Anand Chellappan

LUPUS NEPHRITIS
Male: Female  1:8 for SLE

Lupus Nephritis affects both sexes equally; More severe in children and males

Males  More severe, poor prognosis and more of renal-neurological-hematological manifestations

Blacks, Asians and Hispanics more severe than Caucasians

75% of SLE patients develop renal involvement at some point in time

35% have Lupus Nephritis at diagnosis

Nephropathy is an EARLY manifestation: Develops within 6months to 3 years of diagnosis and within 1
year in 50% of the individuals

Age, gender and race influences the development of nephropathy

Manifestation of Nephropathy in Lupus:

Most common: Proteinuria100%

Nephrotic range proteinuria/ Nephrotic syndrome: 50%

Microscopic hematuria: 80%

Renal insufficiency: 60%

Rapid decline in renal function: 15%

Hypertension: 30%

Tubular abnormalities: 70%

ANCA positivity: 20-25%

ANA Positivity: 95%

Anti dsDNA positivity: 70%

Anti sm: 30%

Apla: 30-50%

LN Specific antibodies: dsDNA and C1q

Acute kidney injury: 1-2%  TMA, AIN, Widespread crescentic disease, renal vascular thrombosis
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Stage Hematuria Proteinuria Decreased GFR Decreased

complement
and elevated
anti dsDNA
1 Mild <1g 15% -
2 Mild <1g 15% -
3 50% 30% Nephrotic Up to 25% >50%

4 Active sediment Universal >50% ; 85% have 85%

90% proteinuria reduced
complement and
anti dsDNA
5 50% 70% Nephrotic Uncommon Uncommon
Can manifest prior
to the onset of
clinical disease

Remission and Relapse rate:

Remission rate with NIH/MMF: 60%

More than 50% remit at 1 yr and another 25 % by 2 years

40% in CR patients

60% in PR patients

Manifestations in Pregnancy:

For the mother:

Who will develop a flare:

Active lupus at the time of conception

Previous lupus nephritis

Not using Hydroxychloroquine

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Anti-Ro Antibody titre > 50U/mL  Fetal heart block; HCQS and dexamethasone treatment can reduce
the incidence of heart block

Anti-La Ab: High chance of developing neonatal cutaneous lupus

40-50% can develop flare during pregnancy

35% occur in 2nd trimester

35% occurs post partum

Majority of the flares are minor

The risk of worsening renal function is related to the pre pregnancy renal functions

For the Fetus:

Fetal mortality: 20-40%

Preterm: 35%

Spontaneous abortion: 15%

Pre eclampsia: 8%

IUGR: 20%

IUD: 4%

Manifestations in ESRD:

10-30% may progress to ESRD over 15 years (44% in class 4)

Disease manifestations and serological activity subside after dialysis initiation

HD=PD w.r.t survival

Increased risk of death in the first 3 months due to infections

PD is associated with increased chance of peritonitis

Manifestations post renal transplant:

5-50% may have a recurrence; No specific time point ; Serological markers are ineffective in detecting
flare ; Biopsy may not show the original lesion and the lesions are usually mild

Causes graft loss in <5%

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Most common causes of graft loss are allograft rejection and CAN  UNOS data
Mild hematuria and proteinuria is the manifestations

Risk factors: Female, Black, Age<33years, Living donors

Not a risk factor: Duration on dialysis and serological status prior to transplant in the absence of
clinically active disease

Patients with a rapid progression to ESRD should be put on a dialysis regimen for 3-6 months prior to
transplantation and should be on 10mg prednisolone and no activity at the time of transplant

For those with slower progression to ESRD such wait is not needed

Survival:

5 year survival:

Survival Patient Kidney Remission status

Without treatment Severe 10% 50%
With treatment 95% 94% Achieved
70% 45% Not achieved

SLE: 92% at 10 years

LN: 88% at 10 years

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MINIMAL CHANGE DISEASE:

Most common age group: 2-7 years

 MCD accounts for 70-90% of the nephrotic syndrome in children > 1yr of age
 MCD accounts for 10-15% of the nephrotic syndrome in adults
 The histological feature is identical in both adults and children
 Since most children respond to steroids, the term Steroid sensitive nephrotic syndrome is often
equated with MCD ; however this is not correct since patients with SSNS may have FSGS in biopsy and
patients with Steroid resistant NS may have MCD changes initially and later go on to develop FSGS.
Definition and Epidemiology:

Male > Female (2-3:1)in children ; Adolescence and Adults: Male = Female

Steroid responsiveness in MCD:

STEROID responsiveness: First critical aspect in determining prognosis and chances of progression to
ESRD.

