1. Minimal change disease

2. Introduction
Nephrotic syndrome is kidney disease with proteinuria, hypoalbuminemia, and edema. Nephrotic range proteinuria is 3 grams per day or more
Nephrotic syndrome may affect adults and children, of both sexes and of any race
MCNS: no changes under light microscopy. No signs of inflammation, immune complex deposition or schlerosis.
FSGS: collapse of the glomerular capillaries with sclerosis and hyalinosis and the formation of adhesions of the glomerular tuft 2

3. Nephrotic syndrome (NS)
Classification
Nephrotic syndrome can be primary, being a disease specific to the kidneys, or it can be secondary, being a renal manifestation of a systemic general illness
In all cases, injury to glomeruli is an essential feature

4. Primary causes of nephrotic syndrome (NS)
Include, in approximate order of frequency :
Minimal-change nephropathy
Focal glomerulosclerosis
Membranous nephropathy
Hereditary nephropathies

5. Secondary causes of NS
Include, again in order of approximate frequency :
Diabetes mellitus
Lupus erythematosus
Amyloidosis and paraproteinemias
Viral infections (eg, hepatitis B, hepatitis C, human immunodeficiency virus [HIV] )
Preeclampsia

6. Minimal change disease
Most common cause of the nephrotic syndrome (NS) in children
~10-15% of NS in adults, third most common after MN and FSGS
More common in Hispanics, Asians, Arabs and Caucasians
Clinical and pathological entity defined by selective proteinuria and hypoalbuminemia that occurs in the absence of
cellular glomerular infiltrates or
immunoglobulin deposits
MCNS: no changes under light microscopy. No signs of inflammation, immune complex deposition or schlerosis.
FSGS: collapse of the glomerular capillaries with sclerosis and hyalinosis and the formation of adhesions of the glomerular tuft

7. NS in infancy and childhood is an important entity
A study from New Zealand found the incidence of nephrotic syndrome to be almost 20 cases per million children under age 15 years 1
In specific populations, such as those of Finnish or Mennonite origin, congenital nephrotic syndrome may occur in 1 in 10,000 or 1 in 500 births, respectively 2
1. J Paediatr Child Health. May 2007;43(5):337-41
2. Pediatr Nephrol. Dec 2004;19(12):1313-8

8. According to the International Study of Kidney Diseases in Childhood (ISKDC)
84.5% of all children with primary nephrotic syndrome have minimal-change nephrotic syndrome (MCNS)
9.5% have focal segmental glomerulosclerosis (FSGS)
2.5% have mesangial proliferation, and
3.5% have membranous nephropathy or another cause of the disease 1,2
MCNS remains the most important cause of chronic renal disease in children
1. Kidney Int. Dec 1981;20(6):765-71
2. J Pediatr. Apr 1981;98(4):561-4

9. Pathophysiology
Primary urine is formed through the filtration of plasma fluid across the glomerular barrier; the glomerular filtration rate (GFR) is 125 mL/min
The plasma flow rate (Qp) is close to 700 mL/min, with the filtration fraction being 20%
The concentration of albumin in serum is 40 g/L, while the estimated concentration of albumin in primary urine is 4 mg/L, or 0.1% of its concentration in plasma
GBM = glomerular basement membrane; Endo = fenestrated endothelial cells; ESL = endothelial cell surface layer (often referred to as the glycocalyx).

10. The barriers that keep protein and blood cells out of the urine
The barriers that keep protein and blood cells out of the urine. These are the endothelial cell, basement membrane and epithelial cell (podocyte). The epithelial cell (podocyte) seems to be most important. Injury to these barriers causes proteinuria and hematuria

11. Pathophysiology (contd.)
The glomerular structural changes that may cause proteinuria are
- (1) damage to the endothelial surface,
- (2) damage to the glomerular basement membrane,
- and/or (3) damage of the podocytes
In congenital nephrotic syndrome, the gene for nephrin, a protein of the filtration slit, is mutated, leading to nephrotic syndrome in infancy

