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Fisiopatologia

5) INSUFFICIENZA RENALE CRONICA

Antonio Nenna

INSUFFICIENZA RENALE CRONICA

L’insufficienza renale cronica (IRC) si instaura con un aumento della creatininemia per oltre tre mesi.

Come per l’IRA, l’aumento deve essere di almeno 0,3 mg/dL rispetto al fisiologico personale o x1,5 rispetto

a un valore precedente.

L’IRA è reversibile (nell’ 80% dei casi), mentre l’IRC è irreversibile e progressiva fino ad arrivare alla sindro- me uremica (ESRD, End Stage Renal Disease), che richiede dialisi o trapianto (o causa morte).

Nell’IRC si ha una fatale progressiva riduzione del GFR. Alcuni nefroni non funzionano, poichè aterosclerotici (impedisce l’autoregolazione della perfusione perchè le arteriole sono indurite). I nefroni funzionanti lavorano anche per quelli non funzionanti, aumentando la loro perfusione (vasodilatazione a monte e vasocostrizione a valle) e aumentando così il loro GFR, tramite l’iperstimolazione del sistema RAA, che aumenta la PAS e causa ipertensione, un fattore aterosclerotico. L’aterosclerosi colpisce i nefroni normali, che si ammalano e progressivamente non funzionano. L’IRC non si può curare definitivamente, ma si può solo rallentare la progressione.

definitivamente, ma si può solo rallentare la progressione. a: terapia precoce b: terapia tardiva c: nessuna

a: terapia precoce b: terapia tardiva c: nessuna terapia

Gestione del rischio di IRC.

- fumo: smettere di fumare

- dieta: ridurre Na + (<2,4 g/die) [sale => acqua => postcarico]

- peso corporeo: BMI < 25 (obesità => ipertensione, diabete, dislipidemia => fattori aterogeni]

- esercizio fisico: 30-60’ di esercizio dinamico moderato

- ipertensione: PA < 130/80 (ACEi, ARB, diuretici, calcio-antagonisti, beta-bloccanti)

- proteinuria: 1 g/kg/die

- diabete mellito: HbA 1C < 7% (glicemia a digiuno: 90-150 mg/dL)

- dislipidemia: LDL < 100 mg/dL

- anemia 1 : EPO per arrivare a Hb: 10-12 g/dL, supplemento di ferro per os

- altro: aspirina 80 mg/die (funzione antiaggregante)

CLASSIFICAZIONE DELL’IRC

 

clearance

stadio

mL/min

categoria

0 > 90

pz a rischio (ipertesi, diabetici,

)

1 > 90

danno renale con GFR normale

2 60 90

lieve riduzione del GFR

3 30 60

moderata riduzione del GFR

4 15 30

grave riduzione del GFR

5 < 15

ESRD

1 per IRC si intende un tempo di tre mesi, mentre il tempo medio di vita di un eritrocita è 120 giorni (quattro mesi), quindi nell’IRC si svilupperà sempre anemia per carenza di EPO

Fisiopatologia

5) INSUFFICIENZA RENALE CRONICA

Antonio Nenna

Patologie dei pazienti a rischio:

- ipertensione arteriosa (130/80)

- diabete mellito (HbA 1C 7%)

- precedente IRA

- danno renale corrente (studio del sedimento urinario: cilindri terrosi in NTA, eosinofiluria in NAI)

- disordine anatomico (reflusso vescico-ureterale)

- storia famigliare di nefropatia

IDENTIFICAZIONE DEL DANNO RENALE:

metodo

raccolta

valori di riferimento

 

urine del mattino

M < 17 D < 25

 

proteinuria

24h

< 30 mg (solo albumina) < 300 mg (tutte le proteine)

La PROTEINURIA può identificare un danno renale o extrarenale, in base alle diverse proteine presenti.

