Update on Membranous Nephropathy

U Penn established an annual one-day seminar in nephrology symposium. This year was titled “New Horizons in Nephrology: Updates in Glomerular Disease”.

Dr. Beck from Boston University gave the update on membranous nephropathy (MN). Previously, we discussed his article in the NEJM in detail, and today we will go over some key points and updates:

• 75% of MN is considered primary (idiopathic).
• IgG4 subclass is predominant in idiopathic MN.
• Anti-PLA2R is highly specific for primary MN
• Co-localization of PLA2R and IgG4 within immune deposits on biopsy.
• The majority of patients with primary MN have circulating autoantibodies against PLA2R.

There is a clear association of anti-PLA2R with disease activity.

- Positive in nephrotic state.

- Declines prior to the decrease in proteinuria.

- Absent in remission.

- Returns with (or prior to) relapse.

- Associated with recurrent MN

Methods of testing:

- Western blot

- Indirect immunofluorescence test

- ELISA : Will likely be the test of choice. Available in Europe, not yet in the US.

Treatment:

- Do NOT use corticosteroid monotherapy or MMF monotherapy for initial therapy of MN.

- No single definitive immunosuppression could be easily identified.

Current Initial therapy :

• Ponticelli regimen: methylprednisolone 1g/d iv x 3 doses followed by oral prednisone 0.5mg/kg/d in months 1,3,5; oral cyclophosphamide (2mg/kg/d) in months 2,4,6.
• Alternative initial therapy for those who refuse or have contraindications to cyclophosphamide is Calcineurin inhibitor (CNI) for at least 6 months.
• Stop if no remission in 6 months.
• If remission is attained, reduce dose every 1-2 mo by 50% and continue for at least 12 months 

Posted by Tarek Alhamad

Too much protein

An internal medicine resident was presenting a consult to our team on a patient with nephrotic-range proteinuria. During his presentation, he stated that he had already ruled out amyloidosis because the patient had a negative SPEP and UPEP by immunofixation.

To evaluate the validity of his statement, we need to go back to pathophysiology to review the mechanism of amyloidosis.

Amyloid is a pathologic proteinaceous substance, deposited in the extracellular space in various tissues and organs of the body in a wide variety of clinical settings. Under light microscopy, with hematoxylin and eosin staining, amyloid appears as an amorphous, eosinophilic, hylaline, extracellular substance that, with progressive accumulation, encroaches on and produces pressure atrophy of adjacent cells. By electron microscopy amyloid is seen to be made up largely of continuous, non-branching fibrils. This electron-microscopic structure is identical in all types of amyloidosis.

The two major kinds of amyloidosis are:

1)     Primary amyloidosis (AL) (Amyloid Light chain)

The AL protein is made up of light chains, mainly composed of λ light chains or their fragments. Its deposition is associated with certain forms of plasma cell tumors.

Diagnosis: With the use of immunochemical techniques, monoclonal immunoglobulin is found in the serum or the urine in nearly 90% of patients. If you add the serum-free light-chain assay, an abnormal result is found in 99% of patients. A biopsy of an affected organ is usually diagnostic also.

Treatment: Debatable

Patients with severe organ dysfunction should receive repeated cycles of Melphalan/Dexamethasone as first line therapy. Patients with less severe organ dysfunction may benefit from high Dose melphalan followed by stem cell transplant as the first line therapy. For patients with relapsed disease, the use of alternative regimens (thalidomide, lenalidomide, cyclophosphamide, or bortezomib) is a reasonable approach that is growing in popularity.

2)     Secondary amyloidosis (AA)

AA fibrils are derived by proteolysis from a larger precursor in the serum called SAA (serum amyloid–associated) protein that is synthesized in the liver under the influence of cytokines such as IL-6 and IL-1. The production of SAA protein is increased in inflammatory states as part of the “acute phase response”; therefore, this form of amyloidosis is associated with chronic inflammation. However, increased production of SAA by itself is not sufficient for the deposition of amyloid. You need to have an enzyme defect that results in incomplete breakdown of SAA, thus generating insoluble AA molecules.