12. Pathophysiology (contd.)
Albuminuria alone may occur, or, with greater injury, leakage of all plasma proteins, (ie, proteinuria) may take place
Proteinuria that is more than 85% albumin is selective proteinuria
In minimal-change nephropathy, proteinuria is selective

13. Minimal Change Disease Pathology

14. Pathogenesis of edema
An increase in glomerular permeability leads to albuminuria and eventually to hypoalbuminemia
In turn, hypoalbuminemia lowers the plasma colloid osmotic pressure, causing greater transcapillary filtration of water throughout the body and thus the development of edema
A reduction in plasma volume, with a secondary increase of sodium and water retention by the kidneys

16. Metabolic consequences of proteinuria
levels of serum lipids are usually elevated
The loss of antithrombin III and plasminogen and increase in clotting factors, especially factors I, VII, VIII, and X, increases the risk for venous thrombosis and pulmonary embolism
Hypovitaminosis D - malabsorption of Ca++
Lower the patient's resistance to infections and increase the risk of sepsis and peritonitis

17. Light microscopy of glomerulus in MCD
MCD has no glomerular lesions by light microscopy.
the thickness of the glomerular capillary walls is normal, the thickness of the glomerular capillary wall (long arrow) is similar to that of the tubular basement membranes
and there is neither expansion nor hypercellularity in the mesangial areas in the central or stalk regions of the tuft (arrows). Courtesy of Helmut G Rennke. 17

18. Immunofluorescence Microscopy
Shows no staining with antisera specific for IgG, IgA, IgM, C3, C4, or C1q. Absence of humoral components of the immune system
There are occasional specimens that will have small amounts of exclusively mesangial immunoglobulin (especially IgM) or complement accumulation that can still be designated minimal change glomerulopathy. A little bit of mesangial IgM and/or C3 without ultrastructural evidence for electron dense deposits is tolerable for a diagnosis of minimal change glomerulopathy.
Well defined mesangial electron dense deposits, however, worsen the prognosis for response to steroids or spontaneous remission. Thus, if there are electron dense deposits, minimal change glomerulopathy is not an appropriate diagnoses.

19. Electron Microscopy
Characteristic histologic finding in MCD is diffuse effacement of the epithelial ceel foot proces on EM. A finding also observed with FGS
Electron micrograph in minimal change disease showing a normal glomerular basement membrane (GBM), no immune deposits, and the characteristic widespread fusion of the epithelial cell foot processes (arrows). Courtesy of Helmut Rennke, MD.

20. The glomerular capillary wall
Normal
MCD
Cross-sections of the glomerular capillary wall in a non-proteinuric patient (A and B) and in a patient with MCNS (C and D) as revealed by electron microscopy. cell bodies of podocytes (P) extend into the urinary space, while their foot processes attach to the GBM.
In normal individuals, foot processes are arranged in a regular interdigitating pattern (B) with interconnecting slit diaphragms (small arrows).
In nephrotic patients, foot processes are irregularly flattened and show distorted slit diaphragms (D; arrowhead).
US, urinary space; CL, capillary lumen. Magnification, × (A and C) and × (B and D).
Van den Berg, Weening, Clinical Science (2004) 107, 125–136

21. Pathogenesis - “Intrinsic factor”
Genetic basis for hereditary NS
NS of the Finnish type
Autosomal-recessive steroid-resistant NS
Familial forms of FSGS
Diffuse mesangila sclerosis associated with Denys-Drash syndrome and with Frasier syndrome
NS associated with nail-patella syndrome
Help elucidate molecular aspect of FSGS
Not clear for MCD
recent genetic approaches to familial idiopathic nephrotic syndromes have been determining factors in elucidating several molecular aspects of focal glomerular sclerosis