Le proteine glomerulari sono:

-

- β2-microglobulina

-

- enzimi (amilasuria per pancreatite)

- peptidi ormonali (cortisoluria per m. di Cushing)

Le proteine tubulari sono:

-

Tamm-Horsfall

- immunoglobuline

-

urochinasi.

albumina

apoproteine

Proteinuria e disturbi associati.

A U /C U < 300 mg/g, proteinuria < 300 mg => microalbuminuria danno renale iniziale da diabete mellito, ipertensione, malattia glomerulare; idiopatico 2

A U /C U 300-3500 mg/g, proteinuria 300-3500 mg => sedimento urinario patologico (emazie sfaldate, cilindri eritrocitari) aggravamento della microalbuminuria CHF (=> ipoperfusione => azotemia prerenale => NTA => IRC), febbre, sforzo fisico

A U /C U > 3500 mg/g, proteinuria > 3500 mg => sedimento urinario patologico (emazie sfaldate, cilindri eritrocitari) aggravamento della microalbuminuria (diabete scompensato) proteinuria da albuminuria (malattia renale, c’è ipoalbuminemia) => sindrome nefrosica, glomerulone- frite (MCD: malattia a lesioni minime. FSGS: glomerulosclerosi focale segmentaria) proteinuria da Ig (malattia extrarenale) => amiloidosi, mieloma multiplo

ELETTROFORESI DELLE PROTEINE URINARIE

Proteine glomerulari

o

proteinuria selettiva (solo albumina) => glomerulonefrite-MCD

o

proteinuria non selettiva => glomerulonefrite-FSGS

Proteine tubulari => NAI o NTA causate da diabete e ipertensione

Proteine anomale [catene leggere delle Ig (λ, κ) => mieloma multiplo]

2 PROTEINURIA BENIGNA ISOLATA (1-10% della popolazione)

- transitoria idiopatica (atleti, giovani, sindrome da schiena dritta) [colonna vertebrale spinge sui reni]

- ortostatica (adolescenti)

- intermittente (predispone a IRC)

- funzionale (febbre, stress, freddo, apnea del sonno dovuta a obesità)

Fisiopatologia

5) INSUFFICIENZA RENALE CRONICA

Manifestazioni cliniche dell’IRC.

- asintomatica fino allo stadio 2

- stadio 3: faticabilità, astenia, sintomi aspecifici lievi

- stadio 4: anemia, sintomi aspecifici gravi

- stadio 5: sindrome uremica (trapianto dialisi morte)

SINDROME UREMICA

Antonio Nenna

Presentazione clinica.

- alito uremico (puzza di pesce, dovuta alla colina che viene esalata)

- ipertensione arteriosa (dovuta a stimolazione del sistema RAA)

- anemia (dovuta alla diminuita produzione di EPO)

- ipocalcemia (dovuta alla minore produzione di vit. D 3 attiva 3 )

- acidosi metabolica

- coma uremico

- tetania (conseguente a ipocalcemia)

Metaboliti abnormi presenti nel sangue: urea (BUN) (4x), fenoli (10x), indoli (10x), β2-microglobulina (20x), ac. guanidilsuccinico (45x). I fenoli e gli indoli hanno struttura simile ai neurotrasmettitori, sono anioni (modificano l’anion gap) e non vengono filtrati dalla dialisi. Questi metaboliti predispongono a nefrolitiasi.

Fisiopatologia della sindrome uremica.

accumulo di prodotti del catabolismo proteico => acidosi metabolica

alterazione dell’omeostasi elettrolitica

o

espansione del volume extracellulare (trattiene acqua)

o

iponatremia (Na < 135 mmol/L per effetto di diluizione dovuto alla maggiore quantità di acqua)

o

iperkaliemia (ridotta secrezione nel tubulo distale)

deficit di EPO => anemia

deficit di vit. D 3 => ipocalcemia, iperfosfatemia

PARAMETRI NORMALI EGA (EMOGASANALISI)

pH

7,40 ± 0,02

 

pCO 2

40 mmHg

pO 2

100 mmHg

HCO 3 -

24 mmol/L

diminuisce, compenso con iperventilazione e pCO 2 diminuisce

Anion Gap

12 mmol/L

Globalmente, la somma di tutti gli anioni e di tutti i cationi è zero.