Steroid responsiveness in MCD is prompt and often COMPLETE. However the time to response is
variable.

50% of children achieve remission within 8 days and most responsive patients within 4 weeks
In adults it may take upto 8 weeks

Pathology:

Indications for renal biopsy in MCD:

1. Age at onset <1 or >12years
2. Gross hematuria
3. Low C3
4. Marked hypertension
5. Renal failure without severe hypovolemia
6. Steroid resistance
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7. CNI therapy

Diffuse mesangial hypercellular variant of MCD: more than 4 mesangial cells per segment affecting at
least 80% of the glomeruli

Focal and segmental distribution of IgM and C3 --> Suspect FSGS

Clinical features:

MC presentation: "Nephrotic syndrome"

Gross hematuria: 3%

Microhematuria: 20%

Nephrotic range proteinuria (>40mg/m2 in children or >200mg/mmol and >3.5g in adults)

Hypoalbuminemia <2g/dL (Increased alpha2 globulin and decreased gamma globulin)

Ig Profile: IgM increased ; IgE unchanged and IgA and IgG reduced(most)

Hyperlipidemia mechanisms:
1. Increased lipoprotein synthesis
2. Decreased Lipoprotein lipase activity
3. Decreased LDL receptor activity

Increased thrombosis risk

Edema of minimal change disease has an abrupt onset over a period of few days.
In FSGS, proteinuria precedes edema for varying duration of time.

Feature Childhood MCD Adult MCD

Incidence 70-90% 10-15%
Features at onset Edema Hypertension and impaired
renal function ; reversible renal
dysfunction due to proteinuria
Hypertension 15% 40%
Thrombotic complications at 3% 24%
onset
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Sex predilection Male Female
Etiology Mostly idiopathic Mostly secondary
IFTA on Biopsy Strongly suggests FSGS MCD can’t be ruled out
Timing of treatment response Shorter Longer
Steroid resistance 10% 25%
Steroid resistance Defined at 4 weeks Defined at 16 weeks
Timing of relapse Frequent and soon Late

The two extremes of MCD:

Children initially steroid resistant and later responding to CsA or Methylprednislone pulse DONOT
relapse after stopping these medications

Children who continue into adulthood with active streroid responsive disease, continue to have relapses
Percentages in MCD:

SSNS in children:

90% steroid sensitive

10% steroid resistant

1/3rd don’t experience any relapse after the first remission

70% experience a relapsing course

20-30% are Infrequent relapsers and 40-50% are frequently relapsing or steroid dependent.

3% progress to ESRD

16-42% relapse in adulthood

Adult MCD:

75% of the adult MCD are steroid sensitive

20% of the adult MCD are steroid resistant

Relapses are less frequent in adults around 30-50%

Relapses decrease with increasing age of the patient

Transient non nephrotic relapses are common

Complete remission with cyclophosphamide is frequent

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12 week cyclosporine is more effective than 8 week cyclosporine

AKI, hematuria, decreased GFR and hypertension are more common.

FSGS:
Most common age group: 18-45 years

Accounts for <20% of the nephrotic syndrome in children

Accounts for 40% of the nephrotic syndrome in adults

Only 40-80% (Average 60%) are steroid sensitive

Of those who have achieved CR 40% will relapse

Of those who have achieved PR more than 50% will relapse

Up to 40% are steroid resistant

It takes up to 3-4 months for FSGS proteinuria to respond

The prognosis is primarily determined by the degree of proteinuria

Non nephrotic proteinuria: Renal survival of 95% at 6-10 years

Nephrotic range proteinuria

Even partial remission is associated with better survival of 80% compared to no remission of 40%.

The 5-year and 10-year kidney survival are 65% and 30% respectively in patients who do not achieve
remission.

