Chronic kidney disease (CKD) is a world-wide public health problem. CKD encompasses a spectrum of different pathophysiologic processes associated with abnormal kidney function and a progressive decline in glomerular filtration rate (GFR). There is growing evidence that some of the adverse outcomes of CKD can be prevented or delayed by preventive measures, early detection, and treatment.

top

World

CKD is a world wide health problem. According to the World Health organization (WHO) Global Burden of Disease Project, diseases of the kidney and urinary tract contribute to global burden with approximately 850,000 deaths every year and 115 million disability adjusted life years. CKD is the 12 th leading cause of death and 17 th cause of disability. This global prevalence, however, may be grossly underestimated for a number of reasons. Patients with CKD are at high risk for CVD and cerebrovascular disease and they are more likely to die of CVD than to develop end-stage renal failure. Moreover, patients with CVD often develop CKD during the course of their disease, which may go unrecognized. Therefore an unknown proportion of people whose death and disability attributed to CVD have kidney disease as well.

India

Chronic diseases have become a major cause of global morbidity and mortality even in developing countries. In the absence of a renal registry, the exact disease burden of CKD in the Indian population cannot be assessed accurately. The approximate prevalence of CKD is 800 per million population (pmp), and the incidence of end-stage renal disease (ESRD) is 150–200 pmp. Data suggests that diabetic nephropathy is the most common cause of CKD in India .

top

  The pathophysiology of CKD involves two broad sets of mechanisms of damage:

1). Initiating mechanisms specific to the underlying etiology (e.g., immune complexes and mediators of inflammation in certain types of glomerulonephritis, or toxin exposure in certain diseases of the renal tubules and interstitium; and

2). A set of progressive mechanisms, involving hyperfiltration and hypertrophy of the remaining viable nephrons, that are a common consequence following long-term reduction of renal mass, irrespective of underlying etiology. 

The responses to reduction in nephron number are mediated by vasoactive hormones, cytokines, and growth factors.  Eventually, these short-term adaptations of hypertrophy and hyperfiltration become maladaptive as the increased pressure and flow predisposes to sclerosis and dropout of the remaining nephrons.  Increased intrarenal activity of the renin-angiotensin axis appears to contribute both to the initial adaptive hyperfiltration and to the subsequent maladaptive hypertrophy and sclerosis, the latter, in part, owing to the stimulation of transforming growth factor b (TGF-b).  This process explains why a reduction in renal mass from an isolated insult may lead to a progressive decline in renal function over many years.

Definition: CKD is defined as kidney damage, as confirmed by kidney biopsy or markers of damage, or glomerular filtration rate (GFR) <60 mL/min/1.73 m 2 for ≥3 months.

Kidney damage: Kidney damage is defined as structural or functional abnormalities of the kidney, with or without decreased GFR. Markers of kidney damage include proteinuria, abnormalities of urine sediment, abnormalities in imaging tests, or abnormalities of blood or urine composition specific for certain syndromes (Table 1).

Table 1: Markers of Kidney Damage

Marker	Findings indicating Kidney Damage
Proteinuria	Increased excretion of albumin or total urine protein
Urine Sediment Abnormalities	Red blood cells*, white blood cells*, cellular casts, coarse granular casts, fat
Imaging Tests	Abnormalities in kidney size Asymmetry in kidney size or function Irregularities in shape (cysts, scars, mass lesions) Stones Hydronephrosis and other abnormalities of the urinary tract Arterial stenosis and other vascular lesions
Abnormalities in Blood or Urine Composition	Nephrotic syndrome Tubular syndromes (renal tubular acidosis, potassium secretory defects, renal glycosuria, renal phosphaturia, Fanconi's syndrome

*Red blood cells (hematuria) or white blood cells (pyuria) may originate at any site in the urinary tract, and do not necessarily indicate kidney damage. Patients with hematuria and pyuria should be evaluated for CKD

Stages of CKD: Among individuals with CKD, the stage of disease is based on the level of GFR (Table 2), irrespective of the cause of kidney disease.

Table 2: Stages of CKD  

Stage	Description	GFR (mL/min/1.73m 2 )
1	Kidney damage with normal or ↑ GFR	≥ 90
2	Kidney damage with mild ↓ GFR	60 – 89
3	Moderate ↓ GFR	30 – 59
4	Severe ↓ GFR	15 – 29
5	Kidney failure	< 15 or dialysis

Data for Stages 1-4 from NHANES III (1988-1994). Population of 177 million with age ≥ 20 years. Data for Stage 5 from USRDS (1998) includes approximately 230,000 patients treated by dialysis and assumes 70,000 additional patients not on dialysis. Percentages total > 100% because NHANES III may not have included patients on dialysis. GFR estimated from serum creatinine using MDRD Study equation based on age, gender, race and calibration for serum creatinine.

a For Stages 1 and 2, kidney damage was assessed by spot albumin-to-creatinine ratio > 17 mg/g (men) or > 25 mg/g (women) on two measurements.

