Dysproteinemias and Kidney Disease

Fig. 13.1

Immunofluorescence microscopy with antisera to kappa light chain shows prominent staining of tubular basement membranes (TBM) in a linear pattern. Staining can also be seen in the glomerulus along some GBM as well as the mesangium in a nodular pattern

Renal impairment and proteinuria are seen in almost all patients with MIDD . The median age of presentation is between 51 and 57 years but ranges from 22 to 94 [6, 9, 15, 16]. Roughly two thirds of the patients were male. Median proteinuria ranges between 2.7and 4.1 g/d from different series [6, 9]. Nephrotic syndrome can be seen in 40 % of the patients. One series found that patients with HCDD may have higher degree of proteinuria. Microscopic hematuria is common (62 %) but gross hematuria is rare (3 %). Renal insufficiency is also nearly universal with an average serum creatinine of 3.8 mg/dl at presentation. During follow-up, 39–57 % of patients had reached end stage kidney disease (ESKD). Median overall survival (OS) varied from 13 months in one study to 90 months in another [9, 16]. Renal histology, presence of MM, and presence of lytic bone lesion were among the factors that influenced survival.

Histologically, the most recognizable lesion of MIDD is the nodular mesangial sclerosis [9, 11, 17, 18]. This is present in two third of the cases [9, 11, 17, 18]. These nodules are positive on PAS stain and Jones’ silver stain and indistinguishable from to Kimmelstiel–Wilson nodules, although some feel there is less variation in size as compared with diabetic nephropathy. Other features include mesangial sclerosis without nodules, membranoproliferative pattern, and even crescents. The diagnosis is made on immunofluorescence (IF) where the monoclonal light chains, heavy chains, or entire immunoglobulin (Ig) can be seen staining in linear pattern diffusely along GBM and tubular basement membranes (TBM). Deposits can also be seen in the mesangium, but it is less reliable than the TBM or GBM. In the vessel walls, the monoclonal protein is deposited in a web-like pattern. Deposits of C3 may also be found in patients with LCHDD and HCDD. The diagnosis is confirmed on EM. The deposits should be electron dense and appear powdery or amorphous in the same compartments as in IF. MIDD often can coexist with other renal lesion in the same kidney. Cases of coexistence with myeloma cast nephropathy (MCN), AL amyloidosis, and fibrillary glomerulonephritis have been reported [19, 20].

One area of controversy is in the diagnostic criteria for MIDD. Some have suggested that both IF and EM deposits are needed for the diagnosis, while others feel that only IF deposits are necessary. In one single center series of 64 patients, every patient had deposits identified on IF and EM [9]. On the other hand, an Italian series of 63 patients found IF was positive in 97 % of cases while EM was only positive in 77 % [6]. This has also been noted in a smaller series where the IF was positive in 95 % of the 40 patients while granular deposits were found in only 73 % of the biopsies [21]. The EM negative cases often had MCN within the same biopsy [6, 22]. It is important to recognize that the sensitivity of the technique depends on the location in the kidney. Deposits nearly are universally found (> 95 %) in the TBM using IF but are more likely to be found in the GBM rather than TBM when using EM (74–47.8 % vs 56–34.8 %, respectively) [9, 21]. Data for the renal outcomes of patients with IF only deposits are not available; however, the coexistence of cast nephropathy does alter the renal and patient outcomes [16].

In older series, a monoclonal protein was not always found in patients with MIDD . For example, monoclonal protein by immunofixation was only identified in the serum in 76 % of the patients, urine in 90 % of the patients, and neither in 6 % of the patients in the Pozzi study [6]. In the Nasr study, 100 % of the patients who had serum-free light chain assay performed had an abnormal result [9]. Serum-free light chain assay is particularly useful in patients with HCDD in which the immunoglobulin heavy chain is often truncated [23]. In these patients, the truncated heavy chains are sometimes difficult to detect by immunofixation technique. However, all these patients have abnormal free light chain and free light chain ratio [9]. On bone marrow biopsy, MM was diagnosed in 59–65 % of cases while 3 % were due to CLL [6, 9]. The rest which were described as idiopathic, would now be classified as MGRS [7].