Considerando solo quelli facilmente calcolabili, cioè Na + (norm: 140 mM), K + (norm: 4 mM) 4 , Cl - (norm: 104 mM), HCO 3 - (norm: 24 mM).

Si definisce Anion Gap (AG) la differenza tra i cationi e gli anioni misurabili nel sangue.

AG = Na + (Cl - + HCO 3 - ) = 12 mmol/L

Se

AG arriva a 20 mmol/L, ho acidosi, poichè l’aumento di acidi causa una diminuzione della concentrazione

di

bicarbonato (che viene utilizzato per tamponare questi acidi), e ho un parallelo (ma quantitativamente

minore) riassorbimento di cloro.

3 vit. D 3 (colicalciferolo) => nel fegato, 25-OH-D 3 => nel rene, 24-25-OH-D 3 oppure 1-25-OH-D 3 4 il potassio viene generalmente escluso per due motivi: la sua concentrazione è molto bassa e può variare di poco poichè la kaliemia è direttamente connessa con l’eccitabilità cardiaca (con K + = 8 mM ho fibrillazione ventricolare)

Fisiopatologia

5) INSUFFICIENZA RENALE CRONICA

Antonio Nenna

Presentazione clinica della acidosi metabolica da IRC.

- respiro di Kussmaul (tipico della chetoacidosi diabetica, con iperpnea, respiro profondo e rumoroso)

- astenia, confusione, obnubilamento, coma

- vasodilatazione, diminuzione dell’inotropismo cardiaco => insufficienza cardiaca ipotensiva

Tipologie di acidosi metabolica da IRC.

- acidosi metabolica senza anion gap (stadi 2 e 3). Per accumulo di prodotti del catabolismo proteico (ri-

tenzione di acidi) o perdita di HCO 3 - dai tubuli (i metaboliti acidi vengono tamponati dai fosfati, e aumenta il

riassorbimento di cloro che riesce a mantenere costante il gap anionico).

- acidosi metabolica con anion gap (stadi 4 e 5). Per accumulo di anioni (fenoli, indoli,

- acidosi renale tubulare. Normalmente, il tubulo prossimale secerne lo ione HCO 3 - (permettendo il com-

penso dell’alcalosi) mentre il tubulo distale secerne H + (ammoniogenesi). In un tubulo con IRC, aumenta la secrezione di HCO 3 - e diminuisce la secrezione di H + .

)

TIPOLOGIE DI ACIDOSI RENALE TUBULARE (RTA)

1 tubulo distale

pH U < 5,5 con ipoK e , iperCl e , iperK U

2 tubulo prossimale

pH U > 5,5 con iperCl e , glucosuria, fosfaturia (rene di Franconi)

3 ereditaria

osteopetrosi, ritardo mentale

4 nefropatia diabetica e tubulointerstiziale da IRC

tubulo distale insensibile all’aldosterone. iperK e , iperCl e (RTA ipoaldosteronemica iporeninemica)

La carenza di vit. D causa ipocalcemia e iperfosfatemia. L’iperfosfatemia viene interpretata dalle paratiroidi come una carenza di PTH, quindi le paratiroidi sono stimolate per cercare di aumentare la calcemia e stimolare la produzione di vit. D (che è assente e non vie-

ne prodotta per il problema renale) per depositare calcio nella matrice ossea. La continua stimolazione del- la paratiroidi quindi causerà osteoporosi (secondaria al danno renale) e porterà:

- ipertrofia (stimolo totale)

- nodulo (stimolo monoclonale)

- iperparatiroidismo (paratiroidi fuori dai sistemi omeostatici, aumenta moltissimo il PTH => ipercalcemia)

CALCIFILASSI L’IRC aumenta il rischio di calcifilassi, che è un fattore predisponente a necrosi e sepsi. Si formano delle calcificazioni metastatiche extraossee, nei tessuti molli e nei vasi. Il rischio esiste se [Ca ++ ] x [PO 4 -- ] > 90 mg.

