Release of obstruction, either by percutaneous nephrostomy or through a ureteral stent, is the fundamental treatment. Recovery of renal function depends on the severity and duration of the obstruction [Kapoor and Chan 2001]. Thus, early discovery and treatment

Although serum creatinine and blood urea nitrogen have been used as standard biomarkers, they are not sufficiently specific and sensitive to detect AKI in the early phase [Choudhury 2010]. Moreover, the resultant inability to meaningfully segregate critical aspects of injury such as type, onset, propagation and recovery from ongoing renal function has hindered successful translation of promising therapeutics. Recently, efforts to identify novel plasma or urine biomarkers for AKI have resulted in discovery about 20 potential candidates. Promising markers include urine or plasma neutrophil gelatinase-associated lipocalin (NGAL), kidney injury molecule-1 (KIM-1), IL-18, cystatin C and liver fatty-acid binding

Human NGAL is a 25-kDa protein expressed by neutrophils and various epithelial cells including cells of the proximal convoluted tubules [Goetz, Holmes, Borregaad et al. 2002]. Urinary NGAL is up-regulated within 2 hours after acute renal cellular injury. Microarray analysis identified NGAL as one of the earliest and most prominently induced genes in the kidneys after ischemic or nephrotoxic renal injury in mouse models and humans [Schmidt-Ott, Mori, Kalandadze 2006, Cowland, Borregaad 1997]. In one study, patients in an intensive care unit with AKI had more than 10-fold increases in plasma NGAL and more than 100-fold increases in urine NGAL levels, when compared with controls [Mori, Lee, Rapoport et al. 2005]. Other studies demonstrated the ability of serum and/or urine NGAL to predict the development of postsurgical AKI before elevation of serum creatinine

Kidney injury molecule-1 (KIM-1) is a transmembrane protein overexpressed in proximal tubule cells of the kidneys in response to ischemic or nephrotoxic injury and has a

[Mishra, Dent, Tarabishi et al. 2005, Dent, Ma, Dastrala et al. 2007].

uropathy vary with the site, degree and rapidity of obstruction [Kapoor, Chan 2001].

phosphate deposition [Baeksgaard, Sorensen 2003].

urinary obstruction [Choudhury 2010].

**3.5 Post-renal causes**

are crucial.

**4.1 NGAL**

**4.2 KIM-1**

**4. Biomarkers of AKI**

protein (L-FABP) [Malyszko 2010].

Cystatin C is a low molecular weight cysteine protease inhibitor. The serum level of cystatin C is determined by the glomerular filtration rate (GFR), indicating that serum and urine levels of cystatin C reflect changes in the GFR [Villa, Jimenez, Soriano et al. 2005]. Although serum creatinine levels do not rise until GFR drops to under 50 ml/min (creatinine blind area), serum cystatin C increases at a GFR of around 70ml/min [Shimizu-Tokiwa, Kobata, Io et al. 2002]. This means that serum cystatin C is superior to serum creatinine in detecting impaired GFR.

#### **4.4 IL-18**

IL-18 is a proinflammatory cytokine and powerful mediator of ischemia induced AKI in animal models [Melnikov, Ecder, Fantuzzi et al. 2001]. Il-18 is induced and cleaved in the proximal tubules and is detected in urine following experimental AKI [Melnikov, Faubel, Siggmund et al. 2002]. In a cross-sectional study, IL-18 levels were significantly higher in patients with established AKI but not in those with urinary tract infections. The AUC for diagnosis of established AKI is 0.95 [Parikh, Jani, Melnikov et al. 2004]. In general, it is considered that IL-18 is specific for ischemic AKI but may also be a nonspecific marker of inflammation and has shown inconsistent results [Moore, Bellomo, Nichol 2010].

#### **4.5 L-FABP**

L-FABP is expressed in various organs including the liver and kidneys. The function of L-FABP is cellular uptake of fatty acids from plasma and promotion of intracellular fatty acid metabolism. Since free fatty acids can be easily oxidized, they can lead to oxidative stress and cellular injury. L-FABP inhibits the accumulation of intracellular fatty acids and prevents oxidation of free fatty acids. L-FABP is an important cellular antioxidant during oxidative stress [Noiri, Doi, Negishi et al. 2009].

L-FABP is filtered by glomeruli and reabsorbed in the proximal tubules. This partly explains the increase of L-FABP in injury of the proximal tubules. Renal L-FABP expression is upregulated and urinary L-FABP excretion is accelerated by accumulation of free fatty acids in proximal tubule injury [Kamijo, Sugaya, Hikawa et al. 2004, ].

In a clinical study, urine L-FABP appeared to to be a more sensitive predictor of AKI than serum creatinine, and differentiated patients with septic shock from those with severe sepsis [Nakamura, Sugaya, Koide 2009]. Urine L-FABP can predict AKI in pediatric cardiopulmonary bypass surgery with AUC of 0.81 at 4-hours post-surgery [Portilla, Dent, Sugaya et al. 2008]. Although urine L-FABP is an early, accurate biomarker of AKI, it appears later than NGAL [Moore E, Bellomo R, Nichol. 2010].

Acute Kidney Injury (AKI) and Management of Renal Tumors 191

ill patients is not superior to that of intermittent hemodialysis [Himmelfarb 2007]. Studies on the dose of intermittent hemodialysis (IHD) or CRRT and their outcomes have shown conflicting results although some clinical trials suggested an improvement in survival with higher doses of RRT [Ronco, Bellomo, Homel et al. 2000, Palvesky, Zhang, O'Connor et al. 2008, Bellomo, Cass, Cole et al. 2009, Tolwani, Cruz, Fumagalli et al. 2008, Boumann, Oudemans-Van Straaten, Tijssen et al. 2002, Saudan, Niederberger, Seigneux et al. 2006]. One of the reasons for this phenomenon is that there is considered to be an inflection point separating the dose-response portion and dose-independent portion between RRT dose and survival. Recent multicenter randomized trials showed that higher intensity of CRRT or IHD did not reduce mortality of critically ill patients with AKI [Palvesky, Zhang, O'Connor et al. 2008, Bellomo, Cass, Cole et al]. If a critically ill patient with AKI is given RRT, the mortality is expected to be over 90%. Under-dialysis for critically ill patients with AKI results in higher mortality because of uremic complications. The correct dose is around the infection point, at which the RRT dose is not too small but

The balance of current evidence suggests that CRRT should be performed with an effluent flow rate higher than 20-25ml/kg/h in hemodynamicaly unstable patients with AKI. Alternative-day IHD is acceptable in more stable patients and minimum single pool Kt/V urea of 1.2-1.4 is recommended [Schiffl 2010]. Clinicians should check whether patients actually receive the current optimal doses of RRT. Higher doses and more intensive therapy can be considered if patients become extremely hypercatabolic or have a volume overload.

Although a large number of studies have been performed on AKI, little is known about its pathophysiology, appropriate diagnosis or treatment. It is hoped that further studies will improve the prognosis of patients with AKI. It appears that suitable treatments should be

This work is partly supported by grants by Ministry of Education, Culture, Sports, Science

Azoulay E, Moreau D, Alberti C et al. (2000). ''Predictors of short-term mortality in critically

Azoulay E, Recher C, Alberti C et al. (1999). ''Changing use of intensive care for

Baeksgaard L, Sorensen JB (2003). ''Acute tumor lysis syndrome in solid tumors- a case report and review of the literature.'' *Cancer Chemother Pharmacol* 51: 187-92.

hematological patients: the example of multiple myeloma.'' *Intensive Care Med* 25:

and Technology of Japan and Ministry of Health, Labor and Welfare of Japan.

Arany I, Safirstein RL (2003). ''Cisplatin nephrotoxicity.'' *Semin Nephrol* 23: 460-64.

ill patients with solid malignancies.'' *Intensive Care Med* 26: 1817-23.

**5.3 Recommendation of RRT for critically ill patients with AKI**

selected for AKI especially in patients with malignancies.

not excessive.

**6. Conclusion**

**8. References**

**7. Acknowledgement**

1395-1401.

#### **5. Treatment**

People who have risk factors of AKI (eg, past history of AKI, CKD or diabetes mellitus) should be treated as carefully as possible [Lamaire, Adam, Becker et al. 1999]. The best method for preventing contrast media induced AKI is to avoid use of contrast media. If contrast media must be used, the most effective prevention is to avoid volume depletion and to assure adequate volume [Davidson, Hlatky, Morris et al. 1989, Cigarroa, Lange, Williams et al. 1989]. The effect of administration of *N*-acetylcysteine (NAC) is controversial [Fishbane 2008] and there is no convincing evidence of benefits in periprocedual blood purification [Frank H, Werner D, Lorusso V et al. (2003), Vogt B, Ferrari P, Schonholzer C et al. (2001)]. Since renal autoregulatory capacity maintains renal blood flow, several vasopressors including dopamine, norepinephrine, vasopressin and terlipressin, have been used or tested for prevention of renal ischemia. There is no clear convincing evidence on the beneficial effects of these agents for treating AKI [Rudnik MR, Kesselheim A, Goldfarb S (2006)].

There are currently no specific pharmacological interventions for patients with established AKI but renal replacement therapy (RRT) is a key component of supportive care. AKI associated with cancer shows substantial morbidity and mortality. Among critically ill cancer patients, 12-49% experience AKI and 9-32% need RRT [Lanore JJ, Brunet F, Pchard st al. 1991, Benoit, Hoste, Depuydt et al. 2005, Azoulay, Recher, Alberti C et al. 1999, Azoulay, Moreau, Alberti et al. 2000, Darmon, Thiery, Ciroldi et al. 2005]. These figures are much higher than those for critically ill patients without cancer. Most of the studies on AKI in cancer patients focus on patients with hematological malignancies whose mortality is over 80% when RRT is necessary [Zager, O'Quigley, Zager et al. 1989]. Studies focusing on AKI in renal tumor patients have not been reported. In a cohort study, the benefits of early organ support including RRT was shown in the patients with non-hematological cancers associated with AKI [Darmon, Thiery, Ciroldi et al. 2007]. AKI, which has multiple causes and shows higher mortality in cancer patients, allows physicians to perform reluctant RRT, but there are no adequate treatment guidelines for AKI in patients with malignancies.

#### **5.1 Dosage in renal replacement therapy (RRT)**

The effectiveness of RRT can be adjusted by the rate of solute clearance (duration of the session) and/or the frequency of RRT sessions. The assessment of RRT dose is traditionally performed by single-pooled Kt/V urea. This refers to fractional clearance of urea (K), which takes into consideration therapy duration (t) and volume of distribution of urea in the body (V). In contrast to end stage kidney disease (ESKD) patients, critically ill patients with AKI have an unstable metabolic status (eg. hypercatabolism and fluid expansion). When continuous RRT (CRRT) is performed, ultrafiltration volume acts as a surrogate for clearance, based on with sieving coefficient of most small solutes such as urea. Therefore, application of Kt/V urea in critically ill patients has its limitations [Schiffl, Lang, Fischer 2002]. The RRT adequacy is more complex than small-solute removal. Fluid overload has been independently associated with increased mortality of AKI [Payen, de Pont, Sakr et al. 2008, Bouchard J, Soroko S Chertow G et al. 2009].

#### **5.2 Intensity of RRT and outcome**

Renal replacement therapy (RRT) is usually performed in critically ill patients by intermittent hemodialysis or continuous RRT (CRRT). CRRT is performed together with hemofiltration, dialysis or a combination of them. The efficacy of CRRT for critically ill patients is not superior to that of intermittent hemodialysis [Himmelfarb 2007]. Studies on the dose of intermittent hemodialysis (IHD) or CRRT and their outcomes have shown conflicting results although some clinical trials suggested an improvement in survival with higher doses of RRT [Ronco, Bellomo, Homel et al. 2000, Palvesky, Zhang, O'Connor et al. 2008, Bellomo, Cass, Cole et al. 2009, Tolwani, Cruz, Fumagalli et al. 2008, Boumann, Oudemans-Van Straaten, Tijssen et al. 2002, Saudan, Niederberger, Seigneux et al. 2006]. One of the reasons for this phenomenon is that there is considered to be an inflection point separating the dose-response portion and dose-independent portion between RRT dose and survival. Recent multicenter randomized trials showed that higher intensity of CRRT or IHD did not reduce mortality of critically ill patients with AKI [Palvesky, Zhang, O'Connor et al. 2008, Bellomo, Cass, Cole et al]. If a critically ill patient with AKI is given RRT, the mortality is expected to be over 90%. Under-dialysis for critically ill patients with AKI results in higher mortality because of uremic complications. The correct dose is around the infection point, at which the RRT dose is not too small but not excessive.