22. Molecular anatomy of the podocyte foot process cytoskeleton
These proteins include molecules that
locate at the slit diaphragm (nephrin, neph1, podocin, CD2AP and the Src family kinase Fyn), transcription factors (WT-1, Lmx1B, Pod1 and Krml1/MafB), cytoskeletal components (α-actinin-4 and RhoGDIα), adhesion molecules (α3 integrin) and components of the GBM (S-laminin/laminin β2)
1. a contractile system composed of actin, myosin-II, -actinin-4, talin, vinculin and synaptopodin that is connected to the GBM via 31 integrin.
2. The linkage of the actin cytoskeleton to the slit diaphragm components, nephrin and P-cadherin, may be mediated by CD2AP or by a complex of ZO-1, -, - and -catenin.
3. The localization of podocin in the podocyte cell membrane remains to be established. The actin cytoskeleton is well suited to integrate different signalling pathways from the matrix:GBM interface, the slit diaphragm or the cell surface. Disruption of any of these pathways may lead to reorganization of the actin cytoskeleton and foot process effacement as seen with nephrotic syndrome. N, nephrin; P-C, P-cadherin; , -catenin; , -catenin; , -catenin; Z, ZO-1; 3, 3-integrin; 1, 1−integrin; V, vinculin; T, talin; P, paxillin; -act-4, -actinin-4; synpo, synaptopodin.
There’s been studies which show that nephrin may be involved in MCD but to date most genetic and animal models have shown FSGS
Nature Genetics  24, (2000)

23. Pathogenesis – extrinsic factor, better explanation for MCD
Clinical Observations - Shalhoub’s hypothesis
MCD frequently remits with measles infection
Corticosteroids and alkylating drugs cause a remission
Association of MCD with Hodgkin disease
Experimental Observations
T cell hybridoma (Koyama KI 1991 (40): )
Removal of glomerular permeability factor leads to normal kidney (Ali Transplantation 1994 Oct 15;58(7):849-52)
“circulating factor”
possible link between T-cell response and glomerular disease
Clinical observations…
-MCD frequently remits with measles infection (viral-associated immunosuppresion)
-the therapeutic benefits of steroids and cyclophosphamide which abate cell-mediated responses
-and the occurrence of this syndrome in Hodgkin's disease support this hypothesis.
Taken together, the data suggest that this syndrome is a clinical expression of a self-limited primary immune-deficiency disease.
Experimental observations…
Clinical observations suggest that lipoid nephrosis is produced by a systemic abnormality of T-cell function resulting in the secretion of a circulating chemical mediator toxic to an immunologically innocent glomerular basement membrane.
In study by Koyama, where T cell hybridomas was derived from the T cells of a patient with MCD, and injection of supernatants from the T-cell hybridoma from patients in relapse into rats caused immediate proteinuria and glomerular podocyte foot process fusion, where as no changes were ntoed when the T-cell hybridoma supernatants from healthy controls was fused.
- ideal of glomerular permeability factor (GPF).
- The molecular weight of the factor and its TNF like activity, we speculated that the factor was a lymphokine, like lymphotoxins.
This is supported by intriguing observation that transplantation of a kidney from a patient with refractory MCD resulted in rapid disappearance of proteinuria in the recipients.

24. MCD is a disorder of T cells
T-cells release a cytokine that injures the glomerular epithelial foot processes
This leads to a decreased synthesis of polyanions
The polyanions constitute the normal charge barrier to the filtration of macromolecules, such as albumin
When the polyanions are damaged, leakage of albumin follows
The identity of this circulating permeability factor is uncertain, although it is postulated that it may be hemopexin

25. Some of the cytokines that have been studied in MCD are interleukin-12 (IL-12) and interleukin-4 (IL-4)
IL-12 levels have been found to be elevated in peripheral blood monocytes during the active phase and normalized during remission
Interleukin-18 (IL-18) can synergize with IL-12 to selectively increase the production of vascular permeability factor from T cells
In addition, levels of IL-4 and CD23 (a receptor for immunoglobulin E [IgE] 1 have been found to be elevated in peripheral blood lymphocytes
1. Am J Med Sci. Oct 2009;338(4):264-7

26. Interleukin-13 (IL-13) has been implicated in the pathogenesis of MCD.
Synaptopodin is a proline-rich protein intimately associated with actin microfilaments present in the foot processes of podocytes
Greater synaptopodin expression in podocytes is associated with a significantly better response to steroid therapy
Interleukin-13 (IL-13) has been implicated in the pathogenesis of MCD.
IL-13 genetic polymorphisms correlate with the long-term outcome of MCD.
IL-13 overexpression can cause podocyte foot process fusion and proteinuria 1
1. May 2007;18(5):