Fisiopatologia

5) INSUFFICIENZA RENALE CRONICA

Antonio Nenna

CHRONIC KIDNEY DISEASE 5

Chronic kidney disease (CKD) encompasses a spectrum of different pathophysiologic processes associated with abnormal kidney function, leading to a progressive decline in glomerular filtration rate (GFR). The term chronic kidney failure applies to the process of continuing irreversible reduction in nefron num- ber, and typically corresponds to CKD stages 3-5. CKD stage 5 is called ESRD (End Stage Renal Disease), and represent a stage where the accumulation of toxins, fluid and electrolytes normally excreted by the kidney results in the uremic syndrome. This syndrome leads to death unless toxins are removed by renal replace- ment or dialysis.

PATHOPHYSIOLOGY OF CHRONIC KIDNEY DISEASE Pathophysiology of CKD involves two mechanisms of damage:

1) initiating mechanisms specific to the underlying etiology (e.g. immune complexes in glomerulonephritis, toxin exposure in renal tubules); 2) progressive mechanisms, involving hyperfiltration and hypertrophy of the remaining nephrons, that are a common consequence following long-term reduction of renal mass, irrespective of underlying etiology. Short-term mechanisms of hypertrophy and hyperfiltration become maladaptive as the increased pres- sure and flow predisposes to sclerosis and dropout of the remaining nephrons. Increased activity of RAA axis contributes both to the initial adaptive hyperfiltration and to the subsequent maladaptive hypertro- phy and sclerosis, owing to stimulation of TGF-β. This process explains the progressive decline in GFR.

CKD STAGES AND ETIOLOGY Risk factors include: hypertension, diabetes mellitus, autoimmune disease, older age, African ancestry, fam- ily history, ARF, proteinuria, abnormal urinary sediment, structural abnormality of the urinary tract. Stages 1 and 2 are usually not associated with any symptoms, because the GFR is slightly below normal. Stages 3 and 4 are associated with anemia, fatigability, malnutrition, abnormalities in calcium-D 3 -PTH, ab- normalities in electrolytes-water, abnormalities in acid-base homeostasis. Stages 5 presents toxin accumulation that cause the uremic syndrome. At least 6% of the adult population has CKD in stages 1 or 2; an unknown subset of this group will progress to more advanced stages of CKD. The most frequent cause of CKD is diabetic nephropathy, most often sec- ondary to diabetes mellitus type 2. Hypertensive nephropathy is a common cause of CKD in the elderly. The incredible interindividual variability in the rate of progression to CKD has an important heritable com- ponent, and a number of loci involved have been identified.

PATHOPHYSIOLOGY OF UREMIA Although serum urea and creatinine are used to measure the excretory capacity of the kidneys, accumula- tion of these two molecules do not account for the many symptoms and signs that characterise the uremic syndrome. Hundreds of toxins that accumulate in CKD have been implied in the uremic syndrome. These compounds are between 500 and 1500 Da, and include guanido compounds, urates, hippurates, products of nucleic acid metabolism, polyamines, myoinositol, phenoles, benzoates and indoles. 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 undertaken by the kidneys are also impaired, and this results in anemia, malnutrition, abnormal metabolism of carbohydrates, fats and

proteins. Plasma levels of many hormones (PTH, insulin, glucagon, sex hormones, prolactin) change with renal failure as a result of urinary retention, decreased degradation or abnormal regulation. Elevated level of C-reactive-protein (CRP) are detected along with other acute-phase-proteins, while levels of negative- acute-phase-protein (albumin) decline with progressive renal impairment. The pathophysiology of the uremic syndrome involves three spheres of dysfunctions:

