|Year : 1999 | Volume
| Issue : 2 | Page : 129-136
|Progression of Chronic Renal Failure: Lessons from the Laboratory: Are the Applicable to Patients?
Abdel Meguid El Nahas1, Nihad A Tamimi2
1 Department of Nephrology, Sheffield Kidney Institute, Northern General Hospital Trust, Sheffield, United Kingdom
2 Kent and Canterbury Hospital, United Kingdom
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|How to cite this article:|
El Nahas AM, Tamimi NA. Progression of Chronic Renal Failure: Lessons from the Laboratory: Are the Applicable to Patients?. Saudi J Kidney Dis Transpl 1999;10:129-36
The progression of chronic renal failure (CRF) leads in the majority of instances to end-stage renal insufficiency and dialysis replacement therapy. The last decade has seen a marked increase in the incidence of end-stage renal disease (ESRD) across the world. In the UK, the incidence of ESRD varies between 45 and 85 patients per million population per year (pmp/year). This is lower than the corresponding figure in the US which was around 268 pmp/year in 1996.  In Europe, there are in excess of 312 pmp on replacement therapy with France having one of the highest prevalence within the continent with 628 pmp.  Further, there are important differences in the incidence of end stage renal failure (ESRD) according to age, gender and race. The incidence of ESRF is higher in males and tends to increase with increasing age reaching around 1000 pmp/year in patients over the age of 65 years. In the United States, the incidence of ESRF is higher in African and native Americans.  This reflects both an increased prevalence of CRF in these ethnic minorities as well as a higher rate of progressions.  This is in keeping with the higher incidence of systemic hypertension and diabetic nephropathy in black and native Americans respectively. 
|How to cite this URL:|
El Nahas AM, Tamimi NA. Progression of Chronic Renal Failure: Lessons from the Laboratory: Are the Applicable to Patients?. Saudi J Kidney Dis Transpl [serial online] 1999 [cited 2021 Apr 18];10:129-36. Available from: https://www.sjkdt.org/text.asp?1999/10/2/129/37217
| Pathophysiology of Progressive CRF|| |
The progression of CRF is associated histologically with progressive glomerulosclerosis, tubulointerstitial fibrosis and vascular sclerosis. Research undertaken over the last quarter of a century has improved our understanding of the pathophysiology of these histological changes.
Glomerulosclerosis is associated with progressive renal scarring regardless of the nature of the initiating nephropathy. Numerous hypotheses have been put forward to explain the progressive sclerosis and fibrosis of the glomeruli. These have included the hypothesis of adaptive hemodynamic or morphological glomerular changes observed in remnant glomeruli after the loss of renal function mass. The compensatory glomerular hyperperfusion, hyperfiltration or hypertension  and/or the associated glomerular hyprtrophy  have all been implicated to contribute to the progression of glomerulosclerosis. The hyperperfusion/ hyperfiltration hypothesis stipulated that a low protein diet would be protective against glomerulosclerosis through the correction of the adaptive hemodynamic changes.  Another hypothesis implicated the nephrotoxicity of lipids linking rise of circulating lipids in CRF with their deposition within scarred glomeruli to the acceleration of the glomerular scarring process.  Since then, a large body of experimental data has confirmed the nephrotoxicity of lipids and in particular oxidized low density lipoproteins. 
It would seem that glomerulosclerosis may evolve in stages involving an initial stage of glomerular endothelial injury and inflammation, a stage of mesangial proliferation and/or activation as well as a final stage of glomerular sclerosis and fibrosis. Throughout the different stages strong similarities exist between the pathogenesis of glomerulosclerosis and that of larger vessel atherosclerosis.  The initial stage of glomerulosclerosis could be initiated by damage to the endothelial cells induced by immune or non-immune (hemodynamic or metabolic) insults. This includes the transmission of systemic hypertension to poorly autoregulated glomeruli leading to a rise in intraglomerular pressure (glomerular hypertension). Damaged endothelium loses its anticoagulant, anti-inflammatory and antiproliferative properties and acquires new procoagulant, pro-inflammatory and mitogenic characteristics. , These are mediated through the release of procoagulation factors such as plateletactivating factor and thromboxane, cytokines such as interleukins 1 and 6, tumor necrosis factor-α, chemokines such as monocyte chemoattractant protein-1 (MCP-1) and macrophage inhibitory protein-2 (MIP-2) and growth factors such as platelet-derived growth factor (PDGF) and transforming growth factor-β (TGF- β). , Damaged endothelium also expresses cell adhesion molecules. All these changes lead to the attraction of platelets and inflammatory cells (neutrophils and monocytes) to the glomerular capillaries. Infiltrating monocytes interact with mesangial cells and stimulate their proliferation either through direct cell-cell interactions or through the release of mitogens such as PDGH. Proliferating and activated mesangial cells have the capacity to revert to a mesenchymal phenotype expressing markers such as α - smooth muscle actin (α-SMA) and synthesizing a range of extracellular matrix (ECM) components TGF- β1 is thought to be the most fibrogenic,  and recently, high circulating levels of TGB-β have been described in patients with progressive renal disease.  The accumulation of ECM within scarred glomeruli and their inability to break it down culminates in fibrosis and the obsolescence of the glomeruli.