27. Overexpression of Interleukin-13 Induces Minimal-Change– Like Nephropathy in Rats
Background
MCD may be a T cell dependent disorder that results in glomerular podocyte dysfunction
Th2 cytokine bias in patients with MCD
MCD associated with atopy and allergy
Relapse MCD with elevated IL-4 and IL-13
Association between MCD and Hodgkins’s disease
IL-13 known to be an autocrine growth factor for the Reed-Sternberg 27

28. Hypothesis
IL-13 may play an important role in the development of proteinuria in MCNS by exerting a direct effect on podocytes, acting through the IL-13 receptors on the podocyte cell surface, initiating certain signaling pathways that eventually lead to changes in the expression of podocyte-related proteins (nephrin, podocin, and dystroglycan)
IL-13 transfected mouse was used as a model

29. Mean 24-h urine albumin excretion (mg/24 h)
Mean 24-h urine albumin excretion (mg/24 h) of control rats (n = 17) and IL-13–transfected rats (n = 41) measured at 14-d intervals. Data are means ± SEM. 29

30. Comparison of control, IL-13-transfected mouse at experiment end (day 70)
Parameter
Control Rats (n=17)
Group 1 (proteinuric rats), n=34
Grp 2: neprhrotic rats n=7
Serum albumin
/- 1.8
/- 1.3
/- 2.2
Urine albumin
0.36 +/- 0.04
/- 0.98
/- 4.07
Serum cholesterol
/- 0.05
/- 0.18
/- 1.09
Serum IL-13
7.1 +/- 1.8
/- 69.5 /
Nephrin
0.16 +/- 0.03
0.11 +/- 0.01
0.01 +/
Podocin
0.25+/- 0.05
0.17 +/- 0.02
Yellow = p <0.001 vs control
Red = p<0.001 vs control and Grp 1

31. Histopathologic features on day 70 at killing (A) Glomerulus of IL-13–transfected rat showing no significant histologic changes (periodic acid-Schiff stain). (B) Glomerulus of IL-13–transfected rat showing fusion of podocyte foot processes (arrows). (C) Glomerulus of control rat showing normal individual podocyte foot processes along the glomerular basement membrane (GBM; arrows).

32. Control
IL-13 infected
Immunofluorescence staining of glomeruli for protein expression of nephrin, podocin, dystroglycan, and synaptopodin
nephrin
podocin
Immunofluorescence examination showed that nephrin, podocin, and dystroglycan all stained strongly as a continuous granular pattern along the GBM in the control rats.
This was in contrast to the nephrotic rats, in which the fluorescence signal was much weaker and in a discontinuous, and sometimes segmental, granular pattern along the GBM
Of note, there was no significant difference between the control and nephrotic rats in the expression of synaptopodin, which showed strong and continuous staining along the GBM. In FSGS usually podocytopenia results where there’s decrease in the number of podocyte 2/2 stress, injury, intrinsic factor. IN MCD, there’s a phenotypic change with decrease in absolute no of podocyte.
dystroglycan
synaptopodin 32

33. Summary IL-13-transfected rats
Developed minimal change like GN, as evidence by LM and EM changes
decrease in the expression of nephrin, podocin, and dystroglycan associated with increased urinary albumin excretion and podocyte foot process effacement
suggesting that these proteins are essential in maintaining the filtration barrier, thus controlling glomerular permeability
decrease was not due to loss of podocytes -
…. , because the glomerular expression of WT-1 and synaptopodin, which are specific cell surface markers of podocytes, showed no significant difference between the control rats and the IL-13–transfected rats 33

34. In patients who develop acute renal failure, endothelin 1 expression is greater in the glomeruli, vessels, and tubules than in the nonacute renal failure group
The glomerular epithelial cells (podocytes) and the slit diaphragm connecting the podocyte foot processes play a primary role in the development of proteinuria
Nephrin is a major component of the slit diaphragm. The slit diaphragm is often missing in MC nephrotic syndrome (MCD) kidneys
The role of nephrin and the slit diaphragm in MCD is not known. However, genetic variants of a glomerular filter protein may play a role in some patients with MCD

