"Chronic kidney disease: Management strategies"

Malvinder S. Parmar MD, FRCPC, FACP

(Reprinted with pith permission, BMJ)

Director of Dialysis. Director, Medical Program
Timmins and District Hospital
Timmins, Ontario. Canada.

atbeat@ntl.sympatico.ca

The number of patients suffering from end-stage renal disease (ESRD) is growing worldwide. There are about 20-30 patients with some degree of renal dysfunction for each patient requiring renal replacement therapy¹. Diabetes and hypertension, the two common causes of ESRD, are associated with higher risk of cardiovascular disease.

Mortality among ESRD patients remains 10-20 times higher than the general population. Hence, the focus in recent years has shifted to optimising care of these patients during the phase of chronic kidney disease, before the onset of ESRD. The goal of this review is to summarize current knowledge about various stages of chronic kidney disease, risk factors that lead to progression of disease, their association with common cardiovascular risk factors and to provide strategies for intervention at an earlier stage of disease process that may be applied by the Primary Care Physician to improve overall morbidity and mortality associated with chronic kidney disease.

Methods:

Recent articles (1992-2001) related to management of chronic kidney disease and its complications were identified from a search of Medline. Key words included chronic kidney disease, chronic renal failure, kidney disease, ESRD, anaemia, erythropoietin, ischaemic heart disease, cardiac disease, lipid disorders, Hyperparathyroidism, calcium, phosphate, nutrition, diabetes and hypertension in relation to kidney disease. The recent clinical practice guidelines² published by the National Kidney Foundation were also incorporated.

Summary points: In chronic kidney disease, Significant renal dysfunction might be present even when serum creatinine is normal or slightly abnormal. Symptoms of renal failure often do not become apparent until advanced renal failure is present. Renal function declines progressively once creatinine clearance falls by about 25% of normal. Baseline urine protein excretion rate is the best single predictor of disease progression.w1 There is higher prevalence of common cardiovascular risk factors - Diabetes, hypertension, hyperlipidaemia and smoking. Early identification and effective control of these risk factors is important to improve outcomes. Cardiovascular disease accounts for 40% of all deathsw2. Look for potentially reversible causes when there is sudden decline in renal function. Irreversible, but modifiable complications - anaemia, cardiovascular disease, metabolic bone disease and malnutrition, begin early in the course of renal failurew3.

Diagnosis:

Chronic renal failure disease is defined as either kidney damage or glomerular filtration rate (GFR) <60 ml/min for > 3 months². This invariably is a progressive process that results in ESRD.

Serum creatinine is commonly used to estimate creatinine clearance but is a poor predictor of GFR, as it may be influenced in unpredictable ways by assay techniques, endogenous and exogenous substances, renal tubular handling of creatinine, and other factors (age, sex, body weight, muscle mass, diet, drugs etc)³. GFR is the "gold standard" for determining kidney function but its measurement remains cumbersome. Hence, for practical purposes, calculated creatinine clearance is used as a correlate of GFR and is commonly estimated (Table 1) using Cockcroft-Gault formula^w4 or recently described Modification of Diet in Renal Disease (MDRD) equation^w5. (126 words)

Stages of chronic kidney disease:

Chronic kidney disease is divided into five stages (Table 2, Figure 1) based on renal function. Pathogenesis of progression is complex and is beyond the scope of this review. However, kidney disease often progresses by "common pathway" mechanisms, irrespective of the initiating insult⁴. In animal models, a reduction in nephron mass exposes the remaining nephrons to adaptive hemodynamic changes that sustain renal function initially but are detrimental in the long-term⁵.

Early detection:

Renal disease is often progressive once GFR falls by 25% of normal. Early detection is important to prevent further injury and progressive loss of renal function.

High-risk patients (table 3) should undergo evaluation for markers of kidney damage (albuminuria, abnormal urine sediment, elevated serum creatinine) and for level of renal function (estimation of GFR from serum creatinine) initially and at periodic intervals depending on the underlying disease process and stage of kidney disease. It is important to identify and effectively treat potentially reversible causes (table 4) if sudden decline in renal function is observed.

