Nephrogenic paraneoplastic syndromes

The term "paraneoplastic" was first applied by Guichard and Vignon in 1949 to relate the multiple nerve deficits in a patient with cervical carcinoma to her malignant disease in pathophysiologic terms.

Paraneoplastic syndromes are a heterogeneous group of different symptom complexes which are not directly caused by the tumor itself or by its metastases, but which are causally or formally genetically linked to the presence of the tumor.

The symptom complexes are caused, on the one hand, by a paracrine alteration of the surrounding microenvironment of the tumor (by paracrine secreted mediators and hormones), and, on the other hand, by humoral tumor products that influence other organs. The clinico-morphologically recognizable paraneoplastic symptoms are specific and thus directly recognizable only in a few cases. They are also not linked to the location of the tumor or its metastases, but often correlate in their severity with the course of the tumor disease. They manifest themselves before or during tumor disease, but may also precede it for a long time under certain circumstances. Thus, they are also assigned an important role as indicators for the early detection of the underlying malignant disease, especially with regard to the possibly still curative treatment of a primarius. Paraneoplastic symptoms may also regress after removal of the primary tumor and its potential metastases, or after successful chemotherapy and radiotherapy.

The nephrogenic paraneoplastic syndromes can be subdivided as follows:

Glomerular diseases

• Membranous glomerulonephritis
• Minimal-change glomerulopathy
• IgA nephropathy

Tubulointerstitial disorders

• Tubulointerstitial nephritis in multiple myeloma
• Hypercalcemic nephropathy
• Uric acid nephropathy

Microvascular disorders

• Thrombotic microangiopathy

Disturbances of water and electrolyte balance

• Paraneoplastic hyponatremia

The pathogenesis of paraneoplastic syndromes often remains unclear. However, symptoms likely arise secondary to substances secreted by the tumor or as a result of antibody formation against tumor cells that cross-react with other tissues. Symptoms may occur in any organ system.

Glomerular diseases: These manifest with the typical signs of glomerulopathy with usually severe proteinuria (often as nephrotic syndrome with protein excretion > 3.5 g per day, edema, hypalbuminemia and hyperlipidemia), hematuria with nephritic sediment or also with the new onset of hypertension or renal insufficiency. Tumor-associated glomerulopathies occur predominantly after the age of 40 and may be a first indication of the presence of a neoplasm. In this age group, an annual malignancy incidence of 0.8% is found with initial manifestation of nephrotic syndrome (Brueggemeyer et al. 1987).

• Membranous glomerulonephritis. The most common paraneoplastic glomerular disease is membranous glomerulonephritis. It occurs in older patients in about 20% of all cases in close temporal relation to tumor disease [Zech et al. 1982]. Tumors of the stomach, lung, and colon predominate, but breast carcinoma, Hodgkin's disease, melanoma, esophageal carcinoma, and others have also been described. The causal role of malignancies in the development of membranous glomerulonephritis has not been proven with certainty. However, clear evidence for an etiologic significance is provided by the fivefold increased incidence of malignancy in patients with this form of glomerulonephritis [Brueggemeyer et al. 1987], the close correlation between the course of tumor disease and the development of the nephrotic syndrome, which has been described several times [Robinson et al. 1984 and others], and also the detection of tumor antigens in the glomeruli of affected patients (see Maesaka et al. 1997].
• Minimal-change glomerulopathy: it occurs much less frequently as a paraneoplastic syndrome. Associations with lymphoproliferative disorders, particularly Hodgkin's disease, have been demonstrated (Weinstein et al. 1990).
• IgA nephropathy: In renal cell carcinoma, a frequent occurrence of IgA nephropathy in the surgical specimen of the affected kidney has been described (Magyarlaki et al. 1999).

Tubulointerstitial disorders: Tubular damage is very common in association with individual malignancies and is caused by different pathogenetic mechanisms. They are usually manifested by increasing renal insufficiency or disturbances of tubular partial functions.

• Monoclonal gammopathies and kidney: Of particular etiological importance are multiple myeloma and Waldenström's disease. Both diseases are associated with renal insufficiency in approximately 50% of cases(Clark et al. 1999). In multiple myeloma, three mechanisms are pathophysiologically significant:
• The clinically most important manifestation is the classic "myeloma kidney", a primary tubulointerstitial disorder caused by toxic effects of glomerularly filtered light chains in large quantities on the tubular epithelium and by obstruction of the tubular apparatus by precipitates of light chains and Tamm-Horsfall proteins.
• In contrast, AL amyloidosis primarily represents glomerular or vascular deposition of light chain fragments, and light chain nephropathy appears as nodular glomerulosclerosis with mesangial light chain deposits, as well as deposits in the glomerular and tubular basement membranes. Therapy of multiple myeloma is also critical for the prognosis of renal insufficiency. Reversibility of renal involvement is possible in the absence of marked chronic tubulointerstitial changes and amyloidosis at the initiation of therapy (Rota et al. 1987).
• Hypercalcemic nephropathy: Tumor-associated hypercalcemia due to multiple myeloma or solid tumors with skeletal metastases or endocrine active tumors with ectopic production of parathyroid hormone or parathyroid hormone-like peptides can cause hypercalcemic nephropathy. Morphologically, there is calcification especially in the distal region of the nephron and reactive inflammatory changes in the surrounding interstitium. Therapy includes consistent treatment of hypercalcemia with forced diuresis, corticosteroids, bisphosphonates, calcitonin and, if necessary, hemodialysis in cases of acute vital danger.
• Uric acid nephropathy: Acute uric acid nephropathy can occur in neoplasms with high cell turnover and is pathogenetically primarily due to precipitation in the collecting system. Prophylaxis is by the use of allopurinol, concomitant hydration, and urinary alkalinization as needed.

Microvascular Diseases:

• Vasculitides: Rarely, renal microvascular changes are also observed in the setting of tumor disease. Renal vasculitis may occur in association with hepatocellular carcinoma in hepatitis C infection with cryoglobulinemia, and also in associations with lung tumors and lymphoma.
• Thrombotic microangiopathy as a nephrogenic manifestation in the sense of hemolytic uremic syndrome usually occurs as a complication of chemotherapy, e.g., with mitomycin or cisplatin, but may rarely be observed independently of therapy in myeloproliferative disorders, prostate, gastric, or pancreatic carcinoma (Maesaka et al. 1997).

Disturbances of water and electrolyte balance:

• Hyponatremia and hypuricemia: Endocrinologic water balance and electrolyte disturbances are observed in ectopic production of ADH(syndrome of inadequate ADH secretion/SIADH/Schwartz-Bartter syndrome) in small cell lung carcinoma.

Therapeutically, the treatment of the underlying diseases is in the foreground in all tumor-associated glomerulopathies. Specific therapeutic measures such as immunosuppression are exclusively performed in the context of chemotherapy of the tumor, if required. Concomitant hypertension control may be required. The use of renal replacement procedures in cases of renal insufficiency requiring dialysis must be discussed in light of the individual prognosis.

Myeloma kidney: A specific therapeutic approach for the treatment of myeloma kidney is plasmapheresis. In the presence of very high paraproteinemia, this is intended to reduce the tubular paraprotein load and thus decrease the progression of renal failure. However, the success of this intervention has not yet been definitively established (Moist et al. 1999). In contrast, the indication for plasmapheresis in the presence of hyperviscosity syndrome is uncontroversial. The use of renal replacement therapy is also established in the presence of a given individual prognosis, since the overall survival of patients is independent of the degree of renal insufficiency present (Sharland et al. 1997).