Lignt chain-associated acute tubulointerstitial nephritis

Clinical presentation  of kidney involvement in plasma cell dyscrasia (PCD) are variable. Patients may present with nephrotic syndrome due to AL amyloidosis or acute kidney injury due to light chain cast nephropathy (LCN). Similarly, histopathology may show severe kidney injury as in LCN or subtle change as in light chain proximal tubulopathy. Cheung et al. reported a poorly recognized kidney involvement in PCD called light chain-associated acute tubulointerstitial nephritis (LC-ATIN). The entity is characterized by tubulointerstitial inflammatory cell infiltrate by LM, linear tubular basement membrane and granular cytoplasmic proximal tubular staining by kappa or lambda light chain by IF and atypical lysosomes in proximal tubular cells with focal granular punctate depostis in TBM by EM.

LM finding is indisguishable from acute tubulointerstitial nephritis due to drug hypersensivity. The detection of monoclonal light chain staining in linear pattern along TBM and granular cytoplasmic in proximal tubules is crucial for diagnosis. The deposition of punctate electron dense deposits along TBM seems to be at least focally, as immunogold EM labeling demonstrated the presence of monoclonal light chain in TBM without deposits. The TBM linear light chain staining and punctate deposits also characterize light chain deposition disease, but LCDD lacks significant tubulointerstitial infiltrate and usually presents with glomerular and/or vascular involvement. It is arguable that LC-ATIN may be an early stage of LCDD.

I

A increased and atypical lysosomes in proximal tubular cells, B punctate deposits along TBM similar to LCDD, C-D immunogold labeling demonstrates monoclonal light chain in lysosomes and TBM (Image from Cheung et al.)

Cheng M, Gu X, Turbat-Herrera EA, Herrera GA. Tubular Injury and Dendritic Cell Activation Are Integral Components of Light Chain-Associated Acute Tubulointerstitial Nephritis. Arch Pathol Lab Med. 2019;143(10):1212-1224. doi:10.5858/arpa.2018-0032-OA

Castleman disease vs. IgG4-related interstitial nephritis

Castleman disease (CD), a benign lymphoproliferative disorder, can involve kidney. Various diseases had been reported in patients with CD, amyloidosis, thrombotic microangiopathy being the most common. Zoshima et al. reported 2 cases of CD with kidney involvement mimicking IgG4-related tubulointerstitial nephritis. Although kidney biopsies show many IgG4+ plasma cells, there was no characteristic storiform fibrosis or IgG staining in tubular basement membrane as seen in majority patients with IgG4 renal disease. Patients with CD had more marked inflammatory response with highly elevated C reactive protein and were not responsive to steroid as favorably as IgG4RD. Imaging study was also different with CD showing no kidney abnormalities in contrast to characteristic low density lesion in IgG4RD.

Patchy plasma cell aggregates without storiform fibrosis in Castleman disease with tubulointerstitial nephritis (Image from Zoshima et al.)

Zoshima T, Yamada K, Hara S, et al. Multicentric Castleman Disease With Tubulointerstitial Nephritis Mimicking IgG4-related Disease: Two Case Reports. Am J Surg Pathol. 2016;40(4):495-501. doi:10.1097/PAS.0000000000000575

Proliferative glomerulonephritis with monoclonal immunoglobulin deposits, light chain variant

Proliferative glomerulonephritis with monoclonal immunoglobulin G deposits (PGNMID) is a type of monoclonal immunoglobulin deposition disease characterized by glomerular injury with membranoproliferative pattern and deposition of monoclonal IgG (usually IgG3). Nasr et al. described a case series of PGNMID with light chain deposition only. 

Unlike PGNMID-IgG, the light chain variant (PGNMID-LC) showed only monoclonal light chain deposits. All 17 patients had either underlying monoclonal gammopathy of renal significance (MGRS) or multiple myeloma. This was in contrast to PGNMID-IgG in which more than two-thirds of patients did not have MGRS or B/plasma cell neoplasm. All 6 patients who had anti-plasma cell therapy with complete hematologic response had renal response.

Although PGNMIC-LC is considered a variant of PGNMID-IgG, its hematological underlying is more like light chain deposition disease (LCDD). 

PGNMID-LC show large subendothelial deposits by LM resembling wire loop in lupus nephritis.
PGNMID-IgG usually has small subendothelial deposits best demonstrated by EM (Image from Nasr et al.)