Diabetes:

Diabetes is a prevalent cause of CRF and accounts for a large part of growth ESRD in the United States^w2. Effective glycemic and blood pressure control blunt its renal complications.

Meticulous blood glucose control has conclusively shown reduction in the development of microalbuminuria by 35% in type 1 diabetes (The Diabetes Control and Complications Trial - DCCT)⁶ and in type 2 diabetes (United Kingdom Prospective Diabetes Study - UKPDS)⁷. Other studies in parallel suggested that glycemic control reduce the progression of diabetic kidney disease⁸. Adequate blood pressure control with a variety of antihypertensive agents including angiotensin converting enzyme (ACE) inhibitors has shown to delay the progression of albuminuria in both type 1⁹ and type 2¹⁰ diabetes mellitus. Recently angiotensin receptor blockers have shown renoprotective effects in both early¹¹ and late^12,13 nephropathy due to type 2 diabetes.

Hypertension:

Hypertension is a well-established cause, common complication, and an important risk factor for progression of kidney disease. Controlling hypertension is the most important intervention to slow the progression therefore.^w6

Any antihypertensive agents may be appropriate but ACE inhibitors are particularly effective in slowing progression of renal insufficiency in patients with and without diabetes mellitus by reducing angiotensin II effects on renal hemodynamics, local growth factors, and perhaps glomerular permselectivity¹⁵. Non-dihydropyridine calcium channel blockers are also shown to retard progression of renal insufficiency in patients with type 2 diabetes mellitus. Recently, angiotensin receptor blockers (Irbesartan and Losartan) have shown renoprotective effect in diabetic nephropathy independent of blood pressure reduction^11-13. Early detection and effective treatment of hypertension to target levels (Table 7) is essential. The benefit of aggressive blood pressure control is most pronounced in patients with urine protein of >3 g/24-h^w6.

Reducing Proteinuria:

Proteinuria, previously considered a marker of kidney disease, is itself pathogenic and is single best predictor of disease progression. Reducing urinary protein excretion slows progressive decline in renal function in both diabetic and non-diabetic kidney disease.

Angiotensin blockade with ACE-inhibitors or angiotensin receptor blockers at comparable levels of blood pressure control are more effective than conventional antihypertensive agents in reducing proteinuria, GFR decline and progression to ESRD ^{11-14, w8-11}.

Dietary Protein Intake:

The role of dietary protein restriction in chronic kidney disease remains controversial^w6,15,16. The largest controlled study initially failed to find an effect of protein restriction¹⁷ but secondary analysis based on achieved protein intake suggested that low protein diet slows the progression. However, early dietary review is necessary to assure adequate energy intake, maintain optimal nutrition and avoid malnutrition. (58 words)

Dyslipidaemia:

Lipid abnormalities may be evident with only mild renal impairment and contributes to progression of chronic kidney disease and increased cardiovascular morbidity and mortality. A meta-analysis of 13 controlled trials showed that HMG-CoA reductase inhibitors (statins) decreased proteinuria and preserved GFR in patients with renal disease, an effect not entirely explained by reduction in blood cholesterol¹⁸ .

Phosphate and PTH control

Hyperparathyroidism is one of the earliest manifestations of impaired renal function¹⁹ and minor changes in bones have been demonstrated in patients with a GFR of 60 ml/min²⁰. Renal tissue calcium-phosphate precipitation begins early and may influence the rate of progression of kidney disease and is closely related to hyperphosphataemia and calcium-phosphate (Ca x P) product. Calcium-phosphate precipitation should be reduced by adequate fluid intake, modest dietary phosphate restriction and administration of phosphate binders to correct serum phosphate (table 8). Dietary phosphate should be restricted before GFR falls below 40 ml/min, and before development of hyperparathyroidism. The use of vitamin D supplements during chronic kidney disease is controversial.