- accumulation of toxins normally undergoing renal excretion (products of protein catabolism)

- loss of other renal function (fluid and electrolyte homeostasis and hormone regulation)

- progressive systemic inflammation, and its vascular consequences

5 Chronic kidney disease, Harrison, cap. 274

Fisiopatologia

5) INSUFFICIENZA RENALE CRONICA

Antonio Nenna

CLINICAL AND LABORATORY MANIFESTATIONS OF CKD AND UREMIA Uremia leads to disturbances in the function of every organ. Chronic dyalisis can reduce the incidence and severity of many disturbances, but is not completely effective (phenoles).

fluid and electrolytes

volume expansion, hyponatremia, hyperkalemia, hyperphosphatemia

endocrine-metabolic

secondary hyperparathyroidism, vit.D deficiency, hyperuricemia, hypertriglyce- ridemia, impaired growth and fertility, β2-microglobulin associated amyloidosis

neuromuscolar

fatigue, sleep disorders, lethargy, peripheral neuropathy, restless legs syn- drome, cramps, coma

cardio-pulmonary arterial hypertension, congestive heart failure, pulmonary edema, pericarditis, dilated cardiomyopathy, uremic lung, atherosclerosis, arrhythmias, vascular calcification

dermatologic

pallor, pruritus, ecchymoses

gastrointestinal

anorexia, nausea, vomiting, peptic ulcer

hematologic

anemia, lymphocytopenia, leukopenia, thrombocytopenia

SODIUM AND WATER HOMEOSTASIS. The total body content of sodium and water is modestly increased. This is due to the impairment of glomerulotubular balance between dietary intake and urinary excretion, leading to sodium retention and extracellular fluid volume (ECFV) expansion. This expansion contributes to hypertension (poorly responsive to therapy), which itself can accelerate the nephron injury. As long as wa- ter intake does not exceed the capacity for water clearance, the ECFV expansion will be isotonic and the pa- tient will have a normal plasma sodium concentration and effective osmolarity. Hyponatremia happens when water retention function is excessive. This can cause acute pulmonary edema. The combination of loop diuretics with metolazone (inhibitor of the sodium-chloride cotransporter of the distal convolute tu- bule) can help effect renal salt excretion. When an extrarenal cause for fluid loss (gastrointestinal loss) is present, these patients may be prone to ECFV depletion because of the inability of the failing kidney to reclaim filtered sodium adequately. Depletion of ECFV, due to GI losses or excessive diuretics, can compromise kidney function on a pre-renal basis, leading to acute-on-chronic kidney failure (ARF on CKD).

POTASSIUM HOMEOSTASIS. The decline in GFR is not necessarily accompained by a parallel decline in uri- nary potassium excretion, which is predominantly mediated by aldosterone-dependent secretory events. Hyperkalemia may be precipitated by: increased potassium intake, protein catabolism, hemolysis, hemorr- hage, metabolic acidosis. Medications can inhibit potassium entry into cells (ACEi, ARB, spironolactone and other potassium-sparing diuretics). Hypokalemia is not common in CKD and usually reflects reduced potassium dietary intake, especially in as- sociation with diuretics or GI losses. Hypokalemia can also occurr as a result of renal potassium wasting in association with other solute transport abnormalities (Franconi’s syndrome, renal tubular acidosis, tubu- lointerstitial disease).

