Chronic kidney disease (CKD) is defined as the presence of kidney damage or an estimated glomerular filtration rate (eGFR) less than 60 ml/min/1.73 mt2, persisting for 3 months or more, irrespective of the cause. It is a state of progressive loss of kidney function ultimately resulting in the need for renal replacement therapy (dialysis or transplantation). Kidney damage refers to pathologic abnormalities either suggested by imaging studies or renal biopsy, abnormalities in urinary sediment, or increased urinary albumin excretion rates. The 2012 KDIGO CKD classification recommends details about the cause of the CKD and classifies into 6 categories based on glomerular filtration rate (G1 to G5 with G3 split into 3a and 3b). It also includes the staging based on three levels of albuminuria (A1, A2, and A3), with each stage of CKD being sub-categorized according to the urinary albumin-creatinine ratio in (mg/gm) or (mg/mmol) in an early morning “spot” urine sample.
The 6 categories include:
The three levels of albuminuria include albumin-creatinine ratio (ACR)
The improved classification of CKD has been beneficial in identifying prognostic indications related to decreased kidney function and increased albuminuria. However, a downside of the use of classification systems is the possible overdiagnosis of CKD, especially in elderly.
The causes of CKD vary globally, and the most common primary diseases causing CKD and ultimately end-stage renal disease (ESRD) are as follows:
CKD may result from disease processes in any of the three categories: prerenal (decreased renal perfusion pressure), intrinsic renal (pathology of the vessels, glomeruli, or tubules-interstitium), or postrenal (obstructive).
Chronic prerenal disease occurs in patients with chronic heart failure or cirrhosis with persistently decreased renal perfusion, which increases the propensity for multiple episodes of an intrinsic kidney injury, such as acute tubular necrosis (ATN). This leads to progressive loss of renal function over time.
Intrinsic Renal Vascular Disease
The most common chronic renal vascular disease is nephrosclerosis, which causes chronic damage to blood vessels, glomeruli, and tubulointerstitium.
The other renal vascular diseases are renal artery stenosis from atherosclerosis or fibro-muscular dysplasia which over months or years, cause ischemic nephropathy, characterized by glomerulosclerosis and tubulointerstitial fibrosis.
Intrinsic Glomerular Disease (Nephritic or Nephrotic)
A nephritic pattern is suggested by abnormal urine microscopy with red blood cell (RBC) casts and dysmorphic red cells, occasionally white blood cells (WBCs), and a variable degree of proteinuria. The most common causes are post-streptococcal GN, infective endocarditis, shunt nephritis, IgA nephropathy, lupus nephritis, Goodpasture syndrome, and vasculitis. 
A nephrotic pattern is associated with proteinuria, usually in the nephrotic range (greater than 3.5 gm per 24 hours), and an inactive urine microscopic analysis with few cells or casts. It is commonly caused by minimal change disease, focal segmental glomerulosclerosis, membranous GN, membranoproliferative GN (Type 1 and 2 and associated with cryoglobulinemia), diabetic nephropathy, and amyloidosis.
Some patients may be assigned to one of these two categories.
Intrinsic Tubular and Interstitial Disease
The most common chronic tubulointerstitial disease is polycystic kidney disease (PKD). Other etiologies include nephrocalcinosis (most often due to hypercalcemia and hypercalciuria), sarcoidosis, Sjogren syndrome, reflux nephropathy in children and young adults, 
There is increased recognition of the relatively high prevalence of CKD of unknown cause among agricultural workers from Central America and parts of Southeast Asia called Mesoamerican nephropathy,
Postrenal (Obstructive Nephropathy)
Chronic obstruction may be due to prostatic disease, nephrolithiasis or abdominal/pelvic tumor with mass effect on ureter(s) are the common causes. Retroperitoneal fibrosis is a rare cause of chronic ureteral obstruction.
The true incidence and prevalence of CKD are difficult to determine because of the asymptomatic nature of early to moderate CKD. The prevalence of CKD is around 10% to 14% in the general population. Similarly, albuminuria (microalbuminuria or A2) and GFR less than 60 ml/min/1.73 mt2 have a prevalence of 7% and 3% to 5%, respectively.
Worldwide, CKD accounted for 2,968,600 (1%) of disability-adjusted life-years and 2,546,700 (1% to 3%) of life-years lost in 2012.
Kidney Disease Outcomes Quality Initiative (KDOQI) mandates that for labeling of chronicity and CKD, patients should be tested on three occasions over a 3-month period with 2 of the 3 results being consistently positive.
