Inherited tubular disorders

Fanconi syndrome (Generalized tubular dysfunction) Multiple tubular defects produce variable clinical

manifestations: Polyuria, polydipsia and dehydration can be prominent

caused by hypokalaemia and impared concentrating ability in the distal tubule.

Phosphaturia and bone disease produces skeletal abnormalities: rickets (children), osteomalacia (adults) and osteoporosis

Aminoaciduria - Amino acids are usually filtered at the glomerulus, before reabsorption by multiple transport carriers in the proximal tubule- in Fanconi syndrome all amino acids appear in the urine in exces, with no clinically significant sequelae and supplementation unnecessary

Fanconi syndrome (Generalized tubular dysfunction)

Hypercalciuria. - rarely induced nephrolithiasis/calcinosis, although these may be precipitated by treatment with vitamin D metabolites (further increse urinary calcium). -serum calcium usually normal.

Renal tubular acidosis. Defective bicarbonate reabsorbtion in the proximal tubule results in systemic acidosis

Glycosuria. Amount varies but serum glucose usually normal. Clinical sequelae are rare, though hypoglycaemia occurs in some forms (e.g. Fanconi-Bikel syndrome –glycogenosis).

Hyponatremia. - if severe, postural hypotension and metabolic alkalosis may occur- salt supplementation occasionally necessary

Fanconi syndrome (Generalized tubular dysfunction) Hypokalemia. causes:

- High delivery of Na + to the distal tubule induce Na+ reabsorbtion at the expense of K+

- Acidosis - Volume depletion (RAS activation)

clinical sequelae are common: muscle weakness, constipation, polyuria, cardiac arrhythmias

suplementation often required. Proteinuria. LMW proteinuria is common (β2

microglobulin, lysozyme, and other tubular proteins), though excretion rates are usually low-moderate.

Isolated tubular defects Carbohydrate tubular transport defect

Renal glycosuria Amino acid tubular transport defects

Hartnups disease Cystinuria and cystinosis

Renal Tubular Acidosis (RTA) Classic (Distal) RTA Proximal RTA

Abnormal water Handling Nephrogenic diabetes inspidus (NDI)

Hereditary disorders of sodium handling without hypertension Barter’s Syndrome Gitelman’ Syndrome

Vitamin D Resistant Rickets

Isolated tubular defectsRenal glycosuria

Reduced proximal tubular glucose reabsorbtion induce glycosuria (despite normal blood glucose)

Genetic mechanisms involved, but inheritance unpredictible.

The amount can be quite significant (normaly 1-30 g/24 hours) but generally a benign condition with no clinical sequelae.

Always need to be distinguished from diabetes mellitus

Isolated tubular defectsAminoaciduria Causes Inborn error of metabolism induce increase plasma levels and

overflow Renal aminoaciduria: defective tubular transport mechanisms.

Amino acid transport is complex, involving transporters specific to single or chemically related groups of amino acids.

The most important isolated aminoaciduria is cystinuria:

a cause of recurrent cystine stone formation. cystinuria may be suspected in childhood stone-formers. mutations in the gene encoding an amino acid transporter

leads to wasting of the cationic amino acids cystine, ornithine, lysine, and arginine.

Isolated tubular defectsPhosphaturia

Defective phosphate transport induce phosphaturia hypophosphataemia disorders of the skeleton

Several described, including X-linked hypophosphataemic rickets (vitamin D resistant rickets)

Isolated tubular defects Hereditary Nephrogenic diabetes Insipidus (NDI) Pathogenesis: Rare monogenic disease; X-linked

mutations of AVPR2, the gene that encodes type 2 vasopresin receptor (VR2), account 90% of cases of hereditary NDI

Clinical features: usually presents in infancy with positive family history, severe resistant polyuria, failure to thrive, dehydration (with seizures and mental retardation) and dilute urine despite the presence of hypernatremia.

