Antoine is a three-year-old male child of African American parents. He had just recovered from a mild upper respiratory infection when his parents noticed that his face appeared “swollen.” On closer examination, they noted that his legs and scrotum also appeared to be “puffy” (a physician would say edematous). Antoine also seems tired and has little appetite. Concerned, his parents take him to the family pediatrician. The pediatrician confirms marked facial and dependent edema (accumulation of fluid in tissue predominantly below the heart, such as the legs). Careful examination of the patient’s fingernails shows a pattern of horizontal lines (Muehrcke lines) in the bed of the nails, which blanch when the nail is pressed. The physician remembers that such lines are sometimes associated with vascular changes that occur when plasma albumin levels are very low, and he orders urinalysis. Antoine’s urine shows extreme proteinuria. The albumin to creatinine ratio is 6 and the urine has a very high specific gravity. These findings would be consistent with loss of protein in the urine because of impaired urinary filtration. The patient’s serum albumin is 2.3 g/dl (dl is the abbreviation for deciliter or 100 ml), which is abnormally low. These findings taken together are consistent with the diagnosis of nephrotic syndrome. Because at least 90 percent of nephrosis in children of Antoine’s age is minimal change disease, no invasive investigation of the kidney (such as a renal biopsy) is undertaken. Even if that were done, light microscopy would not be expected to disclose any changes in the glomerulus. The physician decides to try corticosteroid therapy using prednisone because about 90 percent of children with minimal change disease will respond within two weeks. His parents are told to reduce Antoine’s salt intake to help reduce his edema.
The Happy Ending
Antoine’s proteinuria clears after ten days of therapy, as does his edema. Drug therapy is continued for four weeks at a reduced dose, and no relapse is noted.
The Not-So-Happy Ending
No change is noted in the degree of nephrosis after two weeks of therapy. Antoine complains of increasing abdominal pain, and his blood pressure begins to increase. Therapy with diuretics and antihypertensive medication becomes necessary. His disease is now classified as steroid-resistant nephrotic syndrome (SRNS). Because of his continuing disease, the nephrologist in charge of Antoine’s case decides to request a needle biopsy of Antoine’s kidney. Light microscopic analysis of the glomerular disease is consistent with focal segmental glomerulosclerosis (FSGS) (see Figure 19-13). This was not surprising because 70 percent of children with SRNS have FSGS. Aggressive treatment with increased doses of prednisone and immunosuppressive agents was ineffective. Ultimately Antoine developed end stage renal disease and required a kidney transplant.
Figure 19-13
Discussion
Minimal change disease is thought to be related to an increased level of a number of cytokines that cause T cells to release an agent that damages the function of the epithelial cell foot processes; however, the exact mechanism is unclear. Although no changes to affected glomeruli are noted by light microscopy, damage to the foot processes (fusion or effacement), as disclosed in EM studies, is characteristic of the disease (FIGURE 19-25). The etiology of the disease remains obscure (although it may occur following an upper respiratory tract infection or allergic reaction). Ninety percent of children with minimal change disease respond to prednisone therapy. Failure of response (SRNS) is an indicator of the likelihood of a different disease process, and as noted about 70 percent of children with SRNS have focal segmental glomerulosclerosis. FSGS is significantly increasing in frequency in Caucasian and, notably, in African American populations, where it is the most common cause of adult nephrosis. FSGS is associated with diverse etiologies and diagnostic subclassifications, including primary (idiopathic) disease or secondary disease related infection (HIV), drugs, reduced renal mass and hereditary defects in podocyte genes, and (particularly in African Americans) a circulating protein apolipoprotein L1. The frequency of the variant of the apoL1 gene associated with FSGS susceptibility is more than ten times higher in African Americans than in Caucasians and is associated with an increased risk of FSGS and hypertensive end stage renal disease. The presence of two high-risk alleles of apoL1 is responsible for nearly 20 percent of FSGS. The high-risk alleles of apoL1 are associated with the ability to lyse trypanosomes associated with African sleeping sickness. Individuals with a single high-risk allele are relatively resistant to this parasitic disease, whereas inheritance of two high-risk alleles is associated with a much higher risk of kidney disease. This pattern of heterozygous advantage (versus homozygous disadvantage) is analogous to that seen with sickle cell trait and disease (discussed under diseases of blood circulation) The lack of response by Antoine to steroids and immunosuppressive therapy is consistent with a hereditary condition, but no additional family history or genetic studies are available. However, it is clear that African Americans are at increased risk of FSGS, and hypertensive renal disease is likely to be related in part to hereditary factors.
Etiology and Pathogenesis
Minimal change disease of unknown etiology or steroid resistant nephrosis associated with focal segmental glomerulosclerosis, possibly of hereditary origin involving apoL1 high-risk alleles or podocyte protein defects.
Questions
1. There is much discussion about the appropriate role of racial identification of patients. When do you think doing so is appropriate?
2. Clearly distinguish between nephrosis and nephritis. Which is this Case a good example of and why?
3. Why would immediate renal biopsy of a child with nephrosis be inappropriate? When would this be appropriate?
4. Correlate the laboratory findings in this Case with the disease process.
5. Correlate the EM findings in this Case with the disease process.