beta adrenergic blockers have also been studied widely but the results available are not very encouraging. The deleterious consequences of intra- glomemlar hypertension besides its direct destmctive effect, have been suspected to be due to glomerular endothelial damage. This in turn may precipitate intra-glomerular coagulation46 and increase the mesangial "trafficking" of macromolecules which promote glomemlos­clerosis46
Role of Dietary Proteins
Protein restriction in rats with subtotal renal ablation or streptozotocin-induced diabetes mellitus is associated with a reduction in the functional and structural changes which are known to cause progressive renal failure47. Dietary restriction of protein has been shown to blunt the hyperfiltration response and to reduce glomerular hypertrophy47 There is also a decrease in serum lipid levels48 and a reduced immune cell activation49, both of which are known to contribute to nephrosclerosis. Kidney size, structure and function are markedly influenced by protein intake. When animals are continuously fed on protein rich diet there is an increase in their renal blood flow and GFR which is accompanied by renal hypertro­phy21,50. These haemodynamics and structural cha9es canbe reversed with dietary protein restriction. Studies51-53 have proved that a reduction of dietary protein to 0.6g/kgm/day or even lower levels with supplementation of essential amino acids or their nitrogen free keto analogues would preserve renal function and maintain nitrogen balance. Vetter et al. 54 compared the effects of different diets on the rate of progression of CRF in 60 patients; 20 were treated by protein restriction alone, 20 by protein restriction plus a supplement of essential amino acids and 20 by the same diet plus a supplement of keto-acids. The slowest rate of disease progression was seen in the keto-acid-treated group; the rates of pmgression in the other two groups did not differ from one another. These results lead to the conclusion that protein-re­stricted regimens supplemented with keto-acids can in many cases retani the progression of chronic renal insufficiency toward end-stage renal disease, despite the fact that none of the studies cited included a prospectively randomized control group (with the possible exception of that by Vetteret al.). The only study reporting nepative results used a keto-acid dosage one third of the others55. It seems clear that better results can be achieved when treatment is begun at a relatively early stage than if it is deferred until dialysis is imminent. It also appears that keto-acid supplements are more effective in slowing the progression of renal insufficiency than essential amino acid supplements. Perhaps some metabolic effect associated with the supplement, rather than the associated protein and phos­phate restriction alone, plays a role. Administration of L-arginine in diet prevents the development of hyperfiltration and ameliorates proteinuria in diabetic rats.
Vascular smooth muscle cells have been considered to play a key role in the pathogenesis of atherosclerosis. Since mesangial cells bear a close resemblance to the vascular smooth muscle cells, it has been suggested that accumulation of lipids within the mesangial cells may lead to focal glomerulosclerosis56. Lipid trapping has been shown to stimulate mesangial cell proliferation, increase production of a basement membrane4ike material, neutralize the negative charge on the glomerular basement membrane and increase the adhesion of monocytes to the capillary endothelial cells57; all these are likely to enhance glomerulosclerosis. Filtered lipoprotein could precipitate in the proximal tubules with consequential tubular interstitial injury. Dietary cholesterol supplementation has been reported to induce focal and segmental glomemlar sclerosis in normal animals27,58 and to accelerate sclerosis in rats with diversed renal disease58,59. Recently Rabelink et al demonstrated that Simvastatin administered to nephrotic patients for 48 weeks reduced the magnitude of proteinuria60. In another study, hyper­cholestemlemic diabetic patients with nephropathy were administered pravastatin for a period of 12 weeks. Pravastatin significantly reduced albuminuria61. The obvious challenge with regards to lipids and hypertension is toplan strategies (exercise62, dietary63,64 and pharmacologic65,66 ) for retarding the progression to chronic renal failure. In this regard the most promising strategies are vasoactive and hypolipidemic agents. Vasoactive agents currently being used are calcium antagonist, angiotensin converting enzyme inhibitor and alpha blockers and those which could have great potential are endothelial inhibitors and nitrous oxide agonists.
Glomerular Hypertrophy
Enlargement of the glomemli and proximal convulated tubules accounts for the majority of the parenchymal hypertro­phy67 resulting in disproportional enlargement of the cortex in comparison to the lesser absolute hypertrophy of the renal medullaiy structure. Experimental maneuver which induce glomemlosclerosis, like unilateral nephrectomy, glucocorti­coid administration and high protein diet, have been shown to promote glomerular hypertrophy. The close association be­tween glomerular hypertrophy and glomemlar sclerosis under experimental conditions and the absence of any evidence of a haemodynamic factor which could have caused glomerular hypertrophy68 as led to the suggestion that under certain conditions, some local or circulating growth factor may enhance glomerular sclerosis.
Intraglomerular Coagulation
Intraglomerular fibrinoid material has been found in many forms of glomerular injury and this prompted specula­tion that another mechanism may be contributing to the glomemlar injury i.e., endothelial cell dysfunction leading to intra capillary thrombosis69,70. The administration of heparin or warfarin has been shown to reduce glomemlosclerosis in rats subjected to sub total nephrectomy69,70. Heparin retards the progression not only by its anti-coagulating activity but also suppresses the proliferation of mesangial cells72. The numerous physiological effects of heparin, however have precluded any definite conclusion as to the mcchanism of this protective effect. There should be a measure to predict the course of renal insufficiency in most patients with CRF. Serial measurement of the plasma clearance of a radioisotope(99mTc-DTPA or 51Cr-EDTA) appear to be the most simple and accuratc estimate of the GFR in patients with renal insufficiency. If as in diabetic nephropathy the changes in renal function is linear the changes in the course of renal insufficiency can be analysed easily. A more simple method is to measure the decline in serial values of the reciprocal of the serum creatinine concentration. The relationship is linear in most patients after the semm creatinine rises above 2.5 mg/dl and available data indicate that spontaneous changes in the slope of the reciprocal relationship are unusual. The linearity of this relationship is consistent with reports that GFR and creatinine clearance decline at a constant rate in CRF.