Monoclonal kappa light chains are much more common than their lambda counterparts in LCDD. Approximately 75 % of the reported cases are from a kappa clones [6, 9, 18, 24]; and within the kappa subtypes, V_kI seems to be most common [25]. The reason why kappa light chains are overrepresented may be due to its tertiary and quaternary structure. Analyses of kappa light chains show a β-edge in the CDR2 loop resulting from a conserved cis-proline at position 8 [26]. This proline is in the transposition in lambda light chains. Not only that, in the lambda light chains, it is often followed by another trans-proline at position 9. Exposure of the β-edge promotes spontaneous aggregation of kappa light chains into oligomers that elongate into a fibril. These fibrils do not bind serum amyloid P (SAP) or Congo red-like amyloid fibrils so they do not have amyloid characteristics. These oligomers may form the deposits that are seen in MIDD .

Prognosis both from renal survival and patient survival are quite variable in MIDD and are dependent on several factors. Coexistence with MM or MCN adversely affects both renal and patient survival [16]. Patients who present with both MIDD and MCN rarely 9.1 % recover their renal function versus 43.5 % of those presenting with MIDD alone. Median OS for patients with MIDD is 48 months versus 21 months for those with MIDD and MCN (p = 0.0453). In another study where only 21.0 % of the patients had MM found the patient survival at 5 years was 71 % but the renal survival was 40 % [15]. Inadequate treatment of the MGRS was felt to be the reason for the high rate of ESKD. Obviously, access to effective chemotherapy plays a large role in both renal and patient survival. In a modern series of 64 patients where 20 % had symptomatic MM and access to novel agents for myeloma therapy, the median OS was 90 months [9].

Treatment of MIDD should be based on the clone responsible for the monoclonal protein [27]. In patients with MM or CLL, appropriate treatment of the underlying hematologic malignancy should be used. In patients with MGRS (≤ 10 % bone marrow plasma cells), treatment with cytotoxic therapy is indicated in order to preserve renal function [16]. However, because these patients do not have a malignant condition, minimizing chemotherapy-related toxicity is as important as efficacy. Bortezomib-based therapies have become a popular choice in the treatment of MIDD because of their lack of nephrotoxicity and renal metabolism [28, 29]. It does have some serious long-term side effects such as peripheral neuropathy that requires every effort to reduce as much toxicity as possible especially in patients with only MGRS [30]. Autologous stem cell transplantation either alone or after induction has also produced good results [19, 29, 31–33]. Finally, it is important to note that ESKD patients without MM who are not candidates for kidney transplantation may not require therapy [7, 27].

Kidney transplantation in MIDD may be possible if the clone can be suppressed. Studies have found recurrence to be as high as 80 % in the patients who still have a monoclonal protein [34]. Thus, kidney transplantation should be reserved for those patients who had a hematologic complete response (CR). This is defined as the absence of the monoclonal protein in the serum and urine, absence of clonal plasma cells in the marrow, and normal serum-free light chain ratio. The last criterion is sometimes difficult to assess as the ratio changes with advanced chronic kidney disease [35]. Kidney transplantation is often more difficult in patients with MM since their disease tends to relapse more often than those with MGRS [19].

Membranoproliferative Glomerulonephritis with Monoclonal Deposits

Case #2

A previously healthy 35-year-old female presented with sudden onset of hypertension, microscopic hematuria, and 10 g/d of proteinuria. Creatinine was 0.8 mg/dl. Initial kidney biopsy was read as LHCDD. Serum and urine protein electrophoresis were negative. A bone marrow biopsy was performed which was inadequate for interpretation. Patient was initially started on cyclophosphamide and prednisone. Thalidomide was later added but was discontinued due to side effects. Creatinine increased to 1.4 mg/dl and proteinuria was 8.8 g/d. Proteinuria responded (1.4 g/d) but due to the development of acalculous cholecystitis, cyclophosphamide was stopped. Creatinine increased to 1.9 mg/dl. Patient was started on mycophenolate mofetil but proteinuria began to increase. A course of rituximab was administered without any benefit. Proteinuria increased to 4.5 g/d and cyclophosphamide and prednisone was restarted. Proteinuria stabilized but creatinine began to climb. Tacrolimus was started but both proteinuria and creatinine increased. After 5 years of initial presentation, dialysis was initiated for end-stage kidney disease. After 3 years on dialysis, patient received a kidney transplant. At the time of transplantation, a monoclonal IgA lambda was identified in the blood and urine. After 3 months of posttransplant, the creatinine was 1.4 mg/dl and proteinuria was 1.7 g/d. Serum kappa free light chain was 12.3 mg/dl and lambda was 8.65 mg/dl, with a ratio of 1.43. An allograft biopsy showed membranoproliferative glomerulonephritis (MPGN) with deposits that stain for IgA and lambda but not kappa. The deposits have a crystalline structure with a periodicity of 20 nm. By 4 months posttransplant, creatinine increased to 3.3 mg/dl. If the IF showed no C4D deposition in the above case, what secondary causes have to be considered for the MPGN pattern of injury?