Causes of CKD: Table 3 shows a simple classification of CKD based on cause.

Table 3: Classification of CKD by Diagnosis and Prevalence Among Patients With Kidney Failure  

Disease	Major Types (Examples*)	Prevalence Among Patients with Kidney Failure**
Diabetic kidney disease	Type 1 and type 2 diabetes	33%
Nondiabetic kidney diseases	Glomerular diseases (autoimmune diseases, systemic infections, drugs, neoplasia)	19%
	Vascular diseases (hypertension, renal artery disease, microangiopathy)	21%
	Tubulointerstitial diseases (urinary tract infection, stones, obstruction, drug toxicity	4%
	Cystic diseases (polycystic kidney disease)	6%
Kidney Diseases in the kidney transplant recipient	Allograft nephropathy (chronic rejection)	-NA
	Drug toxicity (cyclosporine or tacrolimus)
	Recurrent diseases (glomerular diseases)
	Transplant glomerulopathy

* Examples of some causes for specific pathologic types. Italics indicate types of kidney disease that may be associated with urine total protein-to-creatinine ratio > 500-1000 mg/g.

** Kidney failure defined as end-stage renal disease [ESRD]. Approximate, prevalence varies with age. Based on USRDS Annual Data Report

a Not recorded as a cause of ESRD in USRDS

Early screening of individuals at risk for CKD is important for early detection and preventing the progression of the disease. Risk factors associated with CKD are shown in Table 4. Laboratory test recommended for all patients at increases risk for CKD are listed in Table 5.

Table 4: Risk Factors for CKD and its Outcomes

Type	Definition	Examples
Susceptibility factors	Increased susceptibility to kidney damage	Older age, family history of CKD, reduction in kidney mass, low birth weight
Initiation factors	Directly initiate kidney damage	Diabetes, high blood pressure, autoimmune diseases, systemic infections, urinary tract infections, urinary stones, lower urinary tract obstruction, drug toxicity
Progression factors	Cause worsening kidney damage and faster decline in kidney function after initiation of kidney damage	Higher level of proteinuria, higher blood pressure level, poor glycemic control in diabetes, smoking
End-stage factors	Increase morbidity and mortality in kidney failure	Lower dialysis (KI/V), temporary venous catheter for vascular access, anemia, low serum albumin, increased calcium x phosphorus concentration product, late referral

Table 5: Laboratory Measurements for Ascertainment of CKD

Figure 1 is a conceptual model of the course of CKD, which defines stages of CKD as well as antecedent conditions, outcomes, risk factors for adverse outcomes, and actions to improve outcomes.

Fig 1. Conceptual model for stages in the initiation and progression of CKD, and therapeutic interventions.

Shaded ellipses represent stages of CKD; unshaded ellipses represent potential antecedents or consequences of CKD. Thick arrows between ellipses represent “risk factors” associated with initiation and progression of disease that can be affected or detected by interventions: susceptibility factors (black); initiation factors (dark gray); progression factors (light gray); and end-stage factors (white).

top

Fig. 2: Symptoms and signs of kidney disease

Stages 1 and 2: Stages 1 and 2 CKD are usually not associated with any symptoms arising from the decrement in GFR.  However, there may be symptoms from the underlying renal disease itself, such as edema in patients with nephrotic syndrome or signs of hypertension secondary to the renal parenchymal disease in patients with polycystic kidney disease, some forms of glomerulonephritis, and many other parenchymal and vascular renal diseases, even with well-preserved GFR. 

Stages 3 and 4: If the decline in GFR progresses to stages 3 and 4, clinical and laboratory complications of CKD become more prominent.  Virtually all organ systems are affected, but the most evident complications include anemia and associated easy fatigability; decreasing appetite with progressive malnutrition, abnormalities in calcium, phosphorus, and mineral-regulating hormones, such as 1.25 (OH) 2 D 3 (calcitriol) and parathyroid hormone (PTH); and abnormalities in sodium, potassium, water, and acid-base homeostasis. 

