Minimal change glomerulopathyN05.0

Minimal change glomerulopathy (and focal segmental glomerulosclerosis s.u. Maas RJ et al.2017) is a disease that has not yet been clearly etiopathogenically clarified. It is associated with changes in the podocytes (the glomeruli) and often leads to a nephrotic syndrome (Hogan J et al. 2013). It is the most common cause of nephrotic syndrome in childhood.

Idiopathic MCD: a large proportion of MCD must be classified as idiopathic.

Secondary (known or suspected causes):

• Medications:
  • non-steroidal anti-inflammatory drugs
  • Other drugs such as: ampicillin, rifampicin, penicillamine, lithium, tiopronin and pamidronate, alpha-interferon.
• Neoplasms(paraneoplastic syndrome):
  • Hematologic neoplasms (very rare): Hodgkin's disease, less commonly non-Hodgkin's lymphoma or leukemia.
  • Other neoplasms: Associations with thymoma, renal cell carcinoma, pancreatic carcinoma, duodenal carcinoma, and prostatic carcinoma have been described. The cause may be secretion of cytokines by tumor cells.
• Immunological causes:
  • Graft-versus-host disease after stem cell transplantation.
  • Systemic lupus erythematosus
  • Myasthenia gravis (Tsai JL et al 2016).
  • IgA nephropathy
  • Food allergies, pollen allergies
  • After bee stings
  • After immunizations
• Infections
  • Chronic Lyme disease (Florens N et al 2017).

The damage to the podocytes leads to a reduced synthesis of polyanions such as heparan sulphate, the charge selectivity of the blood-urine barrier decreases; small, negatively charged protein molecules such as albumin are filtered and appear in the urine. In contrast, the excretion of large, neutral protein molecules increases only slightly (selective proteinuria). The diffuse loss of the podocyte foot processes or their flattening may be due to a reduction of dystroglycans, adhesion molecules with which podocytes are anchored to the glomerular basement membrane (Cara-Fuentes G et al. 2016).

The minimal change glomerulonephritis is characterized by the sudden and abrupt appearance of a nephrotic syndrome with:

• proteinuria
• peripheral edema due to a hypalbuminemia of < 2.5 g/dl in serum and a
• Hyperlipoproteinemia
• Increased risk of infection and thrombosis
• In children, the serum creatinine concentration is usually normal; in adults, it may be slightly elevated. In adults with a protein loss of more than 1 g/m² body surface per day, blood pressure is often elevated. The development of terminal kidney failure is rare.

Under the light microscope the glomeruli usually appear normal. Direct immunohistological (DIF) examination does not reveal any immune complexes. Electron microscopy shows a diffuse widening and a fusion of the foot processes of the podocytes.

Other causes of nephrotic syndrome.

Difficulties are caused by the differentiation from focal segmental glomerulonephritis, in which the changes in the podocyte foot processes cannot be distinguished from minimal change glomerulonephritis. ioptic

The characteristic segmental sclerosing changes are not found in all renal corpuscles in focal segmental glomerulonephritis and may not be detected by biopsy.

C1q nephropathy is a disease that is not yet clearly defined. During immunohistological examination, deposits of the complement component C1q are found in the renal corpuscles. The disease occurs predominantly in children and young adults. Proteinuria responds poorly to corticosteroids and immunosuppressants. If only minimal glomerular changes are found, the prognosis for renal function is favourable.

General therapy of the nephrotic syndrome.

Glucocorticoids are the first choice therapeutics. They lead to a complete remission of proteinuria in > 90% of cases.

Adults:

• In adults, the disease is a rarer cause of nephrotic syndrome and it may take several months before the disease responds to treatment. Therefore, in adults it is necessary to confirm the diagnosis by a kidney biopsy before starting treatment.