Tubular Factors
The most frequently studied experimental model of chronic renal failure is the rat remnant kidney model. Maneuvers which enhance the progression of renal failure and glomerulosclerosis have been shown to produce significant tubulo-interstitial changes characterised by interstitial infil­tration, fibrosis and tubular atrophy associated with active cellular hyperplasia, cellularnecrosis and cystic changes in the tubules of the remnant nephrons9. Several clinical studies have clearly demonstrated a close correlation between tubulointerstitial disease and renal dysfunction in different nephropathies. Moreover, morphological evaluation of human kidneys with chronic renal disease including glomerulonephritis has shown that the severity of renal impainnent, as assessed by glomemlar filtration rate, correlates better with tubulo-inter­stitial changes rather than with glomerular alterations73. These morphological findings have focussed attention on tubulo­interstitial changes in the progression of renal disease.
Interstitial Calcium Deposition
Deposition of calcium salts in the renal interstitium has been shown to cause proogressive loss of renal function in rats with remnant kidneys74. The degree of calcification appears to correlate best with semm phosphorus levels and the deposi­tion is thought to be due to a secondary rise in the calcium phosphorus product75. Lumlertgul et al.76 observed that restriction of dietary intake to phosphorus in experimental animals was beneficial in reducing the progression of renal failure. Ibels et al. 77. Haut et al78 ; D\\\'Angelo et al. 79 have shown that in rats with surgically-induced chronic renal failure, dietary phosphate restriction may prevent hyperphos­phatemia, an increase in fractional phosphate excretion, parenchymal calcification and fibrosis, renal functional dete­rioration and death from uremia. The most convincing evidence for a role of dietary phosphate in the progression of chronic renal failure in humans compare progression before and after instituting a low-protein (0.6 g/kg) diet in two groups of patients, one receiving 6.5 mg/kg of phosphorus and the other 12 mg/kg. Presumably, the patients were randomized, although this is not stated. Progression nearly halted in the first group but continued in the group receiving the higherphosphorus intake. In the 54 patients as a group, highly significant correlations were noted between the rate of progression and urinary phosphate excretion or the serum level of N-terminal parathy­roid hormone. Thus there is strong evidence that dietary phosphate might play an important role inprogression of CRF. Recent experimental studies have, however, shown that the well documented protective effect of phosphate restriction may be related to a fall in the glomerular filtration rate or to suppression of immune responsiveness46. Renal calcification is a known complication of the secondary hyperparathymidism of chronic renal failure. While thyroparathyroidectomy and selective thyroidectomy have been found useful in slowing the progression of renal failure in rat5 with nephrotoxic serum nephritis, isolated parathyroidectomy surprisingly has no effect79, thus implicat­ing thyroxine as a major factor in the progression of renal disease. In a subsequent study, Conger and Falk80 have shown that in experimental animals thyroidectomy retards the progression of renal disease by reducing intraglo merular hypertension. Thyroid replacement in these animals com­pletely negates the protective effect of the therapy. Long term verapamil administration has been shown to decrease renal hypertrophy81 and retard the progression of chronic renal failure, thus suggesting a potential role for Na+ICa++ exchange in the pathogenesis of progression of renal damage.
Increased Ammoniagenesis in Remnant Nephrons
Nathet al.82 incriminated increased ammoniagenesis in the remnant nephrons as a factor in activating the complement cascade and contributing to tubulo-interstitial damage.
Tubular hypermetabolism
Schrieret al. 10 suggested that a critical reduction in renal mass in rats with remnant kidneys results in hypermetabolism in the surviving nephron population. The hypermetabolism leads to increased intra-cellular sodium concentration which activates Na+/K++ ATP ase leading to increased ATP utilisa­tion, mitochondrial CO2 consumption and free oxygen radicle generation. The free oxygen radicles lead to lipid peroxida­tion and tissue damage. The increased intracellular sodium content also activates Na+/Ca++ exchange. The rise in intracellular calcium increases phospholipase activity which causes tissue damage. Phospholipase activity is also enhanced by intracellular alkalinization due to increase in Na+/H+ anti-porter transport per nephron under the influence of increased growth factor response. Several maneuvres like phosphate restriction4, low protein diet47, chronic vera­pamil81 administration and hypothroidism80 have been con­sidered to retard the progression of renal disease by decreasing oxygen consumption and generation of free oxygen radicles10. The role of therapeutic modalities like the administra­tion of glutathione, an oxygen radicle scavenger; inhibitors of xanthine oxidase, which is critical to oxygen radicle genera­tion and amiloride analogues to inhibit the Na+/H+ anti-porter system, is still under review. In conclusion, several glomerular and tubular factors may be involved in the progression of chronic renal failure. Some of the studies reviewed here have enabled us to understand the mechanism which are likely to be of crucial importance in determining the progression of renal damage in spite of no further external insult to the kidney function after the initial injury.


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