Stage 5: If the patient progresses to stage 5 CKD, toxins accumulate such that patients usually experience a marked disturbance in their activities of daily living, well-being, nutritional status, and water and electrolyte homeostasis, eventuating in the uremic syndrome .   This state culminates in death unless renal replacement therapy (dialysis or transplantation) is instituted.

top

History
Initial assessment should include a complete medical history, including

history of and severity of CKD (Table 6); known duration and levels of blood pressure; evidence of CVD; presence of other comorbid conditions such as diabetes and dyslipidemia; symptoms suggesting identifiable causes of hypertension in addition to CKD; extracellular fluid volume status; lifestyle issues which may impact on CKD and blood pressure management; prescribed and other medications (including NSAIDs, herbal remedies, and illicit drugs); results of current and prior antihypertensive therapy; and psychosocial and environmental factors.

Table 6: Clues to the Diagnosis of CKD in Adults from the Patient's History  

Clue	Potential Diagnosis
Review of Systems
Symptoms during urination	Usually suggest disorders of the urinary tract such as infection, obstruction or stones
Recent infections	May suggest post-infectious glomerulonephritis or HIV-associated nephropathy
Skin rash or arthritis	Suggests autoimmune disease, such as systemic lupus erythematosus or cryoglobulinemia
Risk factors for parenterally transmitted disease	May suggest HIV, hepatitis B or hepatitis C infection and associated kidney diseases
Chronic Diseases
Heart failure, cirrhosis, or gastrointestinal fluid losses	Usually suggest reduced kidney perfusion (“pre-renal factors”).
Diabetes*	As a cause of CKD, Diabetic kidney disease usually follows a typical clinical course after onset, first with microalbuminuria, followed by clinical proteinuria, hypertension and declining GFR
Hypertension*	As a cause of CKD: Hypertensive nephrosclerosis is usually characterized by severely elevated blood pressure readings over a long period of time, with associated end-organ damage in addition to kidney disease. Recent worsening of hypertension, in association with findings of diffuse atherosclerosis, suggests large vessel disease due to atherosclerosis. Recent onset of severe hypertension in young women suggests renal artery disease due to fibromuscular dysplasia
Past Medical History
Findings from past “routine” examinations	May reveal a history of hypertension or proteinuria during childhood, during pregnancy, or on examinations for school, military service, or insurance
Past urologic evaluations	Details may disclose radiological abnormalities associated with kidney disease
Family History of Kidney Diseases
Every generation, equal susceptibility in males and females	Suggests an autosomal dominant disease, such as polycystic kidney disease
Every generation; predominant male susceptibility	Suggests a sex-linked recessive disease, such as Alport's syndrome
Less frequent than every generation	Suggests an autosomal recessive disease, such as medullary cystic kidney disease or autosomal recessive polycystic kidney disease

* Extremely common in elderly patients, and often nonspecific. Patients have usually suffered from diabetes or hypertension for 10 years or more before developing CKD. However, because type 2 diabetes and hypertension often go undiagnosed for many years, testing for CKD is needed at first recognition of these predisposing conditions.

Physical examination
A complete physical examination should be performed, to assess severity of hypertension, presence of endorgan damage, and extracellular fluid (ECF)

volume (Table 7). Most kidney diseases do not cause alterations in the physical examination. Infrequently, secondary causes of hypertension other than CKD can be detected.

Table 7: Physical Examination for Evaluation of Hypertension and CKD

Laboratory tests
Routine laboratory test are recommended (Table 8). All patients with hypertension should be tested for albuminuria or proteinuria, since CKD is both a cause and a consequence of hypertension, and since CKD is a risk factor for CVD. Current guidelines define albuminuria as spot urine albumin to creatinine ratio >30 mg/g in both men and women, although some studies have suggested different cut-off values for men and women. The Work Group appointed by National Kidney Foundation (NKF) and Kidney Disease Outcomes Quality Initiative (K/DOQI) has modified this recommendation for the purpose of treatment of hypertension and use of antihypertensive agents since decision-making is based on quantification of albuminuria (spot urine albumin to creatinine ratio >30 mg/g) in diabetic patients, and on quantification of proteinuria (spot urine total protein to creatinine ratio >200 mg/g) in nondiabetic patients.

In addition, basic blood chemistries should be obtained, as well as glucose and fasting

lipid profile. Optional additional tests include thyroid-stimulating hormone, calcium, and uric acid levels.

Table 8: Laboratory Evaluation of Patients with CKD

Other Investigations
All patients should also have a 12-lead EKG, to screen for LVH. The rationale for other laboratory tests is to identify the cause of CKD, in particular causes of nondiabetic kidney disease. Imaging studies should be performed to detect obstruction of the urinary tract, polycystic kidney disease, stones, or congenital disorders.

Renal Biopsy
In the absence of a clinical diagnosis, renal biopsy may be the only resource to establish an etiology in early-stage CKD.  However, once the CKD is advanced and the kidneys are small and scarred, there is little utility and significant risk in attempting to arrive at a specific diagnosis.

