NEPHROTIC SYNDROME IN ADULTS

Dr. Sachin Verma MD, FICM, FCCS, ICFC

Fellowship in Intensive Care Medicine

Infection Control Fellows Course

Consultant Internal Medicine and Critical Care

Web:- http://www.medicinedoctorinchandigarh.com

Mob:- +91-7508677495

References :1. Harrison’s Principle of Medicine, 16th edn.2. Oxford Textbook of Nephrology, 3rd edn.3. The Kidney, 17th edn.

NEPHROTIC SYNDROME

Definition : N.S. is a clinical complex

characterized by a no.of renal and extra

renal features, most prominent of which

are proteinuria of > 3.5 gm per 1.73

m2/24hrs (in practice > 3.0 to 3.5

gm/24hrs), hypoalbuminemia, edema,

hyperlipidemia, lipiduria and

hypercoagulabilty.

6 Entities account for >90% of cases of N.S. in adults.

1. Membranes glomerulopathy2. Focal & segmental glomerulosclerosis (FSGS)3. Minimal change diseases.4. Membranoproliferative glomerulonephritis

(MPGN)5. Diabetic nephropathy6. AmyloidosisOther entities account for <10% of N.S.- Light chain deposition disease- Waldenstrom’s macroglobulimia- Fibrillary immunotactoid glomerulopathy - IgA nephropathy etc.

• The glomerular filter acts as a high capacity

ultrafiltration membrane. It is made up of highly

modified vascular endothelial cells, with only a

thin cytoplasm and large pores allowing almost

direct access of filtrate to the basement

membrane, which has on its outside a unique

pericyte-the glomerular epithelial cell or

podocyte.

PROTIENURIA

• Thus the glomerular wall can be pictured

as having two filtration barriers in series;

an inner, charge : dependent membrane;

and a more external, mainly size selective

barrier in the outer basement membrane

and silt diaphragms of the processes.

• Glomerular filter acts via two phenomenon

size selectivity and charge selectivity

• Proteinuria (Glomerular) develops when

there is alteration in either charge

selectivity and size selectivity depending

on type of glomerularpathy

• Glomerular haemodynamics

(Intraglomerular hypertension and

hyperfiltration) can alter Glomerular

permeabiality.

Selectivity of proteinuria • Excretion of relatively low M.W. protein

(Albumin or transferrin) is known as selective proteinuria while if excretion is predominately high M.W. protein (IgG, IgM or 2 macroglobulin) it is nonselective proteinuria.

• It is also related to relative damage of Glomerular filter.

• If there is predominantly loss of charge selectivity selective proteinuria.

• If there is predominantly loss of size selectivity nonselective proteinuria.

• A clearance of IgG > 20% of transferrin or

albumin represents nonselective proteinuria

and < 10% is selective proteinuria.

Treatment of Proteinuria

• Proteinuira leaking through damaged

glomeruli are toxic to renal tubules.

• So every attempts should be made to prevent

and reduce proteinuria irrespective of serum

protein level or basic disease.

• All available drugs seems to act through

reversible haemodynamic changes are

accompanied by greater or smaller reduction

in GFR.

- Drugs/Tt acting by increasing afferent

glomerular arteriolar tone – NSAIDs, Protein

restriction and cyclosporin.

- Drugs/Tt acting by reducing efferent

glomerular tone – ACE inhibitors, ARBs and

possibly dipyridamole.

• ACE inhibitors : have most favorable results

Linisnopril 5 mg is usually effective in reducing protienuria by 1/3rd. 10mg will halve the protienuria but with a 25% reduction in GFR. A higher dose can further decrease GFR and carry greater risk of ARF.

• Maximum effect of ACE inhibitors will achieved after several weeks.

• NSAIDS : reduce protienuria within week or two but there is risk of inducing ARF,hyperkalemia, salt and water retention etc.

Protien restriction : reduction in protein intake 0.8g/kg/24 hrs reduces proteinuria. But is also important to restrict sodium at same time (50-60 mmol/24hrs), since inhibitory effect on proteinuria is much greater in sodium depleted than sodium repleted patients.

• But there is risk of malnutrition.

Nephrectomy : In a few unfortunate individuals, proteinuria remains torrential despite aggressive treatment, hypotension oedema persists, the plasma creatinine increases, and protein malnutrition becomes increasingly severe.