35. Izzedine et al found a lack of glomerular dysferlin expression associated with minimal-change nephropathy in a patient with limb-girdle muscular dystrophy type 2B. 1
In the same study, 2 of 3 other patients with dysferlinopathy had microalbuminuria
Although a multitude of studies have been published, the mechanism by which T cells increase glomerular permeability has remained unproven
1. Am J Kidney Dis. Jul 2006;48(1):143-50

36. Frequency Asians may be at increased risk.
United States - In preadolescents, minimal-change nephrotic syndrome (MCNS) makes up 85-95% of all cases of nephrotic syndrome
In adolescents and young adults, the prevalence is 50%, while in adults, MCNS accounts for 10-15% of primary nephrotic syndrome cases.
The incidence of nephrotic syndrome is 2-7 new cases annually per 100,000 children, and the prevalence is 15 cases per 100,000 children
Asians may be at increased risk.

38. Incidence of important causes of nephrotic syndrome, in number per million population
The left panel shows systemic causes, and the right panel lists primary renal diseases that can cause nephrotic syndrome.
fgs = focal glomerulosclerosis,
MN = membranous nephropathy,
min change = minimal-change nephropathy
Clin J Am Soc Nephrol. May 2006;1(3):483-7
Nephrol Dial Transplant. 2007;22:

39. Sex / Age It is found twice as frequently in boys than in girls
The frequency is the same between the sexes in adults
The incidence peaks in children aged 2 years, with approximately 80% being younger than 6 years at the time of diagnosis
In adults, the mean age of onset is 40 years.

40. A schema of the average patient ages associated with various common forms of nephrotic syndrome

41. History
Edema may be preceded by an upper respiratory tract infection, an allergic reaction to a bee sting, or the use of certain drugs or malignancies.
Facial edema is noted first.
Malaise and easy fatigability can occur.
Weight gain often is an additional feature.
The patient also may present with the following:
Hypovolemia
Hypertension
Thromboembolism
Infection

42. Physical
BP - usually is normal in childrenbut may be elevated in adults
Dependent edema is the most prominent sign. The retina has a wet appearance. Subungual edema with horizontal lines (called Muehrcke lines) also may occur.
Hernias may be found, and the elasticity of the ears may be decreased.
Heavy proteinuria - leads to a state of protein depletion with muscle wasting, thinning of the skin, and growth failure
Pleural and ascitic fluid can accumulate. Rarely, cellulitis, peritonitis, or pneumonia
Children may have growth failure.

43. Causes
Almost all cases are idiopathic, but a small percentage of cases (approximately 10-20%) may have an identifiable cause
Causes may include the following: Secondary
Drugs - Nonsteroidal anti-inflammatory drugs (NSAIDs), rifampin, interferon, ampicillin/penicillin, trimethadione, mercury-containing cosmetic skin cream
Toxins - Mercury, lithium, bee stings, fire coral exposure
Infection - Infectious mononucleosis, HIV, immunization
Tumor - Hodgkin lymphoma (most commonly), carcinoma, other lymphoproliferative diseases
Posthematopoietic stem cell transplant

44. Laboratory Studies
Urine analysis - profound proteinuria and oval fat bodies observed.
In children, the critical level for diagnosis is more than 40 mg/h/m2.
In adults, the threshold is more than 3.5 g/d/1.73 m2.
Albumin-to-creatinine concentration ratio is in excess of 5.
Urine specific gravity is high because of proteinuria.
A 24-hour urine is obtained for protein and creatinine clearance.
Hypoalbuminemia - Nephrotic syndrome in children is defined by a serum albumin of less than 2.5 g/dL.
Hyperlipidemia also is a feature of a nephrotic state.
Renal function usually is normal except in cases of ARF
Hyponatremia often is observed,
Elevated hemoglobin and hematocrit