Lymphoma

Myeloma

Hepatitis B or C

CLL

Another example of non-organized MG deposition disease is MPGN . Until recently, MG was thought not to be associated with MPGN. However, a new classification scheme based on pathophysiology rather than histology recognized MG as a major contributor to MPGN. In the new classification, MPGN is divided into those with immunoglobulin (Ig) deposits and those with only complement components [36]. The ones with complement deposits only are due to activation of the complement cascade usually due to dysregulation. The ones with Ig deposits are further divided between those with polyclonal Ig deposits which are usually secondary to infections or autoimmune disorders and those with monoclonal Ig [36, 37]. This new classification is supported by a single center study from the Mayo Clinic which found 41 % of the cases were associated with a circulating monoclonal protein and monoclonal Ig deposits in the kidney after excluding cases with hepatitis (B and C) and dense deposit disease (DDD) [38]. While majority of the cases were classified as MGRS, 21 % met criteria for MM. Other hematologic diagnosis included WM, CLL, and other lymphomas.

The injury pattern is that of membranoproliferative pattern. The glomeruli are enlarged with expansion of mesangium and hypercellularity [38]. GBM are thickened often with eosinophilic deposits and double contours as a result of new membrane formation. Cellular elements include mononuclear cells as well and neutrophils. Crescents are not uncommonly seen in many biopsies . Focal global glomerulosclerosis, tubular dropouts, and interstitial fibrosis can be found in more advanced cases. On IF, the monoclonal Ig deposits are most commonly found along the capillary walls. C3 may also be seen in the same areas as the monoclonal Ig. Deposits can also be found in the mesangium but less often than capillary walls. The Ig deposits should be restricted to a single immunoglobulin light chain and immunoglobulin heavy chain subclass. On EM, the electron-dense deposits do not have substructures and are often granular in appearance. They are mainly subendothelial on the capillary walls. Deposits can also be found in the mesangium.

Clinical Case #2 Follow-up and Discussion

A bone marrow biopsy showed 30 % lambda light chain-restricted plasma cells confirming the diagnosis of MM. Patient began treatment with cyclophosphamide, bortezomib, and dexamethasone.

Similar to native kidney MPGN pattern of injury, secondary causes such as viruses and malignancies have to be ruled out. Prognosis of patients depends on the presence of MM. In one series, 50 % of the patients had died within 2 years of follow-up and only one patient had stable chronic kidney disease [38]. Of the 16 patients with MGRS , 6 had stable renal function, 2 had declining renal function, 2 progressed to ESKD, and no data were available for 6 patients. After kidney transplantation, 75 % of the patients with MPGN and monoclonal Ig deposits had a recurrence in the renal allograft [39]. All of the recurrences were detected within 12 months of kidney transplantation .

Proliferative Glomerulonephritis with Monoclonal IgG Deposits (PGNMID)

PGNMID represents another kidney disease characterized by non-organized deposits [40, 41]. As the name suggests, PGNMID usually present with a proliferative glomerulonephritis. This is often in a diffuse endocapillary proliferative glomerulonephritis pattern. This feature is characterized with endocapillary hypercellularity often with leukocyte infiltration and luminal occlusion. PGNMID often overlaps with MPGN pattern and can present with crescents and membranous pattern. On IF, granular staining of monoclonal Ig can be detected often along with C3 deposits. On EM, deposits are confined to the glomerular compartment. They are most often deposited in the subendothelial compartment of the capillary wall but subepithelial and intramembranous deposits can also be found less frequently. In some cases, a crystalline lattice substructure can be identified. An IgA variant has also been described [42].