#### **5.3 Recommendation of RRT for critically ill patients with AKI**

The balance of current evidence suggests that CRRT should be performed with an effluent flow rate higher than 20-25ml/kg/h in hemodynamicaly unstable patients with AKI. Alternative-day IHD is acceptable in more stable patients and minimum single pool Kt/V urea of 1.2-1.4 is recommended [Schiffl 2010]. Clinicians should check whether patients actually receive the current optimal doses of RRT. Higher doses and more intensive therapy can be considered if patients become extremely hypercatabolic or have a volume overload.

#### **6. Conclusion**

190 Topics in Renal Biopsy and Pathology

People who have risk factors of AKI (eg, past history of AKI, CKD or diabetes mellitus) should be treated as carefully as possible [Lamaire, Adam, Becker et al. 1999]. The best method for preventing contrast media induced AKI is to avoid use of contrast media. If contrast media must be used, the most effective prevention is to avoid volume depletion and to assure adequate volume [Davidson, Hlatky, Morris et al. 1989, Cigarroa, Lange, Williams et al. 1989]. The effect of administration of *N*-acetylcysteine (NAC) is controversial [Fishbane 2008] and there is no convincing evidence of benefits in periprocedual blood purification [Frank H, Werner D, Lorusso V et al. (2003), Vogt B, Ferrari P, Schonholzer C et al. (2001)]. Since renal autoregulatory capacity maintains renal blood flow, several vasopressors including dopamine, norepinephrine, vasopressin and terlipressin, have been used or tested for prevention of renal ischemia. There is no clear convincing evidence on the beneficial effects of these agents for treating AKI [Rudnik MR, Kesselheim A, Goldfarb S (2006)]. There are currently no specific pharmacological interventions for patients with established AKI but renal replacement therapy (RRT) is a key component of supportive care. AKI associated with cancer shows substantial morbidity and mortality. Among critically ill cancer patients, 12-49% experience AKI and 9-32% need RRT [Lanore JJ, Brunet F, Pchard st al. 1991, Benoit, Hoste, Depuydt et al. 2005, Azoulay, Recher, Alberti C et al. 1999, Azoulay, Moreau, Alberti et al. 2000, Darmon, Thiery, Ciroldi et al. 2005]. These figures are much higher than those for critically ill patients without cancer. Most of the studies on AKI in cancer patients focus on patients with hematological malignancies whose mortality is over 80% when RRT is necessary [Zager, O'Quigley, Zager et al. 1989]. Studies focusing on AKI in renal tumor patients have not been reported. In a cohort study, the benefits of early organ support including RRT was shown in the patients with non-hematological cancers associated with AKI [Darmon, Thiery, Ciroldi et al. 2007]. AKI, which has multiple causes and shows higher mortality in cancer patients, allows physicians to perform reluctant RRT, but there are no adequate treatment guidelines for AKI in patients with malignancies.

The effectiveness of RRT can be adjusted by the rate of solute clearance (duration of the session) and/or the frequency of RRT sessions. The assessment of RRT dose is traditionally performed by single-pooled Kt/V urea. This refers to fractional clearance of urea (K), which takes into consideration therapy duration (t) and volume of distribution of urea in the body (V). In contrast to end stage kidney disease (ESKD) patients, critically ill patients with AKI have an unstable metabolic status (eg. hypercatabolism and fluid expansion). When continuous RRT (CRRT) is performed, ultrafiltration volume acts as a surrogate for clearance, based on with sieving coefficient of most small solutes such as urea. Therefore, application of Kt/V urea in critically ill patients has its limitations [Schiffl, Lang, Fischer 2002]. The RRT adequacy is more complex than small-solute removal. Fluid overload has been independently associated with increased mortality of AKI [Payen, de Pont, Sakr et al.

Renal replacement therapy (RRT) is usually performed in critically ill patients by intermittent hemodialysis or continuous RRT (CRRT). CRRT is performed together with hemofiltration, dialysis or a combination of them. The efficacy of CRRT for critically

**5. Treatment**

**5.1 Dosage in renal replacement therapy (RRT)**

2008, Bouchard J, Soroko S Chertow G et al. 2009].

**5.2 Intensity of RRT and outcome**

Although a large number of studies have been performed on AKI, little is known about its pathophysiology, appropriate diagnosis or treatment. It is hoped that further studies will improve the prognosis of patients with AKI. It appears that suitable treatments should be selected for AKI especially in patients with malignancies.

#### **7. Acknowledgement**

This work is partly supported by grants by Ministry of Education, Culture, Sports, Science and Technology of Japan and Ministry of Health, Labor and Welfare of Japan.

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Willebrand's factor-cleaving protease in patients with disseminated malignancies.''

with hematological malignancies.'' *Crit Care Med* 19: 346-51.

change the paradigm?'' *Kidney Blood Res* 33: 368-82.

practice.'' *Minerva Anestesiologica* 76(6): 425-40.

*Nephrol* 32(6): 522-32.

7.

110: 1083-91.

1231-8.

21.

454-9.

79.

*Cancer Res* 59: 2244-50.

**12**

*Pakistan*

**Chronic Kidney Disease Update**

*Karachi Medical & Dental College, Abbasi Shaheed Hospital, Karachi*

Chronic kidney disease (CKD) is a worldwide public health issue. In the United States there is a rising incidence and prevalence of kidney failure with poor outcomes and high cost. Most chronic nephropathies are characterized by a progressive course that leads, at a variable rate, to loss of kidney function and the need for renal replacement therapy. The progression of CKD typically moves through phases from initial diminution of renal reserve to mild, moderate and severe reductions in glomerular filtration rate (GFR), to end-stage renal disease (ESRD). There is growing evidence that some of the adverse outcomes of CKD

The definition and classification of CKD may help identify affected patients, possibly resulting in the early institution of effective therapy. To achieve this goal, guidelines were proposed from the National Kidney Foundation of the United States through its Kidney Disease Outcomes Quality Initiative (K/DOQI) program (National kidney Foundation [NKF], 2002). These guidelines have been reviewed and accepted internationally (Levey et

• Evidence of structural or functional kidney abnormalities (abnormal urinalysis, imaging studies, or histology) that persist for at least three months, with or without a decreased GFR. The most common manifestation of kidney damage is persistent albuminuria,

• Decreased GFR (as defined by a GFR of less than 60 ml/min per 1.73 m2), with or

Based upon these definitions, the following is the recommended classification of CKD by stage and the estimated prevalence within the United States of each stage, as determined by a National Health and Nutrition Examination Survey (NHANES) performed in 1999 to 2004 (KDOQI, 2002; Coresh et al., 2003; Levey et al., 2003; Coresh et al., 2005; MMWR, 2007;

• Stage 1 disease is defined by a normal GFR (greater than 90 ml/min per 1.73 m2) and

• Stage 2 disease is a GFR between 60 to 89 ml/min per 1.73 m2 and persistent

persistent albuminuria (1.8 percent of the total United States population)

can be prevented or delayed by preventive measures, early detection and treatment.

**1. Introduction**

**2. Definitions and classification**

al., 2005; Uhlig et al., 2005; Levin et al., 2008).

without evidence of kidney damage.

including microalbuminuria.

albuminuria (3.2 percent)

OR

Coresh et al, 2007).

The K/DOQI working group defined CKD in adults as:

Waqar H. Kazmi and Khurram Danial

### **Chronic Kidney Disease Update**

Waqar H. Kazmi and Khurram Danial

*Karachi Medical & Dental College, Abbasi Shaheed Hospital, Karachi Pakistan*

#### **1. Introduction**

196 Topics in Renal Biopsy and Pathology

Zager RA, O'Quigley J, Zager BK et al. (1989). ''Acute renal failure following bone marrow transplantation: a retrospective study of 272 patients.'' *Am J Kidney Dis* 13: 210-6. von der Maase H, Hansen SW, Roberts SW et al. (2000). 'Gemcitabine and cisplatin versus

study. *J Clin Oncol* 18: 3068-77.

methotrexate, vinblastine, doxorubicin, and cisplatin in advanced or metastatic bladder cancer: results of large, randomized, multinational, multicenter, phase III

> Chronic kidney disease (CKD) is a worldwide public health issue. In the United States there is a rising incidence and prevalence of kidney failure with poor outcomes and high cost. Most chronic nephropathies are characterized by a progressive course that leads, at a variable rate, to loss of kidney function and the need for renal replacement therapy. The progression of CKD typically moves through phases from initial diminution of renal reserve to mild, moderate and severe reductions in glomerular filtration rate (GFR), to end-stage renal disease (ESRD). There is growing evidence that some of the adverse outcomes of CKD can be prevented or delayed by preventive measures, early detection and treatment.

#### **2. Definitions and classification**

The definition and classification of CKD may help identify affected patients, possibly resulting in the early institution of effective therapy. To achieve this goal, guidelines were proposed from the National Kidney Foundation of the United States through its Kidney Disease Outcomes Quality Initiative (K/DOQI) program (National kidney Foundation [NKF], 2002). These guidelines have been reviewed and accepted internationally (Levey et al., 2005; Uhlig et al., 2005; Levin et al., 2008).

The K/DOQI working group defined CKD in adults as:

Based upon these definitions, the following is the recommended classification of CKD by stage and the estimated prevalence within the United States of each stage, as determined by a National Health and Nutrition Examination Survey (NHANES) performed in 1999 to 2004 (KDOQI, 2002; Coresh et al., 2003; Levey et al., 2003; Coresh et al., 2005; MMWR, 2007; Coresh et al, 2007).

Chronic Kidney Disease Update 199

The most reliable assessment of GFR is based on the measurement of kidney clearance of a filtration marker such as Inulin which is a physiologically inert substance that is freely filtered at the glomerulus, and is neither secreted, reabsorbed, synthesized, nor metabolized by the kidney (Rahn et al., 1999). Thus, the amount of inulin filtered at the glomerulus is equal to the amount excreted in the urine, which can be measured. Inulin, however, is in short supply, expensive, and difficult to assay and is not suitable for routine clinical practice, and is cumbersome even for clinical research. Furthermore, the classic protocol for measuring inulin clearance requires a continuous intravenous infusion, multiple blood

Various less cumbersome methods for measuring clearance are available: using alternative filtration markers (such as radioactive or non-radioactive iothalamate, iohexol, DTPA, or EDTA), bolus administration of the marker (subcutaneous or intravenous), spontaneous bladder emptying, and plasma clearance (Rahn et al., 1999; Levey, 1990; Brandstrom et al., 1998). While these methods are simpler, all have disadvantages that limit their application in

In the United States, the most common methods utilized to estimate the GFR are the serum creatinine concentration, the creatinine clearance, or estimation equations based upon the serum creatinine: such as the Cockcroft-Gault equation and Modification of Diet in Renal

The K/DOQI guidelines classified patients by CKD stage, which is defined in part by the estimated GFR (table 1). The GFR should be estimated from the MDRD and Cockcroft-Gault equations, which take into account the serum creatinine concentration, and some or all of

The Cockcroft-Gault formula estimates creatinine clearance in milliliters per minute, and the MDRD equation estimates GFR in milliliters per minute per 1.73 m2, and this difference should be kept in mind when comparing their outputs. However, the estimation equations have not been validated, and may be less accurate, in some populations. These include individuals with high, normal, or near-normal renal function, children, certain ethnic groups, pregnant women, and those with unusual muscle mass, body habitus, and weight (eg, morbid obesity or malnourished). Some, therefore, recommend measuring the creatinine clearance to estimate the GFR in these patients with stable renal function. Most patients with CKD stages 3 to 5 progress relentlessly to ESRD. A straight-line relationship is often found between the reciprocal of serum creatinine (1/SCr) values or the estimated GFR and time. The rate of progression of CKD varies according to the underlying nephropathy

Because of the problems with changes in creatinine production and secretion, other endogenous compounds have been evaluated in an effort to provide a more accurate estimation of GFR including symmetric dimethylarginine (Kielstein et al., 2006) and cystatin C. Perhaps the best studied and most promising is cystatin C, a low molecular weight protein, that is a member of the cystatin superfamily of cysteine protease inhibitors. Cystatin C is filtered at the glomerulus and not reabsorbed. However, it is metabolized in the tubules,

Cystatin C is thought to be produced by all nucleated cells; its rate of production has been thought to be relatively constant, and not affected by changes in diet, although this is not proven. Cystatin C has been purported to be unaffected by gender, age or muscle mass. However, higher cystatin C levels have now been associated with male gender, greater height and weight, and higher lean body mass (Knight et al., 2004; Groesbeck et al., 2008;

samples, and bladder catheterization.

Disease (MDRD) Study equations.

and how the kidney responds to injury.

clinical practice and affect the interpretation of research studies.

the following variables: age, gender, race, and body size.

which prevents use of cystatin C to directly measure clearance.

