A normal kidney contains approximately 1 million nephrons, each of which contributes to the total glomerular filtration rate (GFR). In the face of renal injury (regardless of the etiology), the kidney has an innate ability to maintain GFR, despite progressive destruction of nephrons, as the remaining healthy nephrons manifest hyperfiltration and compensatory hypertrophy. This nephron adaptability allows for continued normal clearance of plasma solutes. Plasma levels of substances such as urea and creatinine start to show measurable increases only after total GFR has decreased 50%. The plasma creatinine value will approximately double with a 50% reduction in GFR. For example, a rise in plasma creatinine from a baseline value of 0.6 mg/dL to 1.2 mg/dL in a patient, although still within the adult reference range, actually represents a loss of 50% of functioning nephron mass. The hyperfiltration and hypertrophy of residual nephrons, although beneficial for the reasons noted, has been hypothesized to represent a major cause of progressive renal dysfunction. The increased glomerular capillary pressure may damage the capillaries, leading initially to secondary focal and segmental glomerulosclerosis (FSGS) and eventually to global glomerulosclerosis. This hypothesis is supported by studies of five-sixths nephrectomized rats, which develop lesions identical to those observed in humans with chronic kidney disease (CKD). Factors other than the underlying disease process and glomerular hypertension that may cause progressive renal injury include the following:
Thaker et al found a strong association between episodes of acute kidney injury (AKI) and cumulative risk for the development of advanced CKD in patients with diabetes mellitus who experienced AKI in multiple hospitalizations. [6] Any AKI versus no AKI was a risk factor for stage 4 CKD, and each additional AKI episode doubled that risk. [6] Findings from the Atherosclerosis Risk in Communities (ARIC) Study, a prospective observational cohort, suggest that inflammation and hemostasis are antecedent pathways for CKD. [7] This study used data from 1787 cases of CKD that developed between 1987 and 2004. In children, the GFR increases with age and is calculated with specific equations that are different than those for adults. Adjusted for body surface area, the GFR reaches adult levels by age 2-3 years. Aspects of pediatric kidney function and the measure of creatinine are informative not only for children but also for adults. For example, it is important to realize that creatinine is derived from muscle and, therefore, that children and smaller individuals have lower creatinine levels independent of the GFR. Consequently, laboratory reports that do not supply appropriate pediatric normal ranges are misleading. The same is true for individuals who have low muscle mass for other reasons, such as malnutrition, cachexia, or amputation. Another important note for childhood CKD is that physicians caring for children must be aware of normal blood pressure levels by age, sex, and height. Prompt recognition of hypertension at any age is important, because it may be caused by primary renal disease. Fortunately, CKD during childhood is rare. Pediatric CKD is usually the result of congenital defects, such as posterior urethral valves or dysplastic kidney malformations. Another common cause is FSGS. Genetic kidney diseases are also frequently manifested in childhood CKD. Advances in pediatric nephrology have enabled great leaps in survival for pediatric CKD and end-stage renal disease (ESRD), including for children who need dialysis or transplantation. The biologic process of aging initiates various structural and functional changes within the kidney. [8, 9] Renal mass progressively declines with advancing age, and glomerulosclerosis leads to a decrease in renal weight. Histologic examination is notable for a decrease in glomerular number of as much as 30-50% by age 70 years. The GFR peaks during the third decade of life at approximately 120 mL/min/1.73 m2; it then undergoes an annual mean decline of approximately 1 mL/min/y/1.73 m2, reaching a mean value of 70 mL/min/1.73 m2 at age 70 years. Ischemic obsolescence of cortical glomeruli is predominant, with relative sparing of the renal medulla. Juxtamedullary glomeruli see a shunting of blood from afferent to efferent arterioles, resulting in redistribution of blood flow favoring the renal medulla. These anatomic and functional changes in renal vasculature appear to contribute to an age-related decrease in renal blood flow. Renal hemodynamic measurements in aged humans and animals suggest that altered functional response of the renal vasculature may be an underlying factor in diminished renal blood flow and increased filtration noted with progressive renal aging. The vasodilatory response is blunted in the elderly when compared with younger patients. However, the vasoconstrictor response to intrarenal angiotensin is identical in young and older human subjects. A blunted vasodilatory capacity with appropriate vasoconstrictor response may indicate that the aged kidney is in a state of vasodilatation to compensate for the underlying sclerotic damage. Given the histologic evidence for nephronal senescence with age, a decline in the GFR is expected. However, a wide variation in the rate of GFR decline is reported because of measurement