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Desribe the pathogenesis of high concentration of urea and creatinine on ARF (mechanism

of urea excretion)

Serum Creatinine
Creatinine merupakan produk hasil metabolisme creatinine diotot skeletal, yang normalnya
dieksresikan oleh ginjal.
Setiap harinya jumlah produksi creatinine konstan (0,8-1,2 mg / dL pada orang dewasa; 0,4-
0,8 mg / dL pada anak-anak) dan akan berubah sampai kira-kira 50% dari fungsi ginjal telah
hilang, jadi kadar serumnya merefleksikan secara langsung fungsi ginjal.
Tidak seperti kebanyakan produk ekskretoris lain, tingkat serum kreatinin umumnya tidak
dipengaruhi oleh asupan makanan atau status hidrasi.
Endogenous Creatinine Clearance
kreatinin difiltrasi melalui glomerulus (meskipun sejumlah kecil mungkin disekresikan),
clearance ginjal terhadap kreatin pada dasarnya sama dengan laju filtrasi glomerulus.
Penentuan cratinine clearance membutuhkan koleksi selama 24 jam untuk spesimen urine
dan serum. Clearence ini dinyatakan dalam mililiter per menit, dengan nilai normal 90-110
mL / menit namun karena massa otot berbeda antara individu, standardisasi lanjut dilakukan
dan nilai clearence 70-140 mL / menit dianggap normal.

Blood Urea Nitrogen


Urea merupakan metabolite primer dari katabolisme protein dan dan di eksresikan oleh
ginjal.
Urea difiltrasi oleh glomerlus sehingga Blood urea nitrogen (BUN) berkaitan dengan GFR.
kadar BUN akan meningkat ketika GRFnya menurun. Nilai normal untuk BUN pada adult
adalah 10-20 mg/dl
Setelah difiltrasi urea akan direabsorbsi tubular, reabsorpsi bergantung pada kecepatan
aliran urin ditubulus. Pada aliran yang cepat maka reabsorpsinya akn berkurang.
Kira-kira 50% urea akan dieksresikan lewat urin dan 50%nya lagi akan di recycled di ginjal.
Recycling urea dari tubulus ke collecting duct berkontribusi terhadap gradien osmotic di
dalam medulla dan ini dibutuhkan untuk menkonsentrasikan atau mendilusikan urine.
Karena urea merupakan produk akhir dari metabolisme protein, seseorang dengan protein
deprivation kurang bisa mengkonsentrasikan urinnya.
Tidak seperti kreatinin, BUN dipengaruhi oleh intake protein, status hidrasi, dan pendarahan
di saluran pencernaan. Peningkatan BUN yang signifikan terjadi ketika kehilangan 2/3
fungsi ginjal jadi peningkatan BUN kurang spesifik untuk renal insufficiency dibandingkan
serum kreatinin. Tapi rasio BUNcreatinine (BUNCr) dapat dijadikan informasi yang spesifik
untuk diagnostik. Normalnya adalah 10:1 ;
o pada pasien dehidrasi dan orang dengan obstruksi saluran kemih bilateral atau
ekstravasasi urin, rasionya bisa mencapai 20:1 sampai 40:1
o pasien dengan insufficiency hati dan pasien yang mengalami overhidrasi kadar BUN
dan rasio BUN-Cr nya rendah.
o Pada pasien dengan insufficiency renal , akan terjadi peningkatan BUN yg ekstrim.
Case !!
Azotemia (from azo, meaning nitrogen, and -emia) merupakan keadaan ketika terjadi
peningkatan BUN dan kreatinin, dan berkaitan dengan penurunan GFR. Azotemia terjadi karena
gangguan pada ginjal baik akut maupun kronik, tapi dapat juga terjadi karena gangguan pada
ekstrarenal.
Prerenal azotemia paling sering terjadi pada AKI, ditandai dengan peningkatan serum creatinine
dan BUN karena tidak memadainya aliran darah di ginjal dan intraglomerular hydrostatic
pressure untuk mensupport filtrasi glomerular. Hal ini dapat terjadi karena hipotensi atau
kehilangan cairan yg banyak karena berbagai sebab, penurunan volume intravaskular karena shock,
CHF atau sirosis hati

Postrenal azotemia terjadi ketika aliran urin terobtruksi dibagian distal dari ginjal. Menghilangkan
obstruksi akan diikuti dengan koreksi azotemianya.