#### **2.1 Estimation of glomerular filtration rate (GFR)**

Patients with kidney disease may have a variety of different clinical presentations. Some have symptoms that are directly referable to the kidney (gross hematuria,or flank pain), or to extrarenal symptoms (edema, hypertension, signs of uremia). Many patients, however, are asymptomatic and are noted during routine examination to have an elevated serum creatinine concentration, or an abnormal urinalysis.

Once kidney disease is discovered, the presence or degree of kidney dysfunction and rapidity of progression are assessed, and the underlying disorder is diagnosed. Although the history and physical examination can be helpful, the most useful information is initially obtained from estimation of the GFR and examination of the urinary sediment.

Estimation of the GFR is used clinically to assess the degree of kidney impairment and to follow the course of the disease. However, the GFR provides no information on the cause of the kidney disease. This is achieved by the urinalysis, measurement of urinary protein excretion, and, if necessary, radiologic studies and/or kidney biopsy.

#### **2.2 Laboratory measurement for diagnosis of CKD**

#### **2.2.1 For all patients at increased risk for CKD**

#### **2.2.2 For patients found to have CKD**

#### **2.2.3 Estimation of GFR**

Once kidney disease is discovered, the presence or degree of kidney dysfunction and rapidity of progression are assessed, and the underlying disorder is diagnosed. Early identification of patients with CKD would allow treatment that could slow the progression to ESRD, improve clinical outcomes, and constrain the growth of costs in the ESRD program. Although the history and physical examination can be helpful, the most useful information is initially obtained from estimation of the GFR and examination of the urinary sediment.

Estimation of the GFR is used clinically to assess the degree of kidney impairment and to follow the course of the disease. However, the GFR provides no information on the cause of the kidney disease. This is achieved by the urinalysis, measurement of urinary protein excretion, and, if necessary, radiologic studies and/or kidney biopsy.

The GFR is equal to the sum of the filtration rates in all of the functioning nephrons, thus, estimation of the GFR gives an approximate measure of the number of functioning nephrons. GFR cannot be measured directly. Instead it is measured as the urinary clearance of an ideal filtration marker.

• Stage 5 disease is a GFR of less than 15 ml/min per 1.73 m2 or ESRD (2.4 percent for

Patients with kidney disease may have a variety of different clinical presentations. Some have symptoms that are directly referable to the kidney (gross hematuria,or flank pain), or to extrarenal symptoms (edema, hypertension, signs of uremia). Many patients, however, are asymptomatic and are noted during routine examination to have an elevated serum

Once kidney disease is discovered, the presence or degree of kidney dysfunction and rapidity of progression are assessed, and the underlying disorder is diagnosed. Although the history and physical examination can be helpful, the most useful information is initially

Estimation of the GFR is used clinically to assess the degree of kidney impairment and to follow the course of the disease. However, the GFR provides no information on the cause of the kidney disease. This is achieved by the urinalysis, measurement of urinary protein

• Albumin-to-creatinine or protein-to-creatinine ratio in a first-morning or random

• Examination of the urine sediment or dipstick for red bloodcells and white blood cells.

Once kidney disease is discovered, the presence or degree of kidney dysfunction and rapidity of progression are assessed, and the underlying disorder is diagnosed. Early identification of patients with CKD would allow treatment that could slow the progression to ESRD, improve clinical outcomes, and constrain the growth of costs in the ESRD program. Although the history and physical examination can be helpful, the most useful information is initially

Estimation of the GFR is used clinically to assess the degree of kidney impairment and to follow the course of the disease. However, the GFR provides no information on the cause of the kidney disease. This is achieved by the urinalysis, measurement of urinary protein

The GFR is equal to the sum of the filtration rates in all of the functioning nephrons, thus, estimation of the GFR gives an approximate measure of the number of functioning nephrons. GFR cannot be measured directly. Instead it is measured as the urinary clearance

obtained from estimation of the GFR and examination of the urinary sediment.

excretion, and, if necessary, radiologic studies and/or kidney biopsy.

• Serum electrolytes (sodium, potassium, chloride and bicarbonate)

obtained from estimation of the GFR and examination of the urinary sediment.

excretion, and, if necessary, radiologic studies and/or kidney biopsy.

• Stage 3 disease is a GFR between 30 and 59 ml/min per 1.73 m2 (7.7 percent) • Stage 4 disease is a GFR between 15 and 29 ml/min per 1.73 m2 (0.21 percent)

**2.1 Estimation of glomerular filtration rate (GFR)**

creatinine concentration, or an abnormal urinalysis.

**2.2 Laboratory measurement for diagnosis of CKD 2.2.1 For all patients at increased risk for CKD**

• Imaging of the kidneys, usually by ultrasound;

• Serum creatinine to estimate GFR;

untimed 'spot' urine specimen;

**2.2.2 For patients found to have CKD**

**2.2.3 Estimation of GFR**

of an ideal filtration marker.

stages.)

The most reliable assessment of GFR is based on the measurement of kidney clearance of a filtration marker such as Inulin which is a physiologically inert substance that is freely filtered at the glomerulus, and is neither secreted, reabsorbed, synthesized, nor metabolized by the kidney (Rahn et al., 1999). Thus, the amount of inulin filtered at the glomerulus is equal to the amount excreted in the urine, which can be measured. Inulin, however, is in short supply, expensive, and difficult to assay and is not suitable for routine clinical practice, and is cumbersome even for clinical research. Furthermore, the classic protocol for measuring inulin clearance requires a continuous intravenous infusion, multiple blood samples, and bladder catheterization.

Various less cumbersome methods for measuring clearance are available: using alternative filtration markers (such as radioactive or non-radioactive iothalamate, iohexol, DTPA, or EDTA), bolus administration of the marker (subcutaneous or intravenous), spontaneous bladder emptying, and plasma clearance (Rahn et al., 1999; Levey, 1990; Brandstrom et al., 1998). While these methods are simpler, all have disadvantages that limit their application in clinical practice and affect the interpretation of research studies.

In the United States, the most common methods utilized to estimate the GFR are the serum creatinine concentration, the creatinine clearance, or estimation equations based upon the serum creatinine: such as the Cockcroft-Gault equation and Modification of Diet in Renal Disease (MDRD) Study equations.

The K/DOQI guidelines classified patients by CKD stage, which is defined in part by the estimated GFR (table 1). The GFR should be estimated from the MDRD and Cockcroft-Gault equations, which take into account the serum creatinine concentration, and some or all of the following variables: age, gender, race, and body size.

The Cockcroft-Gault formula estimates creatinine clearance in milliliters per minute, and the MDRD equation estimates GFR in milliliters per minute per 1.73 m2, and this difference should be kept in mind when comparing their outputs. However, the estimation equations have not been validated, and may be less accurate, in some populations. These include individuals with high, normal, or near-normal renal function, children, certain ethnic groups, pregnant women, and those with unusual muscle mass, body habitus, and weight (eg, morbid obesity or malnourished). Some, therefore, recommend measuring the creatinine clearance to estimate the GFR in these patients with stable renal function. Most patients with CKD stages 3 to 5 progress relentlessly to ESRD. A straight-line relationship is often found between the reciprocal of serum creatinine (1/SCr) values or the estimated GFR and time. The rate of progression of CKD varies according to the underlying nephropathy and how the kidney responds to injury.

Because of the problems with changes in creatinine production and secretion, other endogenous compounds have been evaluated in an effort to provide a more accurate estimation of GFR including symmetric dimethylarginine (Kielstein et al., 2006) and cystatin C. Perhaps the best studied and most promising is cystatin C, a low molecular weight protein, that is a member of the cystatin superfamily of cysteine protease inhibitors. Cystatin C is filtered at the glomerulus and not reabsorbed. However, it is metabolized in the tubules, which prevents use of cystatin C to directly measure clearance.

Cystatin C is thought to be produced by all nucleated cells; its rate of production has been thought to be relatively constant, and not affected by changes in diet, although this is not proven. Cystatin C has been purported to be unaffected by gender, age or muscle mass. However, higher cystatin C levels have now been associated with male gender, greater height and weight, and higher lean body mass (Knight et al., 2004; Groesbeck et al., 2008;

Chronic Kidney Disease Update 201

protein excretion is useful in a variety of clinical settings, particularly to establish the

In normal subjects, low molecular weight proteins and small amounts of albumin are filtered. The actual amount of albumin filtered each day in humans is controversial. The majority view is that no more than about 2 to 4 g of albumin per day are filtered normally, but some investigators claim that as much as 200 g of albumin are filtered each day (with the bulk of this filtered albumin "reclaimed" in the early proximal tubule) (Russo et al., 2007). The filtered proteins enter the proximal tubule where they are almost completely reabsorbed and then catabolized by the proximal tubular cells. Some of the catabolized proteins (including albumin) are excreted as peptides in the urine. These are not detected by dipstick or the immuno-nephelometric albumin-specific assays, but are detected by chromatographic assays. The net result is the normal daily protein excretion of less than 150 mg (usually 40 to

80 mg), of which approximately about 4 to 7 mg is intact, immuno-reactive albumin.

degrees of proteinuria, particularly increased amounts of albuminuria.

protein in the urine consists of albumin.

• Trace — between 15 and 30 mg/dl • 1+ — between 30 and 100 mg/dl • 2+ — between 100 and 300 mg/dl • 3+ — between 300 and 1000 mg/dl

• Negative

• 4+ — >1000 mg/dl

to the concentration of albumin in the sample

concentration will be 100 mg/dl and the dipstick will read 2+.

Previously, abnormal proteinuria was generally defined as the excretion of more than 150 mg of protein per day. However, it is now clear that early renal disease is reflected by lesser

The normal rate of albumin excretion is less than 20 mg/day (15 μg/min); the rate is about 4 to 7 mg/day in healthy young adults and increases with age and with an increase in body weight. Persistent albumin excretion between 30 and 300 mg/day (20 to 200 µg/min) is called microalbuminuria. In patients with diabetes, this is usually indicative of incipient diabetic nephropathy (unless there is some co-existent renal disease). In non-diabetics, the presence of microalbuminuria is associated with cardiovascular disease.Values above 300 mg/day (200 µg/min) are considered to represent overt proteinuria or macroalbuminuria, the level at which the standard dipstick becomes positive. At this level, practically all

The standard urinary dipstick measures albumin concentration via a colorimetric reaction between albumin and tetrabromophenol blue producing different shades of green according

The urine dipstick is, therefore, not very accurate in assessing the severity of proteinuria since the protein concentration is a function of urine volume as well as the quantity of protein present. As an example, suppose a patient excretes 500 mg of protein per day. If the urine volume is two liters, the protein concentration will be 25 mg/dl, resulting in a trace to 1+ findings on the dipstick. However, if the urine volume is only 500 ml, the protein

The urine dipstick is also a relatively insensitive marker for initial increases in protein excretion, not generally becoming positive until protein excretion exceeds 300 to 500 mg/day. Limited data suggest that the combination of specific gravity plus dipstick proteinuria may

The dipstick may also be insufficiently sensitive in multiple myeloma. Given that the dipstick primarily detects urinary albumin, it may be negative in patients with multiple myeloma who

significantly improve the ability to detect proteinuria (Constantiner et al., 2005).

diagnosis and to follow the course of glomerular disease.

Macdonald et al., 2006). Cystatin C levels increase sharply with age (Knight et al., 2004). Analysis of a sub-sample of 7596 participants drawn from National Health and Nutrition Examination Survey III (NHANES III) revealed that more than 50 percent of individuals over age 80 have an elevated cystatin C level, and non-Hispanic whites and males have higher levels of cystatin C (Kottgen et al., 2008). These data were not adjusted for GFR; therefore, it is unclear whether they are related to different levels of kidney function among the populations, or difference in the non-GFR determinants of cystatin C. In addition, cystatin is affected by hyper- and hypothyroidism, and has been correlated with markers of inflammation (C-reactive protein), body size (in particular fat mass), and diabetes (Manetti et al., 2005; Stevens et al., 2009). Together, these data suggest that levels of cystatin C are affected by factors other than GFR.

Although reference ranges have been reported, there is no current standard for serum cystatin C measurements (Shlipak et al., 2005; Mussap & Plebani, 2004). In addition, testing for cystatin C is only available in a limited number of laboratories.

The serum cystatin C concentration may correlate more closely with the GFR than the serum creatinine concentration (Newman et al., 1995; Coll et al., 2000; Fliser & Ritz, 2001; Mussap et al., 2002; Ahlstrom et al., 2004; Hoek et al., 2003; Dharnidharka et al., 2002; Poge et al., 2006; Stevens et al., 2008). In multiple studies, serum cystatin C was more sensitive in identifying mild reductions in kidney function than serum creatinine (Coll et al., 2000; Hoek et al., 2003; Dharnidharka et al., 2002). Using the clearance of radioactive iothalamate as the gold standard, serum cystatin C levels began increasing at GFR levels of approximately 90 mL/min per 1.73 m2, while the serum creatinine only increased when the GFR was approximately 70 mL/min per 1.73 m2. Whether cystatin C correlates better with GFR than serum creatinine in patients with diabetic nephropathy is unclear (Oddoze et al., 2001; Perkins et al., 2005).