Ultrasound-guided percutaneous biopsy is the favored approach, but a surgical or laproscopic approach can be considered, especially in the patient with a single kidney where direct visualization and control of bleeding are crucial.

top

The optimal timing of therapy is usually well before there has been a measureable decline in GFR and certainly before CKD is established.  It is helpful to sequentially measure and plot the rate of decline of GER in all patients.  Any acceleration in the rate of decline should prompt a search for superimposed acute or subacute processes that may be reversible.

Goals of Antihypertensive Therapy in CKD
The Work Group has defined three principal goals of antihypertensive therapy in CKD:

• lowering blood pressure,
• slowing progression of CKD, and
• reducing the risk of CVD.

The Work Group also recommended considering reducing proteinuria an additional therapeutic goal.

Clinical Action Plan
A clinical action plan should be developed for each patient, based on the stages of CKD.

Table 9: Stages of CKD: A Clinical Action Plan

 

Stage	Description	GFR (mL/min/1.73m 2 )	Action*
1	Kidney damage with normal or ↑ GFR	≥ 90	Diagnosis and treatment. Treatment of comorbid conditions, Slowing progression, CVD risk reduction
2	Kidney damage with mild ↓ GFR	60 – 89	Estimating progression
3	Moderate ↓ GFR	30 – 59	Evaluating and treating complications
4	Severe ↓ GFR	15 – 29	Preparation for kidney replacement therapy
5	Kidney failure	< 15 (or dialysis)	Replacement (if uremia present)

CKD is defined as either kidney damage or GFR < 60 mL/min/1.73 m 2 for ≥ 3 months. Kidney damage is defined as pathologic abnormalities or markers of damage, including abnormalities in blood or urine tests or imaging studies.

* includes actions from preceding stages.

Slowing the Progression of CKD
There is variation in the rate of decline of GFR among patients with CKD.  However, the interventions should be considered in an effort to stabilize or slow the decline of renal function.

Dietary and Other Therapeutic Lifestyle Changes: Dietary and other therapeutic lifestyle modifications are recommended as part of a comprehensive strategy to lower blood pressure and reduce CVD risk in CKD (Table 10).

While protein restriction has been advocated to reduce symptoms associated with uremia, it may also slow the rate of renal decline at earlier stages of renal disease. Dietary sodium intake of less than 2.4 g/d (less than 100 mmol/d) should be recommended in most adults with CKD and hypertension. Other dietary recommendations for adults should be modified according to the stage of CKD.

Lifestyle modifications recommended for CVD risk reduction are shown in Table 11.

Table 10: Macronutrient Composition and Mineral Content of the Dietary Approaches to Stop Hypertension (DASH) Diet Recommended by JNC 7, with Modification for Stages 3-4 of CKD

 

Nutrient		Stage of CKD
		Stages 1 – 4
Sodium (g/d)*		< 2.04
Total Fat (% of calories)		< 30
Saturated Fat (% of calories)		< 10
Cholesterol (mg/d)		< 200
Carbohydrate (% of calories)**		50 – 60
	Stages 1 – 2		Stages 3 – 4
Proteins (g/kg/d, % of calories)	1.4 (~ 18)		0.6 – 0.8 (~ 10)
Phosphorus (g/d)	1.7		0.8 – 1.0
Potassium (g/d)	> 4		2 – 4

* Not recommended for patients with “salt-wasting”

** Adjust so total calories from protein, fat and carbohydrate is 100%

Table 11: Other Lifestyle Modifications Recommended by JNC 7

Reducing Intraglomerular Hypertension and Proteinuria: Increased intraglomerular pressure and glomerular hypertrophy develop as a response to loss of nephron number from different kidney diseases. This response is maladaptive, as it promotes the ongoing decline of kidney function even if the inciting process has been treated or spontaneously resolved. Control of systemic and glomerular hypertension is at least as important as dietary protein restriction in slowing the progression of CKD. Therefore, in addition to reduction of cardiovascular disease risk, antihypertensive therapy in patients with CKD also aims to slow the progression of nephron injury by reducing intraglomerular hypertension. Elevated blood pressure increases proteinuria through its transmission to the glomerulus. Conversely, the renoprotective effect of antihypertensive medications is gauged through the consequent reduction of proteinuria. Thus, the more effective a given treatment is in lowering protein excretion, the greater the subsequent impact on protection from decline in GFR.

All antihypertensive agents can be used to lower blood pressure in CKD. Multi-drug regimens will be necessary in most patients with CKD to achieve therapeutic goals. Patients with specific causes of kidney disease and CVD benefit from specific classes of agents (Table 12).

