This lecture was conducted during the Nephrology Unit Grand Ground by Medical Student rotated under Nephrology Division under the supervision and administration of Prof. Jamal Al Wakeel, Head of Nephrology Unit, Department of Medicine and Dr. Abdulkareem Al Suwaida, Chairman of Department of Medicine. Nephrology Division is not responsible for the content of the presentation for it is intended for learning and /or education purpose only.

Presented by: Ameera Al-Ghorabi Medical Student June 2008

Definition Epidemiology Pathophysiology Presentation Renal Biopsy Management

Epidemiology… Prevalence : 40 – 75 %  racial differences in the disease prevalence  risk of nephropathy  definitions of the nephropathy Lupus 2002; 11 : 152 Tow largest cohort studies  among 1000 pt. from 12 clinical centers 16% had nephropathy at Dx of SLE 39% had nephropathy after 8 y of Dx 28% had nephropathy after 10 y of Dx Medicine (Baltimore) 2003; 82:299.

11 378 pt. with SLE 1 y  32 % had renal disease 9y  47% had protein excretion >0.5 g/d  6% had decreased GFR  4% had ESRD Arthritis Rheum 2005; 52:4003. **Most renal abnormality emerge soon after diagnosis and the time course for the development of lupus nephritis varies with gender, age and ethnicity. Am J Med 2002; 112:726.

Definition Epidemiology Pathophysiology Presentation Renal Biopsy Management

Pathogenesis… Immune-complex mediated  DNA-Anti-DNA  site of deposition Glomerulonephritis… mesangium and subendothelial space  histologically : mesangial (I) or (II) focal (III) diffuse (IV)  clinically : urine sediment proteinuria acute decline in renal function Large immune complexes or anionic antigenes

Subepithelial space  histologically : membranous (V)  clinically : protienuria Small complexes or cationic antigenes

Definition Epidemiology Pathophysiology Presentation Renal Biopsy Management

How can it be detected… HTN or signs of nephrotic syndrome Serum U/E Urinalysis

Definition Epidemiology Pathophysiology Presentation Renal Biopsy Management

Renal biopsy… 1)Establishing the specific diagnosis. 2)Identification of the presence and severity of tubulointerstitial or vascular disease. 3)Uncertainty of lupus. Repeat renal biopsy: PP t. on therapy 1) persistent nephrotic syndrome 2) urinary sediment 3) serum creatinine  pt. off therapy 1) late recurrence of the disease * membranous nephropathy Am J Kidney Dis 1999; 34:530.

Definition Epidemiology Pathophysiology Presentation Renal Biopsy Management

Management… Immunosuppressive Therapy Non-immunologic Therapy

Immunosuppressive Therapy… Corticosteroids in combination with a number of agents, such as cyclophosphamide, chlorambucil, cyclosporine, mycophenolate mofetil, azathioprine and tacrolimus. Goal of I.S. therapy  clinical remission * American College of Rheumatology 1 ) Renal function: Imroved = increase GFR Stable = no change in GFR Worsened = decrease GFR 2 )Proteinuria: Complete response  protein : creatinine ratio < 0.2 Partial response  protein : creatinine ratio Stable  no change Worsened  > 100% increase 3 )Urinary sediment: Improved : active  inactive Worsened : inactive  active Arthritis Rheum 2006; 54:421.  Maximum reduction in protien function is much later than the resolution of the activity of urine sediment  There may be some degree of irreversible proteinuria as healing of inflammatory process can lead to permanent glomerular scarring

Importance of clinical remission : Guide us to the necessity of continued the I.S. therapy and the prognosis of the disease  No remission  Partial remission  Complete remission

Management… Immunosuppressive Therapy Non-immunologic Therapy

Non-immunologic Therapy… Aggressive antihypertensive and antiproteinuric therapy with an ACEI, often in combination with an ARB.  BP < 130/80  protein excretion < 500 – 1000 mg/d Aggressive lipid lowering with statin therapy.  serum LDL cholesterol < 80 – 100 mg/dl ** Generally initiated when relevant laboratory values are above these goals…  mild to moderate lupus nephritis  more severe lupus nephritis

