HDCN-MGR: Hematuria and flank pain in a young woman (continued)

Further course: (Continued)

After this patient's prolonged urologic evaluation, she was referred for renal consultation. Because of the unilateral nature of the pain, the temporal relationship of the disease to oral contraceptive use, and the fact that the patient was a young woman, our leading diagnosis prior to biopsy was loin pain hematuria syndrome. This is a difficult diagnosis to confirm clinically or pathologically, occasionally biopsy specimens may demonstrate nonspecific vascular changes (arteriolar thickening).

A renal biopsy was done and the findings were most consistent with IgA nephropathy Photomicrograph and discussion of immunofluorescence.

Discussant:
Dr. Stephen Fishbane Department of Internal Medicine, Winthrop-University Hospital, Mineola, NY and SUNY Stony Brook School of Medicine.

IgA nephropathy (IgAN) is the most common cause of glomerulonephritis in the world. The disease is most common in Asians and Caucasians, with a decreased incidence in blacks. It is possible that the lower incidence reported in blacks may reflect a bias towards decreased use of renal biopsy in lower socioeconomic classes.

Presentation: The clinical presentation of IgA nephropathy is varied, but hematuria is an important feature of most cases. Most commonly patients will experience episodes of gross hematuria temporally related to an upper respiratory infection. Occasionally, this will be accompanied by flank pain. A significant minority of patients with IgAN have persistent microscopic hematuria with or without proteinuria. In addition, many of these patients will ultimately develop episodes of gross hematuria. A small percentage of patients with IgAN will present with a more virulent course, with either RPGN or acute renal failure.

Pathology: IgAN is a diagnosis made pathologically by a predominance of IgA deposits in the mesangium and capillary walls of the glomerulus. The only other renal diseases in which IgA deposition is significant are Henoch-Schönlein purpura (HSP) and lupus nephritis. HSP may be a systemic form of IgAN, with clinical findings such as lower extremity purpuric skin lesions, abdominal pain and arthritis. The distinct clinical features of systemic lupus usually make it easy to differentiate from IgA nephropathy. In difficult cases, pathologic clues to the presence of lupus include greater deposition of IgG than IgA, and significant deposition of C1q.

Prognosis: The prognosis of patients with IgA nephropathy is variable. By 20 years of follow up, approximately 20% will require renal replacement therapy. Findings predictive of an adverse outcome are similar to those in other renal diseases; 1) proteinuria > 1 gram/day, 2) hypertension, 3) male sex, 4) elevated serum creatinine at baseline, 5) interstitial fibrosis or glomerular crescents on biopsy. In addition, patients with persistent microscopic hematuria have a worse prognosis than patients with episodes of gross hematuria. The negative impact of hypertension on prognosis in IgAN was examined in a recent abstract presented at the 1995 ASN conference LINK. It suggested that patients with a familial predisposition for hypertension had a markedly worse outcome in IgAN. Another interesting abstract involved a study of angiotensin converting enzyme gene deletion polymorphism, which has been shown to increase serum ACE levels. This study demonstrated that in IgAN, the deletion polymorphism was a risk factor for progression to renal failure LINK.

Etiology: The etiology of this disease is unknown in most cases. Patients with severe hepatic dysfunction will commonly have IgA deposition in the glomerulus, probably as a result of reduced hepatic IgA clearance. Nevertheless, frank IgAN rarely develops in these patients. Similarly, in patients with celiac disease, increased IgA production leads to nonspecific glomerular deposition. Again, clinically overt disease is rare. A recent interesting association is with Haemophilus parainfluenzae infection. Suzuki et al found a markedly increased incidence of viral antigen deposition in the mesangium in IgAN compared to other glomerular diseases. It is at this point unclear whether H. parainfluenzae plays a role in most cases of IgAN, but further research in this area should be fascinating. Other disease associations with IgA nephropathy that should be kept in mind are mycosis fungoides, dermatitis herpetiformis, HIV infection, minimal change disease, membranous nephropathy and ANCA-related vasculitis.