Table 12: Preferred Antihypertensive Agents for CVD  

Types of CVD	Thiazide or Loop Diuretics	ACE Inhibitors or ARBs	Beta-Blockers	Calcium Channel Blockers	Aldosterone Antagonists
Heart Failure with Systolic Dysfunction	X	X	X a		X
Post MI with Systolic Dysfunction		X	X		X
Post MI			X
Chronic Stable Angina			X	X
High-Risk for Coronary Artery Disease	X	X	X	X
Recurrent Stroke Prevention	X	X
Supraventricular Tachycardias			X	X b

* Only some beta-blockers (carvedilol, bisoprolol, metoprolol succinate)

b Nondihydropyridine calcium-channel blockers

ACE inhibitors and ARBs inhibit the angiotensin-induced vasoconstriction of the efferent arterioles of the glomerular microcirculation.  This inhibition leads to a reduction in both intraglomerular filtration pressure and proteinuria.  Several controlled studies have shown that these drugs are effective in slowing the progression of renal failure in patients with both diabetic and nondiabetic renal failure.

Fig. 3: Algorithm for evaluation and management of hypertension and use of antihypertensive agents in CKD.

Slowing Progression of Diabetic Kidney Disease
Diabetic nephropathy is now the leading cause of CKD requiring renal replacement therapy in many parts of the world, and its prevalence is increasing disproportionately in the developing parts of the world. Forthermore, the prognosis of diabetic patients on dialysis is poor.

Control of Blood Glucose: Excellent glycemic control reduces the risk of kidney disease and its progression in both type 1 and type 2 diabetes mellitus.  It is recommended that plasma values for preprandial glucose be kept in the 5.0 – 7.2 mmol/L (90 – 130 mg/dL) range and hemoglobin A 1C should be <7%. As the GFR decreases with progressive nephropathy, the use and dose of oral hypoglycemics need to be reevaluated. As renal function declines, renal degradation of administered insulin will also decline, so that less insulin may be required for glycemic control.

Control of Blood Pressure and Proteinuria: Hypertension is found in the majority of type 2 diabetic patients at diagnosis. This finding correlates with the presence of albuminuria and is a strong predictor of cardiovascular events and nephropathy. Testing for microalbuminuria is recommended in all diabetic patients, at least annually. Antihypertensive treatment reduces albuminuria and diminishes its progression even in normotensive diabetic patients. In addition to treatment of hypertension in general, the use of ACE inhibitors and ARBs in particular is associated with additional renoprotection.

Table 13: Hypertension and Antihypertensive Agents in Diabetic Kidney Disease

Managing other Complications of CKD
Although the loading dose of most drugs is not affected by CKD because no renal elimination is used in the calculation, the maintainance doses of many drugs will need to be adjusted. For those agents in which >70% excretion is by a nonrenal route, such as hepatic elimination, dose adjustment may not be needed. Some drugs that should be avoided included metformin, meperidine and oral hypoglycemics that are eliminated by the kidney; NSAIDs should be avoided because of the further worsening of kidney function.

Renal Replacement Therapy
Temporary relief of symptoms and signs of impending uremia, such as anorexia, nausea, vomiting, lassitude and pruritis may sometimes be achieved with protein restriction. However, this carries a significant risk of protein energy malnutrition and thus plans for longterm management with maintenance dialysis or kidney transplantation should be in place. Clear indications for initiation of renal replacement therapy for patients with CKD include pericarditis, encephalopathy, intractable muscle cramping, anorexia and nausea not attributable to reversible causes such as peptic ulcer, evidence of malnutrition, and fluid and electrolyte abnormalities, principally hyperkalemia, which are refractory to other measures.

Kidney transplantation offers the best potential for complete rehabilitation, because dialysis replaces only a small fraction of the kidney's filtration functions and none of the other renal functions, including endocrine and anti-inflammatory effects.

top

CKD is one of the important non communicable diseases in the world including India . Because of increasing aging world population and consequent increasing prevalence of hypertension and diabetes, CKD is also on the rise. The key to successful prevention of CKD progression is screening for hypertension, improved testing and diagnosis of predisposing co-morbidities such as diabetes and aggressive treatment to attain goals.

top

1. Americal Journal of Kidney Diseases 2004; 43 (5) Suppl 1: S42-S230
2. Clin Exp nephrol 2009; 13: 96-99
3. Harrison text book of internal medicine 17 th edition. Mcgraw-Hill publishers
4. Nephron Clin Pract 2009; 111:c197-c203
5. Saudi J Kidney Dis Transpl 2008; 19 (5): 847-853

top