Chronic Kidney Disease

Etiology

The causes of CKD vary globally, and the most common primary diseases causing CKD and, ultimately, end-stage renal disease (ESRD) are as follows[3]:

• Diabetes mellitus type 2 (30% to 50%)
• Diabetes mellitus type 1 (3.9%)
• Hypertension (27.2%)
• Primary glomerulonephritis (8.2%)
• Chronic Tubulointerstitial nephritis (3.6%)
• Hereditary or cystic diseases (3.1%)
• Secondary glomerulonephritis or vasculitis (2.1%)
• Plasma cell dyscrasias or neoplasm (2.1)
• Sickle Cell Nephropathy (SCN) which accounts for less than 1% of ESRD patients in the United States[4]

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).

Prerenal Disease

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.[5]

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.[6] The most common causes are post-streptococcal GN, infective endocarditis, shunt nephritis, IgA nephropathy, lupus nephritis, Goodpasture syndrome, and vasculitis. [7]

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, [8]

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.[9]

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.

Epidemiology

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.[10]

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.[3]

Kidney Disease Outcomes Quality Initiative (KDOQI) mandates that for labeling of chronicity and CKD, patients should be tested on three occasions over 3 months, with 2 of the 3 results being consistently positive.[11]

Natural History and Progression of CKD

CKD diagnosed in the general population (community CKD) has a significantly different natural history and course of progression compared to CKD in patients referred to the nephrology practices (referred CKD).

Community CKD is seen mainly in the older population. These individuals have had 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. [12] 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 are the predominant outcome in community-based CKD.[13]

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 in 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, and a non-white ethnicity, which includes African Americans, Afro-Caribbean individuals, Hispanics, and Asians (South Asians and Pacific Asians), all adversely affect CKD progression.

Genetic factors that 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.[14]

Modifiable CKD Risk Factors

These include systemic hypertension, proteinuria, and metabolic factors.[15]

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.[16] 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, reducing marked proteinuria by RAS blockade or 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)[17] and Ongoing Telmisartan Alone and in Combination with Ramipril Global End Point Trial (ONTARGET),[18] 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 to 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 the 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.[19][20]

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.

Pathophysiology

Unlike acute kidney injury (AKI), where the healing process is complete with complete 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 the glomeruli, the tubules, the interstitium, and the vessels. It manifests histologically as glomerulosclerosis, tubulointerstitial fibrosis, and vascular sclerosis.

The sequence of events that lead to scarring and fibrosis are complex, overlapping, and multistage phenomena.

• Infiltration of damaged kidneys with extrinsic inflammatory cells
• Activation, proliferation, and loss of intrinsic renal cells (through apoptosis, necrosis, mesangiolysis, and podocytopenia)
• Activation and proliferation of extracellular matrix (ECM) producing cells including myofibroblasts and fibroblasts
• Deposition of ECM replacing the normal architecture

Mechanisms of Accelerated Progression of CKD

• Systemic and intraglomerular hypertension
• Glomerular hypertrophy
• Intrarenal precipitation of calcium phosphate
• Altered prostanoid metabolism

All these mechanisms lead to a histological entity called focal segmental glomerulosclerosis.[21]

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.[22]

History and Physical

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:

• Nausea
• Vomiting
• Loss of appetite
• Fatigue and weakness
• Sleep disturbance
• Oliguria
• Decreased mental sharpness
• Muscle twitches and cramps
• Swelling of feet and ankles
• Persistent pruritus
• Chest pain due to uremic pericarditis
• Shortness of breath due to pulmonary edema from fluid overload
• Hypertension that's difficult to control
• Physical examination is often not helpful, but patients may have
• Skin pigmentation
• Scratch marks from pruritus
• Pericardial friction rub due to uremic pericarditis
• Uremic frost, where high levels of BUN result in urea in sweat
• Hypertensive fundal changes suggesting chronicity

Evaluation

Establishing Chronicity

When an eGFR of less than 60 ml/min/1.73m is detected in a patient, attention must 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.

1. History of long-standing chronic hypertension, proteinuria, microhematuria, and symptoms of the prostatic disease
2. Skin pigmentation, scratch marks, left ventricular hypertrophy, and hypertensive fundal changes.
3. Blood test results of other conditions like multiple myeloma and systemic vasculitis would be helpful.
4. Low serum calcium and high phosphorus levels have little discriminatory value, but normal Parathyroid hormone levels suggest AKI rather than CKD.
5. Patients who have very high blood urea nitrogen (BUN) values greater than 140 mg/dl and serum creatinine greater than 13.5 mg/dl, who appear relatively well and still pass normal volumes of urine, are much more likely to have CKD than acute kidney disease.

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 m².

CKD is confirmed if previous tests confirm that the low eGFR is chronic or if the repeat blood test results over 3 months are consistent.

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 be assessed by obtaining an early morning urine sample and quantifying the 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.[23]

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 and 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.[8] 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 scans. Radionuclide renal scans 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 also gives information about the extent of fibrosis in the kidney.