• In this situation, it may be useful to contemplate

nephrectomy, dialysis, and intensive nutrition.

• Bilateral surgical nephrectomy through a

midline incision is the standard procedures.

• Medical Nephrectomy using administration of

mercurial diuretics or NSAIDs in very high

doses, cyclosporin and angiotensin, or the

injection of polymers, autologous thrombus,

coils, gelfoam, or fat into renal artery can be

employed.

• It is due to both the proteinuria and due to the increase renal catabolism (in tubules).

• Infact hepatic albumin synthesis is increased from 145±9mg/kg/day to 213±17mg/kg/day in nephrotic patients.

• Transcriptiional regulation of human albumin synthesis is not co-related with plasma oncotic pressure or albumin concentration, but rather with urinary albumin execration.

Treatment :- Reduce proteinuria - Dietary supplementation is not recommended :

- Little effect on serum albumin level

- Hasten the progression of renal failure.

HYPOALBUMINEMIA

- Albumin infusion - has no advantages :

- Very short life

- Risk of pulmonary edema

EDEMA• consequence of abnormal accumulation of

interstitial fluid and becomes obvious if in excess of 10% of B.W.

• Usually present as edema around eyes, ankle swelling, sacral pad and edematous elbows and later may leads to ascitis and pleural effusion.

Pathogenesis of Edema :

The classical under filling hypothesis

hypoalbuminemiadecrease intravascular oncotic pressure

leakage of fluid from blood to interstitium

intravascular volume

activates sympathetic N.S. and RAS and promote vasopressin secretion & suppressing ANP release.

increase salt and water retension

restore intravascular volume

further leakage of fluid to interstitum.But this hypothesis does not explain the occurrence edema in many patients whom plasma volume is expended and are RAA axis is suppressed like adult nephrotic patients who have normal to increased plasma volume. High BP argues against hypovolumia and infact, suggest hypervolumia. In some study, it is seen that sodium retension preceded the reduction in serum protein concentration in some patient and natriuresis developed before protienuria had resolved in others.

these findings suggest that primary renal salt and water retention theory.

TREATMENT OF EDEMA :Not more than 1kg/day due to risk of hypovolaemia and pre-

renal azotemia.

1. Salt restriction : Cornerstone of treatment

Usually 1-2 gm/day

sodium restriction potentiate the

antiproteinuric effects of ACE

inhibitors.

2. Diuretics : Patients with N.S. often show relative

resistance to diuretic.

- Multifactorial decrease delivery of

drug acting site in the tubular brush border of the kidney.

- Diuretics (Fursemide) are protein

bound, so hypoalbuminemia decreases its availability as

well as increase its inactivation to glucuronide with in kidney.

• THIAZIDE sufficient for mild edema.

• POTASSIUM SPARING DIURETIC hypokalemic patients.

• LOOP DIURETICS for moderate to severe nephrotic edema.

Fursemide in used in doses of 40 mg-200 mg/24 hours.

• When efficiency of oral diuretic is impaired a intravenous

administration should be considered. Constant infusion is

preferred to bolus administration because it prevent in post

diuretic sodium reabsorption.

Other drugs may have better bioavailability such as

bumetanide (1-10 mg) or torsemide (10-50 mg), because of

their hepatic rather than renal metabolism.

• Metolazone (5-20 mg) may useful alone or in combination.

1. Albumin infusion

2. Dialysis

HYPERLIPIDEMIA• Due to increase hepatic lipoprotein synthesis that is

triggered by reduced oncotic.

• Defective lipid catabolism has also important role.

• LDL and cholesterol are increased in majority of patients whereas VLDL and triglyceride tends to rise in patients with severe disease.

• It increases the relative risk for MI 5.5 fold and coronary death 2.8 fold. It also increases progression of renal disease.

TREATMENT • Remission of NS leads to optimal resolution of hypercholesteremia

and hypertriglyceridemia.• Dietary therapy provides very little benefits..

- Fish oil has some lipid lowering effect.

- Vegetarian soy protein reach in polyunsaturated fatty acids is also beneficial.

• DRUGS

- HMG COA reductase inhibitors (statins) are most effective agents in reducing cholesterol synthesis.

- Act by

- Upregualtion of hepatic LDL receptors and thus ed clearance LDL from plasma.

- ed triglyceride level by activation of lipoprotein lipase.