Estimation equations based on serum cystatin C have also been formulated (Grubb et al., 2005; Sjostrom et al., 2005; Grubb et al., 2005). It has been proposed that cystatin C-based equations would be more accurate in populations with lower creatinine production, such as the elderly, children, renal transplant recipients, or patients with cirrhosis (White et al., 2005; Poge et al., 2006). In one study of over 3000 patients with known CKD, an equation for the estimated GFR based upon cystatin C was nearly as accurate as GFR estimated from the serum creatinine adjusted for age, sex, and race when compared to GFR measured by iothalamate clearance (Stevens et al., 2008). The addition of age, sex and race to cystatin C reduced bias in some subgroups defined by these variables, and an equation that uses both serum creatinine and cystatin C with age, sex and race was better than equations that used only one of these markers.

Steroid use may affect cystatin C levels, therefore, limiting its use in transplant recipients. As an example, for the same level of cystatin C, measured GFR was 19 percent higher in transplant recipients than in patients with native kidney disease.

Although cystatin C appears to be more accurate for the assessment of GFR than serum creatinine in certain populations, whether measurement of cystatin C levels will improve patient care is at present unknown [Deinum & Derkx, 2000).

#### **2.3 Markers of kidney damage**

Markers of kidney damage include proteinuria, hematuria, and other abnormalities of the urinary sediment, and radiologic evidence of damage. The most common cause of CKD in adults are diabetes and hypertension, and, therefore, the most common marker for kidney damage is increased excretion of protein, and specifically of albumin. Measurement of

Macdonald et al., 2006). Cystatin C levels increase sharply with age (Knight et al., 2004). Analysis of a sub-sample of 7596 participants drawn from National Health and Nutrition Examination Survey III (NHANES III) revealed that more than 50 percent of individuals over age 80 have an elevated cystatin C level, and non-Hispanic whites and males have higher levels of cystatin C (Kottgen et al., 2008). These data were not adjusted for GFR; therefore, it is unclear whether they are related to different levels of kidney function among the populations, or difference in the non-GFR determinants of cystatin C. In addition, cystatin is affected by hyper- and hypothyroidism, and has been correlated with markers of inflammation (C-reactive protein), body size (in particular fat mass), and diabetes (Manetti et al., 2005; Stevens et al., 2009). Together, these data suggest that levels of cystatin C are

Although reference ranges have been reported, there is no current standard for serum cystatin C measurements (Shlipak et al., 2005; Mussap & Plebani, 2004). In addition, testing

The serum cystatin C concentration may correlate more closely with the GFR than the serum creatinine concentration (Newman et al., 1995; Coll et al., 2000; Fliser & Ritz, 2001; Mussap et al., 2002; Ahlstrom et al., 2004; Hoek et al., 2003; Dharnidharka et al., 2002; Poge et al., 2006; Stevens et al., 2008). In multiple studies, serum cystatin C was more sensitive in identifying mild reductions in kidney function than serum creatinine (Coll et al., 2000; Hoek et al., 2003; Dharnidharka et al., 2002). Using the clearance of radioactive iothalamate as the gold standard, serum cystatin C levels began increasing at GFR levels of approximately 90 mL/min per 1.73 m2, while the serum creatinine only increased when the GFR was approximately 70 mL/min per 1.73 m2. Whether cystatin C correlates better with GFR than serum creatinine in patients

Estimation equations based on serum cystatin C have also been formulated (Grubb et al., 2005; Sjostrom et al., 2005; Grubb et al., 2005). It has been proposed that cystatin C-based equations would be more accurate in populations with lower creatinine production, such as the elderly, children, renal transplant recipients, or patients with cirrhosis (White et al., 2005; Poge et al., 2006). In one study of over 3000 patients with known CKD, an equation for the estimated GFR based upon cystatin C was nearly as accurate as GFR estimated from the serum creatinine adjusted for age, sex, and race when compared to GFR measured by iothalamate clearance (Stevens et al., 2008). The addition of age, sex and race to cystatin C reduced bias in some subgroups defined by these variables, and an equation that uses both serum creatinine and cystatin C with age, sex and race was better than equations that used

Steroid use may affect cystatin C levels, therefore, limiting its use in transplant recipients. As an example, for the same level of cystatin C, measured GFR was 19 percent higher in

Although cystatin C appears to be more accurate for the assessment of GFR than serum creatinine in certain populations, whether measurement of cystatin C levels will improve

Markers of kidney damage include proteinuria, hematuria, and other abnormalities of the urinary sediment, and radiologic evidence of damage. The most common cause of CKD in adults are diabetes and hypertension, and, therefore, the most common marker for kidney damage is increased excretion of protein, and specifically of albumin. Measurement of

for cystatin C is only available in a limited number of laboratories.

with diabetic nephropathy is unclear (Oddoze et al., 2001; Perkins et al., 2005).

transplant recipients than in patients with native kidney disease.

patient care is at present unknown [Deinum & Derkx, 2000).

affected by factors other than GFR.

only one of these markers.

**2.3 Markers of kidney damage**

protein excretion is useful in a variety of clinical settings, particularly to establish the diagnosis and to follow the course of glomerular disease.

In normal subjects, low molecular weight proteins and small amounts of albumin are filtered. The actual amount of albumin filtered each day in humans is controversial. The majority view is that no more than about 2 to 4 g of albumin per day are filtered normally, but some investigators claim that as much as 200 g of albumin are filtered each day (with the bulk of this filtered albumin "reclaimed" in the early proximal tubule) (Russo et al., 2007). The filtered proteins enter the proximal tubule where they are almost completely reabsorbed and then catabolized by the proximal tubular cells. Some of the catabolized proteins (including albumin) are excreted as peptides in the urine. These are not detected by dipstick or the immuno-nephelometric albumin-specific assays, but are detected by chromatographic assays. The net result is the normal daily protein excretion of less than 150 mg (usually 40 to 80 mg), of which approximately about 4 to 7 mg is intact, immuno-reactive albumin.

Previously, abnormal proteinuria was generally defined as the excretion of more than 150 mg of protein per day. However, it is now clear that early renal disease is reflected by lesser degrees of proteinuria, particularly increased amounts of albuminuria.

The normal rate of albumin excretion is less than 20 mg/day (15 μg/min); the rate is about 4 to 7 mg/day in healthy young adults and increases with age and with an increase in body weight. Persistent albumin excretion between 30 and 300 mg/day (20 to 200 µg/min) is called microalbuminuria. In patients with diabetes, this is usually indicative of incipient diabetic nephropathy (unless there is some co-existent renal disease). In non-diabetics, the presence of microalbuminuria is associated with cardiovascular disease.Values above 300 mg/day (200 µg/min) are considered to represent overt proteinuria or macroalbuminuria, the level at which the standard dipstick becomes positive. At this level, practically all protein in the urine consists of albumin.

The standard urinary dipstick measures albumin concentration via a colorimetric reaction between albumin and tetrabromophenol blue producing different shades of green according to the concentration of albumin in the sample

The urine dipstick is, therefore, not very accurate in assessing the severity of proteinuria since the protein concentration is a function of urine volume as well as the quantity of protein present. As an example, suppose a patient excretes 500 mg of protein per day. If the urine volume is two liters, the protein concentration will be 25 mg/dl, resulting in a trace to 1+ findings on the dipstick. However, if the urine volume is only 500 ml, the protein concentration will be 100 mg/dl and the dipstick will read 2+.

The urine dipstick is also a relatively insensitive marker for initial increases in protein excretion, not generally becoming positive until protein excretion exceeds 300 to 500 mg/day. Limited data suggest that the combination of specific gravity plus dipstick proteinuria may significantly improve the ability to detect proteinuria (Constantiner et al., 2005).

The dipstick may also be insufficiently sensitive in multiple myeloma. Given that the dipstick primarily detects urinary albumin, it may be negative in patients with multiple myeloma who

Chronic Kidney Disease Update 203

either inactive or cured (Abboud & Henrich, 2010). The institution of measures to help prevent this process, such as antihypertensive therapy with an angiotensin converting enzyme inhibitor or an angiotensin II receptor blocker, may slow progressive disease and even preserve renal function. If these modalities are effective, the benefit is likely to be

Not all individuals have progressive loss of kidney function. Some studies show a high rate of progression, while others report relatively stable disease (Sarnak et al., 2005; Eriksen & Ingebretsen, 2006; Hallan et al., 2006). The rate of progression of CKD from one major stage to another varies based upon the underlying disease, presence or absence of comorbid conditions, treatments, socioeconomic status, individual genetics, ethnicity, and other

Using epidemiologic data, general estimates for the rate of transition from a GFR between 15 to 60 ml/min per 1.73 m2 to end stage disease may be approximately 1.5 percent per year, while the rate of transition from a GFR above 60 to below 60 ml/min per 1.73 m2 may be

Historically, rate of decline in GFR of patients with diabetic nephropathy (DN) has been among the fastest, averaging about 10 ml/min/year. Control of systemic hypertension slows the rate of GFR decline to 5ml/min/year. In non-diabetic nephropathy, the rate of progression of CKD was 2.5 times faster in patients with chronic glumerulonephritis than in those with chronic interstitial nephritis, and 1.5 times faster than in those with hypertensive nephrosclerosis. Polycystic kidney disease (PKD) and impaired renal function may also

The prevalence of CKD has been evaluated based on serum creatinine concentrations and microalbuminuria in the following population studies from the United States, as well as

In the Third National Health and Nutrition Examination Survey (NHANES III), serum creatinine concentration was obtained in a sample of 18,723 individuals aged 12 years and older between 1988 and 1994 (Jones et al., 1998). The prevalence of a serum creatinine level at or above 1.5, 1.7, and 2.0 mg/dl was 5.0, 1.9, and 0.6 percent for men, respectively, and

By extrapolating the results of the NHANES III to the 1990 US Census population, it was estimated that the number of people with serum creatinine at or above 1.5, 1.7, and 2.0 mg/dl is 6.2, 2.5, and 0.8 million, respectively. It should be noted, however, that only a single creatinine measurement per patient was used to estimate the prevalence of CKD, and that serum creatinine was available in only 31 percent of the potentially eligible sample. In a study of nearly 200,000 patients enrolled in a large health maintenance organization (HMO) in the southwestern US in 1997, the prevalence of at least one gender specific elevated serum creatinine (>1.2 mg/dl in women and >1.4 mg/dl in men) was 3.7 percent, and of at least two elevated serum creatinine levels separated by at least 90 days was 1.7

The prevalence estimates from this HMO study, as applied to United States Census data, led to the estimate of 9.1 million Americans in 1990 who had at least one elevated serum creatinine concentration, and 4.2 million Americans who had at least two elevated creatinine

greatest if begun before a great deal of irreversible scarring has occurred.

approximately 0.5 percent per year (Hsu et al., 2004; Fox et al., 2004).

**4. Prevalence of chronic kidney disease**

some other countries.

1.6, 0.7, and 0.3 percent for women.

percent (Nissenson et al., 2001).

values separated by 90 days or greater.

have a faster rate of progression compared to those with other nephropathies.

factors.

may excrete relatively large amounts of monoclonal immunoglobulin light chains. In contrast, testing the urine with sulfosalicylic acid will detect all proteins, as evidenced by the degree of turbidity (Rose, 1987). As a result, any patient with unexplained renal failure, a benign urine sediment, and a negative dipstick for protein should have the urine tested with sulfosalicylic acid. A positive finding suggests the presence of non-albumin proteins in the urine, which in adults usually represents immunoglobulin light chains.

The accurate measurement of protein excretion in the urine can be performed by several different techniques. The gold standard for measurement of protein excretion is a 24 hour urine collection, with the normal value being less than 150 mg/day. However, an adequate collection must be ensured. This is cumbersome for patients and physicians; thus, measurement on random specimens has become an accepted alternative method.

The preferred method of measuring urinary protein excretion in patients with proteinuria is either the total protein-to-creatinine ratio or albumin-to-creatinine ratio for microalbuminuria on a random urine specimen (Eknoyan et al., 2003; KDOQI, 2002).

 Thus, a ratio of 4.9 (as with respective urinary protein and creatinine concentrations of 210 and 43 mg/dl) represents daily protein excretion of approximately 4.9 g/1.73 m2.

The accuracy of the ratio is diminished when creatinine excretion is either markedly increased in a muscular man (the ratio will underestimate proteinuria) or markedly reduced in a cachectic patient (the ratio will overestimate proteinuria).