Treatment in IgA nephropathy is controversial. The most promising development in recent years has been the provocative work of Donadio et al regarding the use of fish oils. They studied patients who predominately had adverse prognostic factors present, evidenced by a 40% risk of death or ESRD in the placebo group over a 4-year period. In contrast, in patients treated with 12 grams of fish oil per day the incidence of death or ESRD was only 10%. The rate of decline of renal function was markedly reduced in the fish oil treated patients. This is a compelling study because it demonstrates the clinical efficacy of a relatively safe medication. The role of this therapy in patients with mild disease is undefined at present.

In the patient presented above, the primary clinical manifestation was unilateral flank pain. Pain in IgA nephropathy is probably due to stretching of the renal capsule. The obvious atypical features in this case were the unilateral location and the persistent nature of the pain. I cannot provide a good explanation for this finding, which led her physicians to seek a urologic etiology for 3 years. There certainly have been patients with glomerular disease where one kidney has been affected more than another due to renal artery stenosis. There was no evidence of renal artery stenosis in this in this case.

Suggested Readings
Donadio JV et al. A controlled trial of fish oil in IgA nephropathy. N Engl J Med 331:1194, 1994

Galla JH et al. IgA nephropathy. Kidney Int 47:377, 1995

D' Amico G. Influence of clinical and histological features on actuarial renal survival in adult patient with idiopathic IgA nephropathy, membranous nephropathy, and membranoproliferative glomerulonephritis. Am J Kidney Dis 20:315, 1992

Suzuki S et al. Haemophilus parainfluenzae antigen and antibody in renal biopsy samples and serum of patients with IgA nephropathy. Lancet 343:12, 1994

Review Questions:

1. Which of the following factors predicts an adverse outcome in patients with IgA nephropathy?

a. Greater than 10 red blood cells per high power field on U/A
b. Repeated episodes of gross hematuria
c. Interstitial fibrosis by renal biopsy
d. All of the above indicate a poor prognosis

2. A feature which would favor a diagnosis of lupus nephritis instead of IgA nephropathy on renal biopsy is:

a. C1q deposition
b. Predominant IgA deposition
c. The presence of both IgA and IgG
d. A mesangial localization of immune deposits

3. A disease NOT associated with IgA nephropathy is:

a. Dermatitis herpetiformis
b. Leptospirosis
c. Membranous nephropathy
d. HIV infection

4. A treatment recently reported to be effective in IgA nephropathy is:

a. Pulse methylprednisolone
b. Alternating courses of steroids and chlorambucil
c. Calcium channel blockers
d. Fish oil

ANSWERS TO QUESTIONS


To me, the red cell cast was important in the diagnosis. This simple finding by the proper analysis of the urine(which is usually overlooked) led me to a diagnosis of an acute nephritic episode. I would ask all nephrologists (a plea, really) to rely on a good urine sediment examination. Thanks for this opportunity to disseminate this belief, based on many years of experience. My feeling is that the modern way of urinalysis, done by a machine, cannot replace (yet) a reliable, (usually done by the nephrologist) examination of the urine.
H Eliahou MD
Ramat Gan, ISRAEL-Friday, April 12, 1996 at 08:19:42 (CDT)

Your discussion on the subject of IgAN was concise, succinct and to the point. Various forms of inflammatory arthritis have also been seen with IgAN. In my experience, the presence of Psoriasis is also a cause (factor??) in the development of IgAN and connotes a poor prognosis.
Vincent R. Pateras M.D. (v-pateras@nwu.edu)
Evanston, IL USA-Wednesday, May 29, 1996 at 22:03:40 (CDT)

I also had a patient with unilateral loin pain, hematuria and with biopsy-proven IgA nephropathy. She was also a young woman, was taking such pills and was extensively investigated for urologic conditions. The clue was her urinary sediment: hematuria with persistent RBC!
Luis F Ferreira
florianopolis, SC Brazil-Wednesday, July 10, 1996 at 06:19:01 (CDT)

I too have a young male caucasian pt. with biopsy proven IgA nephropathy who had an episode of severe bilateral flank pain associated with hematuria.Flank pain with hematuria is known to occur in IgA nephropathy. He also underwent tosillectomy after which his serum creatinine dropped to 1.9 from 3.Beneficial effect of tonsillectomy have been reported by French investigators.
RAJENDRA DAHAL (RDAHAL @ AOL.COM)
MOLINE, IL USA-Monday, January 27, 1997 at 18:26:04 (PST)