methods, race, gender, genetic variance, and other risk factors for renal dysfunction. Most cases of CKD are acquired rather than inherited, although CKD in a child is more likely to have a genetic or inherited cause. Well-described genetic syndromes associated with CKD include autosomal dominant polycystic kidney disease (ADPKD) and Alport syndrome. Other examples of specific single-gene or few-gene mutations associated with CKD include Dent disease, nephronophthisis, and atypical hemolytic uremic syndrome (HUS). APOL1 gene More recently, researchers have begun to identify genetic contributions to increased risk for development or progression of CKD. Friedman et al found that more than 3 million black persons with genetic variants in both copies of apolipoprotein L1 (APOL1) are at higher risk for hypertension-attributable ESRD and FSGS. In contrast, black individuals without the risk genotype and European Americans appear to have similar risk for developing nondiabetic CKD. [10] FGF-23 gene Circulating levels of the phosphate-regulating hormone fibroblast growth factor 23 (FGF-23) are affected by variants in the FGF23 gene. Isakova et al reported that elevated FGF-23 levels are an independent risk factor for ESRD in patients who have fairly well-preserved kidney function (stages 2-4) and for mortality across the scope of CKD. [11] Single-nucleotide polymorphisms A review of 16 single-nucleotide polymorphisms (SNPs) that had been associated with variation in GFR found that development of albuminuria was associated mostly with an SNP in the SHROOM3 gene. [12] Even accounting for this variant, however, there is evidence that some unknown genetic variant influences the development of albuminuria in CKD. This study also suggests a separate genetic influence on development of albuminuria versus reduction in GFR. [12] A genome-wide association study (GWAS) that included over 130,000 patients found 6 SNPs associated with reduced GFR, located in or near MPPED2, DDX1, SLC47A1, CDK12, CASP9, and INO80. [13] The SNP in SLC47A1 was associated with decreased GFR in nondiabetic individuals, whereas SNPs located in the DNAJC16 and CDK12 genes were associated with decreased GFR in individuals younger than 65 years. [13] Immune-system and RAS genes A number of genes have been associated with the development of ESRD. Many of these genes involve aspects of the immune system (eg, CCR3, IL1RN, IL4). [14] Unsurprisingly, polymorphisms in genes involving the renin-angiotensin system (RAS) have also been implicated in predisposition to CKD. One study found that patients with CKD were significantly more likely to have the A2350G polymorphism in the ACE gene, which encodes the angiotensin-converting enzyme (ACE). [15] They were also more likely to have the C573T polymorphism in the AGTR1 gene, which encodes the angiotensin II type 1 receptor. [15] The ability to maintain potassium excretion at near-normal levels is generally maintained in CKD, as long as aldosterone secretion and distal flow are maintained. Another defense against potassium retention in patients with CKD is increased potassium excretion in the gastrointestinal tract, which also is under control of aldosterone. Hyperkalemia usually does not develop until the GFR falls to less than 20-25 mL/min/1.73 m², at which point the kidneys have decreased ability to excrete potassium. Hyperkalemia can be observed sooner in patients who ingest a potassium-rich diet or have low serum aldosterone levels. Common sources of low aldosterone levels are diabetes mellitus and the use of ACE inhibitors, NSAIDs, or beta-blockers. Hyperkalemia in CKD can be aggravated by an extracellular shift of potassium, such as occurs in the setting of acidemia or from lack of insulin. Hypokalemia is uncommon but can develop in patients with very poor intake of potassium, gastrointestinal or urinary loss of potassium, or diarrhea or in patients who use diuretics. Metabolic acidosis often is a mixture of normal anion gap and increased anion gap; the latter is observed generally with stage 5 CKD but with the anion gap generally not higher than 20 mEq/L. In CKD, the kidneys are unable to produce enough ammonia in the proximal tubules to excrete the endogenous acid into the urine in the form of ammonium. In stage 5 CKD, accumulation of phosphates, sulfates, and other organic anions are the cause of the increase in anion gap. Metabolic acidosis has been shown to have deleterious effects on protein balance, leading to the following:
Hence, metabolic acidosis is associated with protein-energy malnutrition, loss of lean body mass, and muscle weakness. The mechanism for reducing protein may include effects on adenosine triphosphate (ATP)–dependent ubiquitin proteasomes and increased activity of branched-chain keto acid dehydrogenases. Metabolic acidosis also leads to an increase in fibrosis and rapid progression of kidney disease, by causing an increase in ammoniagenesis to enhance hydrogen excretion. In addition, metabolic acidosis is a factor in the development of renal osteodystrophy, because bone acts as a buffer for excess acid, with resultant loss of mineral. Acidosis may interfere with vitamin D metabolism, and patients who are persistently more acidotic are more likely to have osteomalacia or low-turnover bone disease. Salt and water handling by the kidney is altered in CKD. Extracellular volume expansion and total-body volume overload