Treatment abundant water intake, salt restriction thiazide diuretics with amiloride (will avoid thaizide-

induced hypokalemia), and indometacin reduce urine output

Isolated tubular defectsBarter’s syndrome and Gitelman’s syndrome

Barter’s syndrome Pathogenesis: genetic mutations of any of 5 ion

transport proteins in the thick ascending limb of Henle’s loop

Clinical features: - rare disorder, present in neonatal period or early childhood- with polyuria, salt craving, and growth retardation- BP is normal or low.- laboratory: hypokalemia, hypochloremic metabolic alkcalosis, decreased urinary concentrating and diluting ability, hypercalciuria, nephrocalcinosis

Isolated tubular defectsBarter’s syndrome and Gitelman’s syndrome

Gitelman’s syndrome Pathogenesis: genetic mutations of thiazide-sensitive Na-Cl

co-transporter in distal convoluted tubule Clinical features:

- neuromuscular symptoms: fatigue, carpopedal spasm, cramps, tetany - severe hypomagnesemia, hypocalciuria, hypokalemia, hypochloremic metabolic alkcalosis

Treatment of Barter’s syndrome and Gitelman’s syndrome: - lifelog therapy with potassium and magnesium supplements- liberal salt intake- high dose of spironolactone (treat hypokaliemia)- NSAID’s (reduce polyuria)

Isolated tubular defectsVitamin D-dependent rickets 2 forms Vitamin D-dependent rickets type I –autosomal recesive

disease from mutations in CYP27B1, the gene that encodes 25(OH)D3 -1α-hydroxylase

Vitamin D-dependent rickets type II- autosomal recesive disease from mutations in the vitamin D receptor.

Clinical findings: tetany (in severe cases), hypocalcemia, hypophosphatemia, elevated PTH levels,

and the skeletal abnormalities of rickets and osteomalacia

Renal vascular diseases

Lecture agenda

Arteriolonephrosclerosis ’’Malignanat ’’hypertension Hypertensive (benign) nephrosclerosis

Large-vessel renal artery occlusive disease Atherosclerotic renal artery stenosis Fibromuscular dysplasia

Atheroembolic renal disease Thromboembolic renal disease

Arteriolonephrosclerosis

’Malignanat ’’hypertension

Hypertensive (benign) nephrosclerosis

Malignant hypertensionDefinition and Epidemiology

Definition: rapidly progressive BP elevations with severe target organ damage including retinal hemorrhages, encephalopathy, and declining kidney function.

Sinonim: Malignant nephrosclerosis Epidemiology Is rare in Western countries, although it persists

in parts of the world where antihypertensive drug therapy are less available.

It most commonly develops in patients with treated hypertension who neglect to take medications, or who use vasospastic drugs (eg. cocaine).

Malignant hypertensionPathogenesis and Histopathology

Pathogenesis failure of renal vessel autoregulation Genetic polymorphisms (MYH9) that are

common in the African-American population and predispose to subtle focal sclerosing glomerular disease (FSG),with secondary hypertension

Histopathology – proliferation endarteritis, fibrinoid necrosis of afferent arteries and capilaries – necrotic glomerulonephritis

Malignant hypertensionClinical findings and lab tests

Clinical findings usssualy African-

American male severe hypertension headache,

encephalopathy, coma

neuroretinopathy dyspneea (left heart

failure)

Laboratory hemolytic anemia

(schistocytes, reticulocytosis)

proteinuria (nephrotic) hematuria rising serum creatinine

(progressing renal dysfunction)

Malignant hypertensionEvolution and prognosis

Evolution: with antihypertensive drug therapy manifestations of vascular injury including microangiopathic hemolysis and renal dysfunction can improve over time.

Prognosis If untreated, patients mortality rates exced 90%

over 6-12 months (‘‘malignant‘‘). Current survival with treatment exceeds 50%.

Malignant hypertension Therapy

therapy of emergent hypertension ICU i.v. antihypertensives (nitrates, urapidil,

labetalol…) hemodialysis mortality – 30%

Hypertensive nephropathy

Based on epidemiologic evidence linking BP with long-term risk of kidney dysfunction, it has long been assumed that lesser degrees of hypertension than ’’malignant’’ HTN induce less severe changes in kidney vessels and loss of kidney function.