- Correct endothelial dysfunction.

- Inhibit proliferation of smooth muscles cell with in vascular wall.

- Have antiinflammatory effects & inhibit cell proliferation and therapy may progression of renal disease.

- Fibrates powerful effect on TGs in nephrotics as in other patient. But reduces LDL cholesterol less effectively.

- Nicotinic acid bile and bile acid binding resins have been used successfully but there have frequent severe side effect which leads to poor compliance.

• Other risk factors such as smoking, obesity hypertension & hyperurecemia must be managed simultaneously.

Multifactorial in origin• Increase urinary loss of antithrombin III.• Altered levels and/or activity of protein C & S.• Hyperfibronogenemia due to increase hepatic synthesis.• Impaired fibrinolysis due to decrease plasminogen. • Increase platelet aggregability – relative immobility

- haemoconcentragtion from hypovolemia.

- hyperlipidemia• Alteration in endothelial function • Corticosteroids increases the concentration of some zymogens

and PT & APTT may be shortened.• On positive side steroid tends to raise conc. of antithrombin III &

inhibit platelet aggregation but at large doses.

HYPERCOAGULABILITY

• Prevalence in adults is 26% (1.8% in children).

• Patients may be develop peripheral arterial or venous thrombosis,

renal vein thrombosis and pulmonary embolism.

• Venous thrombosis is more common then arterial thrombosis.

• Renal vein thrombosis (men >women) is very important and

common (up to 40% adults patients).

- Acute sudden onset flank or abdominal pain gross

hematuria, left sided varicocele, decrease GFR.

- Chronic usually asymptomatic.

- Renal thrombosis usually associated with membranous

nephropathy, MPGN and amyloidosis.

HYPERCOAGULABILITY

TREATMENT OF EVIDENT THROMBOSIS

• Patients should be mobilized.

• Sepsis should be avoided or treated promptly.

• Dehydration from incidental cause (e.g. diarrhoea) should be treated.

• Diuretics used with care & hemoconcentration minimize.

• Heparin act mainly through activation of antithrombin III whose concentration may be diminished in nephrotics. Thus higher doses of heparin are required.warfarin has similar problem as it also bound to albumin.

• Full anticoagulation should be done starting with heparin followed by warfarin with a target INR maintained at 2-3.

TREATMENT OFEVIDENT THROMBOSIS

• It should be given minimum period of 3 months and

with some extra benefits from 6 months. Stopping

warfarin at any time in continuing presence of NS may

lead to rethrombosis so, warfarin until edema remits or

at least the serum albumin is greater than 25 mg/dl.

• Renal vein and venacaval angiogrpahy are probably

indicated only when embolization occur on full

anticoagulation and insertion of a caval filter is

contemplated.

• Prophylactic anticoagluation in nephrotic patients

There is no consensus about it but if in very high risk

sub group aspirin or dipyridamole can be used.

INCREASED SUSCEPTIBILITY TO INFECTION• Due to low levels of IgG

- Increase urinary loss

- Increase catabolism• Due unpredictable changes in pharmacokinetics of

therapeutic agents.• Decreased factor B level which is crucial for alternate

pathway of complements system.• Loss of transferrin which is essential for lymphocyte

function and act as carrier for number of metals including zinc (reduces production of zinc dependent thymic hormone thymuline).

• Peritonitis and cellulitis are common complications.

OTHER COMPLICATIONS OF NS

PROPHYLAXIS AND TREATMENT• Prophylactic pencillin should be given in patients who

already experienced pneumococcal infection atleast during edematous stage.

• The most important feature of treatment for established sepsis in a nephrotic patient is that it should be begin quickly. This in-turn rests with anticipation, suspicion and rapid diagnosis. TLC may be misleading in those taking steroids.

• Parenteral antibiotics should always be used, even when the infection appears to be localized, because septicemia is always present.

• A broad spectrum cephalosporin with an aminoglycoside may used as initial blind treatment.

• Any severe infection should prompt discontinuation of cytotoxic therapy.

FUNCTIONAL CONSEQUENCE OF URINARY LOSS OF

PLASMA PROTEIN• Thyroid binding globulins and thyroxin – may lead to

hypothyroidism.

- But most of patient remain clinically euthyroid.

