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Chronic Kidney Disease

Chronic Kidney DiseaseRafael Joseph C. Villarica

Chronic Kidney Diseaseabnormal kidney function progressive decline in glomerular filtration rate

Chronic kidney disease (CKD) encompasses a spectrum of different pathophysiologic processes associated with abnormal kidney function and a progressive decline in glomerular filtration rate (GFR).


Classification of CKDStageGFR, mL/min per 1.73 m20>901>/=90260-89330-59415-29517mg of albumin per gram of creatinineFemales - >25mg of albumin per gram of creatinine

Measurement of albuminuria is also helpful for monitoring nephron injury and the response to therapy in many forms of CKD, especially chronic glomerular diseases. While an accurate 24-h urine collection is the criterion standard for measurement of albuminuria, the measurement of protein-to-creatinine ratio in a spot first-morning urine sample is often more practical to obtain and correlates well, but not perfectly, with 24-h urine collections. Persistence in the urine of >17 mg of albumin per gram of creatinine in adult males and 25 mg albumin per gram of creatinine in adult females usually signifies chronic renal damage. 9

Stages 1 and 2Not associated with any symptoms due to a decrease in GFR

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. 10

Stages 3 and 4Complications become more prominentAnemia easy fatigabilityDecreasing appetiteAbnormalities in calcium, phosphorous and mineral regulating hormonesAbnormalities in Na, K, water and acid-base homeostasis

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)2D3 (calcitriol), parathyroid hormone (PTH), and fibroblast growth factor 23 (FGF-23); and abnormalities in sodium, potassium, water, and acid-base homeostasis. Many patients, especially the elderly, will have eGFR values compatible with stage 2 or 3 CKD. However, the majority of these patients will show no further deterioration of renal function. 11

Stage 5Uremic syndromeRenal replacement therapy is needed

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. As noted, this state will culminate in death unless renal replacement therapy (dialysis or transplantation) is instituted.12

(I) denotes an abnormality that usually improves with an optimal program of dialysis and related therapy(P) denotes an abnormality that tends to persist or even progress, despite an optimal program(D) denotes an abnormality that develops only after initiation of dialysis therapy.


Leading Categories of Etiologies of CKDDiabetic glomerular diseaseGlomerulonephritisHypertensive nephropathyPrimary glomerulopathy with hypertensionVascular and ischemic renal diseaseAutosomal dominant polycystic kidney diseaseOther cystic and tubulointerstitial nephropathy


Sodium and Water HomeostasisTotal-body content of sodium and water is modestly increasedDietary intake of sodium > urinary excretionSodium retention and attendant ECFV expansion

This expansion may contribute to hypertension, which itself can accelerate the nephron injury. Thiazide diuretics plus loop diuretics.

Thiazide inhibits Na reabsorption in the distal renal tubules resulting in increased excretion of Na and water, also K and H ionsLoop diuretics inhibits reabsorption of Na and CL ions at the proximal and distal renal tubules and loop of Henle by interfering with chloride-binding cotransport system, causes increases in water, calcium, magnesium, Na and Cl.15

Potassium HomeostasisHyperkalemiaIncreased dietary potassium intakeProtein catabolismHemolysisHemorrhageTransfusion of stored red blood cellsMetabolic acidosisACE, ARBS and spironolactone

In CKD, the decline in GFR is not necessarily accompanied by a parallel decline in urinary potassium excretion, which is predominantly mediated by aldosterone-dependent secretory events in distal nephron segments. Another defense against potassium retention in these patients is augmented potassium excretion in the GI tract.Hyperkalemia may be precipitated in certain settings. These include increased dietary potassium intake, protein catabolism, hemolysis, hemorrhage, transfusion of stored red blood cells, and metabolic acidosis. In addition, a host of medications can inhibit renal potassium excretion. The most important medications in this respect include the angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), and spironolactone and other potassium-sparing diuretics such as amiloride, eplerenone, and triamterene.Certain causes of CKD can be associated with earlier and more severe disruption of potassium-secretory mechanisms in the distal nephron, out of proportion to the decline in GFR. These include conditions associated with hyporeninemic hypoaldosteronism, such as diabetes, and renal diseases that preferentially affect the distal nephron, such as obstructive uropathy and sickle cell nephropathy.16

Metabolic AcidosisLess ammonia is producedLess protons is excreted

The majority of patients can still acidify the urine, but they produce less ammonia and, therefore, cannot excrete the normal quantity of protons in combination with this urinary buffer. Hyperkalemia, if present, further depresses ammonia production. The combination of hyperkalemia and hyperchloremic metabolic acidosis is often present, even at earlier stages of CKD (stages 13), in patients with diabetic nephropathy or in those with predominant tubulointerstitial disease or obstructive uropathy; this is a non-anion-gap metabolic acidosis. Treatment of hyperkalemia may increase renal ammonia production, improve renal generation of bicarbonate, and improve the metabolic acidosis.

