COMMON AETIOLOGIES OF CKD

DR. A.O SHITU

INTRODUCTION

• The commonest aetiology of CKD in our environment are• CGN

• DM nephropathy

• Hypertensive nephropathy

• Obstructive nephropathy

• Others • Lupus nephritis

• ADPKD

• Amyloidosis

• Aetiologies should be considered from patient biodata, family history, past medical history and drug history.

• For example• A 20yr old woman: connective tissue disease (SLE)

• A 60yr old man: obstructive nephropathy

• A 30yr old man with family history of renal disease: ADPKD

DM NEPHROPATHY

• Diabetic nephropathy is a clinical syndrome characterized by the following:• Persistent albuminuria of (>300mg/day or >200microg/min), that is confirmed

on at least 2 occasions 3-6month apart

• Progressive decline in glomerular filtration rate

• Elevation in arterial blood pressure

Others include:

• The presence of diabetic retinopathy

• Accompanied by progressive rise in cardiovascular risk

PATHOPHYSIOLOGY

RISK FACTORS FOR DN

• Genetic• Polygenetic

• 1st degree relative with DN have a 83% chance

• The risk is 17% in 1st degree relative with DM without DN

• Increased risk in offspring of mothers with hyperglycaemia in pregnancy, due to decreased formation of nephrons (nephron underdosing)

• Genes being researched• Genetic loci- 3q, 7p, 18q

• Carnosinase gene

• Double deletion polymorphism of ACE gene

• Environmental• Intake of soft drinks – sucrose and high fructose corn syrup

• Uric acid levels – cause oxidative stress and endothelial dysfunction

• Low birth weight

Adapted from comprehensive clinical nephrology 5th edition

• The hallmark of DN is extracellular matrix accumulation, this leads to • Hyperdynamic changes resulting in glomerular hyperfiltraton

• Mesengial expansion and hypertrophy

• Nodular diabetic glomerulosclerosis

• Tubulointerstitial fibrosis

Adapted from comprehensive clinical nephrology 5th edition

PATHOLOGICAL CHANGES IN THE KIDNEY

EARLY CHANGES

• After the onset of DM, there is increase in kidney weight by 15%, this is due to mesangial expansion and hypertrophy of the interstitium

• GBM thickening up to 3x the normal range

ADVANCED DN• Nodular diabetic glomerosclerosis (Kimmestiel-Wilson nodule)

• Acellular nodule, resulting form microaneurysmal dilation of the associated capillary + mensangiolysis with organization the mesangial debris + surrounding foam cells

• Reported in only 10-50%

• Diffuse glomerular lesion seen in 90% of type 1 DM and 25-50% of type 2 DM

• Effacement of the podocytes as well as reduction in number per glomerulus

• Tubular interstitial fibrosis and tubular atrophy• Vasoactive factors, cytokines and proteinuria lead to this• Formation of fibroblast and myofibroblast• Type I, III, V collagen and fibronectin

Adapted from comprehensive clinical nephrology 5th edition

MANAGEMENT OF PATIENTS WITH DN

1. Glycaemic control

2. Rigorous BP control

3. Treatment of dyslipidaemia

4. Patient education, diet and lifestyle modification

Steno type 2 trial: reduction in risk of complications after 7.7years of the therapy regime. With reduction in mortality

Effective blood pressure management is the single most important strategy in DN

HYPERTENSIVE NEPHROPATHY

• A Clinical syndrome of • Long-term hypertension

• Hypertensive retinopathy

• Left ventricular hypertrophy

• Minimal proteinuria

• Progressive renal insufficency

• 2 pathological mechanismsi. Glomerular ischaemia causing HTNsive nephrosclerosis

ii. Glomerulosclerosis may occur because of glomerular hypertension and hyperfiltration

CLINICAL FEATURES

• Patient with hypertension for >10 years with evidence of periods of accelerated or poorly controlled BP• Black race

• Retinopathy

• LVH

• Proteinuria <0.5g/day

• Hypertension before proteinuria

• No evidence of another renal disease

• Biopsy

MALIGNANT HYPERTENSION

• Acclerated hypertension with TOD, mainly retinopathy +/-nephropathy

• Presence of oliguria, uraemic symptoms

• Microangiopathic haemolytic anaemia

• Fibrinoid necrosis of the glomerulus

OBSTRUCTIVE NEPHROPATHY

• Obstruction to flow of urine from the kidney

• Can be intra-mural, extra-mural or mural

• Results in back pressure to the kidney resulting in tubular damage and subsequently glomerular damage

• Kidneys are enlarged with hydronephrosis

RENAL CYSTIC DISEASE

INTRODUCTION/ DEFINITION

Renal cystic disease refers to a wide range of hereditary, development and acquired conditions, including neoplasms with cystic changes that cause the formation of cysts in the kidneys

It can involve one or both kidneys and may or may not occur in the presence of other anormalies

Presentation may be from birth or much later into adult life.