- Free T4 and free TSH are better marker

- Corticosteroid therapy may decreased TSH level in some patients and inhibit conversion of T4 to T3.

• Vit D binding protein – oesteomalasia, but rare

- Total calcium is also low due to low albumin level.

- Concomitant corticosteroid therapy may induced oesteoporosis.

- Replacement of either calcium or vit D is not recommended except in prolonged cases of nephrosis or when steroid is given.

• Transferrin and erythropoietin and – microcytic hypochromic anemia.

• ARF – is rare in nephrotic syndrome. In whom it occur patient are elderly of minimal changes disease / FGSS.

• Also called as lipoid nephrosis or foot process disease.

• It comprises 20% nephrotic cases in adults. While 80%

of nephrotic cases in children.

• Microscopic hematuria present in 20-30%.

Hypertension and renal failure are very rare.

• In children urine contains albumin principally while in

adults proteinuria is typically non selective.

• Light microscopy - no changes.

• Immuno-fluorescence - typically negative for

immunoglobulin and C3.

• Electron microscopy – diffuse effaciment of the foot

processes of visceral epithelial cell.

MINIMAL CHANGE DISEASE

• Idiopathic (majority)

• In association with systemic disease or drugs.

- Drug induced interstitial nephritis induced by NSAIDs, rifampin, interferon alpha.

- Hodgkin’s disease and other lymphoproliferative malignancy.

- HIV infection.

TREATMENT

• MCD is highly steroid responsive and carries an excellent prognosis.

• Approximately 90% children and 50% of adults enter remission following 8 week of high dose oral glucocorticoid.

MAJOR CAUSES OF MCD

Treatment

• Adults – 1-1.5 mg/kg body weight (pridinisone) per day for 4 weeks, followed by 1 mg/kg/day on alternate day for 4 weeks.

• Upto 90% of adults enter remission if therapy extended for 20-24 weeks.

• Steroid dependent – relapse occur whenever dose is reduced or within two weeks of discontinuation of steroid.

• Steroid responder – absence of protein in urine for three consecutive days.

• In frequent relapse - <3 relapse in a year.

• Frequent relapse - > 3 relapse in a year.

• Steroid resistance – no response to treatment after 6 month of therapy

Treatment of relapse and steroid dependent MCD

• Cyclophosphamide – induction of remission with pridinisone followed by institution of cylcophosphamide (2 mg/kg) for 8-12 weeks.

Side effects – hemorrhagic cystitis, infection, gonadal dysfunction, bone marrow supprresion and potential mutagenic events.

• Chlorembucil - 0.1 to 2.0 mg/kg/day

Side effect – higher incidence of malignancy

Treatment of storied resistant MCD

• Causes

- Poor compliance due to toxic side effect

- Alternate day therapy may not provide sufficient amounts of corticosteroid to induce clinical remains.

- Oral steroid therapy may not be well absorbed in

edematous patients.

• Pulse methylprednisolone

- May induce remission in some corticosteroid resistant

children

• Cyclosporine-

- 5mg/kg/day, patient may respond but long term

remission is rare.

• Levamisole –

- 2.5mg/kg/day on alternate day.

- It is an antihelmenthic drug (Immunomodulating role)

- Transient cytopenia may occurs in 2/3rd patients.

• Leading cause of idiopathic nephrotic syndrome in

adults (30 to 40%) with male to female ratio of 2 :1.

• Prtoeinuria is usually non selective, microscopic

hematuria is present in upto 50% of cases,

hypertension in only 10-30% of patients.

• Light microscopy – diffuse thickening of GBM

without evidence of inflammation or cellular

proliferation.

• Immunofluorescence – granular deposition of IgG,

C3 and compliments (C5b-9).

MEMBRANUS GLOMERULOPATHY

Stage I—subepithelial deposits • A few small, flat, electron-dense deposits are seen on the

epithelial surface of the GBM.

Stage II—'spike' formation • 'Spikes' protruding from epithelial surface of GBM become clearly

visible. • The spikes extend between the electron-dense deposits, and are

present in virtually every capillary loop.

Stage III—incorporation of deposits • Electron-dense deposits become surrounded by and incorporated

into the GBM. This results in an irregular thickening of the GBM.

Stage IV—disappearing deposits • The deposits incorporated within the GBM lose their electron

density. Areas of the GBM will have a vacuolated or lucent appearance.