Natural History and Progression of CKD
CKD diagnosed in the general population (community CKD) has a significantly different natural history and the course of progression compared to the CKD in patients referred to the nephrology practices (referred CKD).
Community CKD is seen mainly in the older population. These individuals have had a lifelong exposure to cardiovascular risk factors, hypertension, and diabetes which can also affect the kidneys. The average rate of decline in GFR in this population is around 0.75 to 1 ml/min/year after the age of 40 to 50 years.  In a large study of community based CKD by Kshirsagar et al., only 1% and 20% of patients with CKD stages G3 and G4 required renal replacement therapy (RRT), however, 24% and 45% respectively died predominantly from cardiovascular disease (CVD), suggesting that cardiac events rather than progressing to ESRD is the predominant outcome in community-based CKD.
In contrast to community CKD, patients with referred CKD present at an early age because of hereditary (autosomal dominant polycystic kidney disease ADPKD) or acquired nephropathy (glomerulonephritis, diabetic nephropathy, or tubulointerstitial disease) causing progressive renal damage and loss of function. The rate of progression in referred CKD varies according to the underlying disease process and between individual patients. Diabetic nephropathy has shown to have a rapid rate of decline in GFR averaging around 10 ml/min/year. In nondiabetic nephropathies, the rate of progression is usually faster in patients with chronic proteinuric GN than those with a low level of proteinuria. Patients with ADPKD and renal impairment, CKD stage G3b and beyond, may have a faster rate of progression compared to other nephropathies. In patients with hypertensive nephrosclerosis, good blood pressure control and minimal proteinuria are associated with very slow progression.
Risk Factors for Progression of CKD
Non-Modifiable CKD Risk Factors
Older age, male gender, a non-Caucasian ethnicity which includes African Americans, Afro-Caribbean individuals, Hispanics, and Asians (South Asians and Pacific Asians) all adversely affect CKD progression.
Genetic factors which affect CKD progression have been found in different Kidney diseases. In a population-based cohort study by Luttropp et al., single nucleotide polymorphisms in the genes TCF7L2 and MTHFS were associated with diabetic nephropathy and CKD progression. In the same study, polymorphisms of genes coding for mediators of renal scarring and renin-angiotensin-aldosterone system (RAAS) were found to influence CKD progression.
Modifiable CKD Risk Factors
These include systemic hypertension, proteinuria, and metabolic factors.
Systemic hypertension is one of the main causes of ESRD worldwide and the second leading cause in the United States after diabetes. The transmission of systemic hypertension into glomerular capillary beds and the resulting glomerular hypertension is believed to contribute to the progression of glomerulosclerosis. Night-time and 24-hour blood pressure measurement (ABPM) appear to correlate best with the progression of CKD. Systolic rather than diastolic BP seems to be predictive of CKD progression and has also been associated with complications in CKD.
Multiple studies in patients with diabetic and nondiabetic kidney diseases have shown that marked proteinuria (albuminuria A3) is associated with a faster rate of CKD progression. Also, a reduction in marked proteinuria by RAS blockade or by diet is associated with a better renal outcome. However, in large intervention studies like Avoiding Cardiovascular Events Through Combination Therapy in Patients Living with Systolic Hypertension (ACCOMPLISH) and Ongoing Telmisartan Alone and in Combination with Ramipril Global End Point Trial (ONTARGET), significant declines in GFR were noted despite a marked reduction in albuminuria. Therefore, moderate level albuminuria (A2) is not a reliable surrogate marker for CKD progression and reduction in albuminuria can be associated with both improving and worsening of CKD progression.
Multiple studies have linked the RAAS system in the pathogenesis of hypertension, proteinuria, and renal fibrosis throughout CKD. Subsequently, interventions targeting RAAS have proved effective in slowing the progression of CKD. This has led to widespread use of RAAS blockers in proteinuric and diabetic kidney disease.
Obesity and smoking have been related to the development and progression of CKD. Also, metabolic factors such as insulin resistance, dyslipidemia, and hyperuricemia have been implicated in the development and progression of CKD.
Recommendations for CKD Screening
Screening, mostly targeting high-risk individuals is being implemented worldwide. The KDOQI guidelines recommend screening high-risk populations which include individuals with Hypertension, Diabetes mellitus, and those older than 65 years. This should include urinalysis, a urine albumin-creatinine ratio (ACR), measurement of serum creatinine and estimation of GFR preferably by chronic kidney disease epidemiology collaboration (CKD-EPI) equation. It is the most cost-effective approach, and there is no evidence to justify screening asymptomatic individuals in the general population for CKD.
