IgA Nephropathy

Complicated
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Diagnosis and reasoning

Diabetes Mellitus is a complex disease which slowly but relentlessly damages virtually every major organ in the body over time. Although excellent glycemic control can slow down these deleterious effects, it is a sad fact that by around 10 to 20 years after diagnosis, a significant proportion of these individuals will have developed diabetic nephropathy. Thus, the elevated renal functions in this patient are strongly suspicious of diabetic nephropathy; the presence of concomitant retinopathy and a glove and stocking pattern of neuropathy (both of which typically develop prior to nephropathy) lend further credence to this. Nonetheless, all such patients should be screened for other forms of renal disease via few basic tests, starting with a urinalysis. The urinalysis brings several unusual findings to light: - heavy proteinuria, which when quantified via a spot urinary protein/creatinine ratio test is shown to be in the nephrotic range - an active sediment consisting of microhematuria with dysmorphic cells and erythrocyte casts Furthermore, note that his estimated glomerular filtration rate (eGFR) of 46 mL/min/1.73 m2 indicates that he is now in chronic kidney disease (CKD) Stage 3a. Diabetic nephropathy is a slowly progressive disease; it is highly unlikely that progression from no microalbuminuria to the nephrotic range of protein loss would occur in just 6 months. Even more importantly, note that an active sediment can never occur due to diabetic nephropathy alone; an underlying glomerulonephritis is almost certainly present. The most common non-diabetic glomerular diseases are membranous nephropathy, IgA nephropathy, postinfectious glomerulonephritis, minimal change disease, and focal segmental glomerulosclerosis; it is almost impossible to distinguish between these via clinical and/or biochemical grounds alone. A renal biopsy will allow differentiation, and is probably the test of most value in this clinical context; this should be done as early as possible (particularly because the prognosis in most renal diseases is related to the timeliness of management). This shows features suggestive of IgA nephropathy (IgAN) superimposed upon diabetic nephrosclerosis, clinching the diagnosis. Note that a renal ultrasound scan should always be performed prior to biopsy to assess the kidney size and to rule out other structural renal disease. ACE inhibitors are the first-line therapy for IgAN. These will both reduce the degree of proteinuria and control any associated hypertension, delaying progression towards end stage renal disease (ESRD). In patients with nephrotic level proteinuria, immunosuppression with steroids should also be considered, as this is superior to ACE-inhibitor therapy alone. However, steroid therapy comes with it's own set of problems; as he is diabetic, this may very well worsen his glycemic control; multidisciplinary management along with an endocrinologist should be considered. Note also that the nephrotic syndrome is associated with dyslipidemia and an increased thrombotic risk; his management should take this into consideration as appropriate. While good glycemic control is important to prevent and delay progression of his diabetic complications, tight glycemic control is not recommended now, as this is associated with a high risk of adverse effects (such as hypoglycemia). Renal replacement therapy is currently unnecessary in this patient.


Discussion

IgA nephropathy (IgAN), also known as Berger’s disease, is an immune complex glomerulonephritis characterized by deposition of forms of IgA (predominantly polymeric IgA1) in the glomerular mesangium. Not only is it the most common form of primary glomerulonephritis worldwide, it is also the most common primary glomerular disease giving rise to end-stage renal disease (ESRD). The disease is found in 30% to 40% of renal biopsies conducted in Asia, and in around 10% of biopsies performed in the United States. IgAN can present at any age, although the peak incidence occurs in the 2nd to 3rd decades of life. The disease is most common in persons of Caucasian and East Asian ethnicity, and is more frequent in males. While the vast majority of cases are primary in origin, it is important to note that secondary IgAN is well documented; this can occur in association with diseases of the respiratory and gastrointestinal tracts (such as cystic fibrosis, inflammatory bowel disease and celiac disease). IgAN has a vast spectrum of presentation; a significant number of patients are completely asymptomatic and are only detected upon routine screening or while being investigated for another condition. Some patients (especially in the younger age group) may present with episodic, gross hematuria; this may coincide with a respiratory tract infection, pneumonia, or gastroenteritis. Other patients (particularly the elderly) may manifest micro hematuria and proteinuria. The proteinuria is usually mild, but can extend upto the nephrotic range (>3g/24h). At the extreme end of the spectrum, a minority of patients can present with acute, rapidly progressive glomerulonephritis characterized by edema, hypertension, hematuria and renal insufficiency. Hypertension is not a universal finding, but displays a positive correlation with the duration of disease. Malignant hypertension may rarely be seen. IgAN can only be definitively diagnosed via a renal biopsy with immunohistochemistry; biopsy appearances may range from normal histology by light microscopy to severe necrotizing, crescentic glomerulonephritis or advanced glomerulosclerosis, and tubular atrophy. Immune-complex deposits are found predominantly within the mesangial regions of the glomeruli, possibly with focal paramesangial or subendothelial extension. Based on the histological findings, the disease can be assigned a score using the The Oxford classification of IgA nephropathy; this allows prediction of the likely ultimate renal outcome. IgAN is currently incurable; the key goal of treatment is to prevent or at least slow progression to ESRD. The exact therapeutic regimens are complex and depend on the presentation and patient status. However, broadly, four different clinical scenarios can be identified: - Patients with only minor urinary abnormalities; here the mainstay of therapy is long-term, regular followup to detect disease progression and/or development of hypertension. - Patients presenting with microhematuria, significant but non-nephrotic proteinuria, hypertension, and variable degrees of renal failure. In this group, optimized supportive care is key; this includes therapy with ACE Inhibitors or Angiotensin Receptor Blockers (ARBs). Where there is a poor response, immunosuppression with corticosteroid monotherapy can be considered. Note that there is insufficient data to recommend other immunosuppressives or combination therapy in this group. - Patients presenting with overt nephrotic syndrome, or acute or rapidly progressive kidney injury; here, immunosuppression is key to the management. - Patients with secondary IgAN; in these individuals, the mainstay is treatment of the underlying disease. Patients who progress to ESRD can be treated with dialysis or transplantation; however, even following transplantation, there is a risk of histologic recurrence, with or without evidence of clinical disease. Note that there is no clear evidence that the choice of immunosuppression after renal transplantation affects the clinical manifestation or course of recurrent IgAN. In addition, while certain experts advocate the use of high dose Omega-3 fatty acids (fish oils) in the management of these patients, currently there is insufficient evidence to support their use. Acute renal failure may result from acute tubular necrosis as a consequence of macroscopic hematuria or superimposed crescentic nephritis; this occurs during the course of the disease in approximately 5% of patients. All patients should be followed up regularly with serial measurements of the serum creatinine concentration, urinary protein excretion and eGFR, as well as urinalysis aimed at detecting the presence of an active sediment. While IgAN has been traditionally considered as benign process, it is now known to lead to a slowly progressive decline in renal function, with ESRD developing in upto 30% to 40% of patients 20 years after initial presentation. In this respect, severe proteinuria (>1g/day), persistent hematuria, hypertension, a progressive increase in serum creatinine levels, and the presence of severe lesions (such as hyalinosis and crescents) on the initial renal biopsy, are the most predictive factors for progressive disease. Note that patients who have recurrent episodes of gross hematuria without proteinuria are at low risk for progression.


Take home messages

  1. Kidney disease in a diabetic patient is not always due to diabetic nephropathy; all patients should be screened for other causes.
  2. IgAN is the most common primary glomerulonephritis worldwide; definitive diagnosis requires renal biopsy and immunohistologic examination.
  3. IgAN is currently incurable; however, ACE inhibitors and immunosuppression can slow progression to ESRD.

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