45. Imaging Studies - Renal sonogram is normal.
Procedures
Because of the high prevalence of MCD in children with nephrotic syndrome, an empiric trial of corticosteroids commonly is the first step in therapy
Renal biopsy typically is performed only in resistant cases
Generally, if proteinuria remains after 2 relapses or courses of steroids, a tissue diagnosis should be made before starting cytotoxic or immunosuppressive therapy

46. Medical Care
Corticosteroids are the treatment of choice, leading to complete remission of proteinuria in most cases
Approximately 90% of children respond within 2 weeks to prednisone at a dose of 60 mg/msq/d.
The treatment is continued for another 6 weeks, at lower doses of prednisone, after the remission of proteinuria.
In some children, proteinuria fails to clear by 6-8 weeks, and performing a renal biopsy may be useful to determine if another process may be present

47. Adults respond more slowly than children
A response in up to 80-90% in adolescents and adults
The time to remission is up to 16 weeks. If patients are steroid-resistant or they relapse frequently, a trial of immunosuppressants is given
Immunosuppressants - cyclophosphamide and chlorambucil
Cyclosporine is considered to be an acceptable drug for maintenance therapy in patients with frequent relapses and steroid dependency. However, it is less efficacious than cyclophosphamide at maintaining sustained remission

48. Leg edema in MCD before treatment after treatment

49. Response of patients to steroids is used to divide patients into various groups.
Complete remission: This is defined as complete resolution of proteinuria for at least 3-5 consecutive days.
Partial remission: This is defined as a reduction in the degree of proteinuria without complete clearing.
Relapse: This is defined as a reoccurrence of proteinuria for at least 3-5 consecutive days.

50. Because MCNS accounts for 90% of all cases of idiopathic nephrotic syndrome in children, steroids are started empirically. A biopsy is performed only in those cases where no remission occurs
In comparison, a biopsy is performed in all adults before the initiation of treatment. Adults tend to respond more slowly, with more than 25% taking as long as weeks to undergo complete remission
Initial regimen in adults consists of oral prednisone in a daily dosage of 1 mg/kg of body weight for 8-16 weeks (or for 1 wk after remission has been induced). The patient is then placed on an alternate-day single-dose (1 mg/kg) regimen to minimize the incidence of adverse effects.
If proteinuria disappears or is reduced to a very low level, high-dose alternate-day therapy is continued for several weeks to 1 month and then slowly tapered over several months in an attempt to reduce the likelihood of relapse

51. To prevent relapse, steroids are continued for several weeks after remission.
Steroid-sensitive patients: These patients have complete remission within 8-12 weeks with infrequent relapses. Children usually respond within 4-6 weeks, whereas adults respond in up to 15 weeks. Treatment usually is continued for another 6 weeks after complete remission of proteinuria occurs.
Steroid-dependent patients or frequent relapsers: If remission is followed by recurrence, a second course of steroids is given. Those patients who need steroids repeatedly are categorized as frequent relapsers or steroid-dependent patients. Relapse in these patients can occur either during tapering of steroids or after cessation of therapy.

52. How does steroid work in MCD?
Widely used in treatment but their mode of action is poorly understood
What is its effectiveness in MCD where there is no evident inflammation 52

53. Steroid – quick overview
Inhibitory effects on both innate and acquired immunologic function
Innate Immune function
Reduced Inflammatory response:
inhibit transmigration of leukocytes
attenuate the generation of inflammatory exudates
Phospholipase A2 suppresion
COX-2 suppression
Acquired Immune function
Antigen presenting cells, B cell and T cells
Innate Immune function
reduced inflammatory response
attenuate expression of adhesion molecules on endothelial and leukocytes (via inhibition of IL-1 and TNF) = thereby inhibiting transmigration of leukocytes
Inhibiting generation of inflammatory exudates
Suppressing production of inflammatory eicosanoids in phagocytic cells by inducing the synthesis of lipocortin-1 (annexin I), macrocortin, and/or lipomodulin, all of which inhibit phospholipase A2 (PLA2)-mediated liberation of arachidonic acid from membrane phospholipids [9-12].
Suppressing the synthesis of cyclooxygenase-2 (COX-2), the inducible isoform of cyclooxygenase primarily responsible for production of prostaglandins at sites of tissue injury and inflammation [13]. This effect primarily results from glucocorticoid suppression of NF-kB transcription. Glucocorticoids do not appear to affect the synthesis of constitutive cyclooxygenase-1
Inflammatory response:
-attenuate expression of adhesion molecules on endothelial and leukocytes
-attenuate the generation of inflammatory exudates 53