CLASSIFICATION

• Genetic renal cystic disease

• Non genetic renal cystic disease

Genetic Renal Cystic Disease

• Polycystic kidney disease• ARPKD (Autosomal Recessive PKD)

• ADPKD (Autosomal Dominant PKD)

• Juvenile Nephronophthisis (autosomal recessive)

• Medullary Cystic Disease (autosomal dominant)

• Congenital Nephrosis (autosomal recessive)

• Familial Hypoplastic Glomerulocystic Disease (autosomal dominant)

• Others – e.g. Cystic Fibrosis, Von Hippel-Lindaudisease

Non-Genetic Renal Cystic Disease

• Multicystic Dysplastic Kidney

• Benign Multilocular Cyst (Cystic Nephroma)

• Simple Cysts – Bosniak Classification

• Medullary Sponge Kidney

• Sporadic Glomerulocystic Kidney Disease

• Acquired Renal Cystic Disease

• Calyceal Diverticulum

• Cystic Renal Cell Carcinoma

EPIDEMOLOGY

• Incidence of cystic kidney disease in the US is 1 in 503 or 0.20%. 540,000 people have cystic kidney disease

• 90% of these people have polycystic kidney disease

• In a study done by chijioke et al at UITH, btw jan 1999 and Dec 2008, observing all patients seen by the renal unit• 67 out of 436 patients (15.4%) studied had cystic kidney disease

• The age range was between 20-83 with a mean age of 47.4yrs, peak incidence was in the third and sixth decade

• Male to female ration was 1.3-1

• 38.3% had simple cysts, 53.3% had PKD and 8.9% had multicystic kidney disease

POLYCYSTIC KIDNEY DISEASE

INTRODUCTION

Polycystic kidney diseases are among the most common life-threatening inherited diseases worldwide and frequently cause kidney failure

There are two types1. Autosomal dominant polycystic kidney disease

(that is seen predominantly in adults)

2. Autosomal recessive polycystic kidney disease (which is mainly a disease of childhood)

EPIDEMOLOGY

• ADPKD occurs in 1:400-1:1000 worldwide, while ARPKD occurs in 1:20000 births.

• account for 4% of ESRD in the US

• Affects all ethnic and racial groups equally

• Over 90% of ADPKD occur as result of inherited autosomal trait, while the rest probably represent spontaneous mutations

ADPKD

It’s a systemic disorder resulting for mutation of either of• PKD-1 – which encodes for polycystin-1, a large

receptor like molecule (85% of ADPKD) Ch 16

• PKD-2 – which encodes for polycystin-2, which has features of a calcium channel protein(15% of ADPKD) Ch 4

Both proteins regulate the epithelial cell gene transcription, apoptosis, differentiation, and cell-matrix interaction.

Vasopressin mediated cAMP elevation also plays a major role in the cystogenesis

CLINICAL FEATURES OF ADPKD

• Phenotypic heterogeneity is a hallmark of ADPKD

• Often asymptomatic till the 4th to 5th decade of life. Frequently diagnosis is made before the onset of symptoms

• Those with ADPKD-2 tend to have a later onset and slower progression

• Presenting symptoms and signs include:• Abdominal discomfort (dull, persistent flank pain and

early satiety)

• Haematuria (from cyst rupture or nephrolithiasis(20%))

• Polyuria and nocturia

• Features of a UTI (+ve blood culture, -ve urine culture)

• Incidential discovery of HTN (common and often preceeds renal dysfunction), abdominal masses, elevated serum Cr and cystic kidney on imaging

• Renal function declines progressively over the course of 10-20 yrs from the time of diagnosis

• Risk factors for progressive kidney disease include• Younger age of diagnosis

• Black race

• Male sex

• Presence of polycystin 1 mutation

• HTN

• Not everyone with ADPKD will develop ESRD, it however will occur in 60% of patients by the age of 70yrs

• There are numerous extrarenal manifestation of ADPKD and these highlight the systemic nature of the disease• Saccular aneurysms (2-4 fold risk for subarachnoid or cerebral heamorrhage)

• Aortic root and annulus dilation

• Valvular abnormalities (mitral valve prolapse and aortic regurgitation)

• Hepatic cysts (incidence of 83%)

• Colonic diverticulae

• Abdominal wall and inguinal hernias

DIAGNOSIS & SCREENING IN ADPKD• Diagnosis is most often made from positive family

history and imaging studies showing large kidneys with multiple bilateral cysts and possibly liver cysts