Stage V—reparation stage • During this 'healing' phase, the deposits have become completely

rarified, and the GBM appearance is returning to normal.

• Nephrotic syndrome remits spontaneously and

completely in up to 40% of patients.

• Features that predict a poor prognosis include male gender, older age, hypertension, severe proteinuria and hyperlipidemia, and impaired renal function.

• Controlled trials of glucocorticoids have failed to show consistent improvement.

• Cyclophosphamide, chlorambucil, and cyclosporine have shown to reduce proteinuria and/or slow the decline in GFR in patients with progressive disease in small or uncontrolled study.

• Mycopthenolate mofetil and rituximab are under trial.

• Transplantation is a successful treatment option for patients who reach ESRD.

• Idiopathic (majority)

• In association with systemic diseases or drugs

Infection

Hepatiitis B and C, syphilis, malaria, leprosy, hydatid disease, filariasis, enterococcal endocarditis.

Systemic auto immune diseases

SLE, Rheumatoid arthritis, Sjogren's syndrome, Hashimoto's disease, grave’s disease, primary biliary cirrhosis, ankylosing spondylitis,

myasthenia gravis.

Neoplasia

Ca breast, lung, colon, stomach, and esophagus; melanoma, renal cell carcinoma; neuroblastoma; carotid body tumor.

Drugs

Gold, penicillamine, captopril, NSAIDs, probenecid, trimethadione, mercury

Miscellaneous

Sarcoidosis, diabetes mellitus, sickle cell disease, Crohn's disease, Guillain-Barre syndrome, Fanconi's syndrome alpha-1 antitrypsin

deficiency

CONDITIONS ASSODATED WITH MEMBRANOUS GLOMERALOPATHY

• The pathognomonic morphologic lesion in FSGS is sclerosis with hyalinosis involving portions (segmental) of fewer than 50% (focal) of glomeruli on a tissue section.

• Primary FSGS comprises about one third of cases of NS in adults.

• Secondary FSGS can complicate a number of systemic diseases and sustained glomerular capillary hypertension following nephron loss from any cause.

• In addition to nephrotic proteinuria it presents with hypertension, mild renal insufficiency, and an abnormal urine sediment that contains red blood cells and leukocytes. Proteinuria is nonselective in most cases.

FOCAL AND SEGMENTAL GLOMERULOSCLEROSIS

• Light microscopy - Entrapment of amorphous hyaline material.

• Electron microscopy - evidence of damage to visceral epithelial cell.

• The etiology of primary FSGS is unclear, but appears to be, at least in part, immunologic.

• There is evidence that a circulating nonimmunoglobulin permeability factor, possibly a lymphokine triggers FSGS in at least a subgroup of patients.

• Secondary FSGS is a potential long-term consequence of nephron loss from any cause.

• It appears that >50%, of nephrons must be lost for development of secondary FSGS.

• Idiopathic (majority) • In association with systemic diseases or drugs

HIV infectionDiabetes mellitus Fabry's disease Sialidosis Charcot-Marie-Tooth disease

• As consequence of sustained glomerular capillary hypertension Congenital oligonephropathies

Unilateral renal agenesis Oligomeganephronia

Acquired nephron loss Surgical resection Reflux nephropathy Glomerulonephritis or tubulointerstitial nephritis

Other adaptive responses Sickle cell nephropathy Obesity with sleep apnea syndrome Familial dysautonomia

Miscellaneous Heroin use

ETIOLOGY OF FOCAL AND SEGMENTAL GLOMERULOSCLEROSIS

Response to corticosteroids in adult patients with idiopathic nephrotic syndrome (1961–1986)

Patients ( n )

Complete remissions (%)

Partial remissions (%)

Failures (%)

Minimal changes

301 226 (75.8) 21 (7) 55 (18.2)

Focal sclerosis

153 24 (15.6) 31 (20.2) 98 (64.2)

Biopsy not done

48 31 (64.6) 0 (0) 17 (35.4)

Total 502 281 (55.8) 52 (10.3) 170 (33.9)

RECOMMENDATION

• First, nephrotic FSGS in adults must always be

allowed to benefit from a course of corticosteroid

treatment, followed by other drugs (Azathioprine,

Cyclosporine, Tacroliumus, Mycophenolate, Mofetil)

when ineffective.

• Second, high-dose prednisone is clearly more effective

than dosages less than 1 mg/kg/day.