Smoking Cessation:

Smoking, besides increasing the risk of cardiovascular events, is an independent risk factor for development of ESRD in men with kidney disease²¹. Smoking cessation alone may reduce the risk of disease progression by 30 percent in type 2 diabetes²².

Anaemia:

Anaemia of chronic kidney disease begins when GFR falls below 30-35% of normal and is normochromic and normocytic. This is primarily due to decreased erythropoietin (EPO) production by the failing kidney²³ but other causes might be responsible and should be considered. Whether anaemia accelerates the progression of kidney disease is controversial. However, it is independently associated with the development of left ventricular hypertrophy (LVH) and other cardiovascular complications²⁴ in a vicious cycle (Figure 2).

Treatment of anaemia with erythropoietin (rHuEPO) may slow progression of chronic kidney disease but requires further study. Treatment of anaemia results in partial regression of LVH in both pre-ESRD and dialysis patients²⁵ and has reduced the frequency of heart failure and hospitalisation among dialysis patients²⁶.

Both NKF-DOQI²⁷ and European best practice²⁸ guidelines recommend evaluation of anaemia when haemoglobin (Hb) is <11 g/dL, and consider rHuEPO if Hb is consistently <11 g/dL to keep target Hb of >11 g/dL. (78 words)

Prevention or attenuation of complications and co-morbidities:

Malnutrition:

The prevalence of hypoalbuminemia is high among patients beginning dialysis, of multi-factorial origin and associated with poor outcome. Hypoalbuminemia may be a reflection of chronic inflammation than nutrition per se. Spontaneous protein intake begins to decrease when GFR falls below 50 ml/min. Progressive decline in renal function causes decreased appetite thereby increasing risk of malnutrition. Hence, early dietary review is important to avoid malnutrition. Adequate dialysis is important to maintain optimal nutrition.

Cardiovascular disease (CVD):

The prevalence, incidence and prognosis of clinical CVD is not known with precision in renal failure but begins early and is independently associated with increased cardiovascular and all-cause mortality^w12. Both traditional and uraemia-specific risk factors (anaemia, hyperphosphataemia, hyperparathyroidism) contribute to the increased prevalence of cardiovascular disease²⁹. Cardiac disease, including left ventricular structural and functional disorders, is an important and potentially treatable co-morbidity of early kidney disease.

No specific recommendations exist for either primary or secondary prevention of CVD in patients with CKD. Most of the current practice is derived from studies in diabetic or non-renal patients. At present, in the absence of evidence, clinical judgment suggests effective control of modifiable and uraemia-specific risk factors at an early stage of renal disease; definitive guidelines for intervention await well-designed, adequately powered prospective studies.

 

Preparing patient for renal replacement therapy:

Integrated care by the primary care physician, nephrologist and the renal team from early stage of disease is vital to reduce overall morbidity and mortality associated with chronic kidney disease. Practical points helpful at this stage of kidney disease are summarized below.

• Patients should be referred to nephrologist before serum creatinine is 150-180 mol/L.
• Patients receiving comprehensive care by renal team have shown slower rate of renal function decline, greater probability of commencing dialysis with higher hemoglobin, better calcium control, a permanent access, and more likely to choose peritoneal dialysis^w13.
• Patients with progressive renal failure should be educated to save vessels of the non-dominant arm for future hemodialysis access. They should have a permanent vascular access (preferably arteriovenous fistula) created when GFR falls below 25 ml/min or RRT is anticipated within a year.
• Patients starting dialysis at relatively higher levels of residual renal function (early starts) have better solute clearance, less malnutrition, better volume control and less morbidity and mortality than patients starting at traditional low levels of renal function (late starts)^w14.