• Criteria for diagnosis of ADPKD by USS• 3 or more cysts in one or both in pts 15-39yrs, with

positive predicitive value of 100%; sensitivity varies from 82-96% for persons aged 15-29 and 30-39 respectively

• 2 or more cysts in each kidney, has sensivity of 90% and specificity of 100% for pts aged 40-59yrs

• For subject older than 60yrs the presence of 4 or more cysts in each kidney is required

• CT and T2 weighted MRI are more sensitive• Genetic linkage analysis and mutational screening

for ADPKD 1 and 2 (eqivocal cases and kidney donors with family history

TREATMENT OF ADPKD

• No treatment had been proved to prevent cyst growth or the decline in renal function

• Control HTN

• Studies are on going to see the role of ACEi and ARBs in slowing the growth of of kidney volume and loss of GFR

• Lipid soluble antimicrobials such as septrin and fluoroquinolones, have good cyst penetration in cases of kidney or live cyst infection.

• Pain management requires• Analgesia

• Percutaneous cyst aspiration

• Sclerotherapy with alcohol

• Rarely surgical drainage

• Patients with ADPKD, have better survival advantage on dialysis, than other causes of ESRD. However the survival rate is the same posttransplantation

• Promising therapeutic strategies include• Vasopression V2 receptor antagonist

• Inhibitors of cell dedifferentiation and proliferation that target epidermal growth factor receptor tyrosine kinase

• Mammalian target of rapamycin (mTOR)

ARPKD

• ARPKD gene is on Ch 6p21 (PKHD-1) it encodes transcripts, the largest of which produces fibrocystin (polyductin)

• A large number of different mutations have been identified throughout PKHD1, and most patients have compound heterozygotes. Those with two truncating mutations die shortly after birth

• Mutations in PKHD1 have been identified in children with congenital hepatic fibrosis (carolissyndrome) without evidence of kidney involvement

• The clinical presentation is variable

• 50% die from pulmonary aplasia as a result of olighydraminos from severe intrauterine renal disease

• 80% of those that survive the neonatal period will still be alive after 10yrs, but 1/3rd will develop ESRD

• HTN occurs in the 1st few yrs of life

• Kidney function deteriorates progressively from childhood to early adult life (long term survivors develop periportal fibrosis)

• Impaired urinary concentrating ability and metabolic acidosis ensue as tubular functions decline

• USS reveals large, echogenic kidneys

• Diagnosis can be made in-utero at 24wks gestation in severe cases, but in most cases its only visible at birth

• The absence of renal cysts in either parent on uss helps to distinguish better in ARPKD and ADPKD.

• No specific therapy, improvements in neonatal care, BP control, dialysis and kidney transplantation have lead to longer survival

NEPHRONOPHTHSIS

• Commonest genetic cause of ESRD in childhood and adolesence

• Autosomal recessive in inheritance

• Proteins affected are nephrocystins and inversin

• Impaired tubular function leads to salt wasting and defective urine concentration and acidification

• Kidneys are small and hyperechoic in the juvenile form and large with cysts in the infantile form

MEDULLARY CYSTIC KIDNEY DISEASE

• 2 genetic foci• MCKD1 – Ch 1q21

• MCKD2 – Ch 16q12

• Atrophic kidneys with diffuse interstitial fibrosis and cysts are restricted to the renal medulla

• Salt wasting is milder and ESRD occurs usually btw 20-70yrs

• Associated with presence of hyperuricaemia and gout.

Acquired Renal Cystic Disease

• Associated with ESRD – patients on Hemodialysis

• Hyperplastic renal cysts – increased risk of progression to RCC within 10 years of starting dialysis

• Cysts may regress with transplantation

Simple Renal Cysts

• Common when people begin to age. Usually occurs after 50yrs

• Believed to be cause by injuries and blockage of kidney tubules

• Usually asymptomatic and detected on routine USS or CT. However symptoms could include; pain, fever, frequency and haematuria

Bosniak Classification of Incidental Renal Cysts

Category I Simple benign cyst with (1) good through- transmission (i.e., acoustic

enhancement), (2) no echoes within the cyst, (3) sharply, marginated smooth wall;

requires no surgery.

Category II Looks benign with some radiologic concerns including septation, minimal

calcification, and high density; requires no surgery.

Category II

F

Although calcification in wall of cyst may even be thicker and more nodular than in

category II, the septa have minimal enhancement, especially those with calcium;

requires no surgery.

Category III More complicated lesion that cannot confidently be distinguished from malignancy,

having more calcification, more prominent septation of a thicker wall than a

category II lesion; more likely to be benign than malignant; requires surgical

exploration and/or removal.

Category IV Clearly a malignant lesion with large cystic components, irregular margins; solid

vascular elements; requires surgical removal.

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