—  SPECIALTY CONFERENCE  —

Renal Pathology

Case 5 - Cryoglobulinemic Neprhopathy

Guillermo A. Herrera, Bostwick Lab/Nephrocor, Orlando, FL





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Clinical History
55 y/o diabetic white female who had a history of a previous prolonged admission for acute renal failure in 2001. The acute renal failure resolved but the details of this admission are not available. Her second admission was in 2003 with renal failure after gallbladder surgery. Serum creatinine at the time of this second admission was 2.7 mg/dl and increased to 4 mg/dl prior during the first week of hospitalization. At the time, complement levels were in the lower range of normal. Serological markers for connective tissue disease were all negative. Rheumatoid factor was negative. A renal biopsy was performed (first renal biopsy) which is provided for your evaluation. Patient responded well to plasmapheresis treatment and her acute renal failure improved with her serum creatinine decreasing to 1.1 mg/dl at the time of discharge. She was again admitted to the hospital 7 years later (2010) presenting with a rash, fever, and purpuric lesions which had become progressively more pronounced over a period of 2 weeks prior to admission and had extended from her extremities to her trunk and acute renal failure and renal failure. Her serum creatinine had increased to 2.68 mg/dl and the patient reported decreased urine output. Complement levels were low, especially C4 which was undetectable. Rheumatoid factor was now positive. CBC showed no anemia, leukocytosis, or thrombocytopenia. She had an elevated alkaline phosphatase- 131 with the normal range being 20-87. All other chemistries were normal. U/A showed 0-2 WBCs, 0-2 RBCs, and rare bacteria. A second renal biopsy was then performed because the diagnosed rendered in the first renal biopsy did not correlate with this patient’s clinical behavior. This second biopsy will be discussed together with the first biopsy made available to you.


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Pathological/Microscopic Findings and any Immunohistochemical or Other Studies:
Hypercellular glomeruli with numerous inflammatory cells in partially obliterated capillary spaces and scattered hyaline thrombi in glomerular capillaries and arterioles.

Differential Diagnoses:
Diffuse proliferative lupus nephritis with hyaline thrombi in glomrular capillaries. Thrombotic microangiopathy with secondary inflammatory changes.

Final Diagnosis:
Cryoglobulinemic Neprhopathy

Case Discussion:
The case presented illustrates a rather characteristic example of cryoglobulinemic nephropathy (CN), in terms of pathological manifestations. This entity has become much more common, as it is frequently associated with hepatitis C and the population harboring the hepatitis C virus has increased substantially in the last 2 decades. In addition, many of the publications on this entity are quite old and additions to the pathology literature have been few in the last 10 years.

Clinical presentation of patients with cryoglobulinemia can be quite varied but there are classical clinical signs and symptoms and laboratory findings that should suggest the diagnosis. At least 2 (and generally more) of the following findings are frequently found in these patients:
  • Purpura- commonly an early manifestation

  • Arthralgias

  • Generalized weakness

  • C4 less than 8 mg/dl

  • Positive rheumatoid factor

  • Detectable serum cryoglobulins

In 1933, Wintrobe and Buell described peculiar proteins which precipitated in sera stored at low temperatures (most strikingly at 4 degrees C) and redisolved when incubated at 37 degrees C. Lerner and Watson coined the term of cryoglobulins in 1947 to refer to the above proteins.

In 1974, cryoglobulins were classified into 3 types by Brouet et al. Type I represents a monoclonal type. Type II are composed of a mixture of monoclonal (restricted to usually IgM) with polyclonal (mostly IgG) proteins and Type III encompasses polycloal cryos with more than 1 isotype (IgG and IgM).

There are several recognized clinical associations with the different types of cryoglobulinemia. Type I is associated with hematologic disorders and are seen also in patients with so-called essential cryoglobulinemia (a subgruup now reduced to a small numer of cases) and accounts for about 10-15% of all cases. Type II (accounting for approximately 50-60% of the patients) and III (about 25-30% of the cases) cryos are also referred to as mixed cryoglobulins and are often seen in association with infectious and immunologic disorders- today mostly hepatitis C. Mostly type II and III cryoglobulinemias are associated with rheumatoid factor activity (positive rheumatoid factor).

It has been stated in the literature that approximately 21 to 29% of patients with cryoglobulinemia have renal involvement (though this figure has not been recently updated) and renal disease appears to be quite common in type II and III types and less common with type I cryos. Of all types of cryos, type II seems to have the one most associated renal manifestations.

Renal involvement may manifest in a variety of ways including:
  1. Acute nephritic syndrome (about 55% of cases)

  2. Acute renal failure- generally oliguric- usually associated with 1- (5% of cases)

  3. Nephrotic syndrome (28% of cases)

  4. Isolated proteinuria and hematuria (28% of cases).

Renal involvement generally follows purpuric manifestations by approximately 4 years. Remissions and exacerbations are rather common with relatively few cases with progressive renal disease (about 10% of all cases).