Response rates of 70% are observed with CYC and CSA in SDNS type FSGS and 80% with tacrolimus
(especially if initially CsA responsive)

50% is the ESRD incidence at 10 years

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IgA NEPHROPATHY:
Male: Female 3:1 in Caucasian and 1:1 in Asians

Age of onset 2-3rd decade

Episodic macroscopic hematuria: 40-50%

It is a synpharyngitic type of hematuria appearing within 24-72 hours

The first episode of macrohematuria occurs between 15-30 years , a decade before the biopsy diagnosis
is made

Asymptomatic microhematuria and non nephrotic proteinuria: Most common presentation

Nephrotic syndrome: 5%

AKI:<5%

Accelerated hypertension: 5% of the cases

ESRD incidence:

Less than 10% of the patients have complete resolution of the urinary abnormalities

25-35% of the patients progress to ESRD over 20-25 years

15% patients have CKD 3 at presentation

In under privileged areas they present with dialysis requiring renal failure
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HENOCH SCHONLEIN PURPURA

Most common age group: 3 to 15 years

Most common in winter, spring and autumn

Slight male preponderance exists

Renal disease is often transient and reversible

Hematuria and proteinuria resolve within few weeks

AKI due to crescentic disease is more common than in IgAN

10% will develop ESRD

Classic tetrad:
Palpable purpura/rash – extensor, symmetric and crops. Absent in trunk and face
Abdominal pain – mild to GI hemorrhage, infarction, perforation and intususception
Renal involvement – Asymptomatic hematuria/proteinuria ; NS/AKI are more common in adults
Arthritis/Arthralgia – transient, swelling no chronic damage

Symptoms evolve over days to weeks and can appear in any order
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MPGN:
No sex predilection

Affects children and young adults

1/3rd: Hypertension / Nephrotic syndrome and renal dysfunction

Acute nephritic syndrome (20–30%)

Asymptomatic proteinuria and hematuria detected on routine urinalysis (20–30%)

Recurrent episodes of gross hematuria (10–20%)

Preceding respiratory tract infection in 50%

Anemia out of proportion to renal failure

It is not clinically possible to differentiate the various types of MPGN

Drusen appearing in the 2nd decade and APD are suggestive of MPGN Type 2

C3Nef is positive in 80% of patients with Type 2 MPGN

Complement in various types of MPGN:

1 Classical pathway activation ; Low c4
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2Alternate pathway activation ; Low C3

3Alternate and terminal pathway activation ; Low c3 and Low c5 to 9

Natural history:
Children->more acute presentation and gradual progression to ESRD than adults

40% ESRD by 10 years

Renal dysfunction and nephrotic syndrome at onset and persistent proteinuria are predictors of
progression.

MEMBRANOUS GLOMERULONEPHRITIS
Most common cause of nephrotic syndrome in adults

Slight male preponderance 1.3-2.2:1

Typical onset: 4th to 5th decade

Rare in children (<5%)

There is very little variation in MGN across the globe

70-80% of membranous nephropathy is idiopathic membranous nephropathy

It is the most common type associated with malignancy

10% of MGN is associated with malignancy and 70% of the cases of nephrotic syndrome associated with
malignancies are MGN

For MN associated with malignancy, the two conditions are usually identified within 12 months of
diagnosis of each other in 80% of the individuals.

50-90% present with nephrotic syndrome

30-50% present with hypertension usually with a normal renal function

20% present with abnormal renal function usually of the mild-moderate degree

AKI is rare and should prompt workup for other causes  Diuresis, nephrotoxic medication use,
crescentic transformation and bilateral renal vein thrombosis
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Rule of 1/3rd

1/3rd Spontaneous remission  these occur within a mean of 1 year(but can take upto 2 years) and may
be complete or partial

1/3rd Stable renal function

1/3rd progressive deterioration

Incidence of thromboembolism is increased in MGN compared to other pathologies (3-48%)

Survival:

10-year survival is 100,90 and 50% in patients with complete, partial and no remission

20% patients with heavy proteinuria undergo spontaneous remission

66% of patients with heavy proteinuria(more than 8g/d) progress to ESRD

ANTI GBM DISEASE:

Accounts for 10-20% of the crescentic GN (one fifth)

Biphasic incidence: First peak: 2-3rd decade; Higher in men and presents with pulmonary hemorrhage

Second peak: 6-7th decade; more frequent in women and presents with isolated GN

RPGN with pulmonary hemorrhage as a presentation: 50%

Systemic symptoms are uncommon ; Symptoms related to anemia and renal failure may be manifested

Isolated renal or pulmonary involvement may occur.

Pulmonary hemorrhage manifestations:

Unexplained anemia
Railsed DlCO
CT pulmonary hemorrhages
BAL confirms with hemosiderin laden macrophages

Relapses are rare ; Pulmonary hemorrhage may recur if there are precipitants

Precipitants:
Smoking ; Hydrocarbons ; URTI ; SVV ; MGN ; Lithotrpsy ; Alemtuzumab

Anuria may be the presenting feature of one-fifth of the patients

Macroscopic hematuria is rare

Anand Chellappan