54. Overview of Intracellular Effects
Molecular mechanisms of neurotransmitter and glucocorticoid regulation of cytokine production
Glucocorticoids bind to glucocorticoid receptors in the cytosol, which displaces heat-shock protein 90 (HSP90) and allows receptor dimerization, movement into the nucleus and binding of the glucocorticoid–glucocorticoid-receptor complex to DNA. This leads to transcription and translation of proteins, including inhibitor of nuclear factor-B (IB).
IB then sequesters NF-B, preventing it from activating transcription of pro-inflammatory cytokines.
In addition, the glucocorticoid–glucocorticoid-receptor complex can interact with NF-B directly to suppress cytokine production136 54

55. Could steroid have more direct effect in kidney?

56. Direct effects of dexamethasone on human podocyte – Xing, Saleem, et al
Hypothesis:
Glucocorticoid exert direct protection of podocytes from injury and/or promotion of repair
Nephrin: podocyte specific protein
mutation of NPHS2 gene - cause congenital nephrotic syndrome of Finnish type
Studies show possible downregulation of nephrin in MCD
Study of dexamethasone on FSGS but can be translated to MCD? 56

57. Result – effects of dexamethasone on podocyte maturation at 37 C and expression of nephrin
Immunofluorescent staining
We found that dexamethasone enhanced and accelerated podocyte maturation, with a particularly striking effect on expression of nephrin
Nephrin expression was upregulated after 14 days incubation with dexamethasone (Figure 2).
Immunofluorescent staining is not regarded as a quantitative technique, but there is a striking difference in the amount of fluorescence seen in images taken on identical exposure settings with anti-nephrin rabbit polyclonal antibody K2966 according to the presence or absence of dexamethasone in the culture medium for 14 days (Figure 2a, no dexamethasone, Figure 2b, cells incubated with 10-5 M, Figure 2c negative control immunofluorescence with rabbit immunoglobulin (Ig) for comparison).
Quantitation by Western blot with rabbit polyclonal anti-nephrin antibody K2737 confirmed dose-dependent upregulation of nephrin protein by dexamethasone (Figure 2d, representative of five replicate experiments). Nephrin is a large-molecular-weight membrane-bound protein and is known to be difficult to blot, accounting for the indistinct bands. We therefore show detailed densitometric quantification of three replicate Western blots, which showed nephrin/actin ratios of 1.0:1.33:1.618 with 0, 10-7, and 10-5 M dexamethasone, respectively (P<0.05, Figure 2e).
Reverse transcriptase-polymerase chain reaction (RT-PCR) suggested that this effect was at least partly at the RNA level (Figure 2f, representative of five replicate experiments). Expression of other key podocyte proteins, including podocin,5CD2-associated protein,7 and synaptopodin10 was unaffected by dexamethasone (data not shown).
Quantificaton of nephrin 57

58. Summary
Dexamethasone enhanced and accelerated podocyte maturation, with a particulary striking effect on expression of nephrin 58

59. Other steroid response
In disease state
With dexamethasone
p21
Upregulated
downregulation allow podocyte to enter the cell cycle – enhance ability to repair
VEGF
a mitogen for vascular endotheila cells
Downregulated
p52
Induces apoptosis
downregulated
Podocytes’s capacity for replication
Role of p21
Upregulated in diseases characterized by podocyte injury
Enhanced podocyte survival
p21 downregulation allow podocyte to enter the cell cycle – enhance ability to repair
VEGF, a mitogen for vascular endotheila cells downregulated
Upregulated in MCD

60. Cytotoxic drugs
Can be considered to either induce a remission or decrease the adverse effects of continuous steroid use.
Cyclophosphamide 2 mg/kg/d for 8-12 weeks, can be used in such patients
Cyclosporine (4-6 mg/kg/d) also can be used in patients who continue to relapse or who are steroid-dependent.