results from failure of sodium and free-water excretion. This generally becomes clinically manifested when the GFR falls to less than 10-15 mL/min/1.73 m², when compensatory mechanisms have become exhausted. As kidney function declines further, sodium retention and extracellular volume expansion lead to peripheral edema and, not uncommonly, pulmonary edema and hypertension. At a higher GFR, excess sodium and water intake could result in a similar picture if the ingested amounts of sodium and water exceed the available potential for compensatory excretion. Tubulointerstitial renal diseases represent the minority of cases of CKD. However, it is important to note that such diseases often cause fluid loss rather than overload. Thus, despite moderate or severe reductions in GFR, tubulointerstitial renal diseases may manifest first as polyuria and volume depletion, with inability to concentrate the urine. These symptoms may be subtle and require close attention to be recognized. Volume overload occurs only when GFR reduction becomes very severe. Normochromic normocytic anemia principally develops from decreased renal synthesis of erythropoietin, the hormone responsible for bone marrow stimulation for red blood cell (RBC) production. The anemia starts early in the course of the disease and becomes more severe as viable renal mass shrinks and the GFR progressively decreases. Using data from the National Health and Nutrition Examination Survey (NHANES), Stauffer and Fan found that anemia was twice as prevalent in people with CKD (15.4%) as in the general population (7.6%). The prevalence of anemia increased with stage of CKD, from 8.4% at stage 1 to 53.4% at stage 5. [16] No reticulocyte response occurs. RBC survival is decreased, and bleeding tendency is increased from the uremia-induced platelet dysfunction. Other causes of anemia in CKD include the following:
Renal bone disease is a common complication of CKD. It results in skeletal complications (eg, abnormality of bone turnover, mineralization, linear growth) and extraskeletal complications (eg, vascular or soft-tissue calcification). Different types of bone disease occur with CKD, as follows:
Bone disease in children is similar but occurs during growth. Therefore, children with CKD are at risk for short stature, bone curvature, and poor mineralization (“renal rickets” is the equivalent term for adult osteomalacia). CKD–mineral and bone disorder (CKD-MBD) involves biochemical abnormalities related to bone metabolism. CKD-MBD may result from alteration in levels of serum phosphorus, PTH, vitamin D, and alkaline phosphatase. Secondary hyperparathyroidism develops in CKD because of the following factors:
Calcium and calcitriol are primary feedback inhibitors; hyperphosphatemia is a stimulus to PTH synthesis and secretion. Hyperphosphatemia and hypocalcemia Phosphate retention begins in early CKD; when the GFR falls, less phosphate is filtered and excreted, but because of increased PTH secretion, which increases renal excretion, serum levels do not rise initially. As the GFR falls toward CKD stages 4-5, hyperphosphatemia develops from the inability of the kidneys to excrete the excess dietary intake. Hyperphosphatemia suppresses the renal hydroxylation of inactive 25-hydroxyvitamin D to calcitriol, so serum calcitriol levels are low when the GFR is less than 30 mL/min/1.73 m². Increased phosphate concentration also affects PTH concentration by its direct effect on the parathyroid glands (posttranscriptional effect). Hypocalcemia develops primarily from decreased intestinal calcium absorption because of low plasma calcitriol levels. It also possibly results from increased calcium-phosphate binding, caused by elevated serum phosphate levels. Increased PTH secretion Low serum calcitriol levels, hypocalcemia, and hyperphosphatemia have all been demonstrated to independently trigger PTH synthesis and secretion. As these stimuli persist in CKD, particularly in the more advanced stages, PTH secretion becomes maladaptive, and the parathyroid glands, which initially hypertrophy, become hyperplastic. The persistently elevated PTH levels exacerbate hyperphosphatemia from bone resorption of phosphate. Skeletal manifestations If serum levels of PTH remain elevated, a high ̶ bone turnover lesion, known as osteitis fibrosa, develops. This is one of several bone lesions, which as a group are commonly known as renal osteodystrophy and which develop in patients with severe CKD. Osteitis fibrosa is common in patients with ESRD. The prevalence of adynamic bone disease in the United States has increased, and its onset before the initiation of dialysis has been reported in some cases. The pathogenesis of adynamic bone disease is not well defined, but possible contributing factors include the following:
Low-turnover osteomalacia in the setting of CKD is associated with aluminum accumulation. It is markedly less common than high-turnover bone disease. Another form of bone disease is dialysis-related amyloidosis, which is now uncommon in the era of improved dialysis membranes. This condition occurs from beta-2-microglobulin accumulation in patients who have required chronic dialysis for at least 8-10 years. It manifests with cysts at the ends of long bones. |
A nurse is performing an admission assessment for a client who has severe chronic kidney disease
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