Because of this markedly increased convenience, the total protein-to-creatinine ratio or albumin-to-creatinine ratio are preferred to the 24 hour urine collection for quantitative measurement of significant urinary protein. First morning specimens are preferred, but random daytime specimens are acceptable if first morning specimens are not available (Witte et al., 2009). Specimens obtained in the evening or overnight appear to be least accurate.

The range of the urinary albumin-to-creatinine ratio with microalbuminuria varies by gender, being 20 to 200 mg/g and 30 to 300 mg/g for males and females, respectively. This is a result of the higher muscle mass observed in males.

Hematuria or pyuria originating in the renal parenchyma, glycosuria in the absence of hyperglycemia, and abnormal radiologic or pathologic studies are others diagnostic criteria for CKD.

#### **3. Natural history of CKD**

The kidney is able to adapt to damage by increasing the filtration rate in the remaining normal nephrons, a process called adaptive hyperfiltration. As a result, the patient with mild renal insufficiency often has a normal or near-normal serum creatinine concentration. Additional homeostatic mechanisms (most frequently occurring within the renal tubules) permit the serum concentrations of sodium, potassium, calcium, and phosphorous and the total body water to also remain within the normal range, particularly among those with mild to moderate renal failure. Adaptive hyperfiltration, although initially beneficial, appears to result in long-term damage to the glomeruli of the remaining nephrons, which is manifested by proteinuria and progressive renal insufficiency. This process appears to be responsible for the development of renal failure among those in whom the original illness is

may excrete relatively large amounts of monoclonal immunoglobulin light chains. In contrast, testing the urine with sulfosalicylic acid will detect all proteins, as evidenced by the degree of turbidity (Rose, 1987). As a result, any patient with unexplained renal failure, a benign urine sediment, and a negative dipstick for protein should have the urine tested with sulfosalicylic acid. A positive finding suggests the presence of non-albumin proteins in the urine, which in

The accurate measurement of protein excretion in the urine can be performed by several different techniques. The gold standard for measurement of protein excretion is a 24 hour urine collection, with the normal value being less than 150 mg/day. However, an adequate collection must be ensured. This is cumbersome for patients and physicians; thus,

The preferred method of measuring urinary protein excretion in patients with proteinuria is either the total protein-to-creatinine ratio or albumin-to-creatinine ratio for

These ratios on a random urine specimen correlate fairly closely with daily protein excretion in g/1.73 m2 of body surface area (Ginsberg et al., 1983; Schwab et al., 1987; Abitbol et al., 1990; Steinhauslin & Wauters, 1995; Chitalia et al., 2001; Zelmanovitz et al., 1997; Bakker, 1999). Thus, a ratio of 4.9 (as with respective urinary protein and creatinine concentrations of 210 and 43 mg/dl) represents daily protein excretion of approximately 4.9 g/1.73 m2. The accuracy of the ratio is diminished when creatinine excretion is either markedly increased in a muscular man (the ratio will underestimate proteinuria) or markedly reduced

Because of this markedly increased convenience, the total protein-to-creatinine ratio or albumin-to-creatinine ratio are preferred to the 24 hour urine collection for quantitative measurement of significant urinary protein. First morning specimens are preferred, but random daytime specimens are acceptable if first morning specimens are not available (Witte et al., 2009). Specimens obtained in the evening or overnight appear to be least

The range of the urinary albumin-to-creatinine ratio with microalbuminuria varies by gender, being 20 to 200 mg/g and 30 to 300 mg/g for males and females, respectively. This

Hematuria or pyuria originating in the renal parenchyma, glycosuria in the absence of hyperglycemia, and abnormal radiologic or pathologic studies are others diagnostic criteria

The kidney is able to adapt to damage by increasing the filtration rate in the remaining normal nephrons, a process called adaptive hyperfiltration. As a result, the patient with mild renal insufficiency often has a normal or near-normal serum creatinine concentration. Additional homeostatic mechanisms (most frequently occurring within the renal tubules) permit the serum concentrations of sodium, potassium, calcium, and phosphorous and the total body water to also remain within the normal range, particularly among those with mild to moderate renal failure. Adaptive hyperfiltration, although initially beneficial, appears to result in long-term damage to the glomeruli of the remaining nephrons, which is manifested by proteinuria and progressive renal insufficiency. This process appears to be responsible for the development of renal failure among those in whom the original illness is

measurement on random specimens has become an accepted alternative method.

microalbuminuria on a random urine specimen (Eknoyan et al., 2003; KDOQI, 2002).

adults usually represents immunoglobulin light chains.

in a cachectic patient (the ratio will overestimate proteinuria).

is a result of the higher muscle mass observed in males.

accurate.

for CKD.

**3. Natural history of CKD**

either inactive or cured (Abboud & Henrich, 2010). The institution of measures to help prevent this process, such as antihypertensive therapy with an angiotensin converting enzyme inhibitor or an angiotensin II receptor blocker, may slow progressive disease and even preserve renal function. If these modalities are effective, the benefit is likely to be greatest if begun before a great deal of irreversible scarring has occurred.

Not all individuals have progressive loss of kidney function. Some studies show a high rate of progression, while others report relatively stable disease (Sarnak et al., 2005; Eriksen & Ingebretsen, 2006; Hallan et al., 2006). The rate of progression of CKD from one major stage to another varies based upon the underlying disease, presence or absence of comorbid conditions, treatments, socioeconomic status, individual genetics, ethnicity, and other factors.

Using epidemiologic data, general estimates for the rate of transition from a GFR between 15 to 60 ml/min per 1.73 m2 to end stage disease may be approximately 1.5 percent per year, while the rate of transition from a GFR above 60 to below 60 ml/min per 1.73 m2 may be approximately 0.5 percent per year (Hsu et al., 2004; Fox et al., 2004).

Historically, rate of decline in GFR of patients with diabetic nephropathy (DN) has been among the fastest, averaging about 10 ml/min/year. Control of systemic hypertension slows the rate of GFR decline to 5ml/min/year. In non-diabetic nephropathy, the rate of progression of CKD was 2.5 times faster in patients with chronic glumerulonephritis than in those with chronic interstitial nephritis, and 1.5 times faster than in those with hypertensive nephrosclerosis. Polycystic kidney disease (PKD) and impaired renal function may also have a faster rate of progression compared to those with other nephropathies.

#### **4. Prevalence of chronic kidney disease**

The prevalence of CKD has been evaluated based on serum creatinine concentrations and microalbuminuria in the following population studies from the United States, as well as some other countries.

In the Third National Health and Nutrition Examination Survey (NHANES III), serum creatinine concentration was obtained in a sample of 18,723 individuals aged 12 years and older between 1988 and 1994 (Jones et al., 1998). The prevalence of a serum creatinine level at or above 1.5, 1.7, and 2.0 mg/dl was 5.0, 1.9, and 0.6 percent for men, respectively, and 1.6, 0.7, and 0.3 percent for women.

By extrapolating the results of the NHANES III to the 1990 US Census population, it was estimated that the number of people with serum creatinine at or above 1.5, 1.7, and 2.0 mg/dl is 6.2, 2.5, and 0.8 million, respectively. It should be noted, however, that only a single creatinine measurement per patient was used to estimate the prevalence of CKD, and that serum creatinine was available in only 31 percent of the potentially eligible sample.

In a study of nearly 200,000 patients enrolled in a large health maintenance organization (HMO) in the southwestern US in 1997, the prevalence of at least one gender specific elevated serum creatinine (>1.2 mg/dl in women and >1.4 mg/dl in men) was 3.7 percent, and of at least two elevated serum creatinine levels separated by at least 90 days was 1.7 percent (Nissenson et al., 2001).

The prevalence estimates from this HMO study, as applied to United States Census data, led to the estimate of 9.1 million Americans in 1990 who had at least one elevated serum creatinine concentration, and 4.2 million Americans who had at least two elevated creatinine values separated by 90 days or greater.

Chronic Kidney Disease Update 205

such as renal ultrasonography may be required, such as in patients with a family history of polycystic kidney disease. Once the diagnosis is established and the cause and/or potentially reversible factors are identified and treated, CKD should be staged according to

Regardless of the nature of the underlying nephropathy, the progression of CKD is associated with the progressive sclerosis of glomeruli, tubulointerstitial fibrosis, and vascular sclerosis which can be initiated by endothelial, mesangial, or epithelial cell injury or damage. The kidney responds to injury by adaptive changes that lead to remodeling evolving towards either healing and functional recovery or scarring with loss of kidney function and progressive CKD. Healing is characterized by recovery of kidney function and structure. It occurs primarily in AKI when acutely damaged tubules recover from the initial insult and replace lost tubular cells to reconstitute the integrity of the tubules and to restore

On the other hand, most forms of chronic kidney damage, such as those induced by diabetes, hypertension, chronic glomerulonephritis, or chronic exposure to infections, evolve to progressive scarring with loss of function and CKD. Scarring is characterized by progressive loss of intrinsic renal cells and their replacement by fibrous tissue made of

Within glomerular capillaries, endothelial cells are the first to be exposed to damage induced by hemodynamic, immunologic, or metabolic insults. Glomerular endothelial injury is associated with reduction or loss of their physiologic anticoagulant and antiinflammatory properties and the acquisition of procoagulant and inflammatory

Glomerular endothelial injury can induce proliferation, phenotype change (expression of adhesion molecules), release of vasoactive agents (endothelin, nitric oxide), infiltration of glomerular tufts by inflammatory cells and conversion to a prothrombotic state. Glomerular endothelial injury is characterized by proliferation, apoptosis, detachment, and

Mesangial cells are the glomerular capillary equivalent to the smooth muscle cells and in that capacity respond to injury in a similar fashion; death, transformation, proliferation, and

The mesangial response to injury is characterized by alterations in cell cycle proteins that favor cell proliferation, phenotype change (to an actin positive myofibroblast), extracellular matrix production, and apoptosis. Many of these effects involve agonist interaction with specific receptors on the mesangial cell, including receptors for IgA, toll-like receptors, and transferrin receptors. Platelet derived growth factor (PDGF) appears to be the principal mediator of mesangial cell migration and proliferation in glomerular disease, an effect possibly magnified in hypoxic conditions. Receptors for PDGF are also upregulated. Further support for a role for PDGF is provided by a study that demonstrated prevention of renal

Mesangial cell proliferation is associated with the increased expression of cyclin-dependent kinases and reduced expression of cyclin kinase inhibitors, such as P21 and P27. Mesangial cell proliferation is an essential precursor to subsequent mesangial matrix expansion and

migration as well as synthesis and deposition of extracellular matrix.

scarring by antagonism of PDGF in an animal model of glomerulonephritis.

the classification proposed by the NKF-K/DOQI.

kidney function.

characteristics.

(particularly) thrombosis.

collagenous extracellular matrix.

**6. Mechanisms of progression of chronic kidney disease**

The prevalence of CKD in Norway was estimated from a population-based health survey of Nord-Trondelag County (HUNT II), which included 65,181 adults in 1995 through 1997 (participation rate 70.4%) (Erikson & Ingebretsen, 2006). The primary analysis used genderspecific cutoffs in estimating persistent albuminuria for CKD stages 1 and 2. Total CKD prevalence in Norway was 10.2% (SE 0.5): CKD stage 1 (GFR>90 ml/min per 1.73 m2 and albuminuria), 2.7% (SE 0.3); stage 2 (GFR 60 89 ml/min per 1.73 m2 and albuminuria), 3.2% (SE 0.4); stage 3 (GFR 30 to 59 ml/min per 1.73 m2, 4.2% (SE 0.1); and stage 4 (GFR 15 to 29 ml/min per 1.73 m2, 0.2% (SE 0.01).

Forty two percent of men and 44 percent of women over the age of 85 had an MDRDestimated GFR less than 60 ml/min per 1.73 m2 in the Nijmegen Biomedical Study, a population-based cross-sectional study conducted in the eastern part of the Netherlands. In a report from Taiwan, the prevalence of an estimated GFR <60 ml/min per 1.73 m2 was 7 % (Hsu et al., 2006).

In a population-based survey from Pakistan, Kazmi et al have reported the prevalence of CKD stages 3 and 4 to be about 21 million (Kazmi et al., 2007).

Table 1. National Kidney Foundation K/DOQI Classification of Chronic Kidney Disease based on GFR levels.

#### **5. Screening for chronic kidney disease**

The NKF-K/DOQI guidelines for CKD, which have been reviewed and endorsed by the 2006 Kidney Disease Improving Global Outcomes (KDIGO) Controversies Conference, recommend that all individuals should be assessed as part of routine health examinations to determine whether they are at increased risk for developing CKD (KDOQI, 2002).