As a result, a large portion of patients reaching ESRD without a specific etiologic diagnosis are assigned ’’hypertensive nephrosclerosis’’

Hypertensive nephropathy

The causal relationship between nephrosclerosis and hypertension is still a subject for debate.

Postmortem and biopsy samples from normotensive kidney donors demonstrate similar vessel changes associated with aging, dyslipidemia, and glucose intolerance.

Hypertensive nephropathyEpidemiology According to the 2011 US Renal Data System (USRDS)

data, in the year 2009, hypertensive nephrosclerosis accounted for 28% of patients reaching end-stage renal disease (ESRD).

Hypertensive nephrosclerosis is reportedly the second most common cause of ESRD in white people (23%) and is the leading cause of ESRD in black people (46%)

Even though considered the second most common cause of ESRD, hypertensive nephrosclerosis has been histologically confirmed in very few cases

Race : Hypertensive nephropathy is more frequent in

African Americans.

Pharmacologic treatment of mild-to- moderate hypertension in African Americans has little impact on the incidence of CKD, whereas it significantly reduces the progression in Caucasians

Hypertensive nephropathyEpidemiology

Race and genetic polymorphisms: MYH9 was identified as the associated gene with

clinically diagnosed ‘hypertensive ESRD’ in African Americans.

In chromosomal regions adjacent to MYH9 statistically stronger associations were detected between two independent sequence variants in the APOL1 and nondiabetic nephropathy in African Americans, with odds ratios of 10.5 in idiopathic FSGS and 7.3 in hypertension-attributed ESRD.

Hypertensive nephropathyEpidemiology

Hypertensive nephropathyHistology findings

The most characteristic microscopic lesion is hyalinosis of afferent arterioles (afferent arteriolar thickening with deposition of homogenous eosinophilic material)

Narrowing of vascular lumina

The vascular changes cause glomerular ischemia (retraction of the glomerular tuft with focal or global sclerosis), and in some areas, interstitial fibrosis and tubular atrophy

In other cases the hyalinization of afferent arterioles initially causes glomerular hypertrophy and, in the long term glomerulosclerosis lesions that would favor the development of proteinuria and disease progression

Hypertensive nephropathyHistology findings

Hipertensive nephropathyClinical presentation: History Patients may present with:

hypertension, its complications (eg, heart failure, stroke),

and/or symptoms of uremia.

In most patients, hypertension is present for many years (usually >10 years), with evidence of periods of accelerated or poorly controlled BP.

evidence of hypertension-related target organ damage signs of left ventricular hypertrophy and hypertensive changes in the retinal vessels

- hemorrhages or exudates are characteristic of accelerated hypertension, and - papilledema is a feature of malignant hypertension

ultrasonography: small kidneys

Hipertensive nephropathyClinical presentation: Clinical exam and imagistic data

Features suggesting the diagnosis of hypertensive nephrosclerosis Black race Long-standing or very severe hypertension Hypertension diagnosed prior to the onset of proteinuria Hypertension preceding renal dysfunction Target organ damage due to hypertension

Hypertensive retinal changes Left ventricular hypertrophy Proteinuria less than 0.5 g/d

Biopsy findings compatible with the diagnosis (if available)

No evidence of another renal disease (exclusion diagnosis !)

Hipertensive nephropathyDifferential Diagnosis

Renal atherosclerotic disease (eg. renal artery stenosis)

Atheroembolic renal disease (Cholesterol microembolization)

Malignant hypertension

Hipertensive nephropathy Treatment

Objective: blood pressure control – BP target =130/80 mmHg

Diet: low salt intake ACE inhibitors, sartans, verapamil + other

antihypertensive drugs intensive treatment of other risk factors

(lipids, glycemia)

Large-vessel renal artery occlusive disease Macrovascular renal artery disease can result from any

disorder that reduces perfusion pressure to the kidney: atherosclerotic renal disease (eg. renal artery stenosis)

- is the most common renal artery disease. - usually involves the aortic orifice or the proximal main renal artery. - this disorder is particularly common in patients with diffuse atherosclerosis, but can occur as a relatively isolated renal lesion.

fibromuscular dysplasia (extrinsec compression of the vessel) typically involves the distal main renal artery or the intrarenal branches.