Diagnosis: Biopsies of accessory salivary glands, abdominal fat, and rectal mucosa yield positive results in 50% to 80% of patients. Kidney biopsy is positive in almost 100% of symptomatic patients.

Treatment: Treat the underlying source of inflammation. Eprodisate is a member of a new class of compounds that inhibits polymerization of amyloid fibrils potentially slowing the decline in renal function

Getting back to the resident, I think his statement would be correct in AL (primary amyloidosis), but not valid if the patient has AA (secondary amyloidosis).

Posted by Tarek Alhamad

Calciphylaxis

An ESRD patient on CAPD was recently admitted to our hospital with possible pneumonia. It was noticed that he had painful plaque-like necrosis, with areas of ulceration. Even in the absence of a skin biopsy, the consensus was that he had calciphylaxis based on gross appearance alone and as a result, he was started on intravenous Sodium Thiosulfate 5g three times weekly.

Calciphylaxis (or calcific uremic arteriolopathy) is an uncommon but dreaded complication of renal failure characterized by painful nodular or plaque-like subcutaneous calcification often leading to ischemia, necrosis, ulceration and secondary infection. Calciphylaxis mostly occurs in patients with ESRD receiving hemo- or peritoneal dialysis although it is known to occur also in patients with CKD. Well described risk factors include female sex, hyperphosphatemia, hypercalcemia, hyperparathyroidism, the use of Ca-containing phosphate binders, vitamin D, and hypercoagulable states.

The diagnosis usually is made easily by characteristic clinical, bone scan and x-ray findings of well-defined tumor-like masses of Ca. (see previous posts)

Treatment recommendations have included reduction of serum Ca and P (and the CaxP product) by the use of low Ca dialysis baths, cessation of Ca-containing phosphate binders and vitamin D supplements, use of sevelamer, and possibly parathyroidectomy in refractory cases. Several case reports have reported the successful treatment of calciphylaxis with Sodium Thiosulfate. Sodium thiosulfate pentahydrate (Na2S2O3) has a molecular weight of 248. It distributes throughout extracellular fluids and is normally is excreted unchanged in the urine. It has been used as antidote for acute cyanide poisoning and as a topical treatment for acne and pityriasis versicolor. The theory is that sodium thiosulfate inhibits the precipitation of Ca salts and also leads to dissolution of Ca deposits into a more soluble form (Ca thiosulfate salts). The treatment is required for up to 4-12 months although a reduction of pain is usually seen within a couple of weeks. The main side effect is an anion gap metabolic acidosis that is related to the retention of sulfate salts. It has been suggested that patients who develop this complication can be treated with a high bicarbonate dialysis.

Back to our patient, we increased the dose of sodium thiosulfate to 25g. After 2 weeks treatment, the patient was tolerating the medication well and reported a significant improvement both in the pain, and in the necrotic lesions.

Posted by Tarek Alhamad

To Treat of Not

A 46 year old man with a recent diagnosis of acute leukemia and white count of 90,000 was transferred to our facility with non-oliguric AKI secondary to tumor lysis syndrome. The patient was hypocalcemic (Ca 5.2mg/dl) and hyperphosphatemic (PO4 11 mg/dl). His K was 5.8 mmol/L and his creatinine was 3.5 mg/dl. He was making around 200mls/hr of urine and he was asymptomatic. The Hem/Onc resident called nephrology looking for advice about whether or not the hypercalcemia should be treated and if he would be better off getting D5W with bicarbonate instead of normal saline.

TLS is a result of rapid and massive breakdown of tumor cells, either spontaneously or after the initiation of cytoreductive therapy. Because potassium is stored primarily in the intracellular compartment, its rapid release into the extracellular compartment during TLS can lead to hyperkalemia. Similarly, hyperphosphatemia results from a massive release of intracellularly stored phosphate, that can lead to secondary hypocalcemia. Uric acid is the end product of the catabolism of purines, which are released from the breakdown of nucleic acids. That lead us to the laboratory definition of TLS, that was developed by Cairo and Bishop.