The pathogenesis of tubulointerstitial fibrosis (TIF) has also received increasing attention over recent years. This is justified in view of that fact that the severity of tubulointerstitial changes correlates better with renal function when compared to glomerulosclerosis.  One hypothesis stipulated that adaptive hyper-function of remnant proximal tubules takes place in response to renal functional loss. Other hypotheses include nephrotoxicity of lipids, ammonia, iron and oxygen free radicals.  It has also been suggested that proteinuria itself could be toxic.  This is supported by experimental observations showing that the exposure of proximal tubular cells in culture to albumin, transferring or serum leads to their release of cytokines, growth factors and chemotactic yeptides such as MCP-1 and osteopontin.  Recent evidence also suggests that tubular cells also respond to proteinuria by the synthesis of components of the ECM. 
The attraction of inflammatory cells into the renal interstitium by activated tubular cells would in turn activate and stimulate the proliferation of interstitial and perivascular renal fibroblasts. The activation of these cells also leads to their acquisition of myofibro-blastic phenotypes and the expression of cytoskeletal proteins such as α-SMA.  Another potential source of myofibro-blasts is tubular cells themselves which may revert after injury to a mesenchymal, myofibro-blastic, phenotype expressing α-SMA and vimentin. Myofibroblasts progressively invade the scarred renal interstitium and contribute to the progression of interstitial fibrosis. 
Vascular sclerosis is often an integral feature of the renal scarring process. Renal arteriolar hyalinosis is present in chronic renal diseases at an early stage even in the absence of severe hypertension, and the hyalinosis/sclerosis is often out of proportion to the severity of systemic hypertension. Changes in postglomerular arterioles any further exacerbate interstitial ischemia and fibrosis.  Recent data suggests damage to peritubular capillaries and a decrease in their numbers and function in scarred kidneys.  This would also potentially exacerbate interstitial ischemia and result in further fibrosis. Finally, the vascular adventitia may be a source of interstitial myofibro-blasts contributing to the development of interstitial renal fibrosis.
| Management of Experimental Progressive Renal Failure|| |
The advances and insight made in our understanding of the mechanisms of progressive renal scarring have suggested a broad range of dietary and pharmacological approaches.
In experimental animals, dietary protein restriction attenuates the development of glomerulosclerosis and slows the progression of CRF.  Other dietary interventions which proved to be protective have included dietary restrictions of phosphate, salt, sucrose, calories and saturated fats.  On the other hand, the supplementation of diet with p9lyunsaturated fatty acids, including fish oil (eicosapentanoic acid) and an increase in water intake are also protective against the progression of experimental renal insufficiency. 
Antiplatelet agents and anticoagulants have also been tested with some success in experimental animals with progressive renal disease.  The reduction of renal monocytic infiltration by diets or drugs have also prevented the progression of experimental renal scarring. , Inhibition of cytokines, chemokines and growth factors with neutralizing antibodies or receptor antagonists have been effective in attenuating the severity of glomerulosclerosis and proteinuria and preserving renal function in rats with progressive renal diseases.  Finally, the reduction of systemic hypertension reduces proteinuria and preserve renal function in experimental models of renal scarring.  Some have suggested that angiotensin converting enzyme inhibitors were more effective than other antihypertensive agents in slowing progression of renal failure  as they are capable of reducing both systemic and intraglomerular hypertension  and have anti-proteinuric properties. However, others have argued that the protective effect of antihypertensive agents in rats depend on the quality of systemic blood pressure control regardless of the nature of the antihypertensive agent used.  Perhaps, ACE inhibitors are more effective at reducing proteinuria at high levels of blood pressure while other antihypertensive agents are equally effective when the blood pressure is reduced to below normal levels.
| Clinical Interventions in CRF|| |
As in experimental animals a wide range of interventions have been applied to slow the progression of clinical nephropathies. These have included dietary and pharmacological interventions.