Other less common causes include: - vasculitis (Takayasu’s arteritis), - dissection of the renal artery.- renal artery aneurysm or ccoarctation

Atherosclerotic renal artery stenosisTerminology and Epidemiology Terminology Renovascular diseases – renal arterial stenosis

with/without hypertension Ischaemic nephropathy – bilateral RAS (renal

ischaemia) with renal dysfunction (CKD) Epidemiology Is common in general population (6,8%) above age

65, a prevalence that increases with age Is common in patients with other atherosclerotic

lesions such as coronary artery disease (18-23%) and/or peripheral aortic or lower extremity disease (more than 30%)

Atherosclerotic renal artery stenosis Pathophysiology

Renal blood flow is 3 to 5 fold greater than the perfusion to other organs because it drives glomerular capillary filtration.

Both glomerular capillary hydrostatic pressure and renal blood flow are important determinants of the glomerular filtration rate (GFR).

The GFR is dependent on angiotensin II and other modulators that maintain the autoregulation system between the afferent and efferent arteries

Renovascular hypertension develops as a result of increased renin and angiotensin II levels causing vasoconstriction as well as salt and water retention (volume expansion) due to increased aldosterone level.

Atherosclerotic renal artery stenosis Pathophysiology

In patients with RAS fail to maintain the GFR when renal perfusion pressure drops below 70-85 mm Hg.

Significant functional impairment of autoregulation, leading to a decrease in the GFR, is not likely to be observed until arterial luminal narrowing exceeds 50%.

Atherosclerotic renal artery stenosis Clinical manifestations hypertension Resistant hypertension (difficult-to-control hypertension

despite adequate medical treatment) Hypertension with renal dysfunction or progressive CKD Accelerated or malignant hypertension Hypertension with an asymmetric kidney (on imaging tests) Onset of hypertension occurring in patients younger than 30

years or older than 50 years symptoms of atherosclerotic disease elsewhere recurrent episodes of flash pulmonary edema. sudden worsening of renal function (an increase in serum

creatinine of more than 15%) in a patient who is hypertensive and who was started on an ACE inhibitor

systolic-diastolic abdominal bruits with hypertension

Atherosclerotic renal artery stenosis and ischemic nephropathyRisk factors diffuse atherosclerosis Carotid artery disease Coronary artery disease Peripheral vascular disease Diabetes mellitus Hypertension Obesity Old age Smoking Familial history of atherosclerosis or RAS

Atherosclerotic renal artery stenosis Laboratory Studies Serum creatinine and eGFR. 24-hour urine protein: minimal-to-moderate degrees of

proteinuria, rarely in the nephrotic range. Urinalysis shows absence of red blood cells or red blood

cell casts (a hallmark of glomerulonephritis). Serologic tests for SLE or vasculitis should be

performed if these conditions are suggested (e.g. antinuclear antibodies, C3, C4, antinuclear cytoplasmic antibodies).

Measurement of plasma renin activity: The baseline plasma renin activity is elevated in 50-80% of patients with RVHT.

Renal vein renin ratio ≥ 1.5 between stenotic/contralateral kidney are of considerable value in predicting cure or improvement of HTN with PTA or surgical intervention.

Atherosclerotic renal artery stenosisImaging diagnosis of RAS

Perfusion studies to assess differential renal blood flow Captopril renography Nuclear imaging with technetium mertiatide

Vascular studies to evaluate the renal arteries Duplex ultrasonography Computed tomographic (CT) angiography, Magnetic resonance (MR) angiography, Intra-arterial renal angiography

Atherosclerotic renal artery stenosisDiagnosis of RAS

Atherosclerotic renal artery stenosis Perfusion studies - Captopril renography

Radionuclide renal imaging can be done using Tc99m DTPA, Tc99m MAG3. It is a safe and noninvasive way to evaluate renal blood flow and excretory function.