Some data suggest, however, that screening the general population may decrease the incidence of ESRD resulting from glomerulonephritis. However, screening the general population is unlikely to be cost-effective. Screening for CKD among select patients who are at risk for development of CKD is justified because therapeutic interventions may slow or prevent the progression toward ESRD. Such patients include those with a history of diabetes, cardiovascular disease, hypertension, hyperlipidemia, obesity, metabolic syndrome, smoking, HIV or hepatitis C virus infection, and malignancy. A family history of CKD, age >60 years and treatment with potentially nephrotoxic drugs should also prompt screening for CKD. Testing for CKD can be done with a urinalysis, a first morning or a random "spot" urine sample for albumin or protein and creatinine assessment, and a serum creatinine level. Depending upon the presence of particular risk factors, additional testing

The prevalence of CKD in Norway was estimated from a population-based health survey of Nord-Trondelag County (HUNT II), which included 65,181 adults in 1995 through 1997 (participation rate 70.4%) (Erikson & Ingebretsen, 2006). The primary analysis used genderspecific cutoffs in estimating persistent albuminuria for CKD stages 1 and 2. Total CKD prevalence in Norway was 10.2% (SE 0.5): CKD stage 1 (GFR>90 ml/min per 1.73 m2 and albuminuria), 2.7% (SE 0.3); stage 2 (GFR 60 89 ml/min per 1.73 m2 and albuminuria), 3.2% (SE 0.4); stage 3 (GFR 30 to 59 ml/min per 1.73 m2, 4.2% (SE 0.1); and stage 4 (GFR 15 to 29

Forty two percent of men and 44 percent of women over the age of 85 had an MDRDestimated GFR less than 60 ml/min per 1.73 m2 in the Nijmegen Biomedical Study, a population-based cross-sectional study conducted in the eastern part of the Netherlands. In a report from Taiwan, the prevalence of an estimated GFR <60 ml/min per 1.73 m2 was 7 %

In a population-based survey from Pakistan, Kazmi et al have reported the prevalence of

Stage Description GFR (ml/min/1.73m2) 1 Kidney damage with normal GFR 90 or more 2 Mildly deceased GFR 60 - 89 3 Moderately decreased GFR 30 - 59 4 Severely decreased GFR 15 - 29

Table 1. National Kidney Foundation K/DOQI Classification of Chronic Kidney Disease

The NKF-K/DOQI guidelines for CKD, which have been reviewed and endorsed by the 2006 Kidney Disease Improving Global Outcomes (KDIGO) Controversies Conference, recommend that all individuals should be assessed as part of routine health examinations to determine whether they are at increased risk for developing CKD

Some data suggest, however, that screening the general population may decrease the incidence of ESRD resulting from glomerulonephritis. However, screening the general population is unlikely to be cost-effective. Screening for CKD among select patients who are at risk for development of CKD is justified because therapeutic interventions may slow or prevent the progression toward ESRD. Such patients include those with a history of diabetes, cardiovascular disease, hypertension, hyperlipidemia, obesity, metabolic syndrome, smoking, HIV or hepatitis C virus infection, and malignancy. A family history of CKD, age >60 years and treatment with potentially nephrotoxic drugs should also prompt screening for CKD. Testing for CKD can be done with a urinalysis, a first morning or a random "spot" urine sample for albumin or protein and creatinine assessment, and a serum creatinine level. Depending upon the presence of particular risk factors, additional testing

dialysis/kidney transplant < 15

CKD stages 3 and 4 to be about 21 million (Kazmi et al., 2007).

<sup>5</sup>Advanced kidney failure requiring

**5. Screening for chronic kidney disease**

ml/min per 1.73 m2, 0.2% (SE 0.01).

(Hsu et al., 2006).

based on GFR levels.

(KDOQI, 2002).

such as renal ultrasonography may be required, such as in patients with a family history of polycystic kidney disease. Once the diagnosis is established and the cause and/or potentially reversible factors are identified and treated, CKD should be staged according to the classification proposed by the NKF-K/DOQI.

#### **6. Mechanisms of progression of chronic kidney disease**

Regardless of the nature of the underlying nephropathy, the progression of CKD is associated with the progressive sclerosis of glomeruli, tubulointerstitial fibrosis, and vascular sclerosis which can be initiated by endothelial, mesangial, or epithelial cell injury or damage. The kidney responds to injury by adaptive changes that lead to remodeling evolving towards either healing and functional recovery or scarring with loss of kidney function and progressive CKD. Healing is characterized by recovery of kidney function and structure. It occurs primarily in AKI when acutely damaged tubules recover from the initial insult and replace lost tubular cells to reconstitute the integrity of the tubules and to restore kidney function.

On the other hand, most forms of chronic kidney damage, such as those induced by diabetes, hypertension, chronic glomerulonephritis, or chronic exposure to infections, evolve to progressive scarring with loss of function and CKD. Scarring is characterized by progressive loss of intrinsic renal cells and their replacement by fibrous tissue made of collagenous extracellular matrix.

Within glomerular capillaries, endothelial cells are the first to be exposed to damage induced by hemodynamic, immunologic, or metabolic insults. Glomerular endothelial injury is associated with reduction or loss of their physiologic anticoagulant and antiinflammatory properties and the acquisition of procoagulant and inflammatory characteristics.

Glomerular endothelial injury can induce proliferation, phenotype change (expression of adhesion molecules), release of vasoactive agents (endothelin, nitric oxide), infiltration of glomerular tufts by inflammatory cells and conversion to a prothrombotic state. Glomerular endothelial injury is characterized by proliferation, apoptosis, detachment, and (particularly) thrombosis.

Mesangial cells are the glomerular capillary equivalent to the smooth muscle cells and in that capacity respond to injury in a similar fashion; death, transformation, proliferation, and migration as well as synthesis and deposition of extracellular matrix.

The mesangial response to injury is characterized by alterations in cell cycle proteins that favor cell proliferation, phenotype change (to an actin positive myofibroblast), extracellular matrix production, and apoptosis. Many of these effects involve agonist interaction with specific receptors on the mesangial cell, including receptors for IgA, toll-like receptors, and transferrin receptors. Platelet derived growth factor (PDGF) appears to be the principal mediator of mesangial cell migration and proliferation in glomerular disease, an effect possibly magnified in hypoxic conditions. Receptors for PDGF are also upregulated. Further support for a role for PDGF is provided by a study that demonstrated prevention of renal scarring by antagonism of PDGF in an animal model of glomerulonephritis.

Mesangial cell proliferation is associated with the increased expression of cyclin-dependent kinases and reduced expression of cyclin kinase inhibitors, such as P21 and P27. Mesangial cell proliferation is an essential precursor to subsequent mesangial matrix expansion and

Chronic Kidney Disease Update 207

**Macrophages:** Macrophages are also prominent constituents of several glomerular lesions, particularly ones that exhibit crescent formation such as RPGN, SLE, and cryoglobulinemic nephropathy (Hooke et al., 1987; Rastaldi et al., 2000; Kurts et al., 2007). The importance of monocytes/macrophages in mediating glomerular injury is well-documented by studies, such as macrophage depletion and inhibition of macrophage inhibitory factor (MIF) (Kurts et al., 2007). The protective effect of absent granulocyte macrophage colony stimulating factor is illustrated in GM-CSF -/- mice, which exhibited less infiltration of monocytes compared to wild type and were protected from crescentic glomerular injury (Timoshanko et al., 2005). Macrophages localize to glomeruli via interactions with both deposited immunoglobulins (through Fc receptors) and several chemokines, such as macrophage chemo-attractant protein-1 (MCP-1) and macrophage inflammatory protein-1-alpha (MIP-1alpha) and RANTES (Timoshanko et al., 2005; Shimizu et al., 2003). Unlike neutrophils, macrophages are also readily recruited by lymphocyte-derived molecules, such as MIF, that result from the interaction between specifically sensitized T-cells and intraglomerular antigens (Chitalia et al., 2001). In addition, monocytes also localize through interaction with leukocyte adhesion molecules, such as ICAM-1 and VCAM-1, as well as osteopontin (Kurts et al., 2007;

Thus, macrophages may serve as effector cells in both humoral and cell-mediated forms of immune injury and are presumed to be the principal effector cells in inflammatory glomerular lesions induced by sensitized T-cells in the absence of antibody (Kurts et al., 2007). As with neutrophils, macrophages may generate oxidants and proteases. However, unlike neutrophils, they release tissue factor (which initiates fibrin deposition and crescent formation) and TGF beta (which contributes to the synthesis of extracellular matrix and

**T cells:** T cells are rarely conspicuous in glomerular lesions, but can be detected, particularly in diseases primarily mediated by macrophages such as crescentic GN (Tipping & Holdsworth, 2003; Hooke et al., 1987; Kurts et al., 2007). Although there is experimental evidence that glomerular injury can be induced by systemic T-cells in the absence of antibody deposition, little evidence exists that glomerular T-cells alone are nephritogenic, with the exception of permeability factors (Renneke et al., 1994). Instead, T-cell mediated injury occurs primarily via the release of chemokines and recruitment of macrophages, which subsequently function as effector cells. In addition, T cells may be the source of permeability factors that

**Platelets:** Platelets are prominent in several glomerular lesions, usually ones that involve intraglomerular thrombosis such as SLE, anti-phospholipid antibody syndromes, and thrombotic microangiopathies. In addition to their role in thrombotic processes involving endothelial cell injury, platelets also release a number of products that participate in and augment glomerular injury, more broadly including vasoactive, mitogenic, and chemotactic substances (Barnes, 2001). For example, platelet-derived factors such as PAF and platelet factor 4 enhance glomerular permeability to proteins and immune complex deposition, and PDGF and TGF contribute to mesangial cell proliferation and sclerosis, respectively. Platelets have also been shown to contribute to neutrophil-mediated glomerular injury

All forms of CKD are associated with marked tubulointerstitial injury (tubular dilatation, interstitial fibrosis), even if the primary process is a glomerulopathy (Ong & Fine, 1994;

contribute to non-inflammatory glomerular injury (Kurts et al., 2007).

Okada et al., 2000).

eventual development of sclerosis).

through non-chemotactic mechanisms.

**6.2 Tubulo-interstitial disease (fibrosis)**

sclerosis, due primarily to the actions of TGF and CTGF. Increased prostanoid synthesis, possibly modulated by TGF, may also have a role in this process. Therapeutic interventions, which target mesangial cell proliferation or matrix production, can therefore greatly ameliorate both acute and chronic forms of glomerular injury in those disorders in which glomerular cell proliferation is prominent.

The relative inability of podocytes to replicate in response to injury may lead to their stretching along the GBM, expressing areas of denuded Glomerular basement membrane (GBM) that would attract and interact with parietal epithelial cells leading to the formation of capsular adhesions and subsequent segmental glomerulosclerosis. This may lead to the accumulation of amorphous material in the paraglomerular space and the subsequent disruption of glomerular-tubular junction resulting in atubular glomeruli.

#### **6.1 Extrinsic cells**

**Neutrophils:** Neutrophils are present in the early biopsies of patients with poststreptococcal glomerulonephritis (GN), membranoproliferative GN, Henoch-Schönlein purpura (HSP), systemic lupus erythematosus (SLE), and some forms of rapidly progressive glomerulonephritis (RPGN) [Ishida-Okawara et al., 2004; Tipping & Holdsworth, 2003).

Neutrophil localization in glomerular capillaries is dependent upon the generation of chemotactic factors within and around an inflammatory focus; the most prominent chemoattractants in glomerular disease are C5a (derived from activation of complement) and several chemokines, such as interleukin-8, which can be bound to endothelial cells via heparan sulfate proteoglycans (Segerer et al., 2000; De Vriese et al., 1999; Kitching et al., 2002; Rops et al., 2004; Johnson et al., 2001; Segerer & Schlondorff, 2007).

At the site of immune deposit formation, neutrophils phagocytose the immune complex aggregates, become activated and undergo a respiratory burst that generates reactive oxygen species (Johnson et al., 1987). Several studies have shown hydrogen peroxide to be the principal neutrophil-derived oxidant that mediates glomerular injury. Hydrogen peroxide is nephritogenic because of interactions with another neutrophil-derived cationic enzyme myeloperoxidase (MPO) (which also localizes in glomeruli because of charge) and a halide to form hypohalous acids, which halogenate the glomerular capillary wall (Johnson et al., 1987; Johnson et al., 2001).