Renal injury can result from two components; the deposition of uric acid and calcium phosphate crystals, and non-crystal mechanisms including renal vasoconstriction, alteration in renal autoregulation through inhibition of nitric oxide synthesis and a resulting decrease in endothelial cell nitric oxide, and stimulation of the renin-angiotensin system.

It is best to avoid IV calcium administration unless hypocalcemia is symptomatic because it might increase the risk of calcium phosphate precipitation and the potential for additional kidney injury. It is also best to monitor serum ionized calcium levels, especially in patients with hypoalbuminemia.

When rasburicase is available, hyperuricemia is seldom an indication for dialysis. Rasburicase is a recombinant urate oxidase that converts uric acid to the more water-soluble product allantoin (which is not dependent on urinary pH for its solubility).

Uric acid solubility is low and increases as urinary pH becomes more alkaline. However, calcium phosphate is more soluble at an acidic pH; therefore, urinary alkalinization may lead to increased calcium-phosphate crystallization and precipitation.

Therefore, especially when rasburicase is available to manage the hyperuricemia, urinary alkalinization should be avoided.

Going back to the patient, neither Ca nor bicarbonate was given. Uric acid was not measurable the next day following the use of rasburicase. PO4 decreased gradually over the next few days, and no dialysis was required during the hospitalization.
Update: As a commenter pointed out below, rasburicase continues to work in vitro unless the sample is immediately placed on ice and the "undetectable" uric acid level may have been artefactual.

Posted by Tarek Alhamad

Mercury rising

A patient who had been working in a recycling company that handled thermometers presented with fever, dry cough, fatigue and rash. Based on imaging (CXR showed massive radio-opaque material in the lungs, right atrium and right ventricle; skeletal survey showed radio-opaque deposits in the kidneys, bowel wall, and bladder wall), symptoms, and a positive history of exposure, a diagnosis of mercury intoxication was made. The patient developed multi-organ failure including anuric acute renal failure, and nephrology was consulted. Further background details on the case can be found here. What is the treatment and the role of dialysis in mercury intoxication? 


Metallic mercury has a widespread use both within industry and in many everyday objects such as thermometers, dental amalgams, batteries, fluorescent light bulbs, and many others. Mercury intoxication can result from vapor inhalation, resulting in severe respiratory symptoms, or from injection, usually in cases of attempted suicide. 


The chelating agents 2,3- dimercaptopropanesulfonic acid (DMPS) and meso-2,3-dimercaptosuccinic acid (DMSA) are central to the management of mercury toxicity. DMSA is given orally, and can cause leucopenia and elevated liver enzymes. DMPS is an intravenous medication and its use is associated with hypotension. In our patient, DMSA 500 mg po q 8hrs was given for 4 days, before it was discontinued because of elevated LFTs and leucopenia. We then started DMPS with CRRT but unfortunately, after two weeks of supportive treatment, the patient died. 


Chelators such as DMPS and DMSA work by mobilizing mercury and facilitating its excretion through the kidneys. This creates a management conundrum in the anuric patient, as this route of excretion is not available. Consistent with this, our patient’s blood mercury levels rose dramatically during chelator treatment, despite CRRT. We hypothesize that the administration of DMPS mobilized mercury from extracellular deposits and redistributed it to the blood and organs, but it failed to be adequately eliminated from the body because of anuria. For this reason, intensive CRRT with a high-flux dialyzer is a critical adjunct to chelator therapy. If this is not available, continuous renal replacement therapy with chelators have showed better mercury clearance than conventional dialysis, whereas peritoneal dialysis has been shown to be ineffective at clearing mercury. These principles should be borne in mind in other heavy metal poisonings also. Other management pearls I took from this unusual case were to initiate dialysis early and to give DMSA at a lower and more frequent dose to avoid serious side effects. 


Tarek Alhamad M.D.