Unlike acute kidney injury (AKI), where the healing process is complete with full functional kidney recovery, chronic and sustained insults from chronic and progressive nephropathies evolve to progressive kidney fibrosis and destruction of the normal architecture of the kidney. This affects all the 3 compartments of the kidney, namely glomeruli, the tubules, the interstitium, and the vessels. It manifests histologically as glomerulosclerosis, tubulointerstitial fibrosis, and vascular sclerosis.
The sequence of events which lead to scarring and fibrosis are complex, overlapping, and are multistage phenomena.
Mechanisms of Accelerated Progression of CKD
All these mechanisms lead to a histological entity called focal segmental glomerulosclerosis.
Clinical risk factors for accelerated progression of CKD are proteinuria, hypertension, black race, and hyperglycemia. Also, environmental exposures such as lead, smoking, metabolic syndrome, possibly some analgesic agents, and obesity have also been linked to accelerated progression of CKD.
Early CKD stages are asymptomatic, and symptoms manifest in stages 4 or 5. It is commonly detected by routine blood or urine testing. Some common symptoms and signs at these stages of CKD are:
When an eGFR of less than 60 ml/min/1.73m is detected in a patient, attention needs to be paid to the previous blood and urine test results and clinical history to determine whether this is a result of AKI or CKD that has been present but asymptomatic. The following factors would be helpful.
Assessment of Glomerular Filtration Rate
For patients in whom the distinction between AKI and CKD is unclear, kidney function tests should be repeated in 2 weeks of the initial finding of low eGFR below 60 ml/min/1.73 m.
If previous tests confirm that the low eGFR is chronic or the repeat blood test results over 3 months are consistent, CKD is confirmed.
If eGFR based on serum creatinine is known to be less accurate, then other markers like cystatin-c or an isotope-clearance measurement can be undertaken.
Assessment of Proteinuria
KDIGO recommends that proteinuria should be assessed by obtaining an early morning urine sample and quantifying albumin-creatinine ratio (ACR). The degree of albuminuria is graded from A1 to A3, replacing previous terms such as microalbuminuria.
Some patients may excrete proteins other than albumin and urine protein-creatinine ratio (PCR) may be more useful for certain conditions.
Imaging of Kidneys
If an ultrasound examination of kidneys shows small kidneys with reduced cortical thickness, increased echogenicity, scarring, or multiple cysts, this suggests a chronic process. It may also be helpful to diagnose chronic hydronephrosis from obstructive uropathy, cystic enlargement of the kidney in ADPKD.
Renal ultrasound Doppler can be used in suspected renal artery stenosis to evaluate the renal vascular flow
Computerized tomography: A low dose of non-contrast CT is used to diagnose renal stone disease. It is also used to diagnose suspected ureteric obstruction which cannot be seen by ultrasonography.
Renal angiography has its role in the diagnosis of polyarteritis nodosa where multiple aneurysms and irregular areas of constriction are seen.
Voiding cystourethrography is mainly used when chronic vesicourethral reflux is suspected as the cause of CKD. It is used to confirm the diagnosis and estimate the severity of reflux.
Renal scans can give sufficient information about the anatomy and function of kidneys. They are used predominantly in children as they are associated with lesser radiation exposure compared to CT scan. Radionuclide renal scans are used to measure the difference in function between the kidneys.
Establishing an Accurate Diagnosis
An accurate cause of CKD needs to be established such as when there is an underlying treatable condition that requires appropriate management, for example, lupus nephritis, ANCA vasculitis, among others. In addition, certain diseases carry a higher frequency of recurrence in the kidney after transplantation and accurate diagnosis will influence later management. A kidney biopsy is used to diagnose the etiology of CKD, and it also gives information about the extent of fibrosis in the kidney.
Treat the Reversible Causes of Renal Failure
The potentially reversible causes of acute kidney injury like infection, drugs which reduce the GFR, hypotension such as from shock, instances which cause hypovolemia such as vomiting, diarrhea should be identified and intervened.
Patients with CKD should be evaluated carefully for the use of intravenous contrast studies, and any alternatives for the contrast studies should be utilized first. Other nephrotoxic agents such as aminoglycoside antibiotics and NSAIDs should be avoided.