Ketika azotemianya menunjukkan berbagai tanda dan gejala, yang disebabkan penumpukkan
nitrogenous waste products , hal itu disebut sebagai uremia. Uremia merupakan hallmark dari AKI.
Uremia dapat terjadi karena gagalnya fungsi eksretory ginjal, gangguan metabolisme dan endokrin
yang mengakibatkan kerusakan ginjal. Pasien-pasien uremic biasanya memiliki manifestasi sekunder
yang meliputi gastrointestinal system (e.g., uremic gastroenteritis), peripheral nerves (e.g.,
peripheral neuropathy), and heart (e.g., uremic fibrinous pericarditis).

Pathophysiology and Biochemistry of Uremia


Although serum urea and creatinine concentrations are used to measure the excretory capacity of the
kidneys, accumulation of these two molecules themselves do not account for the many symptoms and
signs that characterize the uremic syndrome in advanced renal failure.
Hundreds of toxins that accumulate in renal failure have been implicated in the uremic syndrome.
These include water-soluble, hydrophobic, protein-bound, charged, and uncharged compounds.
Additional categories of nitrogenous excretory products include guanidino compounds, urates and
hippurates, products of nucleic acid metabolism, polyamines, myoinositol, phenols, benzoates, and
indoles. Compounds with a molecular mass between 500 and 1500 Da, the so-called middle
molecules, are also retained and contribute to morbidity and mortality. It is thus evident that the serum
concentrations of urea and creatinine should be viewed as being readily measured, but incomplete,
surrogate markers for these compounds, and monitoring the levels of urea and creatinine in the patient
with impaired kidney function represents a vast oversimplification of the uremic state.
The uremic syndrome and the disease state associated with advanced renal impairment involve more
than renal excretory failure. A host of metabolic and endocrine functions normally performed by the
kidneys is also impaired or suppressed, and this results in anemia, malnutrition, and abnormal
metabolism of carbohydrates, fats, and proteins. Furthermore, plasma levels of many hormones,
including PTH, FGF-23, insulin, glucagon, steroid hormones including vitamin D and sex
hormones, and prolactin, change with renal failure as a result of urinary retention, decreased
degradation, or abnormal regulation. Finally, progressive renal impairment is associated with
worsening systemic inflammation.
Elevated levels of C-reactive protein are detected along with other acute-phase reactants, while levels
of so-called negative acute-phase reactants, such as albumin and fetuin, decline with progressive renal
impairment, even in nonproteinuric kidney disease. Thus, the inflammation associated with renal
impairment is important in the malnutrition-inflammation-atherosclerosis/ calcification syndrome,
which contributes in turn to the acceleration of vascular disease and comorbidity rate
associated with advanced kidney disease.
In summary, the pathophysiology of the uremic syndrome can be divided into manifestations in three
spheres of dysfunction: (1) those consequent to the accumulation of toxins that normally undergo
renal excretion, including products of protein metabolism; (2) those consequent to the loss of other
renal functions, such as fluid and electrolyte homeostasis and hormone regulation; and (3) progressive
systemic inflammation and its vascular and nutritional consequences.