Neutrophils also store cationic serine proteases, such as elastase and cathepsin G, within azurophilic granules. The activation of neutrophils within glomeruli causes the extracellular release of these proteins, thereby resulting in the degradation of elements of the glomerular capillary wall. MPO and PR3, both cationic proteases localized in the primary granules of neutrophils, are also involved in the pathogenesis of ANCA-positive crescentic glomerulonephritis; they are localized in primary granules and displayed on the cell surface in response to certain cytokines. There they are accessible to ANCA antibody and become activated, resulting in capillary localization and release of oxidants and proteases (Xiao et al., 2005). Evidence in animal models suggests that ANCA-neutrophil interaction also induces release of a complement-activating factor that contributes to the mediation of injury (Huugen et al., 2007; Jennete & Falk, 2008).

sclerosis, due primarily to the actions of TGF and CTGF. Increased prostanoid synthesis, possibly modulated by TGF, may also have a role in this process. Therapeutic interventions, which target mesangial cell proliferation or matrix production, can therefore greatly ameliorate both acute and chronic forms of glomerular injury in those disorders in which

The relative inability of podocytes to replicate in response to injury may lead to their stretching along the GBM, expressing areas of denuded Glomerular basement membrane (GBM) that would attract and interact with parietal epithelial cells leading to the formation of capsular adhesions and subsequent segmental glomerulosclerosis. This may lead to the accumulation of amorphous material in the paraglomerular space and the subsequent

**Neutrophils:** Neutrophils are present in the early biopsies of patients with poststreptococcal glomerulonephritis (GN), membranoproliferative GN, Henoch-Schönlein purpura (HSP), systemic lupus erythematosus (SLE), and some forms of rapidly progressive glomerulonephritis (RPGN) [Ishida-Okawara et al., 2004; Tipping & Holdsworth, 2003). Neutrophil localization in glomerular capillaries is dependent upon the generation of chemotactic factors within and around an inflammatory focus; the most prominent chemoattractants in glomerular disease are C5a (derived from activation of complement) and several chemokines, such as interleukin-8, which can be bound to endothelial cells via heparan sulfate proteoglycans (Segerer et al., 2000; De Vriese et al., 1999; Kitching et al.,

Once attracted, neutrophil localization involves the interaction between adhesion molecules expressed on glomerular endothelial cells, such as selectins, integrins (CD11/CD18), and Iglike molecules (ICAM-1), and their corresponding ligands on the neutrophil (Segerer et al.,

At the site of immune deposit formation, neutrophils phagocytose the immune complex aggregates, become activated and undergo a respiratory burst that generates reactive oxygen species (Johnson et al., 1987). Several studies have shown hydrogen peroxide to be the principal neutrophil-derived oxidant that mediates glomerular injury. Hydrogen peroxide is nephritogenic because of interactions with another neutrophil-derived cationic enzyme myeloperoxidase (MPO) (which also localizes in glomeruli because of charge) and a halide to form hypohalous acids, which halogenate the glomerular capillary wall (Johnson

Neutrophils also store cationic serine proteases, such as elastase and cathepsin G, within azurophilic granules. The activation of neutrophils within glomeruli causes the extracellular release of these proteins, thereby resulting in the degradation of elements of the glomerular capillary wall. MPO and PR3, both cationic proteases localized in the primary granules of neutrophils, are also involved in the pathogenesis of ANCA-positive crescentic glomerulonephritis; they are localized in primary granules and displayed on the cell surface in response to certain cytokines. There they are accessible to ANCA antibody and become activated, resulting in capillary localization and release of oxidants and proteases (Xiao et al., 2005). Evidence in animal models suggests that ANCA-neutrophil interaction also induces release of a complement-activating factor that contributes to the mediation of injury

disruption of glomerular-tubular junction resulting in atubular glomeruli.

2002; Rops et al., 2004; Johnson et al., 2001; Segerer & Schlondorff, 2007).

2000; De Vriese et al., 1999; Johnson et al., 2001; Ito et al., 2001).

glomerular cell proliferation is prominent.

**6.1 Extrinsic cells**

et al., 1987; Johnson et al., 2001).

(Huugen et al., 2007; Jennete & Falk, 2008).

**Macrophages:** Macrophages are also prominent constituents of several glomerular lesions, particularly ones that exhibit crescent formation such as RPGN, SLE, and cryoglobulinemic nephropathy (Hooke et al., 1987; Rastaldi et al., 2000; Kurts et al., 2007). The importance of monocytes/macrophages in mediating glomerular injury is well-documented by studies, such as macrophage depletion and inhibition of macrophage inhibitory factor (MIF) (Kurts et al., 2007). The protective effect of absent granulocyte macrophage colony stimulating factor is illustrated in GM-CSF -/- mice, which exhibited less infiltration of monocytes compared to wild type and were protected from crescentic glomerular injury (Timoshanko et al., 2005).

Macrophages localize to glomeruli via interactions with both deposited immunoglobulins (through Fc receptors) and several chemokines, such as macrophage chemo-attractant protein-1 (MCP-1) and macrophage inflammatory protein-1-alpha (MIP-1alpha) and RANTES (Timoshanko et al., 2005; Shimizu et al., 2003). Unlike neutrophils, macrophages are also readily recruited by lymphocyte-derived molecules, such as MIF, that result from the interaction between specifically sensitized T-cells and intraglomerular antigens (Chitalia et al., 2001). In addition, monocytes also localize through interaction with leukocyte adhesion molecules, such as ICAM-1 and VCAM-1, as well as osteopontin (Kurts et al., 2007; Okada et al., 2000).

Thus, macrophages may serve as effector cells in both humoral and cell-mediated forms of immune injury and are presumed to be the principal effector cells in inflammatory glomerular lesions induced by sensitized T-cells in the absence of antibody (Kurts et al., 2007). As with neutrophils, macrophages may generate oxidants and proteases. However, unlike neutrophils, they release tissue factor (which initiates fibrin deposition and crescent formation) and TGF beta (which contributes to the synthesis of extracellular matrix and eventual development of sclerosis).

**T cells:** T cells are rarely conspicuous in glomerular lesions, but can be detected, particularly in diseases primarily mediated by macrophages such as crescentic GN (Tipping & Holdsworth, 2003; Hooke et al., 1987; Kurts et al., 2007). Although there is experimental evidence that glomerular injury can be induced by systemic T-cells in the absence of antibody deposition, little evidence exists that glomerular T-cells alone are nephritogenic, with the exception of permeability factors (Renneke et al., 1994). Instead, T-cell mediated injury occurs primarily via the release of chemokines and recruitment of macrophages, which subsequently function as effector cells. In addition, T cells may be the source of permeability factors that contribute to non-inflammatory glomerular injury (Kurts et al., 2007).

**Platelets:** Platelets are prominent in several glomerular lesions, usually ones that involve intraglomerular thrombosis such as SLE, anti-phospholipid antibody syndromes, and thrombotic microangiopathies. In addition to their role in thrombotic processes involving endothelial cell injury, platelets also release a number of products that participate in and augment glomerular injury, more broadly including vasoactive, mitogenic, and chemotactic substances (Barnes, 2001). For example, platelet-derived factors such as PAF and platelet factor 4 enhance glomerular permeability to proteins and immune complex deposition, and PDGF and TGF contribute to mesangial cell proliferation and sclerosis, respectively. Platelets have also been shown to contribute to neutrophil-mediated glomerular injury through non-chemotactic mechanisms.

#### **6.2 Tubulo-interstitial disease (fibrosis)**

All forms of CKD are associated with marked tubulointerstitial injury (tubular dilatation, interstitial fibrosis), even if the primary process is a glomerulopathy (Ong & Fine, 1994;

Chronic Kidney Disease Update 209

A variety of chronic kidney diseases progress to ESRD, including chronic glomerulonephritis, diabetic nephropathy, and polycystic kidney disease. Although the underlying problem often cannot be treated, extensive studies in experimental animals and humans suggest that progression in CKD may be largely due to secondary factors that are sometimes unrelated to the activity of the initial disease. These include systemic and intraglomerular hypertension, glomerular hypertrophy, the intrarenal precipitation of calcium phosphate, hyperlipidemia, and altered prostanoid metabolism (tables 2, 3). (Jacobson, 1991; Renneke et al., 1989;

A number of genetic factors (eg, single nucleotide polymorphisms and modifier genes) may influence the immune response, inflammation, fibrosis, and atherosclerosis, possibly contributing to accelerated progression of CKD (Nordfors et al., 2005; Hsu et al., 2006). Indirect evidence in support of such factors can be found in familial clustering of all-cause ESRD, with approximately one-quarter of dialysis patients having relatives with ESRD (Freedman et al., 2005). This is consistent with the hypothesis that common kidney diseases and progression to ESRD are influenced by the inheritance of specific genes. Genetic studies have suggested possible links between CKD and a variety of alterations or polymorphisms of genes coding for putative mediators including the renin angiotensin system, nitric oxide synthase, kallikrein, growth factors including platelet-derived growth

With respect to specific genes, apolipoprotein E (ApoE) polymorphisms may alter the risk of atherosclerotic disease, and, therefore, progression of CKD. The ApoE epsilon-2 allele is associated with elevated lipoprotein and triglyceride levels, whereas the ApoE epsilon-4 allele is associated with elevated levels of high density lipoprotein and lower triglycerides. In a secondary analysis of the Atherosclerosis Risk in Communities Study of 14, 520 patients with a median follow-up of 14 years, individuals with an ApoE epsilon-4 allele (present in 30 percent) had a 15 percent reduction in risk of progression of CKD compared to individuals with ApoE epsilon-3 allele (present in 90 percent) (Hsu et al., 2005). The risk with the ApoE epsilon-2 allele

> Factors predisposing to CKD include genetic and familial predisposition, race, maternal-fetal factors (low birth weight, malnutrition in utero), age (elderly), gender (male)

> Factors directly trigger kidney damage include diabetes, hypertension, cardiovascular disease, dyslipidemia, obesity, hyperuricemia and nephrotoxin exposure

Factors associated with worsening of already established kidney damage include poor glycemia control, poor blood pressure control, cardiovascular disease, proteinuria, alcohol consumption, nephrotoxin exposure, and acute kidney injury

**7. Factors affecting progression of chronic kidney disease**

Loghman-Adham, 1993; Nagata & Kriz, 1942; Yu, 2003).

was not significantly different compared with ApoE epsilon-3**.**

**Risk factors Definition**

Table 2. Types of risk factors for chronic kidney disease and its outcomes.

**7.1 Genetic factors**

factors and cytokines.

Susceptibility factors

Initiation factors

Progression factors

Nath, 1982). Furthermore, the degree of tubulo-interstitial disease is a better predictor of the GFR and long-term prognosis than is the severity of glomerular damage in almost all chronic progressive glomerular diseases, including IgA nephropathy, membranous nephropathy, membranoproliferative glomerulonephritis, and lupus nephritis (Nath, 1982; D'Amico, 1992; Alexopoulos et al., 1990; Bajema et al., 1999; Bazzi et al., 2002; Meyer, 2003). It is possible in these settings that tubulointerstitial disease causes tubular atrophy and/or obstruction, eventually leading to nephron loss.

The mechanism by which tubulointerstitial fibrosis develops is incompletely understood [Alexopoulos et al., 1990; Lan et al., 1991; Eddy, 1994; Nath, 1998). Infiltration of the kidney by macrophage and T lymphocytes (and perhaps bone marrow derived fibroblastlike cells), resulting in the subsequent production of transforming growth factor beta (TGF-beta) and other profibrotic factors, may be central to the development of this process (Lan et al., 1991).

Other possible contributors include calcium phosphate deposition, and metabolic acidosis with secondary interstitial ammonia accumulation.

#### **6.3 Angiotensin II**

Non-hemodynamic effects of angiotensin II also appear to contribute to the development of tubulointerstitial fibrosis, mediated via one of the angiotensin II type 1 receptors that are present in the glomerulus (Ruiz-Ortega et al., 2006). Animal studies have suggested that activation of angiotensin II receptor type 1B, which is largely limited to the glomerulus, but not type 1A, may accelerate renal injury (Crowly et al., 2009). This effect is likely due to the generation of profibrotic factors such as TGF-beta, connective tissue growth factor, epidermal growth factor, and other chemokines (Aros & Remuzzi, 2002). Further support for this role is provided by the finding that the expression of angiotensin II type 1 receptors in podocytes is associated with focal segmental glomerulosclerosis (Hoffmann et al., 2004). It also appears that renin may lead to a receptor-mediated increase in TGF-beta that is independent of angiotensin II (Huang et al., 2006).

Actions of angiotensin II may also be mediated via epidermal growth factor (EGF) receptors, which are present throughout the nephron, and when stimulated, promote cell proliferation and collagen production via transforming growth factor-alpha (TGF-alpha), EGF, and other growth factors (Lautrette et al., 2005; Chen et al., 2006). In experimental models, infusion of angiotensin II induces glomerulosclerosis and tubular atrophy. This effect is not seen in mice lacking EGF receptors or TGF-alpha, and pharmacologic inhibition of angiotensin II prevented these renal lesions. Angiotensin II also participates in cytokine- and chemokinemediated recruitment of inflammatory cells into the kidney.