• Third, response of FSGS to corticosteroids is much

slower in adults than in children and that steroid

resistance cannot be pronounced before a minimum of

4 months of full-dose corticosteroid treatment

• Is characterized by thickening of the GBM and proliferative changes on light micros copy.

• Two major types : Type I MPGN and type II MPGN.

Type I MPGN• The hallmark is presence of subendothelial and

mesangial deposits on electron microscopy that contents C3 and IgG and IgM rarely IgA.

• It is associated with a variety of chronic infection (bacterial endocarditis, HIV, hepatitis B and C), systemic immune complex diseases (SLE, cryoglobulinemia), and malignancies (leukemias, lyphomas).

MEMBRANOPROLIFERATIVE GLOMERULONEPHRITIS

• It has protracted course and about 50% of patients reach ESRD by 10 years.

Type II MPGN

• Type II MPGN is an autoimmune disease in which patients have an IgG autoantibody, termed C3 nephritic factor, that binds to C3 convertase, the enzyme that metabolizes C3, and renders it resistant to inactivation and deposits on GBM.

• Type II MPGN is associated with partial lipodystrophy.

• Poor prognosis than type I MPGN.

• In general, 1/3 pt. Spontaneous remission, 1/3 progressive disease and 1/3 have waxing and waning course.

• No proven therapy for patients with progressive disease beyond eradicating underlying cause.

• Corticosteroid dipyridamole, aspirin, and warfarin with or without cyclophosphamide have been tried.

Treatment approach

1. Adults with idiopathic MPGN, proteinuria (>3 g/day), or impaired renal functions should undergo a trial of therapy with dipyridamole or aspirin.

2. Patients with rapidly progressive renal failure or a recent deterioration in renal function especially those with crescents on histopathology should be treated with pulse methylprednisolone therapy followed by oral prednisone and cyclophosphamide.

3. Patients with microscopic haematuria, proteinuria (<3 g), and normal renal function should be followed up every 3 months. They can be treated with ACE inhibitors.

4. Patients with chronic renal failure should be managed conservatively.

5. Patients with HCV-associated MPGN should be treated with IFN-α and immunosuppressive agents should be avoided.

• Nephropathy complicates 30% of cases of type I DM and approximately 20% of cases type IIDM.

• Risk factors for the development of diabetic nephropathy include hyperglycemia, systemic hypertension, glomerular hypertension and' hyperfilteration, proteinuria, and possibly cigarette smoking, hyperlipidemia and gene polymorphisms affecting the activity of renin angiotensin aldosteron axis.

DIABETIC NEPHROPATHY

• Diabetic nephropathy is usually diagnosed on clinical grounds without a renal biopsy. Supportive clues are the presence of normal sized or enlarged kidneys, evidence, proliferative diabetic retinopathy, and a bland urinary sediments. Retinopathy is found in 90% and 60% of patients with type I and type II diabetes mellitus respectively, who develop nephropathy.

• The earliest morphologic abnormalities nephropathy are thickening of the GBM and expansion mesangium due to accumulation of extracellular matrix.

• Prominent nodular matrix expansion (classical Kimmelsteil-Wilson lesion) are often found.

TREATMENT

• Aim is to control blood sugar, systemic blood pressure and glomerular capillary blood pressure.

• ACE in inhibitor and ARBs are drugs of choice for both systemic blood pressure & intraglomerular hypertension.

RENAL AMYLOIDOSIS• Glomeruli are involved in 75 to 90% of patients.

• Hypertension is present in 20-25%. Renal size is usually normal or slightly enlarged.

• A minority of patients present with renal failure.

• Rectal biopsy and abdominal fat pad biopsy reveal amyloid deposits in about 75% of patients and may obviate the need for renal biopsy.

• Renal biopsy earliest pathologic changes are mesangial expansion by amorphous hyaline material and thickening of GBM. Further deposition results in large nodular esinophilic masses.

• When stained with congo red these deposit show apple – green birefringence under polarized light.

• Electron microscopy reveals non branching extracellular amyloid fibrils.

TREATMENT

• No treatment has shown consistently improvement. However some success has been reported with combination of melphalan and pridinsone.

• Renal replacement therpay is offered to patients with ESRD.

• Most patients die from extra renal complications, particularly cardiovascular diseases.