Uremia leads to disturbances in the function of virtually every organ system. Chronic dialysis can
reduce the incidence and severity of many of these disturbances, so that the overt and florid
manifestations of uremia have largely disappeared in the modern health setting. However, as indicated
in Table 11-4, even optimal dialysis therapy is not completely effective as renal replacement therapy,
because some disturbances resulting from impaired renal function fail to respond to dialysis.
Smith and Tanagho's General Urology, Eighteenth Edition

Robbins & Cotran Pathologic Basis of Disease 9E

Pathophsysiology ,The Biologic Basis for Disease in Adults and Children, Seventh Edition

Harrison's Nephrology and Acid-Base Disorders, 2nd Edition

Plasma Creatinine Concentration


A long-term decline in GFR over weeks or months is reflected in the plasma creatinine (PCR)
concentration (normal value = 0.7 to 1.2 mg/dl). The PCR concentration has a stable value when the
GFR is stable because creatinine has a constant rate of production as a product of muscle metabolism.
The amount filtered is approximately equal to the amount excreted. When the GFR declines, the PCR
increases proportionately. Thus the GFR and PCR are inversely related. If the GFR were to decrease by
50%, the filtration and excretion of creatinine would be reduced by 50% and creatinine would
accumulate in plasma to twice the normal value. Therefore, elevated PCR values represent decreasing
GFR. In the new steady-state, however, the total amount of creatinine excreted in the urine would
remain the same because of the proportionate decrease in GFR and increase in PCR.
The application of this principle is simple and useful for monitoring progressive changes in renal
function. The test is most valuable for monitoring the progress of chronic rather
than acute renal disease because it takes 7 to 10 days for the plasma creatinine level to stabilize when
GFR declines. Serial measures can be obtained over a long time and plotted as a curve of glomerular
function. Normal PCR value decreases with advanced age, since older adults experience a decrease in
lean muscle mass. The PCR value becomes elevated during trauma or breakdown of muscle tissue. In
such instances the value is then
not useful for estimating GFR.

Uric acid is primarily a product of biosynthesis of endogenous purines and is secondarily affected by
consumption of purines in the diet. Persons who excrete excessive uric acid in the urine, such as those
with gouty arthritis, are at particular risk for uric acid stones. A consistently acidic urine greatly
increases this risk. Cystine and xanthine are amino acids that precipitate more readily in acidic urine.
Cystinuria and xanthinuria are genetic disorders of amino acid metabolism, and their excess in urine
can cause cystinuric, or xanthine, stone formation in the presence of a low urine pH of 5.5 or less.

Uremia is a syndrome of renal failure and includes elevated blood urea and creatinine levels
accompanied by fatigue, anorexia, nausea, vomiting, pruritus, and neurologic changes. Uremia
represents numerous consequences related to renal failure, including retention of toxic wastes,
deficiency states, electrolyte disorders, and immune activation promoting a proinflammatory state.
Azotemia is characterized by increased serum urea levels and frequently increased creatinine levels as
well. Renal insufficiency or renal
failure causes azotemia. Both azotemia and uremia indicate an accumulation of nitrogenous waste
products in the blood, a common characteristic that explains the overlap in definitions of terms.

The ratios of the BUN to plasma creatinine concentration and fractional excretion of sodium (the ratio
of filtered sodium to excreted sodium) are helpful diagnostic indicators because the tests reflect renal
tubular reabsorption ability. In prerenal AKI, tubular function is maintained and salt, water, and urea
are reabsorbed. With ATN, reabsorption and urinary concentration abilities are compromised. Other
causes of renal failure
also may exhibit similar clinical findings. Cystatin C, a serum protein constantly produced by nucleated
cells, is freely filtered by the glomerulus, and its concentration can serve as a measure of GFR and may
be useful for detecting early changes in glomerular
filtration rate.146 Serial measurements of plasma creatinine
concentration provide an index of renal function during

Fluid, Electrolyte, and Acid-Base


Disorders
Sodium and water homeostasis
In most patients with stable CKD, the total-body content
of sodium and water is modestly increased, although
this may not be apparent on clinical examination. Normal
renal function guarantees that the tubular reabsorption
of filtered sodium and water is adjusted so that
urinary excretion matches intake. Many forms of renal
disease (e.g., glomerulonephritis) disrupt this glomerulotubular
balance such that dietary intake of sodium
exceeds its urinary excretion, leading to sodium retention
and attendant extracellular fluid volume (ECFV)
expansion. This expansion may contribute to hypertension,
which itself can accelerate the nephron injury.