With worsening renal function, the total urinary net daily acid excretion is usually limited to 3040 mmol, and the anions of retained organic acids can then lead to an anion-gap metabolic acidosis. Thus, the non-anion-gap metabolic acidosis that can be seen in earlier stages of CKD may be complicated by the addition of an anion-gap metabolic acidosis as CKD progresses. In most patients, the metabolic acidosis is mild; the pH is rarely 1 g per 24 h, blood pressure should be reduced to 125/75, if achievable without prohibitive adverse effects. Salt restriction should be the first line of therapy. When volume management alone is not sufficient, the choice of antihypertensive agent is similar to that in the general population. The ACE inhibitors and ARBs slow the rate of decline of kidney function, but occasionally can precipitate an episode of acute kidney injury, especially when used in patients with ischemic renovascular disease. The use of ACE inhibitors and ARBs may also be complicated by the development of hyperkalemia. Often the concomitant use of a kaliuretic diuretic, such as metolazone, can improve potassium excretion in addition to improving blood pressure control. 24

Treatment: Cardiovascular AbnormalitiesManagement of Cardiovascular DiseaseLifestyle changeStatins

Lifestyle changes, including regular exercise, should be advocated but are not often implemented. Hyperlipidemia in patients with CKD should be managed according to national guidelines. If dietary measures are not sufficient, preferred lipid-lowering medications, such as statins, should be used. Again, the use of these agents has not been of proven benefit for patients with advanced CKD.25


A normocytic, normochromic anemia is observed as early as stage 3 CKD and is almost universal by stage 4. The primary cause in patients with CKD is insufficient production of erythropoietin (EPO) by the diseased kidneys. Additional factors include iron deficiency, acute and chronic inflammation with impaired iron utilization ("anemia of chronic disease"), severe hyperparathyroidism with consequent bone marrow fibrosis, and shortened red cell survival in the uremic environment. In addition, comorbid conditions such as hemoglobinopathy can worsen the anemia.

Clinical manifestations include fatigue and diminished exercise tolerance, angina, heart failure, decreased cognition and mental acuity, and impaired host defense against infection. In addition, anemia may play a role in growth retardation in children with CKD. 26

Treatment: AnemiaRecombinant human EPO Modified EPO productsBlood transfusionIron supplementation

Current practice is to target a hemoglobin concentration of 100115 g/L.27

Abnormal HemostasisProlonged bleeding timeDecreased activity of platelet factor IIIAbnormal platelet aggregation and adhesivenessImpaired prothrombin consumption

Clinical manifestations include an increased tendency to bleeding and bruising, prolonged bleeding from surgical incisions, menorrhagia, and spontaneous GI bleeding. Interestingly, CKD patients also have a greater susceptibility to thromboembolism, especially if they have renal disease that includes nephrotic-range proteinuria. The latter condition results in hypoalbuminemia and renal loss of anticoagulant factors, which can lead to a thrombophilic state.


Treatment: Abnormal HemostasisDesmopressinCryoprecipitateBlood transfusionEPO therapy

Abnormal bleeding time and coagulopathy in patients with renal failure may be reversed temporarily with desmopressin (DDAVP), cryoprecipitate, IV conjugated estrogens, blood transfusions, and EPO therapy. Optimal dialysis will usually correct a prolonged bleeding time.Desmopressin synthetic analogue of vasopressin with prompt onset and longer, more specific antidiuretic action, increases water permeability in renal tubular cells, which in turn decreases urine volume and increases urine osmolality. Also produces dose-related increase in Von Willebrand factor VIII and t-PA levels, shortens aPTT and BT29

Neuromuscular AbnormalitiesCentral nervous system (CNS), peripheral, and autonomic neuropathyAbnormalities in muscle structure and function Early manifestations Memory and concentrationSleep disturbanceLate manifestationsNeuromuscular irritabilityAdvancedAsterixisMyoclonus, seizuresComa

Retained nitrogenous metabolites and middle molecules, including PTH, contribute to the pathophysiology of neuromuscular abnormalities. Subtle clinical manifestations of uremic neuromuscular disease usually become evident at stage 3 CKD. Early manifestations of CNS complications include mild disturbances in memory and concentration and sleep disturbance. Neuromuscular irritability, including hiccups, cramps, and fasciculations or twitching of muscles, becomes evident at later stages. In advanced untreated kidney failure, asterixis, myoclonus, seizures, and coma can be seen.


