Tubulointerstitial Disorders

Moderator’s Notes

Tubulointerstitial Disorders
We thank Dr. Yau for his presentation. Our Moderator’s Notes are derived from his live presentation which you can watch here: https://youtu.be/aKbSAF4mUmQ
Author: Dr. Jessica Lapasia
Editors: Dr. Pravir Baxi, Dr. Swati Arora, Dr. Michelle Marie O’Shaughnessy, Dr. Ali Poyan Mehr

Key points:

1. Interstitial nephritis associated with systemic diseases
Sarcoidosis

  • Classic lesion: noncaseating granulomas with multinucleated giant cells. However, granulomas are often absent in sarcoid associated interstitial nephritis, and can be seen in other forms of interstitial nephritis (e.g drug-induced hypersensitivity reactions); thus, they are neither sensitive nor specific for renal sarcoid.
  • Macrophages in granulomas contain 1-alpha hydroxylase and convert 25-hydroxy vitamin D to 1,25-OH vitamin D (active form), leading to increased intestinal absorption of calcium and bone resorption, increased filtered load of calcium, hypercalciuria, and ultimately interstitial nephritis (reaction to hypercalciuria), nephrolithiasis and/or nephrocalcinosis.
  • It can be helpful to check 1,25-dihydroxy vitamin D, which is expected to be elevated.
  • In addition to interstitial nephritis, sarcoid can cause vascular disease (granulomatous arteritis) or glomerulopathies such as membranous nephropathy or FSGS.
  • Treatment: First line is corticosteroids – may respond to much lower doses than 1mg/kg/d. Hypercalcemia responds quickly, but patients may relapse. Relapses tend to respond to repeat course of corticosteroids. Only case reports or small series available to guide treatment in steroid-dependent/frequently relapsing disease.

Sjogrens

  • Patients with Sjogrens rarely undergo kidney biopsy, but acute or chronic tubulointerstitial nephritis are the most common diagnoses among those that do. Distal RTA can be seen clinically. Glomerular disease including FSGS, membranous nephropathy or renal vasculitis are even less commonly seen.
  • Limited data to guide treatment. Expert opinion suggests corticosteroids if active disease on biopsy –improvement post-treatment depends on degree of IF/TA at biopsy; otherwise treatment typically guided by extra-renal manifestations.

Tubulointerstitial nephritis with uveitis (TINU)

  • Autoimmune disorder with strong HLA-association.
  • T-cell mediated plus humoral response. Often triggered by an inciting event (e.g., infection) which activates T-cells and recruits B-cells. This triggers an antigen-antibody response to modified CRP present in the kidney and uvea.
  • Limited data to guide treatment; oral steroids recommended, 1mg/kg/day with taper over several weeks-months. Relapses uncommon as inciting event-triggered.

IgG4-related tubulointerstitial nephritis

  • One of several IgG4-mediated kidney diseases: others include membranous nephropathy and retroperitoneal fibrosis.
  • Classic kidney biopsy finding: “storiform” appearance of predominantly lymphocytic infiltrate in a swirly, concentric pattern. Diagnostic criteria include plasma-cell rich TIN with >10 IgG4+ plasma cells/hpf and systemic organ involvement. Elevated IgG4 levels are not necessary or specific, but are supportive if seen.
  • IgG4-related membranous nephropathy can be seen together with TIN.
  • Very steroid-responsive disease. About 20% of patients relapse and might need a longer steroid taper or alternative immunosuppression (e.g., Rituximab): RCTs are lacking. Patients can successfully receive kidney transplants and appear to achieve disease control with standard immunosuppression regimens.
  • Uncertain role for monitoring serum IgG4 as a biomarker of disease activity.

2. Genetic tubulointerstitial disorders

  • Autosomal dominant, non-polycystic disease –good family history is critical.
  • Three mutations well described: UMOD (most frequent), MUC1, REN.
  • Medullary cysts can be present but are not required for the diagnosis (hence the recent abandonment of the team “medullary cystic kidney disease”)
  • Gout can be present, typically more common in patients with the UMOD mutation, but is not required for a diagnosis. If hyperuricemia is noted, consider treating this with uric-acid lowering agents even in the absence of gout.
  • ESKD develops at a mean age of 45y, but substantial variation, urine sediment is bland.
  • On biopsy, often see severe interstitial fibrosis. Glomeruli are typically spared until very advanced disease.
  • Consider genetic testing when suspected as helpful to identify other affected family members, particularly when screening potential living-related donors.

3. Chinese Herb and Balkan endemic nephropathy

  • Now thought to both be caused by exposure to aristolochic acid.
  • Patients present with reduced GFR, absence of proteinuria, advanced chronic tubulointerstitial nephritis on kidney biopsy.
  • Associated with urothelial malignancy.

4. Mesoamerican Nephropathy

  • A chronic interstitial renal disease of yet unknown cause, which has also been observed in other regions of the world including Egypt, Sri Lanka. (collectively referred to as CKDu)
  • First described in sugarcane workers in Central America, now also in miners, fishermen, farmers in similar environments in different parts of the world.
  • True prevalence likely underestimated due to lack of access to health care, patients may present with late-stage disease/ESKD.
  • Etiology remains unknown. Work environment (heat, dehydration, exposure to chemicals) likely a major contributor, but work is ongoing to elucidate disease mechanisms.

Selected References

  • Renal sarcoidosis: approach to diagnosis and management. Bergner R, et al. Curr Opin Pulm Med. 2018.
  • The Syndrome of Tubulointerstitial Nephritis with Uveitis (TINU). Clive DM, et al. Am J Kidney Dis. 2018.
  • IgG4-Related Disease: Is Rituximab the Best Therapeutic Strategy for Cases Refractory to Conventional Therapy? Results of a Systematic Review. Betancur-Vásquez L, et al. Reumatol Clin. 2019.