Nasr SH, Larsen CP, Sirac C, et al. Light chain only variant of proliferative glomerulonephritis with monoclonal immunoglobulin deposits is associated with a high detection rate of the pathogenic plasma cell clone. Kidney Int. 2020;97(3):589‐601. doi:10.1016/j.kint.2019.10.025

Hemolysis-associated hemoglobin cast nephropathy

Hemolysis-associated hemoglobin cast nephropathy (HAHCN) is a rare cause of acute tubular injury (ATI) characterized by presence of hemoglobin casts in renal biopsy. Patients usually have extensive intravascular hemolysis evidenced by hemoglobinemia/hemoglobinuria and elevated LDH. Common causes are AIHA (autoimmune hemolytic anemia) and drugs with rifampicin in particular.

Renal biopsies in patients with HAHCN show typical pictures of an ATI with hemoglobin casts. The casts present mainly in proximal tubules and have variable appearance morphologically and tinctorially. They closely resemble myoglobin casts, another cause of ATI. Immunohistochemical study is needed to differentiate between the two. RBC casts can be differentiated from hemoglobin casts based on light microscopy. In spite of positive hemoglobin staining, RBC casts contain degenerated "ghost" RBCs. Renal injury by HAHCN is supposed to be due to decreased renal perfusion, direct toxic injury to tubular cells and tubular obstruction.

Renal injury in HAHCN is reversible if the cause of hemolysis is eliminated.

Dvanajscak Z, Walker PD, Cossey LN, et al. Hemolysis-associated hemoglobin cast nephropathy results from a range of clinicopathologic disorders. Kidney Int. 2019;96(6):1400‐1407. doi:10.1016/j.kint.2019.08.026

DGKE nephropathy as cause of atypical HUS

DGKE nephropathy is a form of atypical HUS (aHUS) with underlying genetic defect in DGKE gene encoding diacylglycerol kinase epsilon. The protein expresses in podocyte, endothelium and platelet and has role in regulating thrombogenesis. It may also maintain integrity of slit diaphragm in podocytes. Mutated DGKE  causes aHUS in early childhood with the disease manifests in first 2 year of life. In addition to thrombocytopenia, microangiopathic hemolytic anemia and renal injury, these patients had significant proteinuria, some in nephrotic range or nephrotic syndrome. Most patients experienced relapse in first few year of life with disease on more stable course later. Histopathology revealed chronic thrombotic microangiopathy with double contoured glomerular capillary walls with/without mesangial interposition. No active fibrin thrombi were identified.

Unlike complement-mediated aHUS, patients with DGKE nephropathy do not have mutation of or antibody to complement proteins. Therefore, it does not respond to treatment with eculizumab, an anticomplement drug. Patients who had renal transplant did not have recurrent disease. 

https://dx.doi.org/10.1038%2Fng.2590

https://dx.doi.org/10.1016%2Fj.kint.2020.01.045

Evidence of direct SARS-CoV-2 infection in kidney

The main target of SARS-CoV-2 is respiratory system. Other systems can also be affected including cardiovascular and renal. Su et al. (1) demonstrated corona virus-like particles in autopsy kidneys (proximal & distal tubular cells, visceral epithelial cells). They also showed positive immunostaining for SARS-CoV antigen in tubular cells. Enhanced ACE2 staining was seen in injured tubular cells. Positive ACE2 in parietal and visceral epithelial cells is identified. Control kidney showed weaker ACE2 expression in tubular cells without staining in parietal & visceral epithelial cells. The conclusion is SARS-CoV-2 can directly infect kidney parenchyma via available ACE2 receptor.

However, corona virus-like particles may not be true SARS-CoV-2. They may be normal ultrastructures commonly found in proximal tubular cells and visceral epithelial cells (2).

(1) https://dx.doi.org/10.1016%2Fj.kint.2020.04.003

(2) https://dx.doi.org/10.1016%2Fj.kint.2020.05.012

When to do genetic testing in FSGS?

The histopathologic classification of focal and segmental glomerulosclerosis (FSGS) is not necessarily reflective of etiologies. A more clinically useful practice is to classify FSGS into primary, secondary and genetic. Primary FSGS is caused by unknown circulating mediator injurious to podocytes. Secondary FSGS can be further subclassify into maladaptive, viral and drug-induced. Genetic FSGS has many already-identified and unidentified mutations.

Relevant mutation needed to be identified in order to diagnose genetic FSGS, but not all patients with FSGS need genetic test. De Vriese et al. provide useful algorithm for genetic assessment in FSGS patients.

Secondary FSGS in the diagram refers only to maladaptive form. Viral and drug-induced FSGS must be ruled out by presence of infection or drug exposure.

https://doi.org/10.1681/ASN.2017090958