Whether PGNMID represents a subset of MPGM with monoclonal deposits or is a separate entity is still debated. PGNMID does have some unique features. First, it has a preference for monoclonal IgG3. Approximately two third of cases are IgG3 with IgG kappa making up 50 % of the reported cases. Another characteristic is the low rate of MM. In a series of 37 patients, only 1 patient had symptomatic MM. In fact, less than 30 % of the patients had a detectable circulating monoclonal protein at the time of diagnosis. Despite that, both MPGN associated with a monoclonal protein and PGNMID recur with high frequency after kidney transplantation [39, 43].

Renal prognosis for these patients is poor. During a median follow-up of 30 months, 37.5 % of patients had persistent chronic kidney disease and 21.9 % progressed to ESKD [41]. Death occurred in 15.6 %, two of whom died of metastatic carcinoma. Treatment was received by 56.3 % and only 10 % received cytotoxic or anti-myeloma therapy. Recurrence is high after kidney transplantation. In one series of four patients, recurrence was detected on average 3.8 months after kidney transplantation [43]. Aggressive treatment with rituximab and/or cyclophosphamide resulted in improvement of the proteinuria in these patients; however, graft lost is not uncommon after recurrence. Early detection and initiation of effective therapy may be the difference in some cases .

Case #3

A 75-year-old female presented for evaluation of chronic kidney disease. Patient had a one and a half year history of malaise. She was taking substantial amounts of nonsteroidal anti-inflammatory drugs (NSAIDs) for treatment of degenerative joint disease, primarily of the hands. She developed a cold and began taking decongestant and antihistamine medications. This impaired her driving and ability to write legibly which led her to seek medical attention. Her creatinine was noted to be 3.6 mg/dl up from her baseline of 1.9 mg/dl. Proteinuria was measured at 2 g/d. A kidney biopsy was performed which showed an active tubulointerstitial nephritis. She was treated with 8 weeks of high-dose tapering prednisone. Her symptoms improved but her creatinine remained in the low 3s. Additional testing found an IgG kappa in the serum with an M-spike of 1 g/dl and kappa free light chain of 26.4 mg/dl, lambda of 2.38 mg/dl, and a ratio of 11.1. A bone marrow showed 5–10 % plasma cells. Her kidney biopsy was reviewed and in addition to the tubulointerstitial nephritis, numerous intracytoplasmic crystalline inclusions within tubular epithelial cells, associated with preferential tubular epithelial cell staining for kappa versus lambda light chain (Fig. 13.2). Pertinent laboratory findings include a uric acid level of 2.4 mg/dl, phosphorus of 4.1 mg/dl, glycosuria, and elevated urine cysteine and glycine levels. What is the most likely diagnosis?

MIDD

Light chain Fanconi syndrome

AL amyloidosis

Cast nephropathy

Fig. 13.2

EM showing multiple electron-dense intracellular crystalline structures in the proximal tubules

Deposition (with Organized Deposits)

Light Chain Fanconi Syndrome and Proximal Tubulopathy

Light chain Fanconi syndrome (LCFS) is a rare condition characterized by crystalline deposition of monoclonal light chains in the proximal tubules. The Fanconi syndrome (FS) refers to the electrolytes wasting that occurs. Other crystalline deposition diseases include cryocrystalglobulinemia and crystal storing histiocytosis (CSH). In CSH, the crystals are found in the cytoplasm of histiocytes in the bone marrow and other organs. Like CSH, nearly 90 % of the clones in LCFS are kappa restricted with V_kI seem to be the most common [44, 45]. Nearly half of the patients will have a diagnosis MM. Other diagnoses include WM, CLL, smoldering MM, and MGRS .

Clinical Case #3 Follow-up and Discussion

Patient was treated with six cycles of bortezomib and dexamethasone. Kappa free light chain was reduced to 11.4 mg/dl with a ratio of 5.28 corresponding to a partial response. However, creatinine increased to 4.2 mg/dl. Because of this cyclophosphamide was added and treatment continued for another 15 cycles. Kappa free light chain was reduced to 3.80 mg/dl with a ratio of 4.71, and creatinine decreased to 2.1 mg/dl. Proteinuria was unchanged at 588 mg/d. The above case demonstrates a case of LCFS.