Treatment / Management

General Management

• Adjusting drug doses for the level of estimated glomerular filtration rate (GFR)
• Preparation of renal replacement therapy by placing an arteriovenous fistula or graft

Treat the Reversible Causes of Renal Failure

The potentially reversible causes of acute kidney injury, like infection, drugs that reduce the GFR, hypotension, such as from shock, and instances that cause hypovolemia, such as vomiting and diarrhea, should be identified and intervened.

Patients with CKD should be evaluated carefully for the use of intravenous contrast studies, and any alternatives for 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 that result in the 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, the proteinuria goal should be met.

Multiple studies have shown that smoking is associated with the risk of developing nephrosclerosis, and smoking cessation retards the progression of CKD.[24]

Protein restriction has also been shown to slow CKD progression. However, the type and amount of protein intake are yet to be determined.

Bicarbonate supplementation for the treatment of chronic metabolic acidosis has been shown to delay CKD progression as well. [25] Also, intensive glucose control in people with diabetes has been shown to delay the development of albuminuria and also the progression of albuminuria to overt proteinuria.[26](A1)

Preparation and Initiation of Renal Replacement Therapy

Once the CKD progression is noted, the patient should be offered various options for renal replacement therapy.

• Hemodialysis (home or in-center)
• Peritoneal dialysis (continuous or intermittent)[27]
• Kidney transplantation (living or deceased donor): It is the treatment of choice for ESRD, given better long-term outcomes.
• Patients who do not want renal replacement therapy should be provided with information about conservative and palliative care management.
• The hemodialysis is performed after stable vascular access is placed in a nondominant arm. In this arm, intravenous cannulas are avoided to preserve the veins. The preferred vascular access is AV fistula. The other hemodialysis access options are AV grafts and tunneled hemodialysis catheters. The patency rates of AV fistulas are good, and infections are very infrequent. Higher flows can be achieved through AV fistula, and there is less chance of recirculation.
• Peritoneal dialysis is performed after placing a peritoneal catheter.[27]

Indications for Renal Replacement Therapy

• Pericarditis or pleuritis (urgent indication)
• Progressive uremic encephalopathy or neuropathy, with signs such as confusion, asterixis, myoclonus, and seizures (urgent indication)
• A clinically significant bleeding diathesis is attributable to uremia (urgent indication)
• Hypertension is poorly responsive to antihypertensive medications
• Fluid overload is refractory to diuretics
• Metabolic disorders that are refractory to medical therapy, such as hyperkalemia, hyponatremia, metabolic acidosis, hypercalcemia, hypocalcemia, and hyperphosphatemia
• Persistent nausea and vomiting
• Evidence of malnutrition

Renal transplantation is the best treatment option for ESRD due to its survival benefit compared to long-term dialysis therapy. The patients with CKD become eligible to be listed for the deceased donor renal transplant program when the eGFR is less than 20 ml/min/1.73 m²

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.

Differential Diagnosis

• Acute kidney injury

• Alport syndrome

• Antigiomerular basement membrane disease

• Chronic glomerulonephritis

• Diabetic nephropathy

• Multiple myeloma

• Nephrolithiasis

• Nephrosclerosis

• Rapidly progressive glomerulonephritis

• Renal artery stenosis

Staging

The 6 categories include:

• G1: GFR 90 ml/min per 1.73 m² and above
• G2: GFR 60 to 89 ml/min per 1.73 m²
• G3a: GFR 45 to 59 ml/min per 1.73 m²
• G3b: GFR 30 to 44 ml/min per 1.73 m²
• G4: GFR 15 to 29 ml/min per 1.73 m²
• G5: GFR less than 15 ml/min per 1.73 m² or treatment by dialysis

The 3 levels of albuminuria include albumin-creatinine ratio (ACR):

• A1: ACR less than 30 mg/gm (less than 3.4 mg/mmol)
• A2: ACR 30 to 299 mg/gm (3.4 to 34 mg/mmol)
• A3: ACR greater than 300 mg/gm (greater than 34 mg/mmol)

Prognosis

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 whites. Hispanics have higher incidence rates of ESRD than non-Hispanics.

Early-stage CKD and ESRD are associated with increased morbidity and healthcare 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 was comparable to those in the 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 the general US population.[28] CKD patients are at a higher risk of hospitalization and cardiovascular diseases, and the risk increases with a decline in GFR.

Patients with CKD, particularly end-stage renal disease (ESRD), are at increased risk of mortality, particularly from cardiovascular disease. A review of USRDS 2009 data suggests that the 5-year survival probability in a patient on dialysis is only around 34%.

Complications

Treatment of Complications of Chronic Kidney Disease

Patients with CKD have a diminished ability to maintain a fluid balance after a rapid sodium load, which 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 those 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 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.[29].

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 the 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 with 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 patients on dialysis, 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.

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 or 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

Complications related to cardiovascular, renal, neurologic, and gastrointestinal systems.[30][31]

Common complications include hypertension, dyslipidemia, coronary artery disease from new-onset diabetes mellitus and renal failure, left ventricular hypertrophy, arrhythmias,[31] 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.