CONCLUSION:

Chronic renal failure represents a critical period in the evolution of chronic kidney disease and is associated with complications and co-morbidities that begin early in the course of CRF. These are initially sub-clinical, but progress relentlessly and may eventually become symptomatic and irreversible. Early in the course of CRF, these conditions are amenable to interventions with relatively simple therapies that have the potential to prevent adverse outcomes. Strategies for effective management of chronic renal disease are summarized in Figure 3. By acknowledging these facts, we have an excellent opportunity to change the paradigm of CRF management and improve patient outcomes

DOS-version of a program, that I have developed (with the help of Parmar Jr) based on Figure 3, that after calculating GFR, takes the reader to the computerized figure 3 and highlights the stage the patient is in, what is the main goal at that stage, and what are the major recommendations at that stage of kidney disease. Download here

References:

1. Jones C, McQuillan G, Kusek J, Eberhardt M, Herman W, Coresh J, Salive M, Jones C, Agoda L: Serum creatinine levels in the US population. Third National Health and Nutrition Examination Survey. Am J Kidney Dis 1998; 32:992-999 (erratum 2000; 35:178).
2. National Kidney Foundation – K/DOQI: Clinical practice guidelines for chronic kidney disease: Evaluation, classification and stratification. Am J Kidney Dis 2002; 39(Suppl. 1):S1-S266.
3. Walser M: Assessing renal function from creatinine measurements in adults with chronic renal failure. Am J Kidney Dis 1998; 32:1-22.
4. Remuzzi G, Bertani T: Pathophysiology of progressive nephropathies. N Eng J Med 1998; 339:1448-1456.
5. Brenner BM, Meyer TW, Hostetter TH: Dietary protein intake and the progressive nature of kidney disease: the role of hemodynamically mediated glomerular injury in the pathogenesis of progressive glomerular sclerosis in aging, renal ablation, and intrinsic renal disease. N Eng J Med 1982; 307:652-659.
6. The Diabetes Control and Complications Trial (DCCT) Research Group: Effect of intensive therapy on the development and progression of nephropathy in the DCCT. Kidney Int 1995; 47:1703-1720.
7. UK Prospective Diabetes Study Group: Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 38. BMJ 1998; 317:703-713.
8. Wang P, Lau J, Chalmers T: Meta-analysis of the effects of intensive blood-glucose control on late complications of type 1 diabetes. Lancet 1993; 341:306-1309.
9. Lewis E, Hunsicker L, Bain R, Rhode R: The effect of angiotensin converting enzyme inhibition on diabetic nephropathy. N Eng J Med 1993; 329:1456-1462.
10. Parving H-H, Osterby R, Anderson P, Hsuech W: Diabetic nephropathy, in Brenner B (ed): The Kidney. Philadelphia, PA, Saunders, 1996, pp 1864-1892.
11. Parving H-H, Lehnert H, Brochner-Mortensen J, Gomis R, Anderson S, Arner P, for the Irbesartan in patients with type 2 Diabetes and Microalbuminuria Study Group: The effect of Irbesartan on the development of diabetic nephropathy in patients with type 2 Diabetes. N Eng J Med 2001; 345:870-878.
12. Lewis EJ, Hunsicker LG, Clarke WR, Berl T, Pohl MA, Lewis JB, Ritz E, Atkins RC, Rhode R, Raz I, for the Collaborative Study Group: Renoprotective effect of the Angiotensin-receptor antagonist Irbesartan in patients with nephropathy due to type 2 diabetes. N Eng J Med 2001; 345:851-860.
