1. Glomerulonephritis

2. Glomerulonephritis means 'inflammation of glomeruli’.
Most types of glomerulonephritis seem to be immunologically mediated and several respond to immunosuppressive drugs.

3. Although deposition of circulating immune complexes was previously thought to be a common mechanism, it now seems that most granular deposits of immunoglobulin are formed 'in situ' by antibodies which complex about glomerular antigens, or about other antigens ('planted' antigens, e.g. viral or bacterial ones) that have localised in glomeruli.

4. The simplest explanation for the effect of proteinuria on the development of interstitial nephritis is that increasingly severe proteinuria, carrying activated cytokines and lipoproteins producing reactive oxygen species, triggers a downstream inflammatory cascade in and around epithelial cells lining the tubular nephron. These effects induce T lymphocyte and macrophage infiltrates in the interstitial spaces along with fibrosis and tubular atrophy.

5. Classifications of glomerulonephritis are largely histopathologic.
Systemic hypertension and atherosclerosis can produce chronic glomerulosclerosis. Diabetic nephropathy is associated with thickening of the GBM secondary to the long-standing effects of hyperglycemia.

6. Approach to Glomerular Disease
Patients with glomerular disease usually have some hematuria with varying degrees of proteinuria. Hematuria is typically asymptomatic. As little as 3–5 red blood cells in the spun sediment from first voided morning urine is suspicious. Exception of IgA nephropathy and sickle cell disease is gross hematuria present.
When red blood cell casts or dysmorphic red blood cells are found in the sediment, glomerulonephritis is likely.

7. Sustained proteinuria >1–2 g/24 h is also commonly associated with glomerular disease.
Proteinuria is nonsustained, generally <1 g/24 h, and is sometimes called functional or transient proteinuria. Fever, exercise, obesity, sleep apnea, emotional stress, and congestive heart failure can explain transient proteinuria.
Proteinuria only seen with upright posture is called orthostatic proteinuria.
Selective proteinuria largely composed of albumin, while Nonselective, containing albumin and a mixture of other serum proteins.

8. Urine Assays for Albuminuria/Proteinuria
24-Hour Albumina (mg/24 h)
Albumina/Creatinine Ratio (mg/G)
Dipstick Proteinuria
24-Hour Urine Proteinb (mg/24 h)
8–10
<30 –
<150
Normal
30-300
30–300
–/Trace/1+
Microalbuminuria
>300
Trace–3+
>150
Proteinuria
aAlbumin detected by radioimmunoassay.
bAlbumin represents 30–70% of the total protein excreted in the urine.

9. Spectrum of glomerular diseases

10. Acute nephritic syndrome producing 1–2 g/24 h of proteinuria, hematuria with red blood cell casts, pyuria, hypertension, fluid retention, and a rise in serum creatinine associated with a reduction in glomerular filtration.
Nephrotic syndrome describes the onset of heavy proteinuria (>3.0 g/24 h), hypertension, hypercholesterolemia, hypoalbuminemia, edema/anasarca, and microscopic hematuria; if only large amounts of proteinuria are present without clinical manifestations, the condition is sometimes called nephrotic-range proteinuria.
Primary glomerulonephritis :glomerulonephritis is isolated to the kidney, or is part of a systemic disease (secondary glomerulonephritis).

11. Acute Nephritic Syndromes
Postinfectious Glomerulonephritis: This is most common following infection with certain strains of streptococcus and therefore is often called post-streptococcal nephritis, but it can occur following other infections. It is much more common in children than adults.
The latency is usually about 10 days after a throat infection or longer after skin infection, suggesting an immune mechanism rather than direct infection.

12. Postinfectious Glomerulonephritis
Sodium retention, hypertension and oedema, are particularly pronounced.
Flank pains (due to swelling of the renal capsule) are reported in as many as 50% of cases. Five percent of children and 20% of adults have proteinuria in the nephrotic range.
There is also reduction of GFR, proteinuria, haematuria and reduced urine volume. Characteristically, this gives the urine a red or smoky appearance. There are low serum concentrations of C3 and C4, evidence of streptococcal infection (perform antistreptolysin O (ASO) titre, culture of throat swab, and other swab tests if skin infection is suspected).

13. Postinfectious Glomerulonephritis (cont.)
Typically affects children between the ages of years
Management is by fluid and sodium restriction and use of diuretic and hypotensive agents is usually adequate.
Antibiotic treatment for streptococcal infection should be given to all patients and their cohabitants.