METABOLIC ACIDOSIS. Metabolic acidosis is a common disturbance in CKD. 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. Hyperkalemia and hyperchloremic metabolic acidosis (type 4 renal tubular acidosis, known as hyporeni- nemic hypoaldosteronism) is often seen in patients with diabetic nephropathy; this is a non-AG acidosis. Treatment of hyperkalemia may increase renal ammonia production, and improve renal generation of bi- carbonate, improving the metabolic acidosis. With worsening renal function, only 30-40 mmol of acids are excreted daily, and the anions of organic acids lead to an AG acidosis. Thus, the non-anion gap metabolic acidosis that can be seen in the early stages of CKD may be complicated by the addition of a anion-gap metabolic acidosis as CKD progresses. This acidosis can be corrected with oral sodium bicarbonate supplementation.

Fisiopatologia

5) INSUFFICIENZA RENALE CRONICA

Antonio Nenna

BONE MANIFESTATIONS. Disorders of bone can be classified into:

- diseases associated with high bone turnover with increased PTH (osteitis fibrosa cystica)

- diseases associated with low bone turnover with decreased PTH (osteomalacia)

HIGH TURNOVER BONE DISEASE. The pathophysiology of secondary hyperparathyroidism is related to ab- normal mineral metabolism because the declining GFR leads to reduced excretion of phosphate, and thus phosphate retention, which stimulates synthesis of PTH and growth of parathyroid gland mass; PTH causes decreased levels of calcium, resulting from diminished calcitriol production by the failing kidney as well as phosphate retention. This leads to hypocalcemia. In addition to increased production of PTH from the parathyroid cells, the mass of the parathyroid glands increases progressively with CKD, causing diffuse hyperplasia (polyclonal), nodular growth (monoclonal) or adenoma (diffuse monoclonal hyperplasia, or tertiary autonomous hyperparathyroidism). These condition may require surgical parathyroidectomy. Bone histology shows abnormal osteoid, bone fibrosis, formation of bone cysts with hemorrhagic elements (so that they appear brown in color, hence the term brown tumor). Clinical manifestation of hyperparathy- roidism inclide bone pain and fragility. LOW TURNOVER BONE DISEASE. Low turnover bone diseases can be grouped into adynamic bone disease

or osteomalacia. Osteomalacia is an accumulation of unmineralized bone matrix that may be caused by vit.

D deficiency. Adynamic bone disease is characterised by reduced bone volume and mineralization and may

result from suppression of PTH prodution, and increases the incidence of fracture. Calciphylaxis is a devasting condition associated with advanced CKD. Ingested calcium intake cannot be de- posited in bones because of the low turnover, and therefore is deposited at extraosseous sites, such as the vascular bed and soft tissues. This induces the formation of patches of ischemic necrosis, especially on the

legs. There is evidence of vascular occlusion due to extensive vascular calcification. Patients often succumbs to systemic complications of the necrotic process. Warfarin is used in hemodialysis, and one of the effects

of the warfarin is to decrease the vit.K-dependent regeneration of matrix GLA protein, which is important in

preventing vascular calcification. Thus, warfarin treatment is a risk factor for calciphylaxis.

ISCHEMIC VASCULAR DISEASE. The presence of CKD is a major risk factor for ischemic cardiovascular dis- ease, including occlusive coronary, cerebrovascular and peripheral disease. Traditional risk factor include hypertension, hypervolemia, dyslipidemia, sympathetic overactivity and hyperhomocysteinemia. The CKD- related risk factors comprise anemia, hyperphosphatemia, hyperparathyroidism, sleep apnea and genera- lised inflammation (accelerates vascular occlusive disease).

HEART FAILURE. Abnormal cardiac function secondary to myocardial ischemia, LV hypertrophy and cardi- omyopathy, in combination with the salt and water retention that can be seen with CKD, ofter result in HF or pulmonary edema. A form of “low-pressure” pulmonary edema can occurr in advanced CKD, manifesting as shortness of breath and a bat-wing distribution of alveolar edema fluid on the chest x-ray. This process is associated with normal pulmonary capillary wedge pressure (< 18 mmHg) and is due to the increased per- meability of alveolar capillary membranes as a manifestation of the uremic state.

