Renal Grand Rounds: Correlate Clinically

I recently presented the case of a middle-aged patient with ESRD secondary to Goodpasture syndrome. She presented with AKI 3 months after a kidney transplant. Her creatinine had normalized to 0.9mg/dl post-transplant. However, over the next few months she had multiple hospitalizations for infections, perinephric fluid collections and three episodes of AKI. Her creatinine finally stabilized at 1.5mg/dl. Due to concerns that she was overly immunosuppressed, her mycophenolate was discontinued during her last admission and her prednisone was stopped per weaning protocol. She was continued on tacrolimus. At her post-discharge follow up, she was found to have recurrent AKI with Cr 2 mg/dl She had 1+ blood on UA, but no proteinuria. GBM antibody was negative. She was admitted for a transplant kidney biopsy.

The biopsy demonstrated diffuse linear staining of the glomerular basement membrane. There was no evidence of active glomerulitis or crescent formation. Mild mesangial expansion and moderate thickening of the GBM were noted with no signs of cell-mediated or antibody-mediated rejection.

This prompted the million dollar question: Is this diffuse GBM staining early recurrence of anti-GBM disease or something else?

The inciting event of anti-GBM disease is still unknown (correlations with smoking, cocaine use, solvent exposure, and infections), however the pathophysiology is fairly well established - an insult causes a conformational change of the type IV collagen network in the GBM resulting in exposure of the non-collagenous portion of the alpha-3 chain which elicits an immune response. Based on multiple uncontrolled studies, these patients can be transplanted 6-12 months after their GBM antibody titers become negative and they have similar transplant outcomes when compared to other causes of ESRD.

But how often does it recur after transplant? In 2013, Tang et al retrospectively analyzed 58,000 patients in Australia and New Zealand started on RRT and found 449 diagnosed with anti-GBM disease, 224 of whom were transplanted. Of those transplanted, 2.7% developed biopsy proven recurrence. So... it recurs, but rarely.

What about a false negative GBM antibody titer? Our patient's titer was negative, and the reported false negative rate for the ELISA and western blot is 2-3% making it unlikely. However, there have been case reports of anti-GBM disease with negative ELISA and weakly positive western blot suggesting low or transient antibody production. In addition, alternative immunoglobulins not picked up by the ELISA, such as IgG4, and alternative GBM antigens have been proposed based on case reports.

What else could produce diffuse GBM staining? In monoclonal immunoglobulin deposition disease the physicochemical properties of the monotypic light chains result in high affinity for the GBM and diffuse linear staining. In addition, in diabetic glomerulopathy, there is thought to be a loss of negative charge in the GBM which allows negatively charged species such as immunoglobulin and albumin to collect in and expand the GBM. Our patients SPEP and SFLC were normal, and the donor didn't have a known history of DM. 

In the end, we couldn't answer the million dollar question definitively, but we decided to treat with plasmapheresis, rituximab, and restarting prednisone and mycophenolate. Rituximab was used instead of cyclophosphamide due to previous complications during her initial treatment.  She's currently doing well with Cr stable at 1.5mg/dl

Posted by Patrick Reeves

(Picture is Dr. Ernest Goodpasture who first described this condition while studying victims of the Spanish Flu in 1919)

Renal Grand Rounds - What Lurks in the Gap

I recently presented the case of a middle-aged man with a history of a remote Roux-en-Y gastric bypass, chronic diarrhea, and colon cancer on chemotherapy who initially presented with progressive fatigue and weakness in the setting of increased diarrhea. Shortly after admission he developed agitation that progressed to encephalopathy with dysarthria. His baseline labs from a month prior to presentation were notable for a chronically low serum bicarbonate of 15-17 with no anion gap. When he presented he was hypokalemic to 2.5 and his bicarbonate had dropped to 11 with a new elevated anion gap of 25 and normal L-lactate. Metabolic acidosis was confirmed on VBG. Interestingly, his urine electrolytes demonstrated a positive urine anion gap of 26.

He was ultimately diagnosed with D-lactic acidosis based on his clinical presentation which was confirmed with a serum D-lactate of 6.28. For the week prior to admission, he had been drinking 1.5 L of Gatorade (224 g of sugar!) daily to replace diarrhea losses.

This was a classic presentation of D-lactic acidosis in which overgrowth of gram positive anaerobes in the setting of short bowel syndrome is combined with a large carbohydrate load resulting in bacterial fermentation and D-lactate production.  He even had the classic neurologic findings!  His chronic non-gap acidosis likely represented chronic diarrhea and D-lactate production, and his rising anion gap when he presented was consistent with increased D-lactate production.

In D-lactic acidosis, the findings of hypokalemia and a positive urine anion gap can provide a helpful clue. With elevated serum D-lactate levels, the fractional excretion of D-lactate approaches 100%, i.e. everything that's filtered is excreted. This is because the stereospecificity of the sodium-L-lactate cotransporter in the proximal tubule results in poor reabsorption of D-lactate relative to L-lactate. The negatively charged D-lactate essentially drags positively charged sodium and potassium into the urine causing hypokalemia as well as a positive urine anion gap (Na + K - Cl) due to the increased urine sodium and potassium.


This patient did well after his Gatorade was cut off and he was treated with antibiotics to address gram positive anaerobic overgrowth.

Posted by Patrick Reeves

(Image taken from here - an educational blog for ED residents)

Renal Grand Rounds: Fevers on Dialysis - Not always an Infection

At renal grand rounds this week, I presented a case of a gentleman who presented with fevers, confusion, and lower extremity pain during dialysis. The patient would spike low grade fevers pre-HD and then fevers up to 105 post-HD. He had a tunneled HD line, but blood cultures were negative, and his fevers persisted in spite of changing the line. We were initially concerned for a dialyzer membrane reaction, but the time course of fevers was not consistent with either type A or type B reaction, and his symptoms persisted even after switching to an Exceltra membrane. The patient was worked up further, and his serum electrophoresis revealed 2 M components, serum free light chains showed an elevated Kappa/Lambda ratio, and he had a positive urine Bence Jones protein. His CH50 and C4 levels were undetectable, but C3 was only mildly low. Cryocrit was sent, and was positive for a type 2 cryoprotein with a predominant IgM Kappa component.

It was unclear why the symptoms of cryoglobulinemia worsened with dialysis; it was hypothesized that hemoconcentration with ultrafiltration, along with exposure of blood to cooler temperatures within the dialysis tubing led to transient complement consumption and an inflammatory reaction. The symptoms of mixed cryoglobulinemia are typically nonspecific, and patients usually present with arthralgias, fatigue, palpable purpura, and peripheral neuropathy. C4 and total complement are usually dramatically low, as in this case.

Treatment of cryoglobulinemia usually involves the use of plasmapheresis to remove circulating cryoglobulins. Steroids are suppressive in some patients, and rituximab quells formation of new cryoglobulins.  There are no studies aside from case reports about the use of eculizumab for cryoglobulinemia. Trendelenburg et al analyzed the role of complement in glomerular inflammation using mice models, and showed that mice deficient in C5 had reduced glomerular infiltration by neutrophils. Eculizumab inhibits the conversion of C5a to C5b and subsequent formation of the membrane attack complex; it therefore be theoretically useful in treating cryoglobulinemia, which causes complement mediated renal failure.

The patient was treated with 2 doses of eculizumab and then rituximab for cryoglobulinemia, and is now doing well and tolerating dialysis.

Posted by Shruti Gupta, Renal Fellow MGH/BWH