Dietary interventions have included dietary protein and/or phosphate restrictions as well as the supplementation of diets with fish oil. Dietary protein restrictions have been recommended to patients with progressive CRF for the last 30 years.  Consequently numerous clinical trials have evaluated the effects of a low protein diet (LPD) on the progression of renal diseases. Early studies have suggested that such a diet was protective. However, more scrutiny revealed the majority of the initial clinical trials to be flawed with inadequate controls, limited follow-up, and using serum creatinine measurements as a marker to assess the rate of progression of CRF.  The latter is now known to be an unreliable marker of progression when dietary protein intake is reduced leading to changes in the intake of creatinine, its excretion.  More recently, better controlled, randomized and prospective trials have been undertaken and they have also shown inconclusive and conflicting results.  The largest of these trials, modification of diet in real disease (MDRD), involved 840 patients followed up prospectively over three years and failed to show convincingly that a LPD slows the progression of CRF.  However, subsequent analysis suggested that there was a positive correlation between the dietary protein intake and the rate of progression of renal insufficiency in patients with GFRs between 13 and 24 ml/1.73m 2 ; in this group a reduction of 0.2g/kg/day in protein intake appeared to lead to a slowing of the decline in GFR by 1.15 ml/mn/year. Before advocating dietary protein reduction, it is often associated with wasting and malnutrition. Even the MDRD patients lost weight.  AS malnutrition is a major adverse risk factor on dialysis, it is therefore unreasonable to compromise the nutritional well being of CRF patients with a LPD for a doubtful, or marginal at best, effect on the rate of Progression of their disease. Finally, what is the point of prescribing LPDs when it has been clearly shown that patients with ESRF reduce spontaneously their protein intake to around 0.6g/kg/day. 
Other dietary interventions have focused on dietary restriction of phosphate. The only randomized study addressing this issue failed to show a difference in the progression rate of CRF on such diet.  Studies of dietary supplementation with fish oil in CRF have shown conflicting results. In a trial of fish oil supplementation in patients with IgA nephropathy the main endpoint, which was a 50% increase in serum creatinine, was reduced in three patients on fish oil compared to 14 of the placebo treated patients.  However, this study was criticized for the unusually fast rate of decline of renal function of the control group.
With respect to pharmacological interventions, most have proved of little efficacy in patients with CRF. Antiplatelets agents and anti-coagulants failed to affect the natural history of chronic glomerulonephritis.  Immunosuppression is difficult to evaluate in view of the heterogeneous nature of primary and secondary glomerulonephritides. However, some trials warrant comments if only to highlight the difficulties with long term studies of interventions in progressive CRF. In membranous nephropathy, an Italian group has repeatedly shown that a combination of chlorambucil and steroids slowed the progression of the disease.  When a long term study of the natural history of the disease was compared to the results of these intervention trials it appeared that the progression rate of patients with membranous nephropathy treated with chlorambucil and steroids was comparable to untreated patients.  Furthermore, immunosuppression was not without its associated morbidity and mortality. Studies from the National Institute of Health in the USA on the effect of immunosuppression on the progression of CRF in patients with lupus nephropathies have suggested that combination immunosuppression with steroids and cyclophosphamide may be advantageous.  Careful analysis of these studies highlight their uncontrolled nature as comparisons were made between current interventions and those practiced in the sixties and seventies!.  Furthermore, statistical significance was only noted when the number of patients followed up had fallen drastically, thus casting doubt on the significance of the differences between the groups based on actuarial survival analysis.  In conclusion, we need, as practitioners, to be vigilant in our interpretation of published data. Sometimes, close scrutiny of the literature may avoid unproven, unnecessary and potentially harmful interventions.
It is safe to say that the only intervention of proven benefit in patients with CRF is the control of systemic blood pressure. While even this intervention has not been the subject of rigorous, prospective and randomized testing, retrospective and prospective analysis have suggested a slowing down of the rate of decline in CRF of patients whose blood pressure was well controlled. Two questions follow; the first, what is the optimal level of blood pressure control we should aim for? And the second, which antihypertensive agent should we use?