61. Because cyclophosphamide is cheaper and has a better response rate, it is preferable over cyclosporine in most patients with steroid-dependent or frequently relapsing MCD
Studies in adults and children have shown that both cyclophosphamide and cyclosporine added to steroid treatment may induce remission
If these patients relapse at a later time, they tend to become steroid-sensitive.
Ref: Pediatr Nephrol. Nov 2009;24(11):

62. Pediatr Nephrol. Jun 2009;24(6):1187-92
A study by Swartz et al of 55 children with steroid-resistant or steroid-dependent MCD determined that 23 of these patients also had mesangial IgM that was visible through immunofluorescence (one of the characteristics of IgM nephropathy)
The investigators also found that the children with MCD and immunofluorescently-visible IgM responded better to treatment with cyclosporine than to therapy with cyclophosphamide

63. Kidney Int. Dec 2007;72(12):
Adults are particularly prone to the adverse effects of corticosteroids, but they do well on cyclophosphamide. Cyclosporine may be used as an alternative to cyclophosphamide in order to avoid toxicities associated with the latter
Keeping the dosage of cyclosporine at a minimum and carefully monitoring the drug’s levels have been shown to be helpful in avoiding cyclosporine-associated nephrotoxicity.

64. The treatment of MCD with tacrolimus has produced varying results
Nephrol Dial Transplant. Jun 2008;23(6):
Nephrol Dial Transplant. Jul 2006;21(7):
 Clin Nephrol. Jun 2006;65(6):

65. Mycophenolate mofetil (MMF)
MMF may also be beneficial to patients with frequent relapses. This was suggested by a small study where 7 patients with MCD and FSGS with multiple relapses were treated with MMF (1 g bid). After 1 year, 5 of the 7 patients were still in remission, and the steroid dose was significantly decreased
In addition, the immunomodulator levamisole also has been used in children

66. Rituximab
One case report describes long-term remission with rituximab (an anti-CD20 antibody) 1
Rituximab has been shown to be effective against minimal-change disease.
Relapse has been linked to the reappearance of B19 cells, which rituximab depletes
Rituximab may therefore have a role in the treatment of steroid-dependent and multirelapsing patients
1. Am J Kidney Dis. Jan 2007;49(1):158-61

67. Hypovolemia
Immediate volume expansion with purified plasma protein fraction and isotonic sodium chloride solution
Parenteral albumin infusion is not appropriate long-term management for patients with hypoalbuminemia because it has only a transient effect. Such crises should be avoided with recognition of the earlier signs of hypovolemia, including abdominal pain, increase in hematocrit, and response to contributing factors (eg, diarrhea, septicemia, diuretic therapy).

68. Edema
This condition should be controlled by dietary sodium restriction.
Small amounts of edema are not of much clinical significance.
The use of diuretics should be reserved for patients with severe cases of edema, particularly in the presence of respiratory or gastrointestinal symptoms, and when the condition restricts activity

69. Thrombotic episodes/ Infections
Thrombotic episodes should be prevented by mobilization and meticulous attention to venipuncture and intravenous infusion sites. Established episodes should be managed with heparinization.
Infections
These must be treated aggressively.
Cellulitis, peritonitis, otitis, and pneumonia are common infections.
Susceptibility to pneumococcal infections warrants the administration of penicillin prophylaxis to patients in relapse; corticosteroids increase the problem of infection

70. Diet
An adequate dietary protein intake, in accordance with the recommended daily allowance (RDA) is necessary. No evidence suggests that hepatic albumin synthesis is elevated with protein intake that is higher than the RDA.
Dietary sodium restriction helps forestall the progression of edema and also is prudent in the management of hypertension

71. Activity
Mobilization, rather than bed rest, is indicated to avoid thromboembolic complications
Aidan has Minimal Change Disease

72. Thank You !