Children:

• Because of the frequency of the disease in children and the rapid response to treatment within a few weeks, in most children it is not necessary to confirm the diagnosis by kidney biopsy (Vivarelli M et al. 2017). Start therapy with prednisone in high doses. 1 month after the disappearance of protein from the urine, the dose of prednisone is initially switched to one dose every 2nd day and slowly reduced after another 2 months.
• Most children respond to this treatment within 4 weeks. 30 % of children heal completely. 10-20 % have < 4 rezdive. Some already have more frequent relapses under therapy, or a relapse occurs when the dose of prednisone is reduced.
• Children with frequent recurrences of the children, in whom prednisone could never be completely discontinued, may alternatively be treated with cyclophosphamide for 3 months to avoid the side effects of prednisone. 10% of children do not respond to prednisone. These children have an increased risk of losing kidney function as the disease progresses. In about 20% of children who do not respond to prednisone, a mutation in genes encoding podocyte proteins (NPHS2 gene, WT1 gene) can be detected. Children in whom one of these mutations is detectable should not be treated immunosuppressively. Children in whom there is no evidence of a congenital nephrotic syndrome can be treated with cyclosporine, cyclophosphamide or chlorambucil on a trial basis. If immunosuppressive treatment is unsuccessful or not appropriate, the edema is treated with restriction of salt and fluid intake and with diuretics. Children with persistent nephrotic syndrome are susceptible to infections and should therefore be vaccinated against pneumococcus and varicella.

Adults

• The diagnosis must be confirmed in advance by kidney biopsy. Therapy of choice is prednisone; leads to a sudden (within 2 weeks) and complete remission of proteinuria in more than 90% of adults within several months. Recurrences In 50-60 % of cases. Repeated recurrence is observed in 10-25% of affected adults. Prednisone is administered in high doses for 3-4 months and then slowly reduced over a period of 6 months. Recurrences are treated with higher doses of prednisone over a shorter period of time. Patients with frequent relapses are also treated with prednisone over a longer period of time. Then the dose is gradually reduced. If necessary, prednisone can also be administered every 2nd day. In case of frequent relapses and in case of considerable side effects of steroidal therapy, add cyclophosphamide (2 mg/kg body weight for 12 weeks) or cyclosporine A (initially maximum 5 mg/kg body weight - level: 120-150 ng/ml for initially 12 months). Alternatively to cyclosporin A administration of mycophenolate Mofetil (1000-1500 mg/die). Reserve options are tacrolimus (Xu D et al. 2017), mycophenolate, as well as the anti-CD20 antibody rituximab (Kronbichler A et al. 2014). For persistent proteinuria, addition of ACE inhibitors and/or AT1 antagonists. The lipometabolic disorder is treated with statins. In the case of pronounced nephrotic syndrome, the administration of diuretics and anticoagulants may also be necessary.

Important: Osteoporosis prophylaxis: calcium 1000 mg/die + vitamin D 500 IU/risedronate 5 mg/die .

In general, the prognosis for minimal-change glomerulonephritis is good. In recurrent patients or in patients in whom prednisone cannot be discontinued due to the constant risk of recurrence (steroid-dependent MCD), it must be expected that the disease will persist into adulthood in 10-40% of patients.

1. Cara-Fuentes G et al (2016) Pathogenesis of proteinuria in idiopathic minimal change disease: molecular mechanisms. Pediatric Nephrol 31:2179-2189.
2. Florens N et al (2017) Chronic Lyme borreliosis associated with minimal change glomerular disease: a case report. BMC Nephrol 18:51.
3. Herlitz LC et al (2014) IgA nephropathy associated with minimal change glomerular disease. Clin J Am Soc Nephrol. 2014 9:1033-1039.
4. Hogan J et al (2013) The treatment of minimal change disease in adults. J Am Soc Nephrol 24:702-711.
5. Kronbichler A et al (2014) Rituximab in adult minimal change disease and focal segmental glomerulosclerosis. Nephron Clin Pract 128:277-282.
6. Maas RJ et al (2017) The Clinical Course of Minimal Change Nephrotic Syndrome With Onset in Adulthood or Late Adolescence: A Case Series. On J Kidney Dis. 69:637-646.
7. Tsai JL et al (2016) Minimal change disease in a patient with myasthenia gravis: A case report. Medicine (Baltimore) 95:e5008.
8. Vivarelli M et al (2017) Minimal change disease. Clin J Am Soc Nephrol 12:332-345.
9. Waldman M et al (2007): Adult minimal-change disease: clinical characteristics, treatment, and outcomes. Clin J Am Soc Nephrol 2:445-453
10. Xu D et al. (2017) Tacrolimus improves proteinuria remission in adults with cyclosporine A-resistant or -dependent minimal change disease. Nephrology (Carlton) 22:251-256.
11. Yildiz H et al (2016) Minimal change disease associated with malignant pleural mesothelioma: case report and review of the literature. BMJ Case Rep pii: bcr2016217958.