Retarding the Progression of CKD
The factors which result in progression of CKD should be addressed such as hypertension, proteinuria, metabolic acidosis, and hyperlipidemia. Hypertension should be managed in CKD by establishing blood pressure goals. Similarly, proteinuria goal should be met.
Multiple studies have shown that smoking is associated with risk of developing nephrosclerosis and smoking cessation retards the progression of CKD.
Protein restriction has also been shown to slow the CKD progression. However, the type and amount of protein intake are yet to be determined.
Bicarbonate supplementation for treatment of chronic metabolic acidosis has been shown to delay the CKD progression as well.  Also, intensive glucose control in diabetics has been shown to delay the development of albuminuria and also the progression of albuminuria to overt proteinuria.
Preparation and Initiation of Renal Replacement Therapy
Once the CKD progression is noted, the patient should be offered various options of renal replacement therapy.
Indications for Renal Replacement Therapy
Renal transplantation is the best treatment option of ESRD due to its survival benefit compared to long-term dialysis therapy. The patients with CKD become eligible to be listed for Deceased donor renal transplant program when the eGFR is less than 20 ml/min/1.73m2
Conservative management of ESRD is also an option for all patients who decide not to pursue renal replacement therapy. Conservative care includes the management of symptoms, advance-care planning, and provision of appropriate palliative care. This strategy is often underutilized and needs to be considered for very frail patients with poor functional status with numerous comorbidities. For facilitating this discussion a 6-month mortality score calculator is being used which includes variables such as age, serum albumin, the presence of dementia, peripheral vascular disease, and (yes/no) answer to a question by a treating nephrologist "would I be surprised if this patient died in the next year?"
When to Refer to a Nephrologist
Patients with CKD should be referred to a nephrologist when the estimated GFR is less than 30 ml/min/1.73 mt2. This is the time to discuss the options of renal replacement therapy.
The 6 categories include:
The 3 levels of albuminuria include albumin-creatinine ratio (ACR):
Significant racial and ethnic differences exist in the incidence and prevalence rates of ESRD. The highest incidence is found in African Americans; followed by American Indians and Alaska Natives; followed by Asian Americans, native Hawaiians, and other Pacific Islanders; followed by Caucasians. Hispanics have higher incidence rates of ESRD than non-Hispanics.
Early stage CKD and ESRD are associated with increased morbidity and health care utilization rates. A review of the USRDS 2009 annual data report suggests that the number of hospitalizations in ESRD patients is 1.9% per patient-year. In a study by Khan SS et al., the prevalence of cardiovascular disease, cerebrovascular disease, and peripheral vascular disease in earlier stages of CKD were comparable to those in US dialysis population. It was also found that patients with CKD had 3-fold higher rates of hospitalization and hospital days spent per patient-year compared to general US population. CKD patients are at a higher risk of hospitalization and cardiovascular diseases and the risk increases with a decline in GFR.
Patients with CKD and particularly end-stage renal disease (ESRD) are at increased risk of mortality, particularly from cardiovascular disease. Review of USRDS 2009 data suggests that 5-year survival probability in a patient on dialysis is only around 34%.
Treatment of Complications of Chronic Kidney Disease
Patients with CKD have diminished the ability to maintain a fluid balance after a rapid sodium load and becomes more apparent in stages IV and V of CKD. These patients respond to sodium restriction and a loop diuretic. The 2012 KDIGO guidelines recommend all CKD patients should be sodium restricted to less than 2 gm per day.
Hyperkalemia in CKD can occur specifically in oliguric patients and in whom where aldosterone secretion is diminished. Dietary intake of potassium, tissue breakdown and hypoaldosteronism could result in hyperkalemia. Drugs such as ACE inhibitors and nonselective beta blockers could also result in hyperkalemia.
Metabolic acidosis is a common complication of advanced CKD due to the increased tendency of kidneys in CKD to retain H. Chronic metabolic acidosis in CKD would result in osteopenia, increased protein catabolism, and secondary hyperparathyroidism. These patients should be treated with bicarbonate supplementation to target serum bicarbonate of equal to 23.
CKD is a significant risk factor for CVD and risk increases with increased severity of the CKD.Considerable evidence indicates a significant association between Epicardial adipose tissue(EAT) thickness and the incidence of CVD events in CKD patients.In CKD patients, EAT assessment could be a reliable parameter for cardiovascular risk assessment..