When captopril is administered (especially in unilateral RAS), the GFR of stenotic kidney falls by about 30% and the normal kidney exhibits an increase in the GFR. Sensitivity of this test is about 85-90% and specificity of 93-98%.

Significant azotemia and bilateral RAS adversely affect this accuracy, making it unsuitable for these situations.

Atherosclerotic renal artery stenosis Duplex ultrasound

Renal ultrasonography may show: significant asymmetry of kidney size (i.e. size discrepancy of >1.5 cm). additionally, US may be useful to determine the presence of a solitary kidney.

Duplex ultrasound scanning is a noninvasive diagnostic technique that combines a B-mode ultrasound image with a pulse Doppler unit to obtain flow velocity data. It is relatively inexpensive, and can be used in patients with any level of renal function.

Dynamic gadolinium-enhanced magnetic resonance angiogram (MRA) shows normal renal arteries.

Atherosclerotic renal artery stenosisMagnetic resonance angiogram (MRA)

MRA is a very good noninvasive technique for direct visualization of renal artery lesions without iodinated contrast material.

The limitations of MRA are:- expensive and- contraindicated in patients with metallic clips, pacemakers, intraocular metallic devices, or other implants.

The sensitivity of MRA- > 90% for proximal RAS,- 82% for main RAS, and- very low (0%) for segmental stenosis.

Atherosclerotic renal artery stenosis CT angiography Spiral CT involves the

use of IV. iodinated contrast material and allows 3 - dimensional reconstruction images of the renal arteries.

Spiral CT is a useful technique that avoids arterial catheterization and produces accurate images of renal artery anatomy. CT angiogram illustrating loss of

circulation to the upper pole of the right kidney in a patient with fibromuscular disease and renal artery aneurysm

Atherosclerotic renal artery stenosisIntra renal angiography

This technique remains the gold standard for the identification of renal artery occlusion.

It is an invasive procedure - requires an arterial puncture, - carries the risk of cholesterol emboli, and- uses a moderate amount of contrast material with the risk of contrast-induced acute tubular necrosis (ATN).

Atherosclerotic renal artery stenosis Selection of diagnostic tests When the history is highly suggestive and no risk

for radiocontrast-mediated acute kidney injury (AKI) is present, an intraarterial DSA or conventional angiogram is the appropriate initial test.

In patients at risk for AKI, a carbon dioxide angiogram can determine the presence of a stenosis, and the risk of radiocontrast angiogram is imposed only on those individuals are most likely to benefit.

Perform a spiral CT scan, MRA, or duplex ultrasonography (depending on availability and local experience) when moderate suspicion of renovascular disease exists. A negative test result indicates that an RAS is highly unlikely, while a positive test result can be followed by renal arteriography.

Hypertensive nephropathy

ARAS and Ischaemic nephropathy

age 40-60 > 60race Afroamerican Caucasiancause hypertension atherosclerosismechanism

perfusion change in HT

hypoperfusion

goal lowering of BP stenosis correctionsurvival relatively good poor

Atherosclerotic renal artery stenosis Differential diagnosis

Objectives: BP control preservation of renal function

Prevention – general prevention of atherosclerosis

Medical therapy equaly effective to revascularization procedures in patients with ARAS with stabile renal function; include:

Blockade of the renin-angiotensin system: slow titration of ACEi/AT1 (Cave k.i. bilateral stenosis), other antihypertensives

Statin Aspirin

Atherosclerotic renal artery stenosisRenal arterial stenosis – medical therapy

Procedures: Percutaneous renal artery angioplasty (PTA): • in fibromuscular dysplasia with hypertension/renal

dysfunction (younger females with otherwise normal vessels and a long life expectancy),

• ARAS with resistant hypertension Surgery (aortorenal bypass): in aneurysm, restenosis

Major complications (9% of cases): Renal artery dissection Capsular perforation Hemorrhage Atheoroembolic disease

Evolution after revascularisation - recovery of renal function in 25% of cases, no change in 50% and deterioration of kidney function in others.