13. Brenner BM, Cooper ME, Zeeuw D, Keane WF, Mitch WE, Parving H-H, Remuzzi G, Snapinn SM, Zhang Z and Shahinfar S for the RENAAL Study Investigators: Effects of Losartan on Renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. N Eng J Med 2001; 345:861-869.
14. Mogensen CE, Neldam I, Tikkanen I, Oren S, Viskoper R, Watts RW, Cooper ME for the CALM study group: Randomised controlled trial of dual blockade renin-angiotensin system in patients with hypertension, microalbuminuria, and non-insulin dependent diabetes: the candesartan and lisinopril microalbuminuria (CALM) study. BMJ 2000; 321:1440-1444.
15. Klahr S: is there still a role for a diet very low in protein, with or without supplements, in the management of patients with end-stage renal disease? Curr Opin Nephrol Hypertens 1996; 5:384-387.
16. Levey AS, Adler S, Caggiula AW, England BK, Greene T, Hunsicker LG, Kusek JW, Rogers NL, Teschan PE, for the Modification of Diet in Renal Disease Study Group: Effects of dietary protein restriction on the progression of advanced renal disease in the MDRD study. Am J Kidney Dis 1996; 27:652-663.
17. Modification of Diet in Renal Disease Study Group: Effects of diet and antihypertensive therapy on creatinine clearance and serum creatinine in the Modification of Diet in Renal Disease Study. J Am Soc Nephrol 1996; 7:556-566.
18. Fried LF, Orchard TJ, Kasiske BL: Effect of lipid reduction on the progression of renal disease: a meta-analysis. Kidney Int. 2001; 59:260-9.
19. Martinez I, Saracho R, Montenegro J, Llach F: The importance of dietary calcium and phosphorus in the secondary Hyperparathyroidism of patients with early renal failure. Am J Kidney Dis 1997; 29:496-502.
20. Coen G, Mazzaferro S, Ballant P, Sardella D, Chicca S, Manni M, Bonucci E, Taggi F: Renal bone disease in 76 patients with varying degrees of predialysis chronic renal failure: A cross –sectional study. Nephrol Dial Transplant 1996; 11:813-819.
21. Orth S, Stockmann A, Conradt C, Ritz E, Ferro M, Kreusser W, Piccoli G, Rambausek M, Rocatello D, Schafer K, Sieberth H, Wanner C, Watschinger B, Zucchelli P: Smoking as a risk factor for end-stage renal failure in men with primary renal disease. Kidney Int 1998; 54:926-931.
22. Ritz E, Ogata H, Orth SR. Smoking a factor promoting onset and progression of diabetic nephropathy. Diabetes Metab 2000; 26:Suppl 4:54-63.
23. Eschbach JW: The anemia of chronic renal failure. Kidney Int 1989; 35:134-148.
24. Foley RN, Parfrey PS, Harnett JD, Kent GM, Murray DC, Barre PE: The impact of anemia on cardiomyopathy, morbidity and mortality in end-stage renal disease. Am J Kidney Dis 1996; 28:53-61.
25. Portoles J, Torralbo A, Martin P, Rodrigo J, Herrero J, Barrientos A: Cardiovascular effects of recombinant human erythropoietin in predialysis patients. Am J Kidney Dis 1997; 29:541-548.
26. Eschbach JW, Aquiling T, Haley NR, Fan MH, Blagg CR: The long-term effects of recombinant human erythropoietin on the cardiovascular system. Clin Nephrol 1992; 38:S98-S103.
27. National Kidney Foundation-Dialysis Outcomes Quality Initiative: Guidelines for the treatment of anemia of Chronic Renal failure. Am J Kidney Dis 1997; 30(suppl 3):S150-S191.
28. European Best Practice Guidelines for the management of anaemia in patients with chronic renal failure. Nephrol Dial Transplant 1999; 14(suppl. 5):1-50.
29. Foley RN, Parfrey PS: Cardiac disease in chronic uremia: Clinical outcomes and risk factors. Adv Ren Replace Ther 1997; 4:234-248.