14. Remarkably, the renal lesion in almost all children and most adults seems to resolve completely despite the severity of the glomerular inflammation and proliferation seen histologically.
Recurrent poststreptococcal glomerulonephritis is rare. Overall, the prognosis is good, with permanent renal failure being very uncommon (1–3%), and even less so in children.

15. Subacute Bacterial Endocarditis
A complication of subacute bacterial endocarditis, particularly in patients who remain untreated for a long time, have negative blood cultures, or have right-sided endocarditis.
A normocytic anemia, elevated ESR, hypocomplementemia, high titers of rheumatoid factor.
Primary treatment is eradication of the infection with 4–6 weeks of antibiotics, and if accomplished expeditiously, the prognosis for renal recovery is good.

16. Lupus Nephritis
Most common clinical sign of renal disease is proteinuria, but hematuria, hypertension, varying degrees of renal failure, and active urine sediment with red blood cell casts can all be present.
Anti-dsDNA antibodies that fix complement correlate best with the presence of renal disease. Hypocomplementemia is common in patients with acute lupus nephritis (70–90%) and declining complement levels may herald a flare. Renal biopsy, however, is the only reliable method of identifying the morphologic variants of lupus nephritis.

17. Classification for Lupus Nephritis
Excellent prognosis and generally do not need therapy for their lupus nephritis
Minimal mesangial
Class I
Mesangial proliferation
Class II
Therapy with steroids alone
Focal nephritis
Class III
Treatment must combine high-dose steroids with either cyclophosphamide or mycophenolate mofetil.
Diffuse nephritis
Class IV
Therapy with inhibitors of the renin-angiotensin system
Membranous nephritis
Class V
Renal transplantation
Sclerotic nephritis
Class VI

18. Antiglomerular Basement Membrane Disease
When they present with lung hemorrhage and glomerulonephritis, they have a pulmonary-renal syndrome called Good pasture's syndrome.
Disease in the younger age group is usually explosive, with hemoptysis, a sudden fall in hemoglobin, fever, dyspnea, and hematuria. Hemoptysis is largely confined to smokers, and those who present with lung hemorrhage as a group do better than older populations who have prolonged, asymptomatic renal injury.
Treatment: Plasmapheresis , accompanied by oral prednisone and cyclophosphamide in the first 2 weeks. Kidney transplantation is possible, but because there is risk of recurrence.

19. IgA nephropathy and Henoch-Schönlein purpura
IgA nephropathy is the most commonly recognised type of glomerulonephritis and can present in many ways.
Haematuria is almost universal, proteinuria usual, and hypertension very common. There may be severe proteinuria and nephrotic syndrome, or in some cases progressive loss of renal function.
The disease is a common cause of ESRD. A particular hallmark in some individuals is acute exacerbations, often with gross haematuria, in association with minor respiratory infections. Characteristically, the latency from clinical infection to nephritis is short: a few days or less.

20. In children, and occasionally in adults, a systemic vasculitis occurring in response to similar infections is called Henoch-Schönlein purpura. A characteristic petechial rash (cutaneous vasculitis, typically affecting buttocks and lower legs) and abdominal pain (gastrointestinal vasculitis) usually dominate the clinical picture, with mild glomerulonephritis being indicated by haematuria. When the disease occurs in older children or adults, the glomerulonephritis is usually more prominent. Renal biopsy shows mesangial IgA deposition and appearances indistinguishable from acute IgA nephropathy.

21. The response to immunosuppressive therapy is usually poor
The response to immunosuppressive therapy is usually poor. The management of less acute disease is largely directed towards the control of blood pressure in an attempt to prevent or retard progressive renal disease.
Use of angiotensin-converting enzyme (ACE) inhibitors in patients with proteinuria or declining renal function.
When presenting as RPGN, patients typically receive steroids, cytotoxic agents, and plasmapheresis.

22. RAPIDLY PROGRESSIVE GLOMERULONEPHRITIS (RPGN)
This describes an extreme inflammatory nephritis which causes rapid loss of renal function over days to weeks.
It is typically seen in Goodpasture's disease, but can also be seen in SLE and occasionally IgA and other nephropathies.

23. C3 nephritic factor and partial lipodystrophy Type II
Mesangiocapillary glomerulonephritis (MCGN) (= membranoproliferative glomerulonephritis, MPGN)
Clinical features
Association
Usually proteinuria, may be haematuria Most common pattern found in association with subacute bacterial infection No proven treatments except where cause can be treated
Bacterial infection Hepatitis B virus Cryoglobulinaemia (± hepatitis C virus infection)
Type I
Also known as dense deposit disease
C3 nephritic factor and partial lipodystrophy
Type II

24. Nephrotic Syndrome
Nephrotic syndrome classically presents with heavy proteinuria, minimal hematuria, hypoalbuminemia, hypercholesterolemia, edema, and hypertension.
Consequences of Nephrotic syndrome :
Oedema
Hyperlipidemia.
Hemostasis disorder: venous + arterial thrombosis.
Infections.