The median age of patients with LCFS is 57 years with 58 % male patients. Commonly, these patients present with non-nephrotic range proteinuria and renal insufficiency. In addition, patients often present with glycosuria, bone pain, osteomalacia, nontraumatic fractures, and fatigue. Electrolyte abnormalities including hypouricemia (66 %), hypophosphatemia (50 %), and hypokalemia (44 %) are common [44]. It is important to recognize that the electrolyte abnormalities become less significant as renal function declines. However, aminoaciduria should always be present followed by normoglycemic glycosuria ( 100 %). Phosphaturia is present in less than half of the patients (43 %). Renal tubular acidosis may be present. In cases where glycosuria or phosphaturia is absent, an incomplete FS is diagnosed. Rarely, distal tubular dysfunction including distal renal tubular acidosis and nephrogenic diabetes insipidus can occur along with the proximal tubular dysfunction [46–48]. The mechanism for this is not well understood but it is possible that other renal disease processes may be involved [46].

The most common feature seen on kidney biopsy for LCFS is patchy tubular injury. Intracytoplasmic microcrystals can be seen in flattened or enlarged proximal tubular cells [45, 49]. Crystals can be confirmed with toluidine-blue stain. On IF, the crystals should stain for a single light chain. IF on pronase-digested, paraffin-embedded tissue is more sensitive than standard IF on frozen tissue for demonstrating kappa light chain in the crystals [50]. Crystals are often rhomboid in shape and are seen in the cytoplasm inside lysosomes on EM [51]. Varying degree of tubular atrophy and interstitial fibrosis may be present. Rarely coexistent cast nephropathy can be identified within the same biopsy [52].

The renal outcome in LCFS is variable. In one series, 5 out of 32 patients reached ESKD while 8 out of 11 did in another series [44, 45]. Interestingly, MM does not appear to be a risk factor for progression to ESKD [44]. It is unclear whether ESKD can be prevented by effective therapy since most of the reports came from melphalan and prednisone era. In fact, treatment with alkylator was a risk factor for death as these patients died of treatment related infections. A recent report described improvement or stabilization of renal function after treatment with bortezomib-based therapy in two patients [53]. Both had a significant decrease in their serum kappa FLC levels.

The term light chain proximal tubulopathy is often used with LCFS but consensus is lacking. Some use the term to refer to crystalline deposition with partial FS while others use it to describe proximal tubular injury without crystals [49, 54]. Some feel they are the same disease while others feel they are separate entities [55, 56]. In one series, 3.2 % of the biopsies associated with a paraprotein-related disease were identified as light chain proximal tubulopathy [54]. The definition used was presence of deposits restricted to a single immunoglobulin light chain in the cytoplasm of the proximal tubule . Only 3 out of 13 patients had crystalline deposits and 10 had monoclonal lambda light chain deposits. Of the patients with crystals, 2 had monoclonal kappa light chain deposits. Proteinuria and progressive renal insufficiency with proteinuria were the primary indications for renal biopsy in patients without crystals. Lysosomal or mitochondrial abnormalities along with signs of acute tubular injury such as cytoplasmic swelling or blebbing and flattening or dilatation of tubules and loss of brush border were demonstrated in all patients. Out of 13 patients, 8 were diagnosed with MM. In contrast, only 1 out of 190 biopsies of patients with MM was diagnosed with light chain proximal tubulopathy in another single center study [57]. Clearly, more research is needed to better define light chain proximal tubulopathy .

Immunotactoid Glomerulonephritis

Case #4

A 70-year-old male with a history of psoriatic arthritis presents with 5-month history of progressive renal insufficiency and proteinuria. On routine medical examination, the patient was discovered to have a Scr of 1.63 mg/dl. Baseline creatinine 1 year ago was 1.32 mg/dl. Two months later, it had increased to 2.14 mg/dl. Blood pressure had also become more labile amlodipine and nebivolol were started. Patient had been on celecoxib for approximately 2 years and he took ibuprofen on rare occasions. His other medication includes adalimumab which was recently switched from etanercept. He denies any rashes, fever, chills, or night sweats. He does have some numbness in his right arm which is associated with his neck pain. He had two previous episodes of nephrolithiasis which required lithotripsy. Outside urinalysis shows (3+) proteinuria and (3+) hematuria. Twenty-four hour urine showed 9.1 g/d of proteinuria. Serum and urine protein electrophoresis were negative for monoclonal proteins.