 

 

 

Web-based references: w1. Ruggenenti P, Perna A, Mosconi L, Matalone M, Pisoni R, Gaspari F, Remuzzi G, on the behalf of the "GRUPPO ITAILANO DI STUDI EPIDEMIOLOGICI IN NEFROLOGIA" (GISEN): proteinuria predicts end-stage renal failure in non-diabetic chronic nephropathies. Kidney Int 1997; 52(suppl 63):S54-S57. w2. 2000 report, Volume 1: Dialysis and Renal Transplantation, Canadian Organ Replacement Registry. Canadian Institute for Health Information, Ottawa, Ontario, June 2000. w3. National Institute of Health. Morbidity and mortality of dialysis [consensus statement]. Ann Intern Med 1994;12:62-70. w4. Cockcroft D, Gault M: Prediction of creatinine clearance from serum creatinine. Nephron 1976; 16:31-41. w5. Levey AS, Bosch JP, Lewis KB, Greene T, Rogers N, Roth D: A more accurate method to estimate glomerular filtration rate from serum creatinine: A new prediction equation. Modification of Diet in Renal Disease Study Group. Ann Intern med 1999; 130:461-470. w6. Klahr S, Levey AS, Beck GJ, Caggiula AW, Hunsicker L, Kusek JW, Striker G: The effects of dietary protein restriction and blood pressure control on the progression of chronic renal disease. Modification of Diet in Renal Disease Study Group. N Engl J Med 1994; 330:878-884. w7. The sixth report of the Joint National Committee on prevention, detection, evaluation, and treatment of high blood pressure. Arch Intern Med 1997; 157:2413-46. W8. Ruggenenti P, Remuzzi G: Angiotensin-converting enzyme inhibitor therapy for non-diabetic progressive renal disease. Curr Opin Nephrol Hypertens 1997; 6:489-495. W9. The GISEN Group. Randomised placebo-controlled trial of effect of Ramipril on decline in glomerular filtration rate and risk of terminal renal failure in proteinuric, non-diabetic nephropathy. Lancet 1997; 349:1857-1863. W10. Ruggenenti P, Perna A, Gherardi G, Gaspari F, Benini R, Remuzzi G, on behalf of GISEN. Renal function and requirement for dialysis in chronic nephropathy on long-term Ramipril: REIN follow-up trial. Lancet 1998; 352:1252-1256. W11. Ruggenenti P, Perna A, Gehrardi G, Garini G, Zoccali C, Salvadori M, Scolari F, Schena FP, Remuzzi G: Renoprotective properties of ACE-inhibition in non-diabetic nephropathies with non-nephrotic proteinuria. Lancet 1999; 354:359-364. w12. Muntner P, He J, Hamm L, Loria C, Whelton PK: Renal insufficiency and subsequent death resulting from cardiovascular disease in United States. J Am Soc Nephrol 2002; 13:745-753. w13. Binik YM, Devins GM, Barre PE, et al: Live and Learn: Patient education delays the need to initiate renal replacement therapy in end-stage renal disease. J Nerv Mental Dis 1993; 181:371-376. w14. Obrador GT, Pereira B: Early referral to the nephrologist and timely initiation of renal replacement therapy: A paradigm shift in the management of patients with chronic renal failure. Am J Kidney Dis 1998; 31:398-417.

 

Additional Educational Resources: Tomson CRV. Recent advances: Nephrology. BMJ 2000; 320:98-101 Mason PD, Pusey CD. Fortnightly review: Glomerulonephritis: Diagnosis and Treatment. BMJ 1994; 309:1557-1563 Walker R. Recent advances: General management of end stage renal disease. BMJ 1997; 315:1429-1432. Ifudu O. Current concepts: Care of patients undergoing hemodialysis. New Eng J Med; 1999; 339:1054-1062. Remuzzi G, Schieppati A, Ruggenenti P. Clinical Practice: Nephropathy in patients with Type 2 Diabetes. New Eng J Med 2002; 346:1145-1151. National Kidney Foundation – K/DOQI: Clinical practice guidelines for chronic kidney disease: Evaluation, classification and stratification. Am J Kidney Dis 2002; 39(Suppl. 1):S1-S266.

 

Patient information: Kidney School is an interactive, web-based program designed to help people learn what they need to know to understand kidney disease and its treatment, adjust to kidney disease, make good medical choices, and live as fully as possible. Doc-To-Me presents a concise, informative and authoritative Pre-ESRD lectures – "Staying healthy with bad Kidneys" Kidney Incorporated – provides general information about kidneys, Pre-ESRD care and dialysis therapy.