25. Minimal Change Disease(MCD)
Minimal change disease occurs at all ages but accounts for nephrotic syndrome in most children and about one-quarter of adults.
Proteinuria usually remits on high-dose corticosteroid therapy (1 mg/kg prednisolone for 6 weeks), although some patients who respond incompletely or relapse frequently need maintenance corticosteroids, cytotoxic therapy or other agents. Minimal change disease does not progress to CRF; the main problems are those of the nephrotic syndrome and complications of treatment.
Secondary causes include Hodgkin's disease, allergies, or use of nonsteroidal anti-inflammatory agents.

26. Focal Segmental Glomerulosclerosis (FSGS)
The primary FSGS typically show little response to corticosteroid treatment and often progress to renal failure; the disease frequently recurs after renal transplantation, and sometimes proteinuria recurs almost immediately. However proportion of patients with FSGS do respond to corticosteroids (a good prognostic sign).
Secondary causes include hypertension, VUR disease, heroin misuse, HIV infection and massive obesity, Cholesterol emboli, Alport's syndrome, Sickle cell disease, Lymphoma, radiation and familial cases.

27. FSGS (Cont.)
Treatment of patients with primary FSGS should include inhibitors of the renin-angiotensin system.
There is no role for steroids or other immunosuppressive agents in secondary FSGS.

28. Membranous Nephropathy
This Accounts for approximately 30% of cases of nephrotic syndrome in adults.
Secondary causes:
Infections: HBV and HCV, syphilis, malaria, schistosomiasis, leprosy, filariasis.
Cancer: Breast, colon, lung, stomach, kidney, esophagus.
Drugs: gold, mercury, penicillamine, NSAIDs, probenecid.
Autoimmune diseases: SLE, RA, primary biliary cirrhosis, Sjögren's syndrome, Hashimoto's thyroiditis
Other systemic diseases: Sickle cell anemia, diabetes, Crohn's disease, sarcoidosis, Guillain-Barré syndrome.

29. Eighty percent of patients with MGN present with nephrotic syndrome and nonselective proteinuria.
Of this group, approximately one-third remit spontaneously, one-third remain in a nephrotic state, and one-third show progressive loss of renal function.
In addition to the treatment of edema, dyslipidemia, and hypertension, inhibition of the renin-angiotensin system is recommended.
Treatment with high doses of corticosteroids and alkylating agents (e.g. cyclophosphamide) reserve for those with severe nephrotic syndrome or deteriorating renal function.

30. Diabetic Nephropathy
Is the single most common cause of chronic renal failure accounting for 45% of patients receiving renal replacement therapy.
Approximately 40% of patients with Types 1 or 2 diabetes develop nephropathy, but due to the higher prevalence of Type 2 diabetes (90%) compared to Type 1 (10%).
Renal biopsies from patients with Types 1 and 2 diabetes are largely indistinguishable.

31. Diabetic nephropathy is usually diagnosed without a renal biopsy.
Blood sugar and blood pressure control as well as inhibition of the renin-angiotensin system in retarding the progression of diabetic nephropathy.

32. Inherited Glomerular Disease
Alport’s Syndrome: Most cases arise from a mutation or deletion of the COL4A5 gene on the X chromosome which encodes type IV collagen, resulting in inheritance as an X-linked recessive disorder. Less common and cause autosomal recessive disease.
Approximately 85% of patients with Alport's syndrome have an X-linked inheritance of mutations in the α5(IV) collagen chain on chromosome Xq22–24.
Fifteen percent of patients have autosomal recessive disease of the 3(IV) or α 4(IV) chains on chromosome 2q35–37. Rarely, some kindred have an autosomal dominant inheritance of dominant-negative mutations in α 3(IV) or α 4(IV) chains.

33. Some other basement membranes containing the same collagen are similarly affected, notably in the cochlea, so that Alport's syndrome is associated with sensorineural deafness and ocular abnormalities.
No specific treatment has been devised to slow the progress of this condition, but patients with Alport's syndrome are good candidates for renal replacement therapy as they are young and usually otherwise healthy.