#### **6.4 Vascular sclerosis**

Vascular sclerosis is an integral feature of the renal scarring process. Renal arteriolar hyalinosis is present in CKD at an early stage, even in the absence of severe hypertension. Vascular sclerosis is associated with progressive renal failure in glomerulonephritis. Hyalinosis of afferent arterioles has been implicated in the pathogenesis of diabetic glomerulosclerosis. Changes in postglomerular arterioles and damage to peritubular capillaries may further exacerbrate interstitial ischemia and fibrosis. Ischemia and the ensuing hypoxia are fibrogenic influences that stimulate tubular cells and renal fibroblast to produce ECM components and reduce their collagenolytic activity.

Nath, 1982). Furthermore, the degree of tubulo-interstitial disease is a better predictor of the GFR and long-term prognosis than is the severity of glomerular damage in almost all chronic progressive glomerular diseases, including IgA nephropathy, membranous nephropathy, membranoproliferative glomerulonephritis, and lupus nephritis (Nath, 1982; D'Amico, 1992; Alexopoulos et al., 1990; Bajema et al., 1999; Bazzi et al., 2002; Meyer, 2003). It is possible in these settings that tubulointerstitial disease causes tubular atrophy and/or

The mechanism by which tubulointerstitial fibrosis develops is incompletely understood [Alexopoulos et al., 1990; Lan et al., 1991; Eddy, 1994; Nath, 1998). Infiltration of the kidney by macrophage and T lymphocytes (and perhaps bone marrow derived fibroblastlike cells), resulting in the subsequent production of transforming growth factor beta (TGF-beta) and other profibrotic factors, may be central to the development of this process

Other possible contributors include calcium phosphate deposition, and metabolic acidosis

Non-hemodynamic effects of angiotensin II also appear to contribute to the development of tubulointerstitial fibrosis, mediated via one of the angiotensin II type 1 receptors that are present in the glomerulus (Ruiz-Ortega et al., 2006). Animal studies have suggested that activation of angiotensin II receptor type 1B, which is largely limited to the glomerulus, but not type 1A, may accelerate renal injury (Crowly et al., 2009). This effect is likely due to the generation of profibrotic factors such as TGF-beta, connective tissue growth factor, epidermal growth factor, and other chemokines (Aros & Remuzzi, 2002). Further support for this role is provided by the finding that the expression of angiotensin II type 1 receptors in podocytes is associated with focal segmental glomerulosclerosis (Hoffmann et al., 2004). It also appears that renin may lead to a receptor-mediated increase in TGF-beta that is

Actions of angiotensin II may also be mediated via epidermal growth factor (EGF) receptors, which are present throughout the nephron, and when stimulated, promote cell proliferation and collagen production via transforming growth factor-alpha (TGF-alpha), EGF, and other growth factors (Lautrette et al., 2005; Chen et al., 2006). In experimental models, infusion of angiotensin II induces glomerulosclerosis and tubular atrophy. This effect is not seen in mice lacking EGF receptors or TGF-alpha, and pharmacologic inhibition of angiotensin II prevented these renal lesions. Angiotensin II also participates in cytokine- and chemokine-

Vascular sclerosis is an integral feature of the renal scarring process. Renal arteriolar hyalinosis is present in CKD at an early stage, even in the absence of severe hypertension. Vascular sclerosis is associated with progressive renal failure in glomerulonephritis. Hyalinosis of afferent arterioles has been implicated in the pathogenesis of diabetic glomerulosclerosis. Changes in postglomerular arterioles and damage to peritubular capillaries may further exacerbrate interstitial ischemia and fibrosis. Ischemia and the ensuing hypoxia are fibrogenic influences that stimulate tubular cells and renal fibroblast to

obstruction, eventually leading to nephron loss.

with secondary interstitial ammonia accumulation.

independent of angiotensin II (Huang et al., 2006).

mediated recruitment of inflammatory cells into the kidney.

produce ECM components and reduce their collagenolytic activity.

(Lan et al., 1991).

**6.3 Angiotensin II**

**6.4 Vascular sclerosis**

#### **7. Factors affecting progression of chronic kidney disease**

A variety of chronic kidney diseases progress to ESRD, including chronic glomerulonephritis, diabetic nephropathy, and polycystic kidney disease. Although the underlying problem often cannot be treated, extensive studies in experimental animals and humans suggest that progression in CKD may be largely due to secondary factors that are sometimes unrelated to the activity of the initial disease. These include systemic and intraglomerular hypertension, glomerular hypertrophy, the intrarenal precipitation of calcium phosphate, hyperlipidemia, and altered prostanoid metabolism (tables 2, 3). (Jacobson, 1991; Renneke et al., 1989; Loghman-Adham, 1993; Nagata & Kriz, 1942; Yu, 2003).

#### **7.1 Genetic factors**

A number of genetic factors (eg, single nucleotide polymorphisms and modifier genes) may influence the immune response, inflammation, fibrosis, and atherosclerosis, possibly contributing to accelerated progression of CKD (Nordfors et al., 2005; Hsu et al., 2006). Indirect evidence in support of such factors can be found in familial clustering of all-cause ESRD, with approximately one-quarter of dialysis patients having relatives with ESRD (Freedman et al., 2005). This is consistent with the hypothesis that common kidney diseases and progression to ESRD are influenced by the inheritance of specific genes. Genetic studies have suggested possible links between CKD and a variety of alterations or polymorphisms of genes coding for putative mediators including the renin angiotensin system, nitric oxide synthase, kallikrein, growth factors including platelet-derived growth factors and cytokines.

With respect to specific genes, apolipoprotein E (ApoE) polymorphisms may alter the risk of atherosclerotic disease, and, therefore, progression of CKD. The ApoE epsilon-2 allele is associated with elevated lipoprotein and triglyceride levels, whereas the ApoE epsilon-4 allele is associated with elevated levels of high density lipoprotein and lower triglycerides. In a secondary analysis of the Atherosclerosis Risk in Communities Study of 14, 520 patients with a median follow-up of 14 years, individuals with an ApoE epsilon-4 allele (present in 30 percent) had a 15 percent reduction in risk of progression of CKD compared to individuals with ApoE epsilon-3 allele (present in 90 percent) (Hsu et al., 2005). The risk with the ApoE epsilon-2 allele was not significantly different compared with ApoE epsilon-3**.**

Table 2. Types of risk factors for chronic kidney disease and its outcomes.

Chronic Kidney Disease Update 211

Rubin et al., 1994; Michel et al., 1997). Furthermore, the beneficial effect of lipid lowering may be additive to that of lowering the blood pressure in at least some models of CKD

The factors responsible for the lipid effects are incompletely understood. In different animal models, a high cholesterol intake may be deleterious in association with a rise in intraglomerular pressure (Diamond & Karnovsky, 1987), while lipid-lowering agents may be beneficial without affecting glomerular hemodynamics. These disparate observations suggest that mechanisms other than intraglomerular pressure alone may play a contributory role. It has been shown experimentally, for example, that hyperlipidemia activates the mesangial cells (which have LDL receptors), leading to stimulation of mesangial cell proliferation and to increased production of macrophage chemotactic factors, fibronectin (a component of the extracellular matrix), type IV collagen, plasminogen activator-1 and

Each of these changes could contribute to glomerular injury. In addition, statins may act independent of plasma lipid levels by directly inhibiting mesangial cell proliferation and

The applicability of these findings to human disease is uncertain. There are numerous secondary analyses of data from lipid trials suggesting that high lipid levels are associated with a faster rate of progression, and that statins slow the rate of progression of kidney failure.

Hyperuricemia can develop in patients with CKD due to decreased urinary excretion. It has been proposed that hyperuricemia may contribute to progression, in part by decreasing renal perfusion via stimulation of afferent arteriolar vascular smooth muscle cell proliferation (Ohno

Combined data from two community-based cohorts comprising 13,388 individuals were examined for an association between baseline uric acid and the development of CKD during 9 years of follow-up. Baseline uric acid was associated with increased risk for CKD with odds ratios of 1.07 (95% CI 1.01 to 1.14) and 1.11 (95% CI 1.02 to 1.21) per 1 mg/dl increase

In a Japanese study, hyperuricemic patients with IgA nephropathy had a worse prognosis than those with normal uric acid level, and a serum uric acid greater than 6mg/dl was an

A tendency to phosphate retention is an early problem in kidney disease, beginning as soon as the GFR starts to fall. In addition to promoting bone disease, the excess phosphate also may contribute to progression of CKD. Higher serum phosphorus concentrations have been associated with a greater risk of progression. In an observational study of 985 patients followed for a median of two years, the adjusted hazard ratio for doubling of the serum creatinine was 1.3 for every 1.0 mg/dl [0.33 mmol/l] increase in serum phosphorus

A potential causative mechanism could be calcium phosphate precipitation in the renal interstitium (Gimenez et al., 1987), which might initiate an inflammatory reaction, resulting

et al., 2001; Iseki et al., 2004; Sanchez-Lozada et al., 2005; Schwarz et al., 2006).

in uric acid, in both GFR and serum creatinine based models.

A similar relationship was noted for the calcium-phosphorus product.

(Rubin et al., 1994).

reactive oxygen species.

**7.5 Hyperuricemia**

production of monocyte chemo-attractants.

independent predictor of ESRD in women.

in interstitial fibrosis and tubular atrophy.

**7.6 Phosphate retention**

(Schwarz et al., 2006).

Intraglomerular hypertension and hypertrophy Phosphate retention, with interstitial CaPO4 deposition Increased prostaglandin synthesis Hyperlipidemia, especially in the nephrotic syndrome Metabolic acidosis Obesity Smoking Type of underlying kidney disease Proteinuria Tubulointerstitial disease Retained "uremic" toxins Filtered iron in nephrotic syndrome

Table 3. Secondary factors and progression of CKD.

#### **7.2 Hypertension**

Systemic hypertension is both a cause and consequence of CKD. The incidence of hypertension increases as CKD advances. The prevalence of hypertension requiring treatment in patients with stage 4 CKD is greater than 80%. There is strong evidence that high blood pressure is a risk factor for the progression of CKD in humans. It is believed that the transmission of systemic hypersion into the glomerular capillary beds and the resulting glomerular hypertension contribute to the initiation of glomerulosclerosis and, there is clear evidence that strict control of the blood pressure is beneficial in slowing the rate of progression of CKD.

#### **7.3 Proteinuria**

Proteinuria alone may contribute to disease progression (Burton & Harris, 1996; Eddy et al., 1991; Benigini et al., 2004; Hirschberg & Wang, 2005). Proposed mechanisms include mesangial toxicity, tubular overload and hyperplasia, toxicity from specific filtered compounds such as transferrin/iron and albumin-bound fatty acids, and induction of proinflammatory molecules such as MCP-1 and inflammatory cytokines (Wang et al., 1997). It is possible, for example, that a marked increase in protein filtration and subsequent proximal reabsorption leads to tubular cell injury and the release of lysozymes into the interstitium. To the degree that proteinuria alone might be important, reversing intraglomerular hypertension with protein restriction or antihypertensive therapy may be beneficial both by diminishing hemodynamic injury to the glomeruli and by reducing protein filtration (which is in part dependent upon the intraglomerular pressure), thereby lowering proteinuria.

#### **7.4 Hyperlipidemia**

Hyperlipidemia is common in patients with CKD, particularly those with the nephrotic syndrome. In addition to accelerating the development of systemic atherosclerosis, experimental studies suggest that high lipid levels also may promote progression of the renal disease (Keane, 1994; Grone & Grone, 2008). The major experimental evidence in support of this hypothesis are the observations in experimental animals that cholesterol loading enhances glomerular injury and that reducing lipid levels with a drug such as lovastatin slows the rate of progressive injury (Keane, 1994; Diamond & Karnovsky, 1987;

Systemic hypertension is both a cause and consequence of CKD. The incidence of hypertension increases as CKD advances. The prevalence of hypertension requiring treatment in patients with stage 4 CKD is greater than 80%. There is strong evidence that high blood pressure is a risk factor for the progression of CKD in humans. It is believed that the transmission of systemic hypersion into the glomerular capillary beds and the resulting glomerular hypertension contribute to the initiation of glomerulosclerosis and, there is clear evidence that strict control of the blood pressure is beneficial in slowing the rate of

Proteinuria alone may contribute to disease progression (Burton & Harris, 1996; Eddy et al., 1991; Benigini et al., 2004; Hirschberg & Wang, 2005). Proposed mechanisms include mesangial toxicity, tubular overload and hyperplasia, toxicity from specific filtered compounds such as transferrin/iron and albumin-bound fatty acids, and induction of proinflammatory molecules such as MCP-1 and inflammatory cytokines (Wang et al., 1997). It is possible, for example, that a marked increase in protein filtration and subsequent proximal reabsorption leads to tubular cell injury and the release of lysozymes into the interstitium. To the degree that proteinuria alone might be important, reversing intraglomerular hypertension with protein restriction or antihypertensive therapy may be beneficial both by diminishing hemodynamic injury to the glomeruli and by reducing protein filtration (which is in part dependent upon the intraglomerular pressure), thereby