Bone and Mineral Disorders
Hyperphosphatemia is a frequent complication of CKD due to a decreased filtered load of phosphorous. This leads to increased secretion of a Parathyroid hormone (PTH) and causes secondary hyperparathyroidism. Hyperparathyroidism results in normalization of phosphorous and calcium but at the expense of bone. This results in renal osteodystrophy. Therefore, phosphorus binders along with dietary restriction of phosphorus are used to treat secondary hyperparathyroidism.
Hypertension is a manifestation of volume expansion in CKD. Patients in CKD do not always have edema to suggest volume expansion. Therefore, all patients with CKD should have a loop diuretic added to control the blood pressure which needs to be titrated before considering an increase in antihypertensive therapy.
Anemia in CKD is usually normocytic normochromic. It is primarily due to reduced erythropoietin production from reduced functioning renal mass and also due to reduced red cell survival. Hemoglobin should be checked at least yearly in CKD 3, every 6 months in CKD IV and V, and every 3 months in dialysis patients. Erythropoietin stimulating agents (ESA) in CKD patients should be considered when Hb is less than 10 and provided iron saturation is at least 25% and ferritin greater than 200 ng/mL. In dialysis patients, the goal Hb concentration is 10 to 11.5 gm/dl.
Treatment of Complications of ESRD
Malnutrition in ESRD is due to anorexia and poor protein intake. The diet in ESRD should provide at least 30 to 35 Kcal/kg per day. Low plasma albumin concentration is suggestive of malnutrition.
Uremic bleeding is a complication resulting from impaired platelet function. It results in prolonged bleeding time. Asymptomatic patients are not treated. However, correction of uremic platelet dysfunction is needed during active bleeding, need for a surgical procedure. Some interventions used are desmopressin (dDAVP), cryoprecipitate, estrogen, and initiation of dialysis.
Uremia can present as uremic pericarditis and is an indication for initiation of dialysis. Uremic pericarditis is treated with dialysis and responds well.
Complications of Renal Transplantation
Common complications include hypertension, dyslipidemia, coronary artery disease from new-onset diabetes mellitus and renal failure, left ventricular hypertrophy, arrhythmias, and heart failure. Neurologic complications include stroke and posterior reversible encephalopathy syndrome, central nervous system (CNS) infections, neuromuscular disease, seizure disorders, and neoplastic disease. GI complications include infection, malignancy (posttransplant lymphoproliferative disorder), mucosal injury, mucosal ulceration, perforation, biliary tract disease, pancreatitis, and diverticular disease.
All high-risk groups of patients such as Diabetic patients, hypertensives, should not only be screened for CKD but also be counseled about the symptoms and signs of CKD. Patients with CKD should be taught about the following interventions at home
Eighty percent to 85% of patients with CKD have hypertension, and they should be instructed to measure blood pressure daily and to keep a log of blood pressure, daily weights. They should be prescribed a diuretic as a part of an antihypertensive regimen.
Teaching patients with advanced CKD of home administration of subcutaneous erythropoietin stimulating agents.
There should be a discussion held with patients by nutritionists or physicians about low protein diet which may slow the progression of CKD and potassium containing foods.
All patients with advanced CKD should be instructed about the need to control phosphorus levels. They should be instructed to take phosphate binders with each meal.
CKD patients who are pregnant should be educated that pregnancy may worsen the CKD and how reduced kidney function can adversely effect pregnancy.
CKD has a multitude of manifestations and is optimally managed by an interprofessional team of health care professionals who practice at a single location such as CKD clinic. These clinics focus on guideline driven kidney care, evaluate and treat complications, suggest patient lifestyle modifications, and provide adequate patient education regarding the various modalities of dialysis. Fishbane et al. compared a standard care model with a healthy transitions program where a nurse care manager works with a protocol-driven informatics system which provides daily reports with incomplete steps of the process for each patient. It showed a reduction in hospitalizations, increased use of AV fistulas, a decrease in emergent dialysis, and less use of catheters. Such models decrease the overall cost of health care with saving of billions of dollars. The multidisciplinary CKD clinics have access to a nutritionist who assesses the nutritional status of a patient and also formulates a meal plan. Similarly, a pharmacist performs a medication check and screens for nephrotoxic medications and adjusts the non-nephrotoxic medications to the patient’s renal function. A vascular access nurse also evaluates appropriate patients. Finally, renal transplantation information is provided to eligible patients.
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