Atherosclerotic renal artery stenosisRenal arterial stenosis - revascularization procedures

Atheroembolic kidney disease Embolization of parts (cholesterol crystals) of

atherosclerotic vascular plaque to peripheral circulation (arteries 150-250 um)

spontaneous (aneurysm of aorta, anticoagulation therapy) after angiographic procedures, often of the coronary

vessels ( PTCA, by pass) Epidemiology: increasing incidence with more vascular procedures and

longer life spans; is likely underdiagnosed suspected in 3% of ESRD in elderly subjects more frequent in males with history of diabetes,

hypertension and ischemic heart disease.

Precipitating events: angiography, vascular surgery, anticoagulation with heparin, thrombolitic therapy, or trauma.

Clinical manifestations develop between 1 and 14 days after an inciting event and may continue to develop for weeks:

Fever, abdominal pain, and weight loss (1/2 of patients) Livedo reticularis and localized toe gangrene Worsening hypertension Progressive kidney dysfunction can require dialysis However, in many cases, the disease is chronic, patients are

relatively asymptomatic, and, presumably, the disease is the result of a spontaneous renal cholesterol embolism

These patients may present with nephrotic-range proteinuria.

Atheroembolic kidney diseaseClinical manifestations

Laboratory rising serum creatinine proteinuria, hematuria eosinophilia Elevated sedimentation rate Hypocomplementemia (15% of cases) Histology: kidney biopsy specimens show microvessel

occlusion with cholesterol crystals that leave a ‘‘cleft‘‘ in the vessel (classic needle-shaped crystals in the glomeruli or renal arteries).

Definitive diagnosis is often by exclusion (if histology is not available!)

Atheroembolic kidney diseaseLaboratory and histology findings

Atheroembolic kidney diseaseTherapy

No effective therapy is available Withdrawal of anticoagulation is

recommended Statin may improve outcome Embolic protection devices in the renal

circulation have failed to demonstrate major benefits

Thromboembolic kidney diseaseThrombotic occlusion of renal vessels or branch artery can lead to declining renal function and hypertension. Thrombosis can develop as a result of:Local vessel abnormalities:

local dissection, trauma, or inflammatory vasculitis

Distant embolic events Atrial fibrilation Fat emboli (from traumatized tissues, most commonly bone

fractures) Subacute bacterial endocarditis (cardiac vegetations) Venous circulation (patent foramen ovale with right-to-left

shunting)

Thromboembolic kidney diseaseAcute arterial thrombosis (kidney infarction)

Clinical manifestations: flank pain, fever, nausea and vomiting, rapid developing hypertension, anuria (in bilateral kidney infarction)

Imaging diagnosis with MR angiography, CT angiography or arteriography

Laboratory • rise of LDH• rise of serum creatinine (posible minor changes

if a single kidney is affected; severe changes in bilateral kidney infarction)

Thromboembolic kidney diseaseTreatment

For unilateral disease (e.g. Arterial dissection with thrombosis) anticoagulation may suffice.

For bilateral occlusion depending upon the precipitating event - surgical or thrombolytic therapy

Methods: Antihypertensive therapy Anticoagulation Thrombolytic therapy Endovascular procedures Surgical reconstruction

Renal vein thrombosis (RVT)Epidemiology and Etiology Epidemiology The left vein is more commonly involved Two-thirds os cases are bilateral Etiology Endothelial damage: homocystinuria, endovascular

intervention, surgery Venous stasis: deshydration, compression of the renal

veins from retroperitoneal fibrosis, and abdominal neoplasms

Hypercoagulable states: antiphospholipid antibody syndrome, nephrotic syndrome (particularly membranous nephropathy), protein C, S or antithrombin deficiency, disseminated malignancy and oral contraceptives.

Renal vein thrombosis (RVT)Diagnosis

Diagnosis Doppler ultrasound CT angiography (nearly 100% sensitive test) MR angiography

Treatment teraphy for the underlying cause Anticoagulation Vena cava filters (prevent migration of the

thrombi) Nephrectomy