Gastrointestinal and Nutritional AbnormalitiesUremic fetorDysguesaGastritis, PUD and mucosal ulcerationsConstipationAnorexia, nausea, vomiting

Uremic fetor, a urine-like odor on the breath, derives from the breakdown of urea to ammonia in saliva and is often associated with an unpleasant metallic taste (dysgeusia). Gastritis, peptic disease, and mucosal ulcerations at any level of the GI tract occur in uremic patients and can lead to abdominal pain, nausea, vomiting, and GI bleeding. These patients are also prone to constipation, which can be worsened by the administration of calcium and iron supplements. The retention of uremic toxins also leads to anorexia, nausea, and vomiting.31

Endocrine-Metabolic DisturbancesGlucose metabolism is impairedPlasma levels of insulin are slightly to moderately elevatedMenstrual abdnormalitiesSpontaneous abortion

Glucose metabolism is impaired in CKD, as evidenced by a slowing of the rate at which blood glucose levels decline after a glucose load. Because the kidney contributes to insulin removal from the circulation, plasma levels of insulin are slightly to moderately elevated in most uremic patients, both in the fasting and postprandial states. Because of this diminished renal degradation of insulin, patients on insulin therapy may need progressive reduction in dose as their renal function worsens. Many hypoglycemic agents require dose reduction in renal failure, and some, such as metformin, are contraindicated when the GFR is less than half of normal.32

Dermatologic AbnormalitiesPruritusPigmentationNephrogenic fibrosing dermopathy

Pruritus is quite common and one of the most vexing manifestations of the uremic state. In advanced CKD, even on dialysis, patients may become more pigmented, and this is felt to reflect the deposition of retained pigmented metabolites, or urochromes.

A skin condition unique to CKD patients called nephrogenic fibrosing dermopathy consists of progressive subcutaneous induration, especially on the arms and legs. The condition is similar to scleromyxedema and is seen in patients with CKD who have been exposed to the magnetic resonance contrast agent gadolinium. 33

Laboratory InvestigationCBCUrinalysisSerum albumin levelsLipid profile

Complete blood count (CBC)Basic metabolic panelUrinalysis (Patients with a P/C ratio above 200 mg/mg should undergo a full diagnostic evaluation.A value of greater than 300-350 mg/mg is within the nephrotic range.)Serum albumin levels: Patients may have hypoalbuminemia due to urinary protein loss or malnutritionLipid profile: Patients with CKD have an increased risk of cardiovascular disease


Evidence of Renal-Bone Disease Serum phosphate25-hydroxyvitamin DAlkaline phosphataseIntact PTH levels

Evidence of renal bone disease can be derived from the following tests:Serum phosphate25-hydroxyvitamin DAlkaline phosphataseIntact parathyroid hormone (PTH) levels


OthersSerum and urine protein electrophoresisANA, anti DS DNAComplement levelsC-ANCA, P-ANCAAnti-GBMHepatitis B and CHIVVDRL

Serum and urine protein electrophoresis: Screen for multiple myelomaAntinuclear antibodies (ANA), double-stranded DNA antibody levels: Screen for SLESerum complement levels: Results may be depressed with some glomerulonephritidesCytoplasmic and perinuclear pattern antineutrophil cytoplasmic antibody (C-ANCA and P-ANCA) levels: Positive findings are helpful in the diagnosis of Wegener granulomatosis and polyarteritis nodosa; P-ANCA is also helpful in the diagnosis of microscopic polyangiitisAntiglomerular basement membrane (anti-GBM) antibodies: Presence is highly suggestive of underlying Goodpasture syndromeHepatitis B and C, human immunodeficiency virus (HIV), Venereal Disease Research Laboratory (VDRL) serology: Conditions associated with some glomerulonephritides


ImagingRenal ultrasonographyRetrograde pyelographyCT scanMRIRenal radionuclide scanning


Renal ultrasonography: Useful to screen for hydronephrosis, which may not be observed in early obstruction, or for involvement of the retroperitoneum with fibrosis, tumor, or diffuse adenopathy; small, echogenic kidneys are observed in advanced renal failureRetrograde pyelography: Useful in cases with high suspicion for obstruction despite negative renal ultrasonograms, as well as for diagnosing renal stonesComputed tomography (CT) scanning: Useful to better define renal masses and cysts usually noted on ultrasonograms; also the most sensitive test for identifying renal stonesMagnetic resonance imaging (MRI): Useful in patients who require a CT scan but who cannot receive intravenous contrast; reliable in the diagnosis of renal vein thrombosisRenal radionuclide scanning: Useful to screen for renal artery stenosis when performed with captopril administration; also quantitates the renal contribution to the GFRBiopsies are also indicated to guide management in already-diagnosed conditions, such as lupus, in which the prognosis is highly dependent on the degree of kidney involvement. 37