In answering the first question, data from the multiple risk factor intervention trial (MRFIT) study implies an strong graded relation between levels of systolic and diastolic blood pressure and ESRF.  Some have suggested that patients with a diastolic blood pressure inferior to 90 mmHg had a rate of decline of GFR 50% slower than those with higher values.  In this study, no additional benefit seemed to be gained from a reduction of diastolic blood pressure to values lower than 85-90 mmHg.  The MDRD study suggested a target mean arterial pressure (MAP) of 92 mmHg (125/75 mmHg) in patients with more than 1g/day proteinuria to achieve a similar reduction of in the rate of decline of GFR to those with less proteinuria and mean arterial pressure of 98 mmHg (130/80 mmHg).  Thus, the target of blood pressure control may need to take into consideration the severity of proteinuria with lower targets set for patients with heavy proteinuria. The same study also implied that lower targets should be sought in African-Americans compared to their European countrerparts.  The second question which arises is which drug should we used to treat hypertension in CRF. A growing body of evidence has suggested a therapeutic advantage of angiotension converting enzyme (ACE) inhibitors compared to other antihypertensive drugs. This was often demonstrated in experimental animals and attributed to the reduction of glomerular capillary hypertension by ACE inhibitors, their anti-proteinuric effect as well as the inhibition of angiotensin IImediated trophic and fibrosing effects. Three large prospective studies one in diabetic patients.  and the others in nondiabetic patients., with progressive CRF reported a beneficial effect of ACE inhibitors. These studies have their limitations as they showed a better blood pressure control in patients treated with the ACE inhibitor compared to those on the other agents, thus not excluding the possibility that there was an additional benefit derived from a better overall blood pressure control regardless of the agent used. It has to be noted that in all the studies comparing ACE inhibitors to other antihypertensive agents blood pressure measurements were made casually with no data given on the overall 24 hours blood pressure control. On the other hand, some studies have shown in patients with diabetic and non-diabetic nephropathies that a similar antihypertensive and anti-proteinuric effect can be achieved with other agents. In particular, non-dihydropyridine calcium antagonists (such as Diltiazem) are capable of reducing proteinuria and slowing the progression of nephropathy in non-insulin dependent diabetes mellitus (NIDDM) to the same extent as ACE inhibitors (Lisinopril).  The United Kingdom Prospective Diabetes Study (UKPDS) also showed equal protection afforded by the beta blocker Atenolol and the ACE inhibitor captopril in patients with NIDDM when tight blood pressure control was achieved.  Further, in patients with polycystic kidney disease.  as well as in the elderly,  ACE inhibitors appear to accelerate the rate of decline in renal function. These agents are not without their potential nephrotoxicity in patients with a reduction in residual renal function. It is imperative to be selective and cautious in prescribing ACE inhibitors as they can lead to acceleration in the decline in renal function which can, on occasions, be irreversible.  Finally, the therapeutic potential of ACE inhibitors may be affected by the patients, genotype as in one study patients with the ACE genotype (II) had the best response to treatment with ACE inhibitors while those with the genotype (DD) responded poorly. 
| Clinical Recommendations|| |
In patients with progressive CRF our main aim should be to avoid harm. This entails avoidance of nephrotoxic investigations (radiocontrast material) and drugs (non steroidal anti-inflammatory agents and ACE inhibitors). We should also look for the causes of acute on chronic deterioration in renal function, such as obstruction (prostatic hypertrophy amongst others) or renovascular diseases in the elderly. Both should addressed and corrected to prevent ESRF. We should follow up patients frequently and closely with particular attention to the detection, monitoring and treatment of hypertension. It is reasonable to advise patients with progressive renal failure to avoid a high protein diet, but caution should be exerted when recommending dietary protein restriction with the inherent risk of malnutrition Attention should be paid to the management of complications of CRF such as metabolic acidosis and hypocalcemia with the associated renal osteodystrophy. Finally, it may be better to start dialysis replacement therapy earlier in well nourished patients than risk malnutrition with its associated increases risk of morbidity and mortality on dialysis.
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Abdel Meguid El Nahas
Sheffield Kidney Institute, Northern General Hospital Trust, Herries Road, Sheffield S5 7AU
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