HYPERTENSION. Hypertension is one of the most common complications of CKD, and induces the LV hypertrophy and a more rapid loss of renal function. LV hypertrophy and dilated cardiomyopathy are risk factors for cardiovascular mortality in patients with CKD. In addition, anemia and an arterovenous fistula for hemodialysis can generate a high cardiac output state and consequent heart failure.

PERICARDIAL DISEASE. Pericardial pain with respiratory accentuation, accompained by a friction rub, is di- agnostic of uremic pericarditis. ECG shows PR-interval depression and ST-segment elevation. Pericarditis is observed in advanced uremia.

HEMOSTASIS. Patients with CKD have a prolonged bleeding time, decreased activity of platelet factor III, abnormal platelet aggregation and impaired prothrombin consumption. Clinical manifestations are tenden- cy to bleeding, menorrhagia and spontaneous GI bleeding. They also have easier thromboembolism.

Fisiopatologia

5) INSUFFICIENZA RENALE CRONICA

Antonio Nenna

ANEMIA. Normocytic, normochromic anemia is observed at stage 4 of CKD. The primary cause is insuffi-

cient production of EPO by the diseased kidney. The anemia causes a decreased tissue oxygen delivery, which results in increased cardiac output, ventricular dilatation and ventricular hypertrophy. Clinical ma- nifestation include angina, heart failure, decreased mental acuity. Causes of anemia in CKD:

- relative deficiency of EPO

- diminished red blood cell survival

- bleeding diathesis

- iron deficiency

- hyperparathyroidism (=> bone narrow fibrosis)

- chronic inflammation

- B9 or B12 deficiency

- hemoglobinopathy

- HIV-associated disease

NEUROMUSCOLAR ABNORMALITIES. Retained nitrogenous metabolites (PTH) contribute to neuromusco- lare abnormalities, such as irritability, hiccups, cramps, fasciculations, twitching of muscles, myoclonus, sei- zure and coma. Peripheral neuropathy becomes clinically evident in stage 4. Sensory nerves are involved more than motor, lower extremities more than upper, and distal parts more than proximal. The “restless leg syndrome” is characterised by ill-defined sensations of discomfort in the legs and feet, re- lieved by frequent leg movement. If dialysis is not instituted after onset of sensory abnormalities, motor in- volvement follows, including muscle weakness.

GASTROINTESTINAL ABNORMALITIES. Uremic fetor, a urine-like odor of the breath, derives from the breakdown of urea to ammonia in saliva and is often associated with a metallic taste (dysgeusia). Gastritis, peptic disease and ulceration at any level of GI tract occur in uremic patients and can lead to abdominal pain, nausea, vomiting and GI bleeding. Protein-energy malnutrition, a consequence of low protein and energy intake, is common in advanced CKD.

ENDOCRINE ABNORMALITIES. Glucose metabolism is impaired in CKD, but fasting glucose is usually nor- mal. Because the kidney contribute to insulin removal from the circulation, plasma levels of insulin are ele- vated in uremic patients; insulin therapy may need progressive reduction in dose as renal function worsens.

DERMATOLOGIC ABNORMALITIES. Anemic patient may be pale, and those with defective hemostasis may show multiple ecchymoses. Pruritis is quite common. In advanced CKD, patient may become hyperpig- mented due to deposition of pigmented metabolites called generally urochromes. A skin condition called nephrogenic fibrosing dermopathy causes progressive subcutaneous induration, more on arms and legs.

EVALUATION AND MANAGEMENT OF PATIENTS WITH CKD Particular aspects of the history that need focusing include hypertension, diabetes mellitus and pregnancy loss. There should be found evidences of diabetic retinopathy, which is associated with nephropathy. The most important diagnostic step is distinguish ARF from CKD. It is useful to measure and plot the rate of decline in GFR, because any acceleration in the decline mean ARF-on-CKD, so it is possible to recover the loss attributed to ARF.