In terms of pathologic manifestations, the renal findings are variable. Type II cryoglobulinemic nephropathy is the one most commonly associated with membranoproliferative (MPGN) glomerulonephritis (GN), type I, a pattern that has been intimately linked to cryoglobulinemic nephropathy, but is not the only one found in these cases. Overall, there are cases in which mesangial proliferation is the only finding in glomeruli. Other cases reveal an exudative proliferative glomerulopnephritis and in a small number of cases, glomerular capillary thrombi without significant proliferative or exudative changes represent the only finding. In some cases, monocytoes in glomerular capillary spaces are conspicuous. Therefore, the morphologic manifestations of CN are varied. Furthermore, in a small percentage of cases an inflammatory vasculitis is seen in generally small extraglomerular vessels.

Immunofluorescence staining patterns in affected glomeruli can be quite heterogeneous, depending on the type of cryoglobulins involved in the pathologic process, the pathology observed, and the stage of the disease process. Granular deposits can be demonstrated in every glomerular location and the combination of positive immunoreactants is quite variable, with C3 being the most prevalent.

Electron microscopy is crucial in identifying characteristic substructure in the electron dense deposits identifying them as containing cryoglobulins. While in some cases the ultrastructural findings are quite diagnostic, for example the identification of paired microtubular or annular structures generally measuring 20-30 nm in diameter- some thicker- in the electron dense deposits, there are cases in which the deposits exhibit a variety of appearances, including fibrillary or paracrystalline arrays, and even fingerprints.

A recent study was conducted to determine the morphologic, immunofluorescence, and ultrastructural findings in a large series of patients with CN (12). 3300 renal biopsies were evaluated. 0.8% of all biopsies were diagnosed as cryoglobulinemic nephropathy.

The most salient light microscopic patterns included MPGN (50% of the cases) and proliferative / exudative GN (12% of the cases). Interestingly, capillary thrombi were seen in 65% of the cases, though most often in association with other morphologic findings, as noted above. "Full house" fluorescence staining was detected in glomeruli in 40% of the cases and C3 staining was the most constant immunoreactant noted (in more than 75% of the cases).

Electron microscopy revealed predominantly annular and paired short microtubular structures in association with the electron dense deposits.

This study demonstrated that the immunorphologic patterns associated with CN are heterogeneous. Differential diagnosis may be quite extensive depending on the morphologic pattern detected. Electron microscopy was extremely helpful in substantiating and establishing an unequivocal diagnosis in the great majority of the cases.

In conclusion, glomerular hyaline thrombi represent the most common finding in patients with CN and it is in these thrombi that the most characteristic ultrastructural findings are generally seen, as shown in the case presented. An extensive ultrastructural search is sometimes required to identify the typical substructure in electron dense deposits to clinch a diagnosis of CN. A high degree of suspicion is needed to make the correct diagnosis in a subset of these cases and, undoubtely, some of these CN cases are likely missed due to the lack of specific findings permitting a definitive diagnosis.

Selected References:
  1. Brouet, JC, Clauvel, JP, Danon, F et al: Biologic and clinical significance of cryoglobulins: a report of 86 cases. Am J Med 1974; 57: 775.

  2. Grey, HM, Kohler, PF: Cryoimmunoglobulins. Semin Hematol 1973; 10: 87.

  3. Lerner, AB, Watson, CJ: Studies of cryoglobulins: Unusual purpura associated with the presence of a high concentration of cryoglobulin (cold precipitable serum globulins). Am J Med Sci 1947; 214: 410.

  4. D'Amico, G, Colasanti, Ferrario, F et al: Renal involvement in essential mixed cryoglobulinemia. Kidney Int 1989; 35: 1004.

  5. Schifferli, JA, French, LE, Tissot, JD: Hepatitis C virus infection, cryoglobulinemia, and glomerulonephritis. Adv Nephrol Necker Hosp 1995; 24: 107.

  6. Druet, P, Letoniturier, P, Contet, A et al: Cryoglobulinemia in human renal disease: a study of 76 cases. Clin Exp Immunol 1973; 15: 483.

  7. Dispenzieri, A, Gorevic, PD: Cryoglobulinemia. Hematol Oncol Clin NA 1999; 13 (6): 1315.

  8. Golde, D, Epstein, W: Mixed cryoglobulins and glomerulonephritis. Ann Int Med 1968; 69: 1221.

  9. Tedeshi, A, Barate, C, Minola, E, Morram E: Cryoglobulinemia. Blood Rev 2007; 221: 21: 183.

  10. Feiner, H, Gallo, G: Ultrastructure in glomerulonephritis associated cryoglobulinemia. A report of 6 cases and review of the literature. Am J Pathol 1977; 88: 145.

  11. Herrera, GA, Turbat-Herrera, EA: Cryoglobulinemic nephropathy: Spectrum of clinical and immunomorphologic manifestations. (US-CAP Poster #206, Wednesday afternoon, 2012, Vancouver, Canada).