His blood pressure was 167/94 with a pulse of 68. Heart and lung exam were normal and he had no lower extremity edema. A renal biopsy was performed which showed mesangial and endocapillary proliferative features and focal segmental scarring. IF studies demonstrate reactivity for IgG, C3, and kappa with minimal to negative staining for lambda light chain. IgG subtyping demonstrates predominant staining with IgG1 (2+) and IgG2 (trace) and is negative for IgG3 and IgG4. Ultrastructural studies demonstrate subepithelial and mesangial electron-dense deposits organized in microtubular substructures (Fig. 13.3). A diagnosis of immunotactoid glomerulonephritis (ITG) is made.

What is the range of diameter of the fibrils found in ITG?

7–10 nm

12–30 nm

> 30 nm

Fig. 13.3

EM of mesangium and subepithelial deposits. These deposits are organized in parallel arrays and have a diameter of 35–40 nm. On cross-section, these fibrils have a hollow center which is characteristic of microtubule

ITG is a rare glomerular disease characterized by organized Ig deposition in the glomerulus [58]. The fibrils in ITG are usually much larger than amyloid fibrils and fibrils from fibrillary glomerulonephritis and they do not stain with Congo red. Their mean diameter is 31 nm with a range of 17–52 nm [8]. Amyloidosis fibrils are classically randomly arranged in 7–10 nm and fibrillary GN would have randomly arranged fibrils in the 12–30 nm range. Some have reported fibrils as thin as 9 nm [59]. The one feature that distinguishes ITG from amyloid and fibrillary fibrils is their hollow center which is similar to microtubules [8]. ITG, however, is indistinguishable from cryoglobulins, and by definition cryoglobulinemia must be ruled out. Unlike the fibrils in amyloidosis and fibrillary glomerulonephritis, the microtubules in ITG are usually arranged in parallel arrays [59]. Other differences in the fibrils can be detected using proteomics by mass spectrometry. A small study found the microtubules of ITG have a different ratio of immunoglobulin to SAP component and apolipoprotein E than those of AL amyloid, fibrillary, and cryoglobulin [60]. When fibrillary glomerulonephritis and ITG were first discovered, some had felt that they were two spectrum of the same disease, but evidence based on fibril characteristics and association with hematologic malignancy really support two distinct and separate entities.

Histologically, over half of the cases of ITG show a membranoproliferative patterns on light microscopy [8]. Mesangial expansion and global double contouring are often seen. The next most common pattern is membranous either segmental or global characterized by thickened membranes and spike formation. The least common pattern is endocapillary proliferation with hypercellularity and leukocyte infiltration resulting in luminal obstruction. Eosinophilic hyaline pseudothrombi and crescents are sometimes seen in the glomerulus [59]. IF is usually positive for the entire immunoglobulin, and in contrast to fibrillary glomerulonephritis, shows light chain restriction [57, 59, 61].

Proteinuria is heavy with ITG with a median of 11.1 g/d (range 1.4–36 g/d) [57, 59, 61]. Microscopic hematuria is common. Median Scr at presentation is 1.5 mg/dl (0.7–3.8 mg/dl). Median age of these patients ranges from 59 to 66 years. There is male predominance ranging from 71.4 to 83.0 %. ITG is often associated with an MG . In reported series, it is involved with an MG in 63–86 % of cases which in contrast to fibrillary glomerulonephritis is only involved in 15–17 % of cases. The most common hematologic diagnosis associated with ITG is CLL. In some series, it is up to 50 % of cases. However, it can be associated with MM and was found in 12.5 % of cases in another series [8].

The rarity of ITG makes it difficult to conduct any clinical trials. Treatments successful in reducing the lymphocyte clones also succeeded in maintaining renal function and reducing proteinuria [59]. Treatment with steroids combined with alkylating agents such as cyclophosphamide and melphalan have been successfully used. Chlorambucil-based therapy seems particularly effective at achieving partial and complete remission. Rituximab was reported to have stabilized the proteinuria and renal function in a case of recurrent ITG in a renal allograft [62]. Rituximab followed by alemtuzumab successfully reversed the proteinuria completely in a patient with CLL and ITG [63].

