The role of regulatory T and regulatory B cells is to suppress CMI enough to prevent tissue damage. However, an excessive regulatory response can prevent clearance of Leishmania and could explain the anergy of VL, poor response to drug treatment, development of PKDL, and relapses. A role for regulatory cells in VL has long been suspected. A variety of regulatory T and B cells have been implicated in VL, including Type 1 T helper cells that secrete IL-10 in addition to IFN-γ, natural T reg, Tr1, CD8+ T reg, and B reg. All of these lymphocytes act, at least in part, by secreting IL-10 and other suppressive cytokines.CD4+ T regs are present at increased frequency in the bone marrow of VL patients, are one source of IL-10, and proliferate in response to Leishmania antigen. Levels of FoxP3 mRNA were also up-regulated in lesional tissue from PKDL patients. However, T regs are not elevated in spleen cells from VL patients nor does depletion of T regs increase Leishmania antigen specific IFN-γ secretion The highest levels of IL-10 mRNA in spleen cells is in CD8+ and other non-FoxP3+ T cells. White blood cell CD8+ T cells from VL patients have elevated IL-10 levels. There is a 9.6 fold increase in IL-10 expressing CD8+ T cells among PBMC lymphocytes from PKDL patients. In the one study of T cell clones from VL patients, the clones isolated from VL PBMC were 100% CD8+.
Secondary Causes
Congenital infections: syphilis, cytomegalovirus, toxoplasmosis, rubella, human immunodeficiency virus (HIV), malaria, hepatitis B
Immunologic: maternal systemic lupus erythematosus

Diagnosis
An examination reveals massive fluid retention and generalized swelling. Abnormal sounds are heard when listening to the heart and lungs with a stethoscope. Blood pressure may be high. The patient may have signs of malnutrition.A urinalysis reveals large amounts of protein and sometimes small amounts of blood in the urine. Kidney function may be normal in the first weeks or months of life. Laboratory studies show low serum levels of protein (albumin) and immunoglobulins, and elevated levels of triglycerides and cholesterol. Blood work may also show thyroid and vitamin D deficiency. Kidneys on ultrasound imaging may appear enlarged and brighter (hyperechoic). The disorder can be screened during pregnancy by finding elevated levels of alpha-fetoprotein on a routine sampling of amniotic fluid.Indication for kidney biopsy remains unclear as histologic findings do no reveal the cause of congenital nephrotic syndrome, but findings may help in developing treatment strategies. Findings on light microscopy can vary from minimal change nephropathy to focal segmental glomerulosclerosis or diffuse mesanigial sclerosis. Electron microscopy shows podocyte disruption (loss of foot processes or slit diaphragm).Genetic analysis and infectious workup are needed to determine the precise cause of congenital nephrotic syndrome. Understanding the underlying cause can assist in disease management, prognosis, and genetic counseling. Treatment
Genetic forms of nephrotic syndrome are typically resistant to steroid and other immunosuppressive treatment.