Definition Epidemiology Pathophysiology Presentation Renal Biopsy Management

Classification…

Classification… Class I  minimal mesangial Lupus Nephritis Class II  mesangial proliferative Lupus Nephritis Class III  Focal proliferative Lupus Nephritis Class IV  diffuse proliferative Lupus Nephritis Class V  membranous Lupus Nephritis Class VI  advanced sclerosis Lupus Nephritis

Class I …Minimal mesangial Lupus Nephritis  mesangial immune deposits  earliest and mildest Class II … Mesangial proliferative Lupus Nephritis Histologically  mesangial hypercellularity Clinically  microscopic heamaturia or proteinuria  No HTN or Renal insufficiency not indicated ** Therapy is not indicated excellent ** Prognosis is excellent

Class III …Focal proliferative Lupus NephritisClass III …Focal proliferative Lupus Nephritis * Histologically  subendothelial deposits,, < 50 % (25% – 50% )  mesangial deposits  subclasses *Clinically  heamaturia,, proteinuria,, HTN,, raised Cr  Renal dysfunction uncommon *Therapy  Mild ( < 25 %)  Severe ( 50 %) *Prognosis  Mild ( < 25 %)  Severe ( >25 %)

Class IV … Diffuse Proliferative Lupus NephritisClass IV … Diffuse Proliferative Lupus Nephritis *most common and most severe form of lupus nephritis * Histologically  subendothelial deposits,, > 50 %  mesangial deposits  subclasses *Clinically  heamaturia,, proteinuria,, N.S.,, HTN,, Renal insufficiency  hypocomplementeneamia,, raised anti-DNA levels,, ** crescent formation**

Class IV … Diffuse Proliferative Lupus NephritisClass IV … Diffuse Proliferative Lupus Nephritis *Therapy Induction Therapy :  pulse corticosteroid ( IV methylprednisolone )  cytotoxic agents ( cyclophosphamide,, mycophenolate,,) Maintenance Therapy : 1) oral azathioprine or mycophenolate 2) IV cyclophosphamide 3) cyclosporin

Class IV … Diffuse Proliferative Lupus NephritisClass IV … Diffuse Proliferative Lupus Nephritis * Prognosis  Aggressive I.S. Therapy will lead to improvement in 50% – 70 %  recurrence = 50 % and 1/3 = ESRD cyclophosphamide prednisolone ** one study showed that avoiding ESRD at 10 – 20 y was 90% following therapy with cyclophosphamide v.s. only 20% with prednisolone alone. Kidney Int 1986; 30:769

Class V … membranous Lupus NephritisClass V … membranous Lupus Nephritis * *Histologically  supepithelial immune deposits  diffuse basement membrane thickening  mesengeal findings ** subendothelial deposits * Clinically signs of N.S.  signs of N.S.  micro. heamaturia,, HTN,,  plasma Cr. Is usu. normal * It may present with no other signs of SLE however,,, 1 ) Tubuloreticular structures in endothelial cells 2)Subendothelial or Mesangial deposits 3) Immune deposits along the tubular basement membranes and in the small blood vessels Kidney Int 1983; 24:377.

Class V … membranous Lupus NephritisClass V … membranous Lupus Nephritis *Therapy 1) Asymptomatic non-nephrotic proteinuria 2) Nephrotic syndrome 3) Marked nephrotic syndrome or a rising serum creatinine * Prognosis  normal serum Cr. For 5 y and pt. may not need IS therapy  with IS Kidney survival rate = 93% Clin Nephrol 1993; 39:175.

Class VI … Advanced sclerosis Lupus NephritisClass VI … Advanced sclerosis Lupus Nephritis  Represents : *Healing of prior inflammatory injury *Advanced stage of chronic class III, IV, or V lupus nephritis  Histologically :* Global sclerosis of more than 90 percent of glomeruli *Active lupus nephritis should not be observed. slowly progressive renal dysfunction  Clinically : slowly progressive renal dysfunction in association with a relatively bland urine sediment  Therapy and Prognosis : immunosuppressive therapy is unlikely to be beneficial for inactive inflammatory disease.