Clinical Case #4 Follow-up and Discussion

The diameters in ITG are usually in > 30-nm range. Correct answer is c. Adalimumab was discontinued without any benefit to his renal function. Creatinine rose to 4.0 mg/dl. Cyclophosphamide and prednisone were started and creatinine improved to 2.3 mg/dl. Proteinuria improved to 3.9 g/d. Unfortunately, patient developed profound diarrhea and anemia requiring hospitalization. Cyclophosphamide was discontinued. Creatinine slowly increased after discontinuation of cyclophosphamide despite 30 mg of prednisone daily. Patient began to develop steroid myopathy. The decision was made to switch therapy to rituximab. While waiting for insurance approval, creatinine began to rise. Intravenous cyclophosphamide was administered without any benefits. Creatinine rose to 4.3 g/d. Rituximab was finally approved and administered. Creatinine fell to 2.8 mg/dl and proteinuria was reduced to 0.7 g/d. Five months later, creatinine again rose to 3.7 mg/dl. Proteinuria was stable. Rituximab was administered again. Creatinine has been stable for the past 6 months.

Cryoglobulinemia

Cryoglobulins are immunoglobulins that reversibly precipitate in cold temperatures. The precipitation results in vasculitic symptoms including rash, ulcers, ischemia, arthralgia, neuropathy, fatigue, renal disease, etc. [64]. Cryoglobulins are categorized into three types. Type I cryoglobulins are the composed of monoclonal Igs usually IgM and IgG. Type II cryoglobulinemia is characterized by the both monoclonal IgM and polyclonal IgG which is the rheumatoid factor activity that is unique to type II cryoglobulinemia. Only polyclonal Igs usually IgG is in type III cryoglobulinemia. Type II and III can be the result of chronic infections particularly hepatitis C and autoimmune diseases such as Sjorgren’s syndrome.

Approximately 30 % of cryoglobulinemia involve the kidney [64, 65]. Clinically, patients present with proteinuria, hematuria, renal insufficiency, hypertension, and other signs of vasculitis. Histologically, cryoglobulinemia often present in a membranoproliferative pattern. Glomerular cellular proliferation, segmental necrotizing lesions, and hyaline thrombi in the glomerular capillaries are common features. Vasculitic features are sometime present in arterioles and small-sized vessels. In type I and II cryoglobulinemia, hyaline thrombi should show light chain restriction. Cryoglobulins on EM have a characteristic appearance of paired, curved microtubular structures that are between 20and 30 nm in diameter. Deposits can be found in the epimembranous, subendothelial, and mesangial region of the glomerulus. Unfortunately, these features are not specific and are reminiscence of those of ITG. Distinction must be based on biologic characteristics of the Ig.

Type I and II cryoglobulins contain monoclonal Ig. Type I cryoglobulinemia is often the result of LPL causing WM, but other low grade non-Hodgkin lymphomas such as marginal zone lymphoma, follicular lymphoma, mantle cell lymphoma can also produce cryoglobulins [64, 66, 67]. CLL and IgM myeloma are rare causes of cryoglobulinemia. A small case series found type I cryoglobulinemia is much more common in men but there is no predilection for kappa versus lambda light chain [66]. Type II can be the result of a clonal disorder or infections. The most common infection causing cryoglobulinemia in the world is hepatitis C. In these patients, antiviral therapy should be tried first. Rituximab can be used along with antiviral therapy and can be quite effective. In patients with clonal disease, treatment should be directed toward the clone responsible for producing the cryoglobulin [27]. Treatment using standard myeloma therapy has been successful [66, 68]. This would include corticosteroids, alkylating agents, and novel agents such as thalidomide, lenalidomide, and bortezomib [66, 67]. Treatment of cryoglobulinemia as a result of a lymphoma should include corticosteroids and rituximab. Purine analog and chlorambucil may be used in cases involving CLL. Renal response with steroids alone is approximately 60 % while response to rituximab as frontline agent is 85 %. Multivariate analysis found rituximab plus steroids were more effective than steroids alone in achievement of a CR but alkylating agents plus steroids were only more effective at achieving a lower steroid dose [67]. Rituximab plus steroids were associated with more severe infections as compared to corticosteroids alone. Alkylating agents plus steroids resulted in the least severe infections but no differences were noted in the death rates among the three regimens. Cryoglobulinemia can recur after kidney transplantation [64]. Treatment should be the same as native kidney disease.

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