34. Cholesterol Emboli
Aging patients with clinical complications from atherosclerosis sometimes shower cholesterol crystals into the circulation—either spontaneously or, more commonly, following an endovascular procedure
One may see cerebral transient ischemic attacks; livedo reticularis in the lower extremities; Hollenhorst plaques in the retina with visual field cuts; necrosis of the toes and acute glomerular capillary injury leading to focal glomerulosclerosis sometimes associated with hematuria, mild proteinuria, patients have fever, eosinophilia, or eosinophiluria. A skin biopsy of an involved area may be diagnostic.

35. Cholesterol Emboli
There is no therapy to reverse embolic occlusions, and steroids do not help. Controlling blood pressure and lipids and cessation of smoking are usually recommended for prevention

36. Nephrotic Syndrome
Nephrotic syndrome is kidney disease with proteinuria, hypoalbuminemia, and edema. Nephrotic range proteinuria is 3 grams per day or more.
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.

37. Primary causes of nephrotic syndrome include, in approximate order of frequency:
Minimal-change nephropathy
Focal glomerulosclerosis
Membranous nephropathy
Hereditary nephropathies
Secondary causes include, again in order of approximate frequency:
Diabetes mellitus
Lupus erythematosus
Amyloidosis and paraproteinemias
Viral infections (eg, hepatitis B, hepatitis C, HIV)
Preeclampsia
Others: IgA nephropathy, Sickle cell disease.

38. Pathogenesis of edema
Hypoalbuminemia : lowers the plasma colloid osmotic pressure.
Renal sodium retention occurs because of the proteinuria.
Enhanced peripheral capillary permeability to albumin .

39. Metabolic consequences of proteinuria
Lipids are usually elevated: a) hypoproteinemia that stimulates protein, including lipoprotein, synthesis by the liver, and (b) diminution of lipid catabolism caused by reduced plasma levels of lipoprotein lipase.
Risk for venous thrombosis: The loss of antithrombin III and plasminogen via urine
Vitamin D–binding protein may be lost in the urine, leading to hypovitaminosis D.
Urinary immunoglobulin losses may lower the patient's resistance to infections

40. History
Swelling of the face; this is followed by swelling of the entire body. Adults can present with dependent edema.
Foamy urine may be a presenting feature.
A thrombotic complication, such as deep vein thrombosis of the calf veins or even a pulmonary embolus.

41. Physical
Edema , increase in weight, the development of ascites, or pleural effusions.
Hematuria and hypertension manifest in a minority of patients.
Features on exam will vary according to cause

42. Laboratory Studies
Urinalysis is the first test used in the diagnosis of nephrotic syndrome.
The serum albumin is classically low in nephrotic syndrome
Urine protein electrophoresis.
Serum tests for kidney function are essential.
Ultrasonographic scanning
Hepatitis B and C, HIV
May require a renal biopsy for diagnosis

43. Management
Specific treatment of nephrotic syndrome depends on the disease's cause.
Hospitalization should be considered if there is respiratory distress, if a patient has tense scrotal or labial edema, in the presence of complication.
Diuretics will be needed; furosemide (1 mg/kg/d) and spironolactone (2 mg/kg/d) will help when fluid retention is severe, provided no signs of renal failure or volume contraction are evident. And even metolazone may be used
When the patient's serum albumin level is less than 1.5 g/dL. Albumin at 1 g/kg may be given, followed by intravenous furosemide.

44. With regard to infection, oral penicillin can be prescribed as prophylaxis for children with gross edema. Abdominal paracentesis should be performed if the patient develops signs of peritonitis.
Anticoagulation has been advocated by some for use in preventing thromboembolic complications, but its use in primary prevention is of unproven value.
Hypolipidemic agents may be used, but if the nephrotic syndrome cannot be controlled, there will be persistent hyperlipidemia.
In secondary nephrotic syndrome, such as that associated with diabetic nephropathy, ACEI and/or ARB are widely used. These may reduce proteinuria by reducing the systemic blood pressure, by reducing intraglomerular pressure, and also by direct action on podocytes.

45. A diet with no added salt will help to limit fluid overload.
Diet: Diet should provide adequate energy (caloric) intake and adequate protein (1-2 g/kg/d). Supplemental dietary protein is of no proven value.
A diet with no added salt will help to limit fluid overload.
Management of hyperlipidemia could be of some importance if the nephrotic state is prolonged.
Fluid restriction per se is not required.
Activity: There are no activity restrictions for patients with nephrotic syndrome. Ongoing